Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[CH3:11][S:12]([O-:14])=[O:13].[Na+]>CN1C(=O)CCC1.CCOC(C)=O.[Cu]I>[OH:10][C:5]1[CH:4]=[CH:3][C:2]([S:12]([CH3:11])(=[O:14])=[O:13])=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: CS(=O)[O-]
Reactant: O=Cc1cc(Br)ccc1O
Agent: [Cu]I
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1ccc(O)c(C=O)c1
Temperature: 140 °C
Reaction time: 8 h

Procedure:
5-Bromosalicylaldehyde (0.402 g, 2.0 mmol), sodium methanesulfinate (0.918 g, 9.0 mmol), and copper(I) iodide (1.71 g, 9.0 mmol) were combined in NMP (16 mL) and stirred under N2 at 140° C. overnight. The mixture was diluted with 1:1 EtOAc:hexanes (150 mL) and filtered through a pad of Celite. The filtrate was washed three times with H2O, and then dried, filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]([CH2:21][C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[C:24]#[N:25])[C:10](=[O:20])[C:11]([C:14]#[C:15][Si](C)(C)C)=[CH:12][N:13]=2)[CH2:3]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]([CH2:21][C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[C:24]#[N:25])[C:10](=[O:20])[C:11]([C:14]#[CH:15])=[CH:12][N:13]=2)[CH2:3]1
Reactant: C[Si](C)(C)C#Cc1cnc(N2CCC[C@@H](N)C2)n(Cc2ccccc2C#N)c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cnc(N2CCC[C@@H](N)C2)n(Cc2ccccc2C#N)c1=O
Yield: 71 %

Procedure:
Deprotection of 2-[2-(3-(R)-amino-piperidin-1-yl)-5-trimethylsilylethynyl-6-oxo-6H-pyrimidin-1-ylmethyl]-benzonitrile (168 mg) was carried out by stirring the intermediate in THF (2 mL) with TBAF (1 N in THF, 0.8 mL, 0.8 mmol) for 1 h. The reaction was purified by silica gel chromatography (4 to 8% MeOH/CHCl3) to give 98 mg (71%) of the title compound as a faintly yellow oil/foam. 1H NMR (400 MHz, DMSO-d6): δ8.01 (s, 1H), 7.81 (dd, 1H, J=7.6, 1.2 Hz), 7.63 (dt, 1H, J=7.6, 1.2 Hz), 7.45 (t, 1H, J=7.6 Hz), 7.19 (d, 1H, J=7.6 Hz), 5.22 (AB q, 2H, J=16.4, 15.2 Hz), 4.13 (s, 1H), 3.25-3.46 (m, 2H), 2.82-2.89 (m, 1H), 2.70-2.77 (m, 1H), 2.58-2.63 (m, 1H), 1.74-1.82 (m, 1H), 1.63-1.71 (m, 1H), 1.45-1.57 (m, 1H), 1.11-1.19 (m, 1H). MS (ES) [m+H] calc'd for C19H19N5O, 334; found 334.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:32]=[CH:31][C:15]2[NH:16][C:17]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[N:18][C:14]=2[CH:13]=1)[C:3]([OH:5])=O.[CH:33]([N:36](C(C)C)[CH2:37]C)(C)C.CNC>CN(C=O)C>[CH3:33][N:36]([CH3:37])[C:3](=[O:5])[CH:2]([OH:1])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:32]=[CH:31][C:15]2[NH:16][C:17]([CH2:19][O:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=3)=[N:18][C:14]=2[CH:13]=1
Reactant: O=C(O)C(O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Solvent: CN(C)C=O
Product: CN(C)C(=O)C(O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Reaction time: 12 h
Yield: 88 %

Procedure:
To a solution of hydroxy-{2-[2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazol-5-yl]-phenyl}-acetic acid (0.030 g, 0.0678 mmol) in DMF (0.5 mL) was added (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) (0.033 g, 0.0745 mmol), diisopropylethylamine (DIPEA) (0.05 mL, 0.272 mmol), and dimethylamine (0.05 mL, 0.102 mmol, 2.0M solution in THF). After stirring for 12 hours, the crude product was purified by chromatography (silica, CH2Cl2: MeOH, 5:1) to afford the title compound as a white solid (0.028 g, 83%). 1H NMR (400 MHz, CD3OD) δ (ppm): 7.71-7.67 (m, 2H), 7.63 (d, 2H, J=8.4 Hz), 7.41-7.37 (m, 5H), 7.25 (d, 2H, J=8.8 Hz), 5.46 (s, 2H), 5.24 (s, 1H), 2.85 (s, 3H), 2.36 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C25H23F3N3O3: 470.5 (M+H), Found 470.3.
Reaction SMILES: [CH:1]([NH:3][C@@H:4]1[C:9](=[O:10])[O:8][C:6](=[O:7])[CH2:5]1)=[O:2].Cl.[CH3:12][O:13][C:14](=[O:24])[C@H:15]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH2:16].C([O-])(=O)C.[Na+].C(O)(=O)C>C(OCC)(=O)C>[CH3:12][O:13][C:14](=[O:24])[C@H:15]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH:16][C:9](=[O:10])[C@H:4]([CH2:5][C:6](=[O:7])[OH:8])[NH:3][CH:1]=[O:2]
Reactant: O=CN[C@H]1CC(=O)OC1=O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC=O
Yield: 65.5 %

Procedure:
In 100 g of ethyl acetate, 14.3 g (0.1 mole) of N-formyl-L-aspartic anhydride and 21.6 g (0.1 mole) of L-phenylalanine methyl ester hydrochloride were suspended and 9.2 g (0.11 mole) of sodium acetate was added to the suspension during 30 minutes at 20°-25° C. with stirring. The mixture was reacted for 5 hours with stirring at the same temperature. Thereafter 14.3 g of acetic acid was added and stirred for an hour at the same temperature. Precipitated crystals were filtered, washed and dried. Crystals of N-formyl-α-L-aspartyl-L-phenylalanine methyl ester were obtained in a yield of 21.1 g (65.5% yield on L-Phenylalanine methyl ester hydrochloride). The crystals obtained were analyzed by high performance liquid chromatography to give a ratio of α-isomer:β-isomer of 98.0:2.0.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.C([O-])(=O)C.[Na+].[Br:17]Br>C(O)(=O)C.[Fe]>[Br:17][C:4]1[C:5]([OH:6])=[C:7]([O:8][CH3:9])[CH:10]=[CH:11][C:3]=1[CH:2]=[O:1]
Reactant: COc1ccc(C=O)cc1O
Reactant: BrBr
Agent: [Fe]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(C=O)c(Br)c1O
Yield: 78.2 %

Procedure:
To a stirred suspension of isovanillin (10 g, 66 mmol), powdered anhydrous sodium acetate (10.82 g, 0.132 mol) and iron powder (0.3 g, 5.4 mmol) in glacial acetic acid (60 mL) under argon, was added drop-wise over 15 min a solution of Br2 (3.7 mL, 0.0726 mol) in acetic acid (12.5 mL). The reaction temperature rose during the course of addition, and the mixture became viscous. After all the starting material was consumed, as determined by TLC, the mixture was poured onto ice cold water, and the resulting precipitate filtered under vacuum. The precipitate was washed several times with cold water and air-dried. Crystallization from boiling ethanol gave 8 (11.93 g, 79% yield) as a gray powder. Rf=0.10 (1:5 EtOAc/hexanes). M.p. 196-200° C. IR (thin film) 3215, 1662, 1588, 1561, 1491, 1273 cm−1. 1H NMR (300 MHz, CDCl3) δ 10.27 (1H, s), 7.59 (1H, d, J=9 Hz), 6.96 (1H, d, J=9 Hz), 6.02 (1H, bs), 4.00 (3H, s). 13C NMR (75 MHz, CDCl3) δ 56.58, 109.24, 112.84, 113.84, 122.74, 143.25, 151.65, 190.87. HRMS calcd. for C8H8O3Br (MH+) 230.9657. Found 230.9652.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]([F:14])([F:13])[F:12])[CH:5]=1.[CH3:16][O:17][C:18](=[O:23])[CH2:19][C:20]([CH3:22])=O.C[O-].[Na+]>CO>[CH3:16][O:17][C:18]([C:19]1[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]([F:14])([F:13])[F:12])[CH:5]=2)=[N:2][O:1][C:20]=1[CH3:22])=[O:23]
Reactant: ON=C(Cl)c1cccc(OC(F)(F)F)c1
Reactant: COC(=O)CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(-c2cccc(OC(F)(F)F)c2)noc1C
Yield: 67.8 %

Procedure:
In a similar manner as described in Preparation Example 17, by using methanol (160 mL), N-hydroxy-3-(trifluoromethoxy)benzimidoylchloride (8.00 g, 33.39 mmol), methylacetoacetate (7.76 g, 66.78 mmol) and sodium methoxide (5.41 g, 100.17 mmol), a white solid required compound (6.82 g, 22.64 mmol, 68%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:11]2[C:6]([C:7](=[O:31])[N:8]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=3)[C:9](=[O:19])[NH:10]2)=[CH:5][CH:4]=1.C(O)C.[H][H]>[C].[Pd].O1CCOCC1>[NH2:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][N:8]2[C:7](=[O:31])[C:6]3[C:11](=[C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:10][C:9]2=[O:19])=[CH:23][CH:24]=1
Reactant: CCCCCOc1c(OC)ccc2c(=O)n(CCc3ccc([N+](=O)[O-])cc3)c(=O)[nH]c12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Product: CCCCCOc1c(OC)ccc2c(=O)n(CCc3ccc(N)cc3)c(=O)[nH]c12
Temperature: 50 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
7-Methoxy-3-[2-(4-nitrophenyl)ethyl]-8-pentyloxy-1H-quinazoline-2,4-dione (45.0 g, 105 mmol) obtained in Example 7-39, ethanol (1300 ml) and dioxane (700 ml) were mixed, and 10% palladium-carbon catalyst (4.5 g) was added to this solution. The reaction mixture was stirred in a stream of hydrogen at room temperature for 16.5 hours, followed by filtration. Activated charcoal (2.6 g was added to the filtrate, and the reaction mixture was stirred at 50° C. for 1 hour and then filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (chloroform/ethyl acetate=3/1). The precipitated crude crystals were recrystallized from ethanol-hexane to give 3-[2-(4-aminophenyl)ethyl]-7-methoxy-8-pentyloxy-1H-quinazoline-2,4-dione (33.82 g, 81%) as pale-yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:25](=N)[N:24]([CH2:27][CH3:28])[C:12]2[N:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1.C(OC(=O)C)(=[O:31])C.Cl>O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:25](=[O:31])[N:24]([CH2:27][CH3:28])[C:12]2[N:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCn1c(=N)c(-c2c(Cl)cccc2Br)cc2cnc(Nc3ccccc3)nc21
Agent: Cl
Solvent: O
Product: CCn1c(=O)c(-c2c(Cl)cccc2Br)cc2cnc(Nc3ccccc3)nc21

Procedure:
(6-(2-Bromo-6-chlorophenyl)-8-ethyl-7-imino-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-phenylamine (150 mg) was added to 1 mL of acetic anhydride and heated at reflux for 5 minutes. The reaction was cooled and concentrated resulting in an oil which was heated at reflux with 10 mL of 6N HCl for 10 minutes. The reaction was cooled, and 30 mL of water was added causing precipitation. The precipitate was removed by filtration and washed with water. The resulting solid was dried to give 130 mg of 6-(2-bromo-6-chlorophenyl)-8-ethyl-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one; mp softens at 195° C. and melts at 210°-214° C.
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][C:8]([CH3:11])([CH3:10])[S:7][C:6]1=[NH:12])[CH2:2][CH2:3][CH3:4].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([O:23][CH3:24])=[C:18]([CH:22]=1)[C:19](O)=[O:20].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH2:1]([N:5]1[CH2:9][C:8]([CH3:11])([CH3:10])[S:7]/[C:6]/1=[N:12]\[C:19](=[O:20])[C:18]1[CH:22]=[C:14]([Cl:13])[CH:15]=[CH:16][C:17]=1[O:23][CH3:24])[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(Cl)cc1C(=O)O
Reactant: CCCCN1CC(C)(C)SC1=N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Product: CCCCN1CC(C)(C)S/C1=N\C(=O)c1cc(Cl)ccc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.5 %

Procedure:
A mixture of the compound from Example 2A (1.2 g, 6.4 mmol), 5-chloro-2-methoxy-benzoic acid (1.4 g, 7.7 mmol), EDCI (2.45 g, 12.8 mmol), HOBt (1.7 g, 12.8 mmol) and DMAP (78 mg, 0.64 mmol) in pyridine (40 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, diluted with water, and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, eluting with ethyl acetate/hexanes 1:3) to provide 919 mg of title compound. MS (APCI) m/z 355 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (t, J=7.4 Hz, 3H) 1.31 (m, 2H) 1.45 (s, 6H) 1.60 (m, 2H) 3.53 (m, 2H) 3.63 (t, J=7.4 Hz, 2H) 3.77 (s, 3H) 7.09 (d, J=8.9 Hz, 1H) 7.45 (dd, J=8.9, 2.8 Hz, 1H) 7.64 (d, J=2.8 Hz, 1H).
Reaction SMILES: [CH3:1]C(C1NC(=O)N(CC=C)C1=O)C.N1C2C(=CC=CC=2)[CH:16]=[C:15]1[CH2:23][CH:24]1[NH:28][C:27](=[O:29])[N:26]([CH2:30][CH:31]=[CH2:32])[C:25]1=[O:33]>>[CH3:1][CH:15]([CH3:16])[CH2:23][CH:24]1[NH:28][C:27](=[O:29])[N:26]([CH2:30][CH:31]=[CH2:32])[C:25]1=[O:33]
Reactant: C=CCN1C(=O)NC(Cc2cc3ccccc3[nH]2)C1=O
Reactant: C=CCN1C(=O)NC(C(C)C)C1=O
Product: C=CCN1C(=O)NC(CC(C)C)C1=O

Procedure:
5-(1-methylethyl)-3-(2-propenyl)-2,4-imidazolidinedione; 5-(1H-indol-2-ylmethyl)-3-(2-propenyl)-2,4-imidazolidinedione;
Reaction SMILES: [CH2:1]([CH:8]1[CH2:10][O:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]([C:21]2[CH:22]=[N:23][NH:24][CH:25]=2)=[O:20])[CH2:13][CH2:12]1>C(O)(C)C>[OH:9][CH:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]([C:21]2[CH:25]=[N:24][NH:23][CH:22]=2)=[O:20])[CH2:13][CH2:12]1
Reactant: O=C(NCC1CCNCC1)c1cn[nH]c1
Reactant: c1ccc(CC2CO2)cc1
Solvent: CC(C)O
Product: O=C(NCC1CCN(CC(O)Cc2ccccc2)CC1)c1cn[nH]c1
Temperature: 60 °C

Procedure:
To a solution of 2-benzyloxirane (0.01 mL, 0.07 mmol) in iso-propyl alcohol (5 mL) was added 1H-pyrazole-4-carboxylic acid (piperidin-4-ylmethyl)-amide (EXAMPLE 137, Step 1) (15 mg, 0.07 mmol). The resulting reaction mixture was heated to 60° C. for 24 h. The reaction mixture was concentrated, partitioned between EtOAc and aqueous sodium bicarbonate. The organic phase was dried, the solvent evaporated, and the crude product purified by reverse phase HPLC to give 1H-Pyrazole-4-carboxylic acid [1-(2-hydroxy-3-phenyl-propyl)-piperidin-4-ylmethyl]-amide.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[CH2:5][C:6](=[O:21])[CH:7]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(O)C.CCOCC>[CH3:1][N:2]([CH3:3])[CH2:5][C:6](=[O:21])[CH:7]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(CBr)C(c1ccccc1)c1ccc(F)cc1
Reactant: CNC
Solvent: CCO
Solvent: CCOCC
Product: CN(C)CC(=O)C(c1ccccc1)c1ccc(F)cc1
Reaction time: 0.75 h

Procedure:
Dimethylamine in ethanol (30 ml s of 33% solution) was added to a solution of 3-bromo-1-p-fluorophenyl-1-phenyl-propan-2-one (13g) in dry ether. After 45 minutes, the reaction mixture was extracted with dilute hydrochloric acid and ether. Basification of the acid extract and subsequent isolation through ether in the usual manner gave 3-dimethylamino-1-p-fluorophenyl-1-phenyl-propan-2-one isolated as the hydrochloride (5 8g., 53%), m.p. 219° - 220°.
Reaction SMILES: C([O:5][C:6](=[O:12])[C@H:7]([CH3:11])[C@H:8]([NH2:10])[CH3:9])(C)(C)C.C[O:14][C:15]([C:17]1[N:18]=[C:19]([C:35]#[N:36])[C:20]2[C:25]([C:26]=1[OH:27])=[CH:24][CH:23]=[C:22]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:21]=2)=O.C(N(CC)CC)C>CCO>[C:35]([C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[C:22]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:21]=2)[C:26]([OH:27])=[C:17]([C:15]([NH:10][C@H:8]([CH3:9])[C@@H:7]([CH3:11])[C:6]([OH:5])=[O:12])=[O:14])[N:18]=1)#[N:36]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: C[C@@H](N)[C@@H](C)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[C@@H](NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)[C@@H](C)C(=O)O
Temperature: 140 °C
Yield: 29.7 %

Procedure:
A mixture of (2R,3R)-3-amino-2-methyl-butyric acid tert-butyl ester (20 mg, 0.117 mmol), 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (25 mg, 0.078 mmol), and triethylamine (0.050 mL) in EtOH (2 mL) was heated in a microwave reactor at 140° C. for 6 h. The resulting mixture was concentrated to dryness, and the residue was re-dissolved in CH2Cl2 and passed through a plug of silica gel. After evaporating the solvent, the residue was dissolved in CH2Cl2 (3 mL) and treated with trifluoroacetic acid (2 mL) for 2 h. The mixture was concentrated in vacuo, and the resulting residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH ˜2 and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 9.4 mg of the title compound as a pale pink solid. MS: (−) m/z 404.32 (M−1).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8](Cl)[N:7]=1.[H][H]>[OH-].[K+].CO>[CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[CH:9]=[CH:8][N:7]=1
Reactant: [H][H]
Reactant: CN(C)CCNc1cc(C(F)(F)F)cc(Cl)n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN(C)CCNc1cc(C(F)(F)F)ccn1

Procedure:
A solution of 2-(2-dimethylaminoethylamino)-4-trifluoromethyl-6-chloropyridine (5.8 g., 0.022 mole) (from Example 53 Part A) in 2.5% potassium hydroxide in methanol (75 ml.) containing 5% palladium-on-calcium carbonate (0.5 g.) in hydrogenated in a Parr apparatus at 50 psi of hydrogen until 0.022 mole of hydrogen is taken up (24 hours). The catalyst is filtered and the solvent removed under vacuum. The residue is dissolved in water and the product is extracted into methylene chloride, dried over anhydrous sodium sulfate and evaporated to give the oily product (5.0 g.) which is used without further purification in the succeeding step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]([OH:10])[C:7]([OH:9])=[O:8].[C:18](Cl)(=[O:20])[CH3:19]>>[C:18]([O:10][CH:6]([C:5]1[CH:11]=[C:12]([O:16][CH3:17])[C:13]([O:14][CH3:15])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:7]([OH:9])=[O:8])(=[O:20])[CH3:19]
Reactant: COc1cc(C(O)C(=O)O)cc(OC)c1OC
Reactant: CC(=O)Cl
Product: COc1cc(C(OC(C)=O)C(=O)O)cc(OC)c1OC

Procedure:
3,4,5-Trimethoxymandelic acid (80.5 g) was treated with acetyl chloride (150 ml) at room temperature for three hours. The clear solution was concentrated to dryness under vacuum, and the oily residue was crystallized from toluene (280 ml) giving pure α-acetoxy-3,4,5-trimethoxyphenylacetic acid (80.9 g), m.p. 135-139° C.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][C:10]([N:12]1[CH2:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[O:15][C:14]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:13]1=2)=[O:11].Cl.[N:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37](O)=[O:38])=[CH:31][CH:30]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[ClH:27].[Cl:27][C:25]1[CH:24]=[CH:23][C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[CH2:18][N:12]([C:10](=[O:11])[CH2:9][NH:8][C:37](=[O:38])[CH2:36][CH2:35][C:32]3[CH:33]=[CH:34][N:29]=[CH:30][CH:31]=3)[C:13]=2[CH:26]=1
Reactant: NCC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: O=C(O)CCc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CCc1ccncc1)NCC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Temperature: 5 °C
Reaction time: 0.08 h

Procedure:
Triethylamine (0.8 mL) was added to a stirred mixture of 10-(aminoacetyl)-8-chloro-10,11-dihydrodibenz-[b,f][1,4]oxazepine (0.77 gram) and 4-pyridinepropanoic acid, monohydrochloride (0.50 gram) in dimethylformamide (10 mL) at room temperature under a nitrogen atmosphere. After 5 minutes, the mixture was cooled to 5° C. in an ice bath, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride (0.56 gram) was added. The reaction was stirred at room temperature under a nitrogen atmosphere for 60 hours, partitioned between saturated aqueous sodium bicarbonate (100 mL) and ethyl acetate (75 mL), and filtered. The layers of the filtrate were separated, and the aqueous layer was extracted with ethyl acetate (2×50 mL). The ethyl acetate extracts were combined, washed with aqueous saturated sodium bicarbonate (2×100 mL), water (100 mL), and brine (100 mL), dried over MgSO4, and evaporated in vacuo. The crude product was purified by flash chromatography through silica gel 60 (350 mL) using 9:1 ethyl acetate:ethanol. The purified product was taken up in ethyl acetate and treated with 9.5 M HCl in ethanol to pH 1. The precipitated product was collected by filtration and dried in vacuo at 80° C. Yield: 0.233 gram (19%). Analysis calculated for C23H20ClN3O3 ×1 HCl: C, 60.27; H, 4.62; N, 9.17; Cl, 15.47. Found: C, 59.88; H, 4.66; N, 8.99; Cl, 15.58.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH2:4]([C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(Cl)[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CO>[CH2:4]([C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([O:2][CH3:1])[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C=CCOC(=O)C(Cl)(Cc1ccccc1)c1ccccc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: C=CCOC(=O)C(Cc1ccccc1)(OC)c1ccccc1
Reaction time: 2 h
Yield: 94.7 %

Procedure:
Into a solution of 1.1 g of sodium methylate in 20 cc of methanol was added a solution of 6.0 g of allyl α-benzyl-α-chlorophenylacetate in 10 cc of methanol under cooling, and the mixture was stirred for 2 hours, whereby white precipitates were deposited. The reaction mixture was poured in water and the resultant was subjected to extraction with ether. The ether extract was washed with an aqueous solution saturated with sodium chloride and dried over sodium sulfate, and thereafter evaporation of ether gave 5.6 g of oily allyl α-benzyl-α-methoxyphenylacetate, nD25 1.5486.
Reaction SMILES: CN(CCN(C)C)C.[CH3:9][C:10]([CH3:28])([CH3:27])[CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:15]=1.[Li]CCCC.CN([CH:37]=[O:38])C>CCOCC>[CH3:9][C:10]([CH3:28])([CH3:27])[CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:15]=1[CH:37]=[O:38]
Reactant: CN(C)C=O
Reactant: CC(C)(C)CCOc1cccc(OCCC(C)(C)C)c1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)CCOc1cccc(OCCC(C)(C)C)c1C=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 90.8 %

Procedure:
TMEDA (23.0 g, 0.198 mol), 1,3-di(3,3-dimethylbutoxy)benzene (46.2 g, 0.166 mol) and ether (500 mL) were brought together in a two-neck 1-L flask fitted with a nitrogen inlet and a pressure-equalizing addition funnel. The reaction mixture was cooled to 0° C., and deaerated. n-BuLi (2.5 M solution in hexanes, 0.18 mol) was added dropwise over a period of 30 min via the addition funnel. The mixture was stirred for 3 h, following which that time it was warmed to room temperature. At this point DMF (23.0 g, 0.315 mol) was added dropwise; after 2 h of stirring, the reaction was quenched with water, extracted with ether (4×300 mL), separated, and evaporated. The product was purified by chromatography on silica using 9:1 hexanes:ethyl acetate as the eluant, giving 36.6 g of product (72% yield, based on 46.2 g of the 1,3-di(3,3-dimethylbutoxy)benzene starting material). 1H NMR (250 MHz, CDCl3): 10.49 (s, 1H), 7.37 (t, 1H, J=8.5 Hz), 6.52 (d, 2H, J=8.5 Hz), 4.06 (t, 4H, J=7.2 Hz), 1.76 (t, 4H, J=7.2 Hz), 0.96 (s, 18H). HRMS (ESI+) m/z: 329.2107 (calcd for C19H30O3Na (M+Na)+ 329.2092).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][C:12]4([CH2:17][CH2:16]4)[N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:27][CH2:26][C:23]3[CH:22]=[N:21][C:20]([C:19]([F:29])([F:18])[F:28])=[CH:25][CH:24]=3)[C:6]3[CH2:11][C:12]4([CH2:16][CH2:17]4)[N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1Cc2c([nH]c3ccc(Cl)cc23)CC12CC2
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1Cc2c(n(CCc3ccc(C(F)(F)F)nc3)c3ccc(Cl)cc23)CC12CC2

Procedure:
The title compound is prepared from a mixture of 8′-chloro-2′-methyl-1′,2′,4′,5′-tetrahydrospiro[cyclopropane-1,3′-pyrido[4,3-b]indole], 2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18]O>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:18][CH2:17][N:16]([CH3:20])[CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1O
Reactant: CN(C)CCO
Product: COc1cc2c(Cl)ncnc2cc1OCCN(C)C

Procedure:
The compound was synthesised according to GP 4 from 4-chloro-7-hydroxy-6-methoxy-quinazoline and 2-Dimethylamino-ethanol. LC/ESI-MS: m/z=282 [M+H].