Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([CH:19]2[CH2:21][CH2:20]2)([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24]I.O>CN(C)C=O>[CH:1]([N:14]1[CH2:17][C:16]([CH:19]2[CH2:20][CH2:21]2)([O:18][CH3:24])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: OC1(C2CC2)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC1(C2CC2)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
334 mg of 1-benzhydryl-3-cyclopropylazetidin-3-ol was dissolved in dimethylformamide, and 72 mg of 60% sodium hydride was added thereto, and the mixture was stirred at room temperature for 30 minutes. 112 μl of methyl iodide was added thereto, and the mixture was further stirred at room temperature for 2 hours. To the reaction solution was added water and the mixture was subjected to extraction with diethyl ether, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 280 mg of the objective compound.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([O:24][CH:25]([CH3:27])[CH3:26])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([O:24][CH:25]([CH3:27])[CH3:26])[CH:17]=1
Reactant: CC(C)Oc1cc(Cl)ccc1CO
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: CC(C)Oc1cc(Cl)ccc1COc1ccnn1-c1cc(C#N)ccn1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-chloro-2-propan-2-yloxyphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, DMSO-d6): δ 1.34 (6H, d, J=6.0 Hz), 4.56-4.62 (1H, m), 5.21 (2H, s), 5.77 (1H, d, J=1.6 Hz), 6.90 (1H, d, J=1.2 Hz), 6.93 (1H, dd, J=1.6 Hz, 8.0 Hz), 7.34 (1H, d, J=8.0 Hz), 7.39 (1H, dd, J=1.2 Hz, 5.2 Hz), 7.57 (1H, d, J=1.6 Hz), 8.04 (1H, s), 8.70 (1H, d, J=4.8 Hz). [M+H] Calc'd for C19H17ClN4O2, 369; Found, 369.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([O:7][CH2:17][CH3:18])=[O:6]
Reactant: CCO
Reactant: Cc1ccc(C(=O)O)cc1I
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(C)c(I)c1

Procedure:
40.61 g of 3-iodo-4-methylbenzoic acid was suspended in 406 ml of ethanol and 9.1 ml of concentrated sulfuric acid was added, and then the mixture was heated at reflux for 24 hours. After the solvent was distilled off under reduced pressure, the residue was mixed with iced water, made basic with an aqueous saturated sodium hydrogen carbonate solution, followed by extraction with ethyl acetate twice. The extracts were washed in turn with water and saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 44.44 g of a crude product as a brown oily product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[H-].[Na+].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CN(C=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:3][CH:4]=1
Reactant: Oc1ccc(Br)cn1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(OCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
2-Hydroxy-5-bromopyridine (1.00 g, 5.75 mmol) was dissolved in N,N′-dimethylformamide (23 mL), and the resultant mixture was added with sodium hydride (purity 50%) (253 mg, 6.32 mmol) under an argon atmosphere under ice-cold conditions. Five minutes later, the resultant mixture was added with benzyl bromide (6.82 mL, 6.90 mmol) at the same temperature, and stirred at room temperature for 1 hour. Under ice-cold conditions, the reaction solution was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, then concentrated in vacuo, and purified using silica-gel column chromatography (n-hexane/ethyl acetate=1/1). 5-Bromo-2-(benzyloxy)pyridine (1.51 g, yield 99%) was obtained as a pale yellow solid.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:26]=[CH:25][C:10]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][Si](C)(C)C)=[CH:15][CH:14]=2)=[O:12])=[CH:9][CH:8]=1)(C)C.[OH-].[K+]>CO>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:11]([C:10]2[CH:9]=[CH:8][C:7]([C:6]#[CH:5])=[CH:26][CH:25]=2)=[O:12])=[CH:14][CH:15]=1)#[CH:20]
Reactant: C[Si](C)(C)C#Cc1ccc(C(=O)c2ccc(C#C[Si](C)(C)C)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1ccc(C(=O)c2ccc(C#C)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
To a flask containing a mixture of 4,4'-dibromobenzophenone (5.0 g, 14.7 mmol), PdCl2 (PPh3)2 (0.42 mg, 0.60 mmol), and CuI (60 mg, 0.30 mmol) was added THF (100 mL), iPr2NH (20 mL) and trimethylsilylacetylene (4.6 mL, 32.5 mmol) under a nitrogen atmosphere. The mixture was stirred at room temperature for 40 hours. The solvent was removed under vacuum, and the residue was extracted with CH2Cl2 /H2O. The organic layer was collected, dried over MgSO4, filtered through Al2O3, and pumped dry. The residue was recrystallized from CH2Cl2 /hexane at -30° C. to afford pale brown crystalline 4,4'-bis(trimethylsilylethynyl)benzophenone in 96% yield (5.29 g). 1H NMR (300 MHz, C6D6, 25° C., TMS): δ=0.25 (s, 18 H, CH3), 7.53 (d, J=8.6 Hz, 4 H, C6H4), 7.69 (d, 4 H, C6H4). To a mixture of 4,4'-bis(trimethylsilylethynyl)benzophenone (1.0 g, 2.67 mmol) and KOH (0.30 g, 5.36 mmol) was added 50 mL of MeOH and the solution was stirred at room temperature for 3 hours. The solution was then extracted with Et2O. The Et2O solution was pumped dry and the residue was chromatographed using EtOAc/hexane (1:50 to 1:5) as eluent to afford 4,4'-diethynylbenzophenone in 68% yield (0.42 g).
Reaction SMILES: NCCN[C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6].[CH3:22][O:23][C:24](=[O:27])[CH2:25][NH2:26]>>[CH3:22][O:23][C:24](=[O:27])[CH2:25][NH:26][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6]
Reactant: NCCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12
Reactant: COC(=O)CN
Product: COC(=O)CNC(=O)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (2-amino-ethyl)-amide using amino-acetic acid methyl ester instead of tert-butyl-2-amino ethyl carbamate. LCMS (ESI) 331 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.55 (1H, br. s.) 10.22 (1H, s) 8.54 (1H, t, J=5.76 Hz) 8.04 (1H, d, J=5.42 Hz) 7.83 (1H, d, J=5.42 Hz) 7.51 (1H, d, J=5.47 Hz) 7.32 (1H, dd, J=3.49, 2.37 Hz) 6.86 (1H, d, J=5.47 Hz) 6.41 (1H, dd, J=3.54, 1.83 Hz) 4.00 (2H, d, J=5.81 Hz) 3.66 (3H, d, J=0.10 Hz)
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[CH3:32][C:23]1[CH:28]=[CH:27][C:26]([C:29]([O:13][CH:10]2[CH2:9][CH2:8][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Cc1ccc(CN2CCC(O)CC2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(CN2CCC(OC(=O)c3ccc(C)cc3)CC2)cc1
Yield: 82.4 %

Procedure:
0.31 g (0.0015 mol) of 1-(4-methyl-benzyl)-piperidin-4-ol and 0.52 ml (0.00375 mol) of triethylamine were dissolved in 15 ml of toluene, treated with 0.25 ml (0.001875 mol) of p-toluoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:4). 0.4 g (83%) of 1-(4-methyl-benzyl)-piperidin-4-yl 4-methyl-benzoate was obtained as yellow crystals; m.p. 66°-77°.
Reaction SMILES: C1(CS(O[CH2:12][CH2:13][C@H:14]([NH:16][S:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:19])=[O:18])[CH3:15])(=O)=O)C=CC=CC=1.[Cl-:27].[Na+].CN(C)C=O>CCOC(C)=O>[Cl:27][CH2:12][CH2:13][C@H:14]([NH:16][S:17]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:19])=[O:18])[CH3:15]
Reactant: C[C@H](CCOS(=O)(=O)Cc1ccccc1)NS(=O)(=O)Cc1ccccc1
Reactant: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](CCCl)NS(=O)(=O)Cc1ccccc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 38.9 %

Procedure:
To the crude (R)-3-(phenylmethylsulfonamido)butyl phenylmethanesulfonate (23.6 mmol) was added sodium chloride (984 mg, 16.8 mmol) and dimethylformamide (37 mL) and the reaction was stirred at 80° C. for 16 hours. The reaction was then diluted with EtOAc, washed with water (×2) and brine, dried with MgSO4, concentrated and purified by silica gel column chromatography (0-50% Acetone in Heptane, 216 nM) to give (R)—N-(4-chlorobutan-2-yl)-1-phenylmethanesulfonamide (1.71 g, 6.53 mmol, 58% yield over 2 steps). LCMS (ESI), m/z, 261 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])[C:9]([N:18]2[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.N1C=CN=C1.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>CN(C)C=O>[Si:30]([O:24][CH:21]1[CH2:20][CH2:19][N:18]([C:9]2[C:10]([C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])=[CH:11][C:2]([Cl:1])=[C:3]3[C:8]=2[N:7]=[CH:6][CH:5]=[CH:4]3)[CH2:23][CH2:22]1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CON(C)C(=O)c1cc(Cl)c2cccnc2c1N1CCC(O)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cc(Cl)c2cccnc2c1N1CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
To a mixture of 5-chloro-8-(4-hydroxypiperidin-1-yl)-N-methoxy-N-methylquinoline-7-carboxamide (372 mg, 1.06 mmol) and 1H-imidazole (0.362 g, 5.32 mmol) in N,N-dimethylformamide (2 mL) was added tert-butyldimethylsilyl chloride (0.240 g, 1.60 mmol). The reaction was stirred at room temperature overnight, then quenched with sat. sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulfate and evaporated to dryness. The residue was purified on silica gel, eluting with 0 to 40% ethyl acetate in hexane, to give the desired product (0.312 g, 63%). LCMS calculated for C23H35ClN3O3Si (M+H)+: m/z=464.2; Found: 464.2.
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6](=[O:14])[C:5]([CH3:15])=[C:4]([CH3:16])[N:3]=1.O=[CH:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:22]([O:23][CH3:24])[C:20]=1[OH:21]>CC(O)=O>[OH:21][C:20]1[C:22]([O:23][CH3:24])=[CH:25][CH:26]=[CH:27][C:19]=1[CH:18]=[CH:1][C:2]1[N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:6](=[O:14])[C:5]([CH3:15])=[C:4]([CH3:16])[N:3]=1
Reactant: COc1cccc(C=O)c1O
Reactant: Cc1nc(C)n(-c2ccccc2)c(=O)c1C
Solvent: CC(=O)O
Product: COc1cccc(C=Cc2nc(C)c(C)c(=O)n2-c2ccccc2)c1O
Temperature: 150 °C
Yield: 58 %

Procedure:
A mixture of 2,5,6-trimethyl-3-phenylpyrimidin-4(3H)-one (4) (403 mg, 1.88 mmol) and O-vanillin (286 mg, 1.88 mmol) in AcOH (4 mL) was heated at 150° C. for 2 h in a microwave oven. Acetic acid was evaporated under reduced pressure, and the product was purified by column chromatography (EtOAc/hexanes 1:1) to afford 5 as a yellow solid (380 mg, 58%); MS m/z: 349 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH:20]4[CH2:26][CH2:25][C:24]5[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=5[C:22](=[O:31])[O:21]4)[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.Br[Mg][CH2:34][CH2:35][CH2:36][CH2:37][Mg]Br>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH:20]([OH:21])[CH2:26][CH2:25][C:24]4[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=4[C:22]4([OH:31])[CH2:37][CH2:36][CH2:35][CH2:34]4)[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1OC(c2cccc(OCc3ccc4ccc(Cl)cc4n3)c2)CCc2ccccc21
Reactant: Br[Mg]CCCC[Mg]Br
Solvent: C1CCOC1
Product: OC(CCc1ccccc1C1(O)CCCC1)c1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Reaction time: 0.5 h

Procedure:
To the lactone of Step 4 (1.004 g, 2.335 mmol) in 5 mL of anhydrous THF at r.t., a suspension of 0.70M 1,4-di(bromomagnesio)butane in THF (J. Org. Chem., 45, 1828 (1980); 5.3 mL, 3.7 mmol) was added dropwise and the mixture was stirred for 30 min and was quenched at 0° C. with cold 25% aq NH4OAc. The title cyclopentanol was extracted with EtOAc, dried over Na2SO4 and purified by flash chromatography on silica using EtOAc:toluene 15:85 and 20:80. Yield: 1.006 g, 88%.
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:14](Cl)=[N:13][N:12]=[N:11]1>O>[CH:7]1[CH:6]=[C:5]([N:10]2[NH:11][N:12]=[N:13][C:14]2=[O:1])[C:4]([Cl:3])=[CH:9][CH:8]=1
Reactant: Clc1ccccc1-n1nnnc1Cl
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=c1nn[nH]n1-c1ccccc1Cl
Temperature: 110 °C
Yield: 95.8 %

Procedure:
A solution of sodium hydroxide (13 g, about 45% by weight) in water, 1-(2-chloro-phenyl)-5-chlorotetrazole (12.9 g) in water (6.5 ml) were mixed and the mixture was heated to 110° C. The reaction was initiated and the temperature increased to 115° C. After 3 minutes from the initiation of the reaction, the temperature was lowered to room temperature and then water (20 ml) was added. The insoluble matter was extracted with toluene (10 ml) and the aqueous solution was adjusted to a pH of 1. The solid matter was collected by filtration followed by washing with water and drying to obtain a pale tan solid 1-(2-chlorophenyl)-5(4H)-tetrazolinone (11.3 g) (yield: 96%). melting point: 123°-125° C.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][C:7]([C:13]([OH:15])=[O:14])=[CH:6]2.[C:16](C1(C(O)=O)C2C(=CC=C(O)C=2)CCN1)(OC(C)(C)C)=[O:17]>>[CH3:16][O:17][C:12]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]([OH:15])=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C1(C(=O)O)NCCc2ccc(O)cc21
Reactant: COc1ccc2cnc(C(=O)O)cc2c1
Product: COc1ccc2cc(C(=O)O)ncc2c1
Yield: 17 %

Procedure:
0.25 g (17% in 4 steps) 7-methoxy-isoquinoline-3-carboxylic acid was prepared according to procedure described for the synthesis of 6-methoxy-isoquinoline-3-carboxylic acid (in Example 294) starting from 2.0 g (6.8 mmol) of boc-7-hydroxy-tetrahydroisoquinoline carboxylic acid using 179 mg (0.824 mmol). LCMS: 204 (M+1)+.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH:42]=O)[C:38]2=[N:44][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:49][CH2:48][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:46])=[CH:28][C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:51][CH:52]([NH2:54])[CH3:53].C([BH3-])#N.[Na+]>O1CCCC1.CO>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH2:42][NH:54][CH:52]([CH3:53])[CH3:51])[C:38]2=[N:44][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:49][CH2:48][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:46])=[CH:28][C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)N
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C=O)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(CNC(C)C)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Reaction time: 2 h

Procedure:
Methyl(2S)-2-(tert-butoxy)-2-[(22S)-17-fluoro-5-formyl-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate (40 mg, 0.058 mmol, 1.0 equiv) was mixed with propan-2-amine (6.90 mg, 0.117 mmol, 2.0 equiv) in Tetrahydrofuran (583 μl) and Methanol (146 μl). The solution was stirred for 2 hours. LCMS show about 50% conversion to imine. Then to this solution was added sodium cyanoborohydride (21.99 mg, 0.350 mmol, 6.0 equiv) and stirred for 2 hours. The mixture was used for next reaction directly. LCMS (ESI, M+1): 729.4.
Reaction SMILES: S(Cl)(C)(=O)=O.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][CH2:17][CH:16]2[CH2:20]O)=[CH:11][CH:10]=1)([O-:8])=[O:7].C(N(CC)CC)C.[Cl-:29].[Na+]>CN(C=O)C>[Cl:29][CH2:20][CH:16]1[CH2:17][CH2:18][CH2:19][N:15]1[C:12]1[CH:13]=[CH:14][C:9]([N+:6]([O-:8])=[O:7])=[CH:10][CH:11]=1
Reactant: [Cl-]
Reactant: O=[N+]([O-])c1ccc(N2CCCC2CO)cc1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(N2CCCC2CCl)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 882.2 %

Procedure:
27.9 ml (0.36 mol) of mesyl chloride were added dropwise to a solution of [1-(4-nitrophenyl)pyrrolidin-2-yl]methanol (66.7 g, 0.03 mol), 300 ml of anhydrous DMF and 58.5 ml (0.42 mol) of anhydrous triethylamine, cooled in an ice bath. The temperature was allowed to rise to 20° C. over one hour with stirring. 35.2 g (0.6 mol) of sodium chloride were added and the mixture was heated at 100° C. for one hour. The reaction medium was poured into 1.4 l of ice-water. The precipitate was filtered off, washed with water, dried and recrystallized from isopropanol. 63.7 g of a yellow powder (1) were thus obtained.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18](=[O:28])[C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([C:26]#[N:27])[CH:20]=2)[C:12]=1[F:29])[CH2:9][CH3:10])(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:18](=[O:28])[C:13]2[C:14]([Cl:17])=[CH:15][CH:16]=[C:11]([C@H:8]([NH2:7])[CH2:9][CH3:10])[C:12]=2[F:29])=[CH:20][C:21]=1[C:26]#[N:27]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2ccc(N)c(C#N)c2)c1F
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC[C@@H](N)c1ccc(Cl)c(C(=O)c2ccc(N)c(C#N)c2)c1F
Reaction time: 60 h
Yield: 93.3 %

Procedure:
Step 4 To a solution of {(R)-1-[3-(4-amino-3-cyano-benzoyl)-4-chloro-2-fluoro-phenyl]-propyl}-carbamic acid tert-butyl ester (66 mg, 0.15 mmol) in DCM (2 mL) was added 4M HCl in dioxane (0.19 mL, 0.76 mmol, 5 eq.) and the reaction mixture was stirred for 60 hours. The mixture was partitioned between DCM (10 mL) and water (10 mL) made basic with 5M NaOH. The aqueous phase was extracted with further DCM (10 mL) and then the combined organics were dried (MgSO4), filtered and concentrated to give 2-Amino-5-[3-((R)-1-amino-propyl)-6-chloro-2-fluoro-benzoyl]-benzonitrile (46 mg, 0.14 mmol) as a viscous gum.
Reaction SMILES: C(OC(=O)C)(=O)C.[N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:9]=1[CH3:10].[N+:19]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O)([O-:21])=[O:20]>O>[N+:19]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)/[CH:25]=[CH:10]/[C:9]1[CH:11]=[CH:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1)([O-:21])=[O:20]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: Cc1ccc2ccccc2n1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=[N+]([O-])c1cccc(/C=C/c2ccc3ccccc3n2)c1
Temperature: 160 °C
Reaction time: 4 h
Yield: 87.1 %

Procedure:
To 3.1 g of acetic anhydride, 7.2 g of quinaldine and 7.6 g of m-nitrobenzaldehyde were added and the resulting mixture was stirred under nitrogen atmosphere at 160° C. for 4 hours. After completion of the reaction, water was added to the reaction mixture and the resulting solid was collected by filtration and dried. Recrystallization from toluene gave 12.1 g (yield: 88%) of the captioned compound as an yellow powder.
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[C:4]1[CH:22]=[CH:21][C:7]([CH:8]=[N:9][NH:10][C:11](=[O:20])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:2].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1>>[CH2:23]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[N:9][N:10]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)[C:11](=[O:20])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:21][CH:22]=1)[CH3:24]
Reactant: Cc1ccc(CBr)cc1
Reactant: CCN(CC)c1ccc(C=NNC(=O)c2ccc(OC)cc2)cc1
Product: CCN(CC)c1ccc(C=NN(Cc2ccc(C)cc2)C(=O)c2ccc(OC)cc2)cc1

Procedure:
Referring to FIG. 2, thus, a two-step procedure was explored whereby the amine of compound 1 was protected prior to conversion to compound 3. Specifically, the amino group of compound 1 was protected by reacting with α-bromo-p-xylene to give 4-methoxy-benzoic acid N′-(4-diethylamino-benzylidene)-N-(4-methyl-benzyl)-hydrazide (compound 2). This was followed by the simultaneous demethylation and deprotection of the N-benzyl group of compound 2 by ether cleavage with boron tribromide. This produced compound 3, with an overall yield of 27%.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:11][N:10]=[N:9][C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.C([Sn](CCCC)(CCCC)[C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)CCC>CN1CCCC1=O.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:2]1[C:3]2[NH:11][N:10]=[N:9][C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: Nc1nc(Cl)c2[nH]nnc2n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Nc1nc(-c2ccco2)c2[nH]nnc2n1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A solution of 7-chloro-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (570 mg, 3.34 mmol) in N-methyl-2-pyrrolidinone (4 mL) was treated with PdCl2(PPh3)2 (117 mg, 0.17 mmol) and 2-(tributylstannyl)furan (1.05 mL, 1 mmol), stirred at 80° C. for 5 h, diluted with EtOAc, filtered through a silica pad and concentrated in vacuo. The residue was triturated with diethyl ether and the title compound isolated as a yellow solid (438 mg, 65%).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[CH:4]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)=O>>[CH2:1]([NH:3][CH2:4][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCN
Reactant: N#Cc1ccc(C=O)cc1
Product: CCNCc1ccc(C#N)cc1

Procedure:
prepared by reaction of ethylamine with 4-formyl-benzonitrile
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:25][O:24][C:22](=[O:23])[C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccc(OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(OCC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(4-methoxycarbonyl-phenoxymethyl)-piperidine-1-carboxylic acid t-butyl ester (8.5 g, 24.61 mmol) in DCM (150 mL) was added TFA (45 mL) and the mixture was stirred for 2 hrs at room temperature. The volatiles were evaporated in vacuo and the residue crystallised from addition of diethyl ether. The solid was filtered off washed with a small portion of diethyl ether and dried. This afforded 8.8 g (99%) of 4-(piperidin-4-ylmeth-oxy)-benzoic acid methyl ester as a TFA salt.