Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:20]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH3:20])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COc1cccc(NS(=O)(=O)c2ccc(Br)cc2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cccc(N(C)S(=O)(=O)c2ccc(Br)cc2)c1
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
To a stirred mixture of the product of Step A (0.5 g 1.46 mmol) and K2CO3 (0.5 g) in anhydrous DMF (7 ml) was added CH3I (1 ml) and the stirring continued for 0.5 h at 50° C. The mixture was diluted to 50 ml with H2O and extracted with EtOAc (50 ml). The organic layer was washed with H2O and dried over MgSO4, passed through silica gel bead and the filtrate was evaporated to dryness to give the title compound (0.5 g, 96%) as pale solid. 1H-NMR (CDCl3) 7.58 (d, 2H, J=8.64 Hz); 7.40 (d, 2H, J=8.67 Hz); 7.18 (t, 1H, J=8.15 Hz); 6.80 (dd, 1H, J=8.34, 2.5 Hz); 6.69 (t, 1H, J=2.20 Hz); 6.58 (bd, 1H); 3.75 (s, 3H, OMe); 3.14 (s, 3H, N-Me).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][N:4]=1.[CH3:16][NH2:17].C(Cl)Cl.CO>C(O)C>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:17][CH3:16])[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][N:4]=1
Reactant: CSc1ncc(-c2ccccc2)c(Cl)n1
Reactant: CN
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: CNc1nc(SC)ncc1-c1ccccc1

Procedure:
Prepared from 2-methylsulphenyl-4-chloro-5-phenyl-pyrimidine by reacting with methylamine in ethanol at 90° C., Rf value: 0.63 (silica gel; methylene chloride/methanol=20:1)
Reaction SMILES: Cl.[C:2]([NH2:8])(=[NH:7])[C:3]([CH3:6])([CH3:5])[CH3:4].C[O-].[Na+].C[O:13][CH:14]=[C:15]([C:20](OC)=O)[C:16]([O:18][CH3:19])=[O:17]>CO>[C:3]([C:2]1[N:8]=[C:14]([OH:13])[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][N:7]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: COC=C(C(=O)OC)C(=O)OC
Reactant: CC(C)(C)C(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cnc(C(C)(C)C)nc1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45 %

Procedure:
Pivalamidine hydrochloride (5.00 g, 37 mmol) dissolved in methanol (80 mL) was treated with NaOMe (2.0 g, 37 mmol) and stirred at RT for 15 min. To this was added dimethyl 2-(methoxymethylene)malonate (6.4 g, 37 mmol) and the solution stirred at RT overnight. The solution was heated at reflux for 1 h, then cooled to RT and concentrated. The oily mass was dissolved in H2O (125 mL) and the pH adjusted to ˜3 (wet litmus) with AcOH. The precipitated solids were collected by filtration, washed with H2O (50 mL) and dried to yield methyl 2-t-butyl-4-hydroxypyrimidine-5-carboxylate (3.50 g, 45%). 1H NMR (400 MHz, DMSO-d6): δ 1.29 (s, 9H), 2.97 (s, 3H), 8.47 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[O:21].C(O)C.C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1>C1(C)C=CC=CC=1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>[NH2:32][C:33]1[CH:38]=[C:37]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]3=[O:21])[CH:36]=[CH:35][CH:34]=1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: Nc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3cccc(N)c3)ccn2c1=O
Yield: 48.4 %

Procedure:
92.7 mg of ethyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was suspended in 1 ml of toluene. 0.5 ml of ethanol, 0.5 ml of 2 M aqueous sodium carbonate solution, 50 mg of 3-aminophenylboronic acid hydrochloride and 10 mg of bis(triphenylphosphine) palladium (II) chloride were added to the obtained suspension, and they were heated under reflux in argon atmosphere for 3 hours. Ethyl acetate was added to the reaction mixture. The organic layer was taken, washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resultant residue was purified by the silica gel column chromatography (eluent: chloroform/ethyl acetate=4/1) to obtain 50.6 mg of ethyl 8-(3-aminophenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate.
Reaction SMILES: [CH:1]([N:4]([C:6]1[CH:7]=[C:8]([OH:14])[C:9](=[CH:12][CH:13]=1)[CH:10]=O)[CH3:5])([CH3:3])[CH3:2].[CH2:15]([NH2:18])[CH2:16][NH2:17]>>[CH:1]([N:4]([C:6]1[CH:7]=[C:8]([OH:14])[C:9](=[CH:12][CH:13]=1)[CH:10]=[N:17][CH2:16][CH2:15][N:18]=[CH:10][C:9]1[C:8](=[CH:7][C:6]([N:4]([CH3:5])[CH:1]([CH3:2])[CH3:3])=[CH:13][CH:12]=1)[OH:14])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)N(C)c1ccc(C=O)c(O)c1
Reactant: NCCN
Product: CC(C)N(C)c1ccc(C=NCCN=Cc2ccc(N(C)C(C)C)cc2O)c(O)c1

Procedure:
Synthesis and working up are carried out as in Example 9, starting from 500 mg (2.59 mmol) of 4-(N-isopropyl-N-methylamino)salicylaldehyde and 90 mg (1.5 mmol) of ethylenediamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[C:6]([NH2:8])[CH:7]=1.[CH3:10][N:11]([CH2:13][C:14](O)=[O:15])[CH3:12].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:8][C:6]1[CH:5]=[C:4]([NH:9][C:14](=[O:15])[CH2:13][N:11]([CH3:12])[CH3:10])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Nc1cc(N)cc(Cl)c1
Reactant: CN(C)CC(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)CC(=O)Nc1cc(N)cc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-chloro-benzene-1,3-diamine (3 g, 21 mmol) and dimethylamino-acetic acid (2.2 g, 21 mmol) in CH2Cl2 (300 mL) was added EDC (5 g, 25 mmol), HOBt (2.9 g, 21 mmol), and DIEA (5 mL). The reaction mixture was stirred at RT for overnight. Solvent was removed in vacuum and the residue was purified through flash chromatography on silica gel (0-8% MeOH in EtOAc) to give the desired compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[CH:11]=[O:12]
Reactant: Cc1cc(CO)ccc1[N+](=O)[O-]
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1cc(C=O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (3-methyl-4-nitrophenyl)methanol (1.0 equiv.) in dichloromethane, pyridinium chlorochromate (1.1 equiv.) was added and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered through celite and the filtrate was evaporated. The residue was adsorbed on silica (100-200 mesh) and purified by flash chromatography on silica gel, eluting with 5% ethyl acetate in petroleum ether (60-80), to provide the title compound in the form of creamish crystals (93%); 1H NMR (300 MHz, CDCl3) δ: 2.66 (s, 3H), 7.84-7.87 (m, 2H), 8.04-8.07 (d, J=8.7 Hz, 1H), 10.12 (s, 1H); IR (KBr) 3104, 3079, 2981, 2857, 2743, 1702, 1607, 1518, 1383, 1361, 1308, 1226, 1153, 1008, 832, 735 cm−1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])([O-:3])=[O:2].C1(C)C=CC(S([CH2:26][N:27]=[C:28]=O)(=O)=O)=CC=1.[H-].[Na+].O>CS(C)=O.C(OCC)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:26][NH:27][CH:28]=1)([O-:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)CN=C=O)cc1
Reactant: CCOC(=O)CCc1ccccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOCC
Product: CCOC(=O)c1c[nH]cc1-c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 41 %

Procedure:
A solution of ethyl 3-(2-nitrophenyl)propanoate (120 mmol; 26.6 g) and 4-toluenesulfonylmethyl isocyanate (TosMIC) (130 mmol; 25.4 g) in a mixture of dimethyl sulfoxide and anhydrous ethyl ether (150 and 300 ml) was added dropwise to a suspension of 60% sodium hydride in paraffin (260 mmol; 10.4 g) in anhydrous ethyl ether (300 ml), under a stream of argon. After the addition, the mixture was stirred at room temperature for 25 minutes, water (500 ml) was then added and the resulting solution was extracted with ethyl acetate (3×600 ml). The combined organic phases were washed with saturated NaCl solution (3×300 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product obtained was purified on a column of alumina (eluting with a 1/1 chloroform/ethyl acetate mixture) to give 12.8 g (41%) of final product having the following characteristics:
Reaction SMILES: O1CCCCC1[O:7][C@@H:8]([CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:9][CH2:10][CH2:11][C:12]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])(C([O-])=O)[C:13](OC(C)(C)C)=[O:14].CS(OCCC[C@@H](OC1CCCCO1)CCCCC)(=O)=O.CS(OCCC[C@H](OC1CCCCO1)CCCCC)(=O)=O.O1CCCCC1OC(CCCCC)CCCC(CCCCCCC(OCC)=O)(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O.O[C@H](CCCCC)CCCC(CCCCCCC(OCC)=O)(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O.C(O[C@H](CCCCC)CCCC(CCCCCCC(OCC)=O)(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)(=O)C.C(C(CCC[C@@H](OC(=O)C)CCCCC)CCCCCCC(OCC)=O)(O)=O.ClC(C(CCC[C@@H](OC(=O)C)CCCCC)CCCCCCC(OCC)=O)=O.C(C(CCC[C@@H](OC(=O)C)CCCCC)CCCCCCC(OCC)=O)(=O)[NH2:255].C(C(CCCCCC(C(=O)N)CCC[C@@H](O)CCCCC)C(O)=O)C>>[C:13]([CH:12]([CH2:11][CH2:10][CH2:9][C@H:8]([OH:7])[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])(=[O:14])[NH2:255]
Reactant: CCCCC[C@@H](CCCC(CCCCCCC(=O)OCC)(C(=O)[O-])C(=O)OC(C)(C)C)OC1CCCCO1
Reactant: CCCCC[C@@H](CCCC(CCCCCCC(=O)OCC)C(N)=O)OC(C)=O
Agent: CCCCCC(CCCC(CCCCCCC(=O)OCC)(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)OC1CCCCO1
Agent: CCCCC[C@@H](CCCC(CCCCCCC(=O)OCC)C(=O)Cl)OC(C)=O
Agent: CCCCC[C@@H](CCCC(CCCCCCC(=O)OCC)C(=O)O)OC(C)=O
Product: CCCCC[C@@H](O)CCCC(CCCCCCC(=O)O)C(N)=O

Procedure:
The synthesis of this compound is carried out exactly according to the procedure described for the 12-(S) compound of Example 13 except that in Step B, the (4S)-1-methylsulfonyloxy-4-(2-tetrahydropyranyloxy)-nonane is replaced by an equimolar amount of (4R)-1-methylsulfonyloxy-4-(2-tetrahydropyranyloxy)nonane (Example I, Step 7). The product of Step B is thus di-tert.-butyl 2-[4-(2-tetrahydropyranyloxy)nonyl]-2-(6-ethoxycarbonylhexyl)malonate. Subsequent steps yield: di-tert.-butyl 2-(4-(R)-hydroxynonyl)-2-(6ethoxycarbonylhexyl)malonate (B-1); di-tert.-butyl 2 -(4-(R)-acetoxynonyl)-2-(6-ethoxycarbonylhexyl)malonate (B-2); ethyl 8-carboxy-12-(R)-acetoxyheptadecanoate (C); ethyl 8-chlorocarbonyl-12-(R)-acetoxyheptadecanoate (D); ethyl 8-carbamoyl-12-(R)-acetoxyheptadecanoate (E); and 8-carbamoyl-12-(R)-hydroxheptadecanoic acid (F).
Reaction SMILES: [C:1]([N:9]([C:18]([C:20]1[C:29]2[C:24](=[C:25]([C:32]([F:35])([F:34])[F:33])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)=[O:19])[CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O.O>[C:1]([N:9]([C:18]([C:20]1[C:29]2[C:24](=[C:25]([C:32]([F:33])([F:35])[F:34])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)=[O:19])[CH2:10][C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(C(=O)N(CC(=O)OC(C)(C)C)C(=O)c3ccccc3)cccc2c1C(F)(F)F
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(C(=O)N(CC(=O)O)C(=O)c3ccccc3)cccc2c1C(F)(F)F
Yield: 34.2 %

Procedure:
A solution of N-benzoyl-N-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]glycine, 1,1-dimethylethyl ester (6.03 g, 12.4 mmole) in trifluoroacetic acid (40 mL) was stirred at room temperature for 10 minutes, then diluted with water (600 mL) and extracted with ether (2×300 mL). The extracts were combined, washed with saturated aqueous sodium chloride (1×100 mL), dried with magnesium sulfate, and the ether was removed. The resultant oil was suspended in water (300 mL) and the aqueous phase was slowly neutralized to pH 5 with 10% aqueous sodium hydroxide solution. The precipitate was collected by suction filtration, washed with water (2×25 mL), dried and flash chromatographed (9:1 chloroform:acetonitrile, 5% phosphoric acid in methanol treated silica). The solid was then recrystallized in 2:1 benzen:hexane to provide the product as white crystals (1.83 g, 33%), m.p. 143°-145° C. (dec.).
Reaction SMILES: [Cl:1][O-].[Na+].[NH:4]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:5]1>CC(O)=O>[CH2:12]([O:11][C:9]([C:8]1[C:7]([Cl:1])=[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:5][N:4]=1)=[O:10])[CH3:13]
Reactant: [O-]Cl
Reactant: CCOC(=O)c1cc(C(=O)OCC)[nH]n1
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1n[nH]c(C(=O)OCC)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.3 %

Procedure:
Sodium hypochlorite (2.79 mL, 5.89 mmol) was added to a solution of diethyl 3,5-pyrazoledicarboxylate (0.5 g, 2.36 mmol) in AcOH (10 mL) and the mixture was stirred at room temperature for 16 hours. Then, the solvent was evaporated in vacuo and the mixture was acidified with a 1N solution of HCl and extracted with AcOEt. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; MeOH in DCM 0/100 to 05/95). The desired fractions were collected and the solvents evaporated in vacuo to yield 4-chloro-1H-pyrazole-3,5-dicarboxylic acid diethyl ester (450 mg, 66% yield) as a white solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[N:17][C:18]([NH2:21])=[N:19][CH:20]=3)=[N:13][CH:14]=2)O1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[CH:31]=[N:32][C:33]([NH2:36])=[N:34][CH:35]=1>>[NH2:36][C:33]1[N:32]=[CH:31][C:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[N:19][C:18]([NH2:21])=[N:17][CH:16]=3)=[N:13][CH:14]=2)=[CH:35][N:34]=1
Reactant: Nc1ncc(-c2ccccc2Br)cn1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)nc2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3ccccc3-c3cnc(N)nc3)cn2)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 427 using 5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amine and 5-(2-bromophenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C19H15N7, 341.14; m/z found, 342.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.97 (s, 2H), 8.47 (dd, J=2.3, 0.9, 1H), 8.16 (s, 2H), 7.86 (dd, J=8.2, 0.9, 1H), 7.80 (dd, J=8.2, 2.3, 1H), 7.59-7.49 (m, 4H).
Reaction SMILES: [ClH:1].[NH:2]1[CH2:6][CH2:5][C@@H:4]([CH2:7][C:8]#[N:9])[CH2:3]1.C(C[C@H]1CCN(C(OC(C)(C)C)=O)C1)#N>>[ClH:1].[NH:2]1[CH2:6][CH2:5][C@H:4]([CH2:7][C:8]#[N:9])[CH2:3]1
Reactant: N#CC[C@@H]1CCNC1
Agent: CC(C)(C)OC(=O)N1CC[C@H](CC#N)C1
Agent: Cl
Product: N#CC[C@H]1CCNC1

Procedure:
Prepared by proceeding in a similar manner to Intermediate 205, starting from tert-butyl (R)-3-cyanomethylpyrrolidine-1-carboxylate (Intermediate 211) and used without further characterisation.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=3)[N:9]=2)[CH:5]=[CH:4][C:3]=1[C:19]1[NH:23][C:22](=[O:24])[O:21][N:20]=1.ClC1C=CC2C(=CC=C(O)C=2)N=1.C(C1C=CC(B(O)O)=C([F:48])C=1)#N>>[F:48][C:7]1[CH:2]=[C:3]([C:19]2[NH:23][C:22](=[O:24])[O:21][N:20]=2)[CH:4]=[CH:5][C:6]=1[C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=2)[N:9]=1
Reactant: N#Cc1ccc(B(O)O)c(F)c1
Reactant: O=c1[nH]c(-c2ccc(-c3ccc4cc(O)ccc4n3)cc2F)no1
Agent: Oc1ccc2nc(Cl)ccc2c1
Product: O=c1[nH]c(-c2ccc(-c3ccc4cc(O)ccc4n3)c(F)c2)no1

Procedure:
Followed procedure described for Compound 20 in Example 20 starting from 2-chloroquinolin-6-ol (Intermediate 2) and 4-cyano-2-fluorophenylboronic acid. 1H NMR (DMSO-d6, 300 MHz): δ 10.22 (1H, s), 8.27-8.33 (2H, m), 7.97 (1H, d, J=9 Hz), 7.77-7.82 (2H, m), 7.39 (1H, dd, J=3, 9 Hz), 7.21 (1H, d, J=3 Hz) ppm. MS (ESI): m/z 324.0 [M+1]+.
Reaction SMILES: Cl.ClC1C=CC(NN)=CC=1.Cl.Cl[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]([CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][CH2:35]C[CH2:33]2)N)=[CH:24][CH:23]=1.C(OC(OCC)CCCNC)C.ClC1C=C2C(=CC=1)N(CCN1CCCCC1)C=C2CCNC.C=O.C(O)(C(F)(F)F)=O>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[Cl:21][C:22]1[CH:23]=[C:24]2[C:25](=[CH:26][CH:27]=1)[N:28]([CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:30]1[CH2:31][N:32]([CH3:33])[CH2:37][CH2:36][C:35]2=1
Reactant: NN(CCN1CCCCC1)c1ccc(Cl)cc1
Reactant: ClCCN1CCCCC1
Agent: C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCOC(CCCNC)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CN1CCc2c(n(CCN3CCCCC3)c3ccc(Cl)cc23)C1

Procedure:
The title compound was prepared by following General Methods 2, 3 and 4 using 4-chlorophenylhydrazine hydrochloride, 1-(2-chloroethyl)piperidine hydrochloride, and tetra-n-butylammonium chloride (General Method 2), 1-(4-chlorophenyl)-1-(2-(piperidin-1-yl)ethyl)hydrazine (Example 3) and 4,4-diethoxy-N-methylbutan-1-amine (General Method 3) and 2-(5-chloro-1-(2-(piperidin-1-yl)ethyl)-1H-indol-3-yl)-N-methylethanamine (Example 12), formaldehyde and TFA in acetonitrile (General Method 4).
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:3]1.CS(C)=[O:19]>O>[O:19]=[C:3]1[CH:4]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:2]1
Reactant: O=C(O)CCCc1c[nH]c2ccccc12
Reactant: CS(C)=O
Agent: Cl
Solvent: O
Product: O=C(O)CCCC1C(=O)Nc2ccccc21
Yield: 96 %

Procedure:
Concentrated HCl (16.6 mL) was added dropwise with stirring, over 10 minutes, to a solution of 4-(3-indolyl)butanoic acid [II: R1 =R3 =H, R2 =(CH2)3COOH] (2.00 g) in DMSO (7.0 mL) at room temperature (method of Savige WE, Fontana A, J. Chem. Soc. Chem. Commun. 1976:599). After 15 minutes reaction, the mixture was diluted with water (80 mL) and extracted with EtOAc (4×100 mL). Removal of the solvent gave crude 4-(2-oxo-3-indolinyl)butanoic acid [III: R1 =R3 =H, R2 =(CH2)3COOH] (2.07 g, 96%) as a green-brown solid; mp (water) 169°-171° C. (Hinman RL, Bauman CP, J. Org. Chem, 1964;29:1206 record mp 170°-171° C.).
Reaction SMILES: C([O:5][C:6](=[O:32])[CH2:7][C@@H:8]([CH2:28][CH:29]1[CH2:31][CH2:30]1)[C:9](N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)CC(C)C)=[O:10])(C)(C)C.CN(C)C(=O)CN([C@H](C1C=CC=CC=1)C)C(=O)C[C@@H](CC1N=C(N)SC=1)C(N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)CC(C)C)=[O:42].[OH-].[Li+].OO>>[CH:29]1([CH2:28][C@H:8]([CH2:7][C:6]([OH:5])=[O:32])[C:9]([OH:10])=[O:42])[CH2:31][CH2:30]1
Reactant: CC(C)C[C@H](O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](CC(=O)OC(C)(C)C)CC1CC1
Reactant: CC(C)C[C@H](O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](CC(=O)N(CC(=O)N(C)C)[C@@H](C)c1ccccc1)Cc1csc(N)n1
Agent: OO
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)C[C@@H](CC1CC1)C(=O)O

Procedure:
The protected amide, 3(R)-(cyclopropylmethyl)-4-{[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]amino}-4-oxobutanoic acid tert-butyl ester: Following the procedure of section (g) of example 2, the product of section (b) of this example (10.2 g, 30 mmol) was reacted with lithium hydroxide-hydrogen peroxide to give the desired monoprotected dicarboxylic acid, i.e. the 4-tert-butyl ester of 2(R)-(cyclopropylmethyl)butanedioic acid, as a colorless oil (6.65 g, 97%); [α]D23 +16.1° (c 2.61, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH:25]([OH:29])[CH2:26][O:27][CH3:28])[CH2:19]4)[C:14]([F:30])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[Li+].[OH-]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH:25]([OH:29])[CH2:26][O:27][CH3:28])[CH2:19]4)[C:14]([F:30])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COCC(O)CN1CCC[C@H](Nc2nc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(Cl)cc34)ncc2F)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COCC(O)CN1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 120 °C

Procedure:
To a solution of 1-[(3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-1-piperidyl]-3-methoxy-propan-2-ol, 1d, (0.15 g, 0.24 mmol) in THF was added 1N LiOH solution. The reaction mixture was heated in a microwave reactor at 120° C. for 5 minutes. The reaction mixture was diluted with water and the aqueous phase was extracted with EtOAc (twice). The combined organic phases were dried (MgSO4), filtered and concentrated under vacuo. The resulting solid was purified by silica gel chromatography (5-20% MeOH: CH2Cl2) to afford the desired product (537) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH:8]([N:16](C)[C:17](=O)OC(C)(C)C)[CH2:7]1.[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH:8]([NH:16][CH3:17])[CH2:7]1.[C:31]([OH:33])([C:30]([F:35])([F:34])[F:29])=[O:32]
Reactant: CN(C(=O)OC(C)(C)C)C1Cc2ccccc2N(Cc2ccc(Cl)c(Cl)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC1Cc2ccccc2N(Cc2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 1-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydroquinolin-3-yl(methyl)carbamate (0.760 g, 1.8 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (6 mL). The mixture was stirred at room temperature for 1 hour. Solvent was removed under reduced pressure and the residue triturated with hexane and dried under vacuum to give 1-(3,4-dichlorobenzyl)-N-methyl-1,2,3,4-tetrahydroquinolin-3-amine as its solid TFA salt (580 mg). 1H NMR (DMSO) 400 MHz δ 7.57 (m, 2H), 7.28 (dd, J=2.0 Hz and 19.2 Hz, 1H), 7.01 (m, 2H), 6.63 (t, J=7.2 Hz, 1H), 6.54 (d, J=7.6 Hz, 1H), 4.50 (q, J=17.2 Hz, 2H), 3.68 (br, 1H), 3.58 (d, J=12 Hz, 1H), 3.39 (m, 1H), 3.20 (dd, J=5.2 Hz and 16.8 Hz, 1H), 2.89 (dd, J=5.6 Hz, and 16.4 Hz, 1H), 2.63 (t, J=5.2 Hz, 3H). LCMS m/e 321 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH:10]2O[CH:13]=[N:12][CH:11]2S(C2C=CC(C)=CC=2)(=O)=O)=[CH:4][C:3]=1[O:25][CH3:26].[CH3:27][NH2:28].C1COCC1>CO.CCOC(C)=O>[Br:1][C:2]1[C:3]([O:25][CH3:26])=[CH:4][C:5]([C:10]2[N:28]=[CH:27][N:12]([CH3:13])[CH:11]=2)=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1cc(C2OC=NC2S(=O)(=O)c2ccc(C)cc2)cc(OC)c1Br
Reactant: CN
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(-c2cn(C)cn2)cc(OC)c1Br
Temperature: 135 °C
Yield: 21 %

Procedure:
To an oven-dried pressure tube was added 5-(4-bromo-3,5-dimethoxyphenyl)-4-tosyl-4,5-dihydrooxazole (0.4 g, 0.91 mmol), methylamine-THF solution (1.8 mL of a 2.0 M solution, 3.6 mmol), and xylenes (5 mL). The tube was sealed under argon then heated at 135° C. for 15 hours. After cooling to room temperature, the reaction mixture was transferred and concentrated in vacuo then partitioned between EtOAc and H2O. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organics were washed with brine twice, dried over Na2SO4 and concentrated. Purification by chromatography (50-100% EtOAc-hexanes then 2-5% MeOH-EtOAc) provided 4-(4-bromo-3,5-dimethoxyphenyl)-1-methyl-1H-imidazole as a light yellow solid (0.056 g, 21% yield).
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[Cl:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1/[CH:25]=[CH:26]/[C:27](O)=[O:28]>>[Cl:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1/[CH:25]=[CH:26]/[C:27]([NH:16][C:14]1[CH:13]=[N:12][N:11]([CH2:10][C:8]2[O:9][C:5]([C:2]([F:1])([F:4])[CH3:3])=[CH:6][CH:7]=2)[CH:15]=1)=[O:28]
Reactant: O=C(O)/C=C/c1ccc(F)cc1Cl
Reactant: CC(F)(F)c1ccc(Cn2cc(N)cn2)o1
Product: CC(F)(F)c1ccc(Cn2cc(NC(=O)/C=C/c3ccc(F)cc3Cl)cn2)o1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(2-chloro-4-fluoro-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.12 min; [M+H]+=410.06.