Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[OH:15].[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:17]1[C:25]([NH:27][C:28]1([C:34](O)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:26].OC1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:17]1[C:25]([NH:27][C:28]1([C:34]([NH:1][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:4][CH:3]2[OH:15])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCC(N)C(O)C1
Reactant: O=C(NC1(C(=O)O)CCCCC1)c1cc2ccccc2o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 67.2 %

Procedure:
To the solution of tert-butyl 4-amino-3-hydroxypiperidine-1-carboxylate (20 g, 92 mmol) obtained in step 4 of Preparation Example 1 and 1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarboxylic acid (26 g, 92 mmol) obtained in step 2 of Preparation Example 2 in 150 ml of dimethylformamide, were added hydroxybenzotriazole(HOBt; 24 g, 180 mmol) and diisopropylethylamine (DIEA; 23 g, 180 mmol). The reaction mixture was cooled to 0° C. and was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC-HCl; 35 g, 180 mmol) thereto. The reaction mixture was stirred for 4 hours at room temperature, diluted with 300 ml of ethyl acetate, and washed with 10% citric acid solution, a saturated sodium bicarbonate solution and brine. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was purified with column chromatography to give 30 g of the titled compound.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C([O-])(=O)C.[Na+].[CH3:10][C:11]([NH:14][S:15]([C:18]1[CH:22]=[CH:21][N:20](C)[C:19]=1[CH:24]=O)(=[O:17])=[O:16])([CH3:13])[CH3:12].O>CO>[CH3:13][C:11]([NH:14][S:15]([C:18]1[CH:22]=[CH:21][NH:20][C:19]=1[CH:24]=[N:4][O:3][CH3:2])(=[O:17])=[O:16])([CH3:10])[CH3:12]
Reactant: CON
Reactant: Cn1ccc(S(=O)(=O)NC(C)(C)C)c1C=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CON=Cc1[nH]ccc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Yield: 96.2 %

Procedure:
To a suspension of 3.91 g (46.8 mmol) of methoxyamine hydrochloride in 60 mL of methanol was added 3.84 g (46.8 mmol) of sodium acetate. After stirring the white suspension for ca. 15 minutes 5.72 g (23 mmol) of N-(1,1-dimethylethyl)-2-formyl-1-methyl-1H-pyrrole-3-sulfonamide was added in one portion. The white suspension was heated at a gentle reflux overnight ca. 16 hours. The reaction mixture was cooled to room temperature and poured into 500 mL of water. The aqueous mixture was extracted with four 100 mL, portions of methylene chloride. The combined extracts were washed with water, dried (MgSO4) and concentrated in vacuo yielding 5.74 g of the title compound as a white solid, m.p. 99°-101° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:14]=3[O:13]2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[C:23](Cl)(=[O:26])[CH2:24][CH3:25].C(OCC)(=O)C>N1C=CC=CC=1>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH:11]=[C:12]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([O:22][C:23](=[O:26])[CH2:24][CH3:25])=[CH:21][C:14]=3[O:13]2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(C=C2Oc3cc(O)ccc3C2=O)cc(OC)c1
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCC(=O)Oc1ccc2c(c1)OC(=Cc1cc(OC)cc(OC)c1)C2=O
Temperature: 25 °C

Procedure:
After 2-[(3,5-dimethoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.525 g was dissolved in pyridine 5 ml, propionyl chloride 0.218 ml was added, and the mixture was refluxed for 1.5 hours. The reaction mixture was cooled to room temperature, ethyl acetate 50 ml was added, and the mixture was washed with 2N-hydrochloric acid 50 ml, saturated sodium bicarbonate solution 50 ml, and a saturated sodium chloride solution 50 ml. The ethyl acetate solution was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was fractionated by silica gel column chromatography (silica gel: 50 g, eluted with solvent 500 ml of hexane:ethyl acetate=1:1) and the fraction was concentrated to dryness at a temperature of 40° C. under reduced pressure to obtain crystals. The crystals were recrystallized with ethyl acetate 5 ml/hexane 10 ml and filtered. The crystals were dried over phosphorous pentoxide at a temperature of 60° C. for five hours under reduced pressure to obtain the desired compound 275.1 mg.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][C@@H:13]([OH:15])[CH2:12][C@H:11]1[C:16]([OH:18])=[O:17])=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1.Cl>CN(C=O)C.C(OCC)(=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:14][C@@H:13]([O:15][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=2)[CH2:12][C@H:11]1[C:16]([OH:18])=[O:17])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CO[C@H]2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 36.4 %

Procedure:
Sodium hydride (0.97 g, 24 mmol) was suspended in DMF (15 mL) under nitrogen at 0° C. A solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (2.0 g, 8.7 mmol) in DMF (20 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 10 min and treated with a solution of methyl 4-(bromomethyl)benzoate (2.3 g, 10 mmol) in DMF (5 mL). The reaction mixture was stirred at 0° C. for 1 h, and mixed with ethyl acetate and 1N HCl solution. The EtOAc layer was separated, washed with brine, and dried over MgSO4. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (eluting with 20% EtOAc/DCM) to afford the title compound as a white solid (1.2 g, 37%). 1H NMR (CDCl3) δ 7.99 (d, J=8.1 Hz, 2H), 7.36 (d, J=3.5 Hz, 2H), 4.78-4.26 (m, 3H), 4.19-4.11 (m, 1H), 3.90 (s, 3H), 3.71-3.46 (m, 2H), 2.84-2.39 (m, 1H), 2.23-2.04 (m, 1H), 1.48 (br. s., 9H); MS(ESI+) m/z 324.0 (M-55)+.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)=[C:11]([NH2:14])[CH:12]=2)[N:7]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2].Cl[C:33]([O:35][CH3:36])=[O:34].C(OC(=O)C)(=O)C.C(NC1C=C2C(=CC=1C1C=NN(C3CC3)C=1)N(C(OC(C)C)=O)C[C@H](C)N2C(=O)C)(=O)C>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:15]3[CH:16]=[CH:17][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:19][CH:20]=3)=[C:11]([NH:14][C:33]([O:35][CH3:36])=[O:34])[CH:12]=2)[N:7]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2cc(N)c(-c3ccc(S(C)(=O)=O)cc3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Reactant: COC(=O)Cl
Agent: CC(=O)Nc1cc2c(cc1-c1cnn(C3CC3)c1)N(C(=O)OC(C)C)C[C@H](C)N2C(C)=O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)Nc1cc2c(cc1-c1ccc(S(C)(=O)=O)cc1)N(C(=O)OC(C)C)C[C@H](C)N2C(C)=O

Procedure:
Isopropyl (S)-4-acetyl-6-((methoxycarbonyl)amino)-3-methyl-7-(4-(methylsulfonyl)phenyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate was synthesized from isopropyl (S)-4-acetyl-6-amino-3-methyl-7-(4-(methylsulfonyl)phenyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate and methyl chloroformate (instead of acetic anhydride) according to the procedure described above for isopropyl (S)-6-acetamido-4-acetyl-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (Example 235). MS (ESI, pos. ion) m/z 504 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].C(N(CC)CC)C.Cl[CH2:21][C:22](Cl)=[O:23].[H-].[Na+]>C1COCC1>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]2[NH:1][C:22](=[O:23])[CH2:21][O:12][C:3]=2[CH:4]=1)=[O:7]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)c1ccc(N)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)OCC(=O)N2
Yield: 93.7 %

Procedure:
Using methyl 4-amino-3-hydroxybenzoate (2 g, 12 mmol), triethylamine (2.17 mL, 16 mmol) and chloroacetyl chloride (1.13 mL, 13 mmol) in THF (70 mL) followed by sodium hydride (1.0 g of a 60% suspension in oil, 24 mmol) to yield the title compound as a brown solid (2.33 g, 94%). δH (DMSO-d6) 3.81 (3H, s), 4.65 (2H, s), 6.99 (1H, d, J 8.3 Hz), 7.43 (1H, d, J 1.5 Hz). 7.59 (1H, dd, J 8.5, 1.9 Hz), 11.10 (1H, br s). LCMS (ES+) 208 (M+H)+.
Reaction SMILES: [CH:1]([CH:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2].[OH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([O-:18])=[O:17])=[CH:14][CH:13]=1.[Na+].CS(C)=O>O>[OH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([O:18][CH:3]([CH:1]=[CH2:2])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:17])=[CH:14][CH:13]=1
Reactant: O=C([O-])c1ccc(O)cc1
Reactant: C=CC(Cl)c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=CC(OC(=O)c1ccc(O)cc1)c1ccccc1
Yield: 92.3 %

Procedure:
71.5 g of vinylbenzyl chloride and 75.0 g of sodium p-hydroxybenzoate were added to 250 ml of dimethylsulfoxide and stirred and reacted at 40° C. for 4 days. Then 1,000 ml of water was added thereto, and the resulting mixture was extracted with 200 ml of ethyl acetate. After distilling off ethyl acetate, recrystallization of the residue from benzene-hexane mixture solvent yielded 110 g of vinylbenzyl p-hydroxybenzoate (m.p. 83°-85° C.).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1Cl)=[O:13])[CH2:8]2.[NH:21]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1[N:21]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:13])[CH2:8]2
Reactant: C1CCCNCC1
Reactant: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Product: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1N1CCCCCC1

Procedure:
Heating a mixture of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Example 5, 60 mg; 0.20 mmol) and azepane (0.23 mL; 2.0 mmol) to 250° C. under microwave irradiation according to the procedure described in Example 14 provided after purification by reverse phase HPLC, 5-azepan-1-yl-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (41 mg, 58%) as an off-white powder. ES-HRMS m/e calcd for C21H33N4O (M+H+) 357.2649, found 357.2644.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23]>>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]([NH:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1)=[O:23]
Reactant: O=C=Nc1ccccc1Cl
Reactant: CCOC(=S)c1cnc(C)nc1N
Product: CCOC(=S)c1cnc(C)nc1NC(=O)Nc1ccccc1Cl
Temperature: 102.5 °C
Reaction time: 14 h
Yield: 94.8 %

Procedure:
To a suspension of ethyl 4-amino-2-methylthiopyrimidine-5-carboxylate (1215 g, 5.7 moles) in 2600 mL xylenes heated at 100-105° C. was added (956.5 g, 6.23 moles 2-chlorophenylisocyanate so as to maintain the temperature at 100° C. The temperature of the reaction mixture was raised to 120° C. and stirred for 14 hours. Heating was stopped and slow cooling to 110° C. was begun. When crystallization began, slow addition of 5256 mL ethyl acetate completed the crystallization. The mixture was cooled to 20° C. and filtered. The cake was washed with ethyl acetate and was placed in a vacuum oven and dried for 10-12 hours at 60° to 80° C. to give 1895 g (90.7%)of ethyl 4-{[(2-chlorophenyl)amino]carbonylamino}-2-methylthiopyrimidine-5-carboxylate, m.p.172.3-172.6° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:1][C:2]2[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Product: O=C(O)c1cc(NCc2ccc(Cl)cc2)ccc1O
Yield: 53 %

Procedure:
By following the similar procedure in Synthesis Example 1 by using 5-aminosalicylic acid (500 mg, 3.26 mmole) and 4-chlorobenzyl chloride (630 mg, 3.91 mmole), 480 mg (53% yield) of 5-(4-chlorobenzyl)aminosalicylic acid was obtained as a white solid.: mp 227-228° C.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([C:11](=[O:13])[CH3:12])[CH2:7][CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:35])=[CH:19][N:18]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)([O-])[O-]>C(O)(C)C>[C:11]([N:6]1[C:5]2[CH:14]=[CH:15][C:2]([NH:1][C:17]3[N:22]=[C:21]([NH:23][C:24]4[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:25]=4[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:35])=[CH:19][N:18]=3)=[CH:3][C:4]=2[O:10][CH2:9][CH2:8][CH2:7]1)(=[O:13])[CH3:12]
Reactant: CC(=O)N1CCCOc2cc(N)ccc21
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)OCCCN3C(C)=O)ncc1Cl

Procedure:
1-(3-Amino-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-ethanone (97 mg, 0.47 mmol), 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide (169 mg, 0.536 mmol), and 10-Camphorsulfonic acid (16 mg, 0.070 mmol) in Isopropyl alcohol (4 mL) was irradiated in a CEM microwave (120° C., 30 min). The mixture was neutralized with MP-carbonate (0.3 mmol) and purified on silica gel (ISCO, 2×12 g, 0-100% EtOAc:Hex) to afford 2-[2-(9-Acetyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamino)-5-chloro-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide as off white solids (122 mg, 53%). MP=226-228° C.; LCMS: 485 (M+H); 1H-NMR (DMSO): 9.51 (s, 1H), 9.42 (s, 1H), 9.56 (m, 1H), 8.21 (s, 1H), 7.49 (m, 2H), 7.42 (m, 1H), 7.36 (s, 1H), 7.17 (m, 1H), 7.05 (d, 1H, J=8.5 Hz), 4.54 (m, 1H), 4.32 (m, 1H), 3.55 (m, 1H), 2.74 (d, 3H, J=4.5 Hz), 1.92 (m, 1H), 1.71 (m, 4H), 1H obscured by solvent.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].C(OC1C=CC(C([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:41][CH2:40][C:35]4([O:39][CH2:38][CH2:37][O:36]4)[CH2:34]3)=[C:29]([F:42])[CH:28]=2)=O)=CC=1)CCC>>[CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[O:36]1[C:35]2([CH2:40][CH2:41][N:33]([C:30]3[CH:31]=[CH:32][C:27]([NH2:26])=[CH:28][C:29]=3[F:42])[CH2:34]2)[O:39][CH2:38][CH2:37]1
Reactant: CCCCOc1ccc(C(=O)Nc2ccc(N3CCC4(C3)OCCO4)c(F)c2)cc1
Agent: CCCCOc1ccc(C(=O)O)cc1
Product: Nc1ccc(N2CCC3(C2)OCCO3)c(F)c1

Procedure:
4-Butoxy-N-[4-(3-oxopyrrolidin-1-yl)-phenyl]benzamide was obtained using 4-butoxybenzoic acid in an analogous way. Likewise, 4-butoxybenzoic acid and 4-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)-3-fluorophenylamine initially resulted in 4-butoxy-N-[4-(1,4-dioxa-7-azaspiro[4.4]non-7-yl )-3-fluorophenyl]benzamide which, after methylation by method F and treatment with para-toluenesulfonic acid as described above, afforded 4-butoxy-N-[3-fluoro-4-(3-oxopyrrolidin-1-yl)phenyl]benzamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][C:6](C(O)=O)=[C:5]2[CH3:15].BrC1C(C)=C2C(=CC=1)NC(C(O)=O)=C2C.CCOCC.Cl>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][CH:6]=[C:5]2[CH3:15]
Reactant: Cc1cc2[nH]c(C(=O)O)c(C)c2cc1Br
Agent: [Cu]
Agent: Cc1c(Br)ccc2[nH]c(C(=O)O)c(C)c12
Agent: Cl
Solvent: c1ccc2ncccc2c1
Solvent: CCOCC
Product: Cc1cc2[nH]cc(C)c2cc1Br
Temperature: 240 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
A 1:1 mixture of 5-bromo-3,6-dimethyl-1H-indole-2-carboxylic acid and 5-bromo-3,4-dimethyl-1H-indole-2-carboxylic acid (4.39 g, 16.4 mmol) in quinoline (10 mL) with copper powder (250 mg) was stirred at 240° C. for 3 h to give the corresponding mixture of the decarboxylated products. Upon cooling, ether (200 mL) was added and the mixture acidified with 5N HCl. The layers were separated, the organics were washed with brine, dried and evaporated. Chromatography (silica, 15% CH2Cl2 in hexane) and crystallization from a CH2Cl2/hexane mixture afforded the title compound (1.35 g 37%). 1H NMR (300 MHz, CDCl3). 7.74 (s, 1H), 7.21 (is, 1H), 6.90 (s, 1H), 2.48 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[O:7][CH2:8][C@H:9]([OH:12])[CH2:10][CH3:11].[C:13](OC=C)(=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH:9]([O:12][C:13](=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][CH3:11]
Reactant: C=COC(=O)CCCCC
Reactant: CC[C@@H](O)CO[C@H]1CCCCO1
Product: CCCCCC(=O)OC(CC)COC1CCCCO1
Temperature: 38 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
A mixture of 23 g of enzyme lipase "Amano" CES (produced by Amano Pharmaceutical Co., Ltd), 40 g of (R,S)-1-tetrahydropyranyloxy-2-butanol and 16.5 g of vinyl caproate was reacted with stirring at 38° C. for eight hours. After the reaction was stopped, the enzyme was removed by filtration, and the enzyme on the filter paper was washed by using n-heptane. n-Heptane was distilled away from the filtrate, the residue was purified with a chromatograph over silical gel, and 21.5 g of optically active 1-tetrahydropyranyloxy-2-butanol and 23 g of 1-tetrahydropyranyloxy-2-caproyloxybutane were obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:9]=[C:8]([Cl:10])[C:7]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:6][C:4]=1[NH2:5].[C:15](O)(=O)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>[OH-].[NH4+]>[Cl:10][C:8]1[C:7]([S:11](=[O:13])(=[O:14])[NH2:12])=[CH:6][C:4]2[NH:5][C:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[N:2][C:3]=2[CH:9]=1
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1N
Reactant: CCCCCC(=O)O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: CCCCCc1nc2cc(Cl)c(S(N)(=O)=O)cc2[nH]1

Procedure:
To 50 ml of 4 N hydrochloric acid containing 11.8 g of 2-amino-4-chloro-5-sulfamylaniline was added 9.2 g of hexanoic acid and the suspension refluxed for 6 hours. Concentration in vacuo provided a solid which was then slowly added with stirring to 100 ml of 38% ammonium hydroxide. After collecting the solid by filtration, the precipitate was added to 400 ml of methanol and the suspension brought to a boil. Charcoal was then added and the mixture filtered through filter paper, cooled, and filtered through Celite. Concentration in vacuo gave brown crystals which upon recrystallization from acetonitrile provided 2.6 g of product, mp 183°-185°.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31](C(O)=O)[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].C(Cl)Cl.C[OH:41].[C:42](O)(=O)[CH3:43]>>[OH:41][C:4]1[CH:43]=[CH:42][C:1]([C:5]2[N:9]([CH2:10][C:11]3[CH:12]=[CH:13][C:14]([C:17]4[C:18]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:15][CH:16]=3)[C:8]3[CH:30]=[CH:31][CH:32]=[CH:33][C:7]=3[N:6]=2)=[CH:2][CH:3]=1
Reactant: CCCCc1nc2ccc(C(=O)O)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: CO
Reactant: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccccc1-c1ccc(Cn2c(-c3ccc(O)cc3)nc3ccccc32)cc1

Procedure:
tert.butyl 4'-[(2-n-butyl-6-carboxy-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.90 (Silica gel: methylene chloride/methanol/acetic acid=9:0.8:0.2)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]([O-])=[O:21])=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH2:4][CH2:3]1.[Li+].ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[CH:36]1([C:39]2[C:47]3[C:46]([NH2:48])=[CH:45][CH:44]=[CH:43][C:42]=3[N:41]([CH2:49][C:50]3[S:51][C:52]([CH3:55])=[N:53][N:54]=3)[N:40]=2)[CH2:38][CH2:37]1>CN1CCCC1=O.O>[CH:36]1([C:39]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][C:46]=3[NH:48][C:20]([C:17]3[N:14]4[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)=[CH:12][C:13]4=[N:19][CH:18]=3)=[O:21])[N:41]([CH2:49][C:50]3[S:51][C:52]([CH3:55])=[N:53][N:54]=3)[N:40]=2)[CH2:37][CH2:38]1
Reactant: Cc1nnc(Cn2nc(C3CC3)c3c(N)cccc32)s1
Reactant: CN1CCN(CCOc2ccn3c(C(=O)[O-])cnc3c2)CC1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: [Li+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1nnc(Cn2nc(C3CC3)c3c(NC(=O)c4cnc5cc(OCCN6CCN(C)CC6)ccn45)cccc32)s1
Temperature: 88 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
To lithium 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (Example 56, Step A; 70.5 mg, 0.23 mmol) was added N-Methylpyrrolidinone (1 mL). The suspension was heated in order to affect dissolution. The reaction mixture was cooled in an ice-water bath under nitrogen, and 2,4,6-trichlorobenzoyl chloride (35.5 μL, 0.23 mmol) was added dropwise. The cold bath was removed once the addition was complete and the reaction mixture was stirred for a further 1 hour. The reaction mixture became cloudy. A solution of 3-cyclopropyl-1-((5-methyl-1,3,4-thiadiazol-2-yl)methyl)-1H-indazol-4-amine (48 mg, 0.168 mmol) in anhydrous N-Methylpyrrolidinone (1 mL) was then added to the reaction mixture, and the mixture was heated to 88° C. for 13.5 hours. The reaction mixture was cooled, diluted with water, and extracted multiple times with dichloromethane. The combined dichloromethane extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by preparative thin-layer chromatography (silica, eluting with 7N ammonia/MeOH:MeOH:DCM in a 3:7:90 ratio) to afford the product (51.6 mg) as a dark yellow solid. MS (ES+APCI) m/z=572 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[NH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[H-].[Na+].[CH3:18]I>O1CCCC1>[CH3:1][O:2][C:3]1[C:11]2[N:10]=[C:9]([C:12]([F:15])([F:13])[F:14])[N:8]([CH3:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2nc(C(F)(F)F)[nH]c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc2c1nc(C(F)(F)F)n2C
Reaction time: 8 h
Yield: 107.3 %

Procedure:
To a solution of 4-methoxy-2-trifluoromethylbenzimidazole (1.4 g) in tetrahydrofuran (40 ml) under nitrogen was added sodium hydride (0.32 g; 60% dispersion in oil). The mixture was stirred for 20 minutes at room temperature before methyl iodide (1.35 g) was added. Stirring was continued overnight. The reaction was quenched by the addition of water (10 ml) and the solvent removed in vacuo. Ethyl acetate (50 ml) was added and the organic layer washed with saturated sodium bicarbonate solution (20 ml), water (20 ml) and brine (20 ml). Drying over anhydrous magnesium sulfate followed by the removal of the solvent in vacuo gave the title compound (1.6 g) as an oil which solidified on standing.
Reaction SMILES: C(OC([N:8]1[C@H:17]([C:18]([OH:20])=[O:19])[CH2:16][C@@H:15]2[C@@H:10]([CH2:11][CH2:12][C@H:13]([O:21][C:22]3[CH:27]=[C:26]([N:28]4[CH:32]=[CH:31][CH:30]=[N:29]4)[CH:25]=[CH:24][C:23]=3[C:33]3[N:34]=[N:35][NH:36][N:37]=3)[CH2:14]2)[CH2:9]1)=O)(C)(C)C.[ClH:38]>C(Cl)Cl.C(OCC)C>[ClH:38].[N:28]1([C:26]2[CH:25]=[CH:24][C:23]([C:33]3[N:37]=[N:36][NH:35][N:34]=3)=[C:22]([CH:27]=2)[O:21][C@H:13]2[CH2:12][CH2:11][C@@H:10]3[C@@H:15]([CH2:16][C@@H:17]([C:18]([OH:20])=[O:19])[NH:8][CH2:9]3)[CH2:14]2)[CH:32]=[CH:31][CH:30]=[N:29]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CC[C@H](Oc3cc(-n4cccn4)ccc3-c3nn[nH]n3)C[C@@H]2C[C@H]1C(=O)O
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(O)[C@@H]1C[C@H]2C[C@@H](Oc3cc(-n4cccn4)ccc3-c3nn[nH]n3)CC[C@H]2CN1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 0.040 g of the material from Step C, above, dissolved in 5 mL CH2Cl2, is added 3 mL 2M HCl in diethyl ether. After stirring four hours at ambient temperature, the reaction is concentrated in vacuo.