Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.[NH2:29][CH2:30][CH2:31][CH2:32][S:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:29][CH2:30][CH2:31][CH2:32][S:33][C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)=[O:8])=[CH:2]1
Reactant: O=C(O)c1ccsc1
Reactant: NCCCSc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Product: O=C(NCCCSc1ccncc1)c1ccsc1
Yield: 76 %

Procedure:
To a solution of 1.00 g (7.80 mmol) of thiophene-3-carboxylic acid and 1.08 g (10.1 mmol) of N-hydroxysuccinimide in 70 ml of methylene chloride, 1.80 g (9.36 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 1 hour. Further, 1.31 g (7.80 mmol) of 4-(3-aminopropylthio)pyridine was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: methanol/ethyl acetate=1:10) to obtain 1.65 g of the desired compound (yield: 76.1%, colorless powder).
Reaction SMILES: N[C@@H]([C:10]([OH:12])=O)CC1C=CC=CC=1.C[N:14]1CCOCC1.C(OC(Cl)=O)C(C)C.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>C1COCC1.CCOCC>[N:28]1([C:10]([NH2:14])=[O:12])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Reactant: C1COCCN1
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94 %

Procedure:
A solution of 100 mg (0.296 mmol) of carboxylic acid derived from D-phenylalanine in 10 mL of THF at -8° C. was treated with 39.0 mg (0.385 mmol) of N-methylmorpholine followed by 54.7 mg (0.400 mmol) of isobutylchloroformate. After stirring for 5 min 34.8 mg (0.400 mmol) of morpholine was added and the reaction mixture allowed to warm to room temperature. After 15 min at room temperature, 50 mL of Et2O was added and the mixture dried over MgSO4, filtered, and concentrated under reduced pressure to afford a residue which was chromatographed (silica, gradient elution 30→100%: EtOAc/hexanes) to provide 112.8 mg (94% yield) of the morpholino amide derived from D-phenylalanine: [a]D24 -95° (c 0.85, CHCl3) ; IR (CHCl3) 3495 (w), 3000 (s), 2980 (w), 1745 (m), 1700 (s), 1635 (m), 1495 (s), 1445 (m), 1230 (m), 1165 (m), 1115 (m), 1075 (w), 1045 (m), 1025 (w) cm-1 ; 1H NMR (500 MHz, CDCl3) d 7.27-7.22 (m, 3 H), 7.04-7.02 (m, 2 H), 5.71 (s, 1 H), 3.91 (d, J=15.3 Hz, 1 H), 3.75 (s, 3 H), 3.69-3.57 (m, 7 H), 3.50-3.46 (m, 2 H), 3.01 (d, J=13.3 Hz, 1 H), 2.91 (d, J=15.5 Hz, 1 H), 1.46 (s, 9 H); 13C NMR (62.5 MHz, CDCl3) d 172.37, 168.08, 154.19, 135.20, 129.57 (2C), 127.97 (2C), 126.88, 79.18, 66.68, 66.54, 62.44, 52.41, 46.11, 41.81, 40.92, 38.12, 28.20 (3C); high resolution mass spectrum (CI, methane) m/z 407.2123 [(M+H)+ ; calculated for C21H31N2O6 : 407.2182].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][C:37]1[C:38]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH2:48][CH2:47]2)=[CH:39][C:40]([O:44][CH3:45])=[C:41]([CH:43]=1)[NH2:42].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:41]3[CH:43]=[C:37]([CH3:36])[C:38]([N:46]4[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH2:48][CH2:47]4)=[CH:39][C:40]=3[O:44][CH3:45])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1N
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 120 °C
Yield: 47 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (100 mg, 0.203 mmol), 5-methyl-2-(methyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}aniline (Example 148, step D) (60 mg, 0.183 mmol), and p-toluenesulfonic acid (93 mg, 0.49 mmol) were weighed into a 20 mL vial. 10 mL of iPrOH was added and the mixture was heated to 120° C. for 48 h. The mixture was transferred to a 50 mL round bottom and neutralized with 2 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (65 mg, 0.086 mmol, 49%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.77 (s, 1H), 9.35 (s, 1H), 8.45 (s, 1H), 8.22 (d, J=5.31 Hz, 1H), 8.09 (d, J=2.01 Hz, 1H), 7.76 (dd, J=8.61, 2.01 Hz, 1H), 7.68 (d, J=8.97 Hz, 1H), 7.49 (s, 1H), 7.40-7.45 (m, 1H), 7.33-7.40 (m, 1H), 7.27 (d, J=8.79 Hz, 1H), 7.17 (t, J=8.06 Hz, 2H), 6.94 (t, J=6.87 Hz, 1H), 6.75 (s, 1H), 6.55 (d, J=5.31 Hz, 1H), 3.97 (s, 3H), 3.79 (s, 3H), 3.31-3.35 (m, 2H), 3.05 (s, 3H), 2.82-2.90 (m, 4H), 2.76 (t, J=6.68 Hz, 2H), 2.53-2.65 (m, 4H), 2.13 (s, 3H). MS (ESI): 783 [M+H]+.
Reaction SMILES: [NH3:1].CO[C:4](=[O:35])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19](Cl)[C:14]3=[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:22]=3)[N:12]=2)[CH:6]=1.[NH3:36].CC(O)C>>[NH2:1][C:19]1[C:14]2[N:15]([C:11]([C:7]3[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=3)[C:4]([NH2:36])=[O:35])=[N:12][C:13]=2[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:22]=2)[CH:16]=[CH:17][N:18]=1
Reactant: COC(=O)c1cccc(-c2nc(-c3cccc(OCc4ccccc4)c3)c3c(Cl)nccn23)c1
Reactant: N
Solvent: CC(C)O
Product: NC(=O)c1cccc(-c2nc(-c3cccc(OCc4ccccc4)c3)c3c(N)nccn23)c1
Temperature: 110 °C

Procedure:
Gaseous NH3 was condensed into a cooled (−78° C.) solution of 3-[1-(3-benzyloxyphenyl)-8-chloroimidazo[1,5-a]pyrazin-3-yl]-benzoic acid methyl ester (102 mg, 0.216 mmol) in NH3/i-PrOH (2M, 3 mL) in a pressure tube until the volume had doubled. The tube was sealed and heated to 110° C. for 2 d. After excess NH3/i-PrOH was removed in vacuo, the crude material was taken up in CH2Cl2, adsorbed onto Hydromatrix, and purified by chromatography on silica gel [Jones Flashmaster, 5 g/25 mL cartridge, eluting with MeOH:CH2Cl2 1%→5%], yielding the title compound, as an off-white solid; 1H NMR (d-DMSO, 400 MHz) δ 5.18 (s, 2H), 6.30 (s, br, —NH2), 7.10-7.18 (m, 2H), 7.25-7.58 (m, 9H), 7.67 (t, J=7.6 Hz, 1H), 7.81 (d, J=4.4 Hz, 1H), 8.00 (d, J=7.6 Hz, 2H), 8.16 (s, 1H), 8.31 (s, 1H); MS (ES+): m/z 436.0 (100) [MH+].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[S:16]([C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25]Br)=[CH:22][CH:21]=1)(=[O:19])(=[O:18])[NH2:17]>>[S:16]([C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25][N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH2:9][CH2:8]3)[CH2:3][CH2:2]2)=[CH:22][CH:21]=1)(=[O:18])(=[O:19])[NH2:17]
Reactant: c1ccc2c(c1)CCN2C1CCNCC1
Reactant: NS(=O)(=O)c1ccc(CCBr)cc1
Product: NS(=O)(=O)c1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Yield: 10.5 %

Procedure:
1-(Piperidin-4-yl)indoline (300 mg) and 4-sulfamoylphenethyl bromide (400 mg) were treated as in Example 2 to give the title compound (60 mg) as a pale yellow powder (yield: 10%).
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[N:9]=[CH:8][C:7]([C@@H:10]([NH:19][CH2:20][CH:21]([O:24][CH3:25])[O:22][CH3:23])[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:6][CH:5]=1.ClC(Cl)(O[C:31](=[O:37])OC(Cl)(Cl)Cl)Cl.CCN(CC)CC.[N:46]1[C:55]2[NH:54][CH2:53][CH2:52][CH2:51][C:50]=2[CH:49]=[CH:48][C:47]=1[CH2:56][CH2:57][CH2:58][NH2:59]>C(Cl)Cl.ClCCCl>[F:26][CH:2]([F:1])[O:3][C:4]1[N:9]=[CH:8][C:7]([C@@H:10]([N:19]([CH2:20][CH:21]([O:24][CH3:25])[O:22][CH3:23])[C:31]([NH:59][CH2:58][CH2:57][CH2:56][C:47]2[CH:48]=[CH:49][C:50]3[CH2:51][CH2:52][CH2:53][NH:54][C:55]=3[N:46]=2)=[O:37])[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:6][CH:5]=1
Reactant: NCCCc1ccc2c(n1)NCCC2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(CN[C@@H](CC(=O)OC(C)(C)C)c1ccc(OC(F)F)nc1)OC
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(CN(C(=O)NCCCc1ccc2c(n1)NCCC2)[C@@H](CC(=O)OC(C)(C)C)c1ccc(OC(F)F)nc1)OC
Reaction time: 2 h
Yield: 68.1 %

Procedure:
To a stirred solution of compound 8 (375 mg, 0.99 mmol, 1.0 equiv.) in dry DCM (5 mL), cooled to 0° C., triphosgene (1.50 mL, 2.99 mmol, 3.00 equiv., 20% in PhMe) followed by Et3N (0.30 mL, 2.09 mmol, 2.10 equiv) were added. The reaction mixture was slowly brought to RT and stirred for 2 h. After completion of the starting material, volatiles were evaporated to afford the crude compound 9, which was used directly in the next step without purification. A solution of compound 9 in DCE (2 mL) was added to a solution of compound 6b (400 mg, 1.32 mmol, 1.32 equiv.) in DCM (5 mL), Et3N (0.55 mL, 3.98 mmol, 4.00 equiv) at 0° C. and stirred at RT for 4 h. After consumption of the starting material (monitored by TLC), the reaction mixture was concentrated under reduced pressure to give the crude residue which was purified by column chromatography (2% MeOH/DCM) to afford compound 10 (0.40 g, 67%) as a thick syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C:10]([O:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)(=[O:15])[CH2:11][C:12]([CH3:14])=O.[NH2:32]/[C:33](/[CH3:39])=[CH:34]\[C:35]([O:37][CH3:38])=[O:36]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]2[C:34]([C:35]([O:37][CH3:38])=[O:36])=[C:33]([CH3:39])[NH:32][C:12]([CH3:14])=[C:11]2[C:10]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)=[O:15])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)/C=C(/C)N
Reactant: O=Cc1cccc(Cl)c1
Reactant: CC(=O)CC(=O)OCCN1CCN(c2ccc(F)cc2)CC1
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCN(c3ccc(F)cc3)CC2)C1c1cccc(Cl)c1
Yield: 34.1 %

Procedure:
A mixture of m-chlorobenzaldehyde, 2-[4-(4-fluorophenyl)-1-piperazinyl]ethyl acetoacetate and methyl 3-aminocrotonate was worked up in isopropyl alcohol in the same manner as Example 1 to give 2-[4-(4-fluorophenyl)-1-piperazinyl]ethyl methyl 4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate as a light yellow powder, m.p. 44°-49° C. (sintering). Yield 34.1%. IR(Nujol)cm-1 : 3430, 1700, 1685. NMR(CDCl3) δ: 2.30(3H,s, ##STR58## 2.34(3H,s, ##STR59## 3.63(3H,s,--COOCH3), 4.18(2H,t,J=6,--COOCH2CH2 --), 4.99(1H,s,C(4) --H), 5.69(1H,s,NH).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](SC)[N:3]=1.[CH:17]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([NH:23][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: NC1CCCCC1
Reactant: CSc1nc(N)nc(-c2ccco2)c1C#N
Solvent: CCO
Product: N#Cc1c(NC2CCCCC2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-(2-furyl)-6-(methylthio)-5-pyrimidinecarbonitrile and cyclohexylamine in ethanol. EI-MS m/e (%): 283 (M+, 22), 282 ([M—H]+, 20), 240 ([M—C2H5]+, 16), 226 ([M—C4H9]+, 36), 201 ([M—C6H10]+, 100).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[O:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1.O>C(COC)OC>[O:17]1[CH2:22][CH2:21][C:20](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:19][CH2:18]1.[O:17]1[CH2:18][CH:19]=[C:20]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:21][CH2:22]1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=C1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C=C1CCOCC1
Product: CCOC(=O)CC1=CCOCC1
Reaction time: 0.75 h

Procedure:
55% Sodium hydride (2.6 g) was suspended in dimethoxyethane (150 ml). Ethyl diethylphosphonoacetate (9.6 ml) was added dropwise under nitrogen atmosphere under ice-cooling over five minutes, and the mixture was stirred at the same temperature for 45 minutes. A solution of tetrahydro-4H-pyran-4-one (4.0 g) in dimethoxyethane (10 ml) was added dropwise thereto over five minutes. The mixture was stirred at room temperature for 10 minutes and then heated under reflux for one hour. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (developed with ethyl acetate-hexane) to give the title compounds ethyl tetrahydro-4H-pyran-4-ylideneacetate (1.7 g) and ethyl 3,6-dihydro-2H-pyran-4-ylacetate (2.2 g) both as colorless oils.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([OH:12])=[CH:6][C:3]=1[CH:4]=[O:5].S(=O)(=O)([OH:15])N.CCOC(C)=O.[Cl:24]([O-:26])=[O:25].[Na+:27]>O>[Cl:24]([O-:26])=[O:25].[Na+:27].[Br:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([OH:12])=[CH:6][C:3]=1[C:4]([OH:15])=[O:5]
Reactant: NS(=O)(=O)O
Reactant: COc1cc(Br)c(C=O)cc1O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(Br)c(C(=O)O)cc1O
Temperature: 5 °C
Yield: 89 %

Procedure:
1 Kg of 2-bromo-5-hydroxy-4-methoxy benzaldehyde (B2) and 1.255 Kg of sulfamic acid were added with stirring into a mixture of 4.473 Kg of EtOAc and 8 L of water. The reaction mixture was stirred until all of the solid had dissolved. The reaction mixture was cooled to between −10 and 0° C. An aqueous solution of sodium chlorite was prepared by dissolving 505 g of sodium chlorite in 3 L of water. The sodium chlorite solution was added to the pre-cooled B2 solution at a rate that maintained the reaction temperature under 5° C. After the complete addition of sodium chlorite solution, the reaction mixture was stirred for another hour at 0° C. and was then allowed to warm up to room temperature. The reaction was monitored by TLC. After the TLC analysis showed completion of the reaction, the aqueous layer was separated. The aqueous layer was extracted with EtOAc (1.789 Kg) and the combined organic layer was transferred to another flask and EtOAc was removed by vacuum distillation at 40° C. 6.92 Kg of toluene was added at between 30 to 40° C., the slurry was cooled to between −10 to 0° C. and the precipitate was collected by filtration to give about 950 g (89% (yield) of 2-bromo-5-hydroxy-4-methoxy benzoic acid (B13). 1H NMR (CDCl3) δ 3.95 (3H, s, CH3), 7.22 (1H, s, CH), 7.46 (1H, s, CH).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C@@H:11](O)[CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=1)=O.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2[N:17]1CCC2.COC(C1C=CC2C(=O)CCCC=2C=1)=O.CO>C1(C)C=CC=CC=1.C1COCC1>[NH2:17][C@@H:11]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:6]=[C:5]([CH2:3][OH:2])[CH:14]=[CH:13][C:12]1=2
Reactant: COC(=O)c1ccc2c(c1)CCC[C@@H]2O
Reactant: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: COC(=O)c1ccc2c(c1)CCCC2=O
Solvent: CO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: N[C@@H]1CCCc2cc(CO)ccc21
Temperature: -10 °C

Procedure:
Preparation 5(S)-Hydroxy-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid methyl ester: To an oven-dried 2 L round-bottomed flask equipped with an argon inlet/outlet and magnetic stirring was added (R)-2-methyl-CBS-oxazaborolidine (7.4 mL of a 1M soln in toluene, 7.4 mmol, Aldrich). Toluene 190 mL was added and the reaction was cooled in an ice-salt bath (bath temp. =−10° C.). BH3—SMe2 was added (17 mL, 180 mmol, Aldrich), then 5-oxo-5,6,7,8-tetrahydro-naphth-alene-2-carboxylic acid methyl ester (30 g, 150 mmol, Albany Molecular) in 200 mL of THF was added over 5 h using a syringe pump. After the addition was complete, the mixture was stirred for an additional 1 h. The mixture was poured into an addition funnel, and the mixture was added to 200 mL of MeOH, cooled in a ice-salt bath, over 30 min at such a rate that the internal temp. was kept below 0° C. The mixture was concentrated in vacuo. Et2O (1 L) was added, and the mixture was washed with 1M H3PO4 (3×), satd NaHCO3, and brine (ca. 400 mL each wash). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved in Et2O again (500 mL), and the mixture was washed with 1M H3PO4 (3×200 mL), satd NaHCO3, and brine. After drying the organic layer over MgSO4, the mixture was filtered and concentrated in vacuo, which gave the title compound as a white-yellow solid. MS (+ion ESI) m/z=207 (MH+), 189 (MH+—H2O).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH:9]([CH2:13][CH:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])[C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:28]I.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH:9]([CH2:13][CH:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH3:28])[C:15]2=[O:23])[C:10]([OH:12])=[O:11])=[O:7])=[CH:24][CH:25]=1
Reactant: CI
Reactant: O=C(NC(CC1C(=O)Nc2ccccc21)C(=O)O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)C(CC(NC(=O)c2ccc(Cl)cc2)C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
479 Milligrams of 2-(4-chlorobenzoylamino)-3-(oxindol-3-yl)propionic acid 1/4-hydrate prepared in Example 3 and 70 mg of 50% sodium hydride (in oil) were admixed in 5 ml of dimethylformamide, and the mixture was stirred at a room temperature for 1 hour. Then a solution containing 0.23 g of methyl iodide in 3 ml of dimethylformamide was added dropwise gradually to the mixture, and the whole reaction mixture was stirred at a room temperature for 4 hours. The reaction mixture was poured into a large volume of water, and the organic material was extracted with chloroform, then the chloroform layer was washed with water and dried. Chloroform was removed by evaporation to yield 125 mg of 2-(4-chlorobenzoylamino)-3-(1-methyloxindol-3-yl)propionic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[CH:3]=1.[NH:9]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10]1.Br[C:16]1[S:17][C:18]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[C:19]([C:21](=[O:29])[NH:22][C:23]2[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=2)[N:20]=1>>[OH:14][C@H:11]1[CH2:12][CH2:13][N:9]([C:4]2[CH:3]=[C:2]([C:16]3[S:17][C:18]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[C:19]([C:21](=[O:29])[NH:22][C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)[N:20]=3)[CH:7]=[CH:6][CH:5]=2)[CH2:10]1
Reactant: Brc1cccc(Br)c1
Reactant: O[C@H]1CCNC1
Reactant: Cn1cc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)cn1
Product: Cn1cc(NC(=O)c2nc(-c3cccc(N4CC[C@H](O)C4)c3)sc2NC(=O)OC(C)(C)C)cn1
Yield: 40 %

Procedure:
Following the procedure for Example 273 starting with 1,3-dibromobenzene and (S)-pyrrolidin-3-ol and tert-butyl 2-bromo-4-(1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate gave (S)-tert-butyl 2-(3-(3-hydroxypyrrolidin-1-yl)phenyl)-4-(1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a yellow solid (110 mg, 40%). LCMS (ES+) m/z 485 (M+1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=4)[CH2:21][CH2:20][CH2:19]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:30]([O:32]C)=[O:31])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].CC(O)=O>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=4)[CH2:21][CH2:20][CH2:19]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:30]([OH:32])=[O:31])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4ccc(OC)cc43)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)N(c1nc3cc(C(=O)O)ccc3nc1-c1ccc(F)cc1)CCC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 68.7 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-(7-methoxy-1,2,3,4-tetrahydroquinolin-1-yl)quinoxaline-6-carboxylate (88 mg, 0.20 mmol) in methanol (30 ml) was added sodium hydroxide (32 mg, 0.80 mmol) and water (2 ml). The reaction was stirred for 2 days at room temperature. The resulting solution was diluted with water (15 ml), adjusted to pH 5 with AcOH, extracted with ethyl acetate (2×20 ml) and the organic layers were combined and concentrated in vacuo to afford 2-(4-fluorophenyl)-3-(7-methoxy-1,2,3,4-tetrahydroquinolin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid (59 mg, 69%).
Reaction SMILES: [N:1]1([C:10]2[N:18]=[C:17]([Cl:19])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH2:20][C@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]1[NH2:27]>CS(C)=O>[ClH:19].[ClH:19].[N:1]1([C:10]2[N:18]=[C:17]([NH:20][C@@H:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]3[NH2:27])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: N[C@H]1CCCC[C@@H]1N
Reactant: Clc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Solvent: CS(C)=O
Product: Cl
Product: N[C@@H]1CCCC[C@H]1Nc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Temperature: 120 °C
Yield: 74.5 %

Procedure:
200 mg of product obtained in stage 1 above are mixed with 3 ml of DMSO and 420 mg (5 equivalents) of (1S,2S)-(−)-1,2-diaminocyclohexane, and the mixture is then heated at 120° C. for approximately 4 days. The mixture is allowed to return to ambient temperature. Purification is carried out by chromatography on silica with a CH2Cl2-MeOH—NH4OH: 95-5-0.33 mixture for eluent. 4 ml of ethanol and 4 ml of HCl-EtOH (hydrochloric acid-ethanol) are added. Evaporation to dryness is carried out and a paste is then formed in ethyl ether. Drying is carried out under vacuum. 116 mg of expected product are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2[CH2:16][CH2:17][CH2:18][CH2:19][C:11]1=2>C(O)(=O)C>[OH:1][C:2]1[CH:3]=[C:4]([N:5]2[C:13](=[O:14])[C:12]3[CH2:16][CH2:17][CH2:18][CH2:19][C:11]=3[C:10]2=[O:15])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Nc1ccc(Cl)c(O)c1
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1ccc(Cl)c(O)c1

Procedure:
Employed 47.5 g of 3-hydroxy-4-chloroaniline (0.33 mol); 38.2 of 3,4,5,6-tetrahydrophthalic anhydride (0.25 mol) and 350 ml of glacial acetic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1.[Br:14]Br>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[C:7]([Br:14])[CH:6]=1
Reactant: BrBr
Reactant: COC(=O)Cc1ccc(SC)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)Cc1ccc(SC)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.9 %

Procedure:
A solution of (4-methylsulfanyl-phenyl)-acetic acid methyl ester (7.28 g, 37.1 mmol) in carbon tetrachloride (150 mL) was slowly treated with bromine (2.5 mL, 48.23 mmol). The reaction mixture was stirred at 25° C. for 3 h, at which time, thin layer chromatography still indicated the presence of a substantial amount of starting material. The reaction mixture was treated with more bromine (2.5 mL, 48.23 mmol). The reaction mixture was stirred an additional 1 h at 25° C. and then quenched with a 10% aqueous sodium bisulfite solution (200 mL). The reaction mixture was concentrated in vacuo to remove carbon tetrachloride. The resulting aqueous layer was extracted with ethyl acetate (3×200 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 9/1 hexanes/ethyl acetate) afforded (3-bromo-4-methylsulfanyl-phenyl)-acetic acid methyl ester (8.57 g, 84%) as a light yellow oil: EI-HRMS m/e calcd for C10H11BrO2S (M+) 273.9663, found 273.9661.