Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29](=[O:32])(=[O:31])[NH2:30])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CCOC(C)=O.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29](=[O:32])(=[O:31])[NH:30][C:34](=[O:41])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:8]([Cl:14])=[CH:9][CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
N-(2,6-Dichlorobenzoyl)-4-(2-sulfamoylphenyl)-L-phenylalanine methyl ester (100 mg) was dissolved in anhydrous pyridine (5 mL). To this solution was added benzoyl chloride (50 μL) and the mixture was stirred for 12 h at room temperature under N2. EtOAc and satd. NaHCO3 were added to the mixture and the EtOAc phase was washed with 1 N HCl, dried (MgSO4) and evaporated. The residue was purified by flash column chromatography (silica gel; eluent: EtOAc/hexanes 1:2) to give N-(2,6-dichlorobenzoyl)-4-[2-(N-benzoylsulfamoyl)phenyl]-L-phenylalanine methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[H-].[Na+].CS(O[CH2:21][CH2:22][CH2:23][C:24]1([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1)(=O)=O>O.C(OCC)(=O)C.CN(C)C=O.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][C:9](=[O:13])[N:10]2[CH2:21][CH2:22][CH2:23][C:24]2([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:26][CH2:25]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2ncc(=O)[nH]c2c1
Reactant: CCOC(=O)C1(CCCOS(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C1(CCCn2c(=O)cnc3ccc(OC)cc32)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
10 mL of an N,N-dimethylformamide solution containing 1.0 g of 7-methoxyquinoxalin-2(1H)-one was subjected to azeotropic dehydration with toluene, then 0.24 g of 60% sodium hydride was added thereto at room temperature, and the mixture was stirred at 60° C. for 30 minutes. Thereto was added 2 mL of an N,N-dimethylformamide solution containing 2.3 g of 1-tert-butyl 4-ethyl 4-(3-((methanesulfonyl)oxy)propyl)piperidine-1,4-dicarboxylate, and the mixture was stirred at the same temperature for 6 hours and then left to stand for 13 hours. Thereto was further added 0.12 g of 60% sodium hydride, and the mixture was stirred for 1 hour. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added thereto. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed sequentially with water and an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; hexane:ethyl acetate 2:1] to obtain 0.60 g of a yellow oily substance, 1-tert-butyl 4-ethyl 4-(3-(7-methoxy-2-oxo-1,2-dihydroquinoxalin-1-yl)propyl)piperidine-1,4-dicarboxylate.
Reaction SMILES: [CH3:1][C:2]12[O:38][CH2:37][CH2:36][N:35]1[C:33](=[O:34])[C:5]1[C:6]([OH:32])=[C:7]3[C:13]4[C:14]([C:16]5[C:27](=[O:28])[C:26]6[C:21](=[CH:22][C:23]([O:30][CH3:31])=[C:24]([OH:29])[CH:25]=6)[O:20][C:17]=5[C:18](=[O:19])[C:12]=4[CH:11]=[CH:10][C:8]3=[CH:9][C:4]=1[CH2:3]2)=[O:15].N[C:40]1C=CC=CN=1.CN(C1C=CC=CN=1)C.CC1(O)C2CC3CC(CC1C3)C2>C(OCC)(=O)C.O.O1CCCC1>[CH3:1][C:2]12[O:38][CH2:37][CH2:36][N:35]1[C:33](=[O:34])[C:5]1[C:6]([OH:32])=[C:7]3[C:13]4[C:14]([C:16]5[C:27](=[O:28])[C:26]6[C:21](=[CH:22][C:23]([O:30][CH3:31])=[C:24]([O:29][CH3:40])[CH:25]=6)[O:20][C:17]=5[C:18](=[O:19])[C:12]=4[CH:11]=[CH:10][C:8]3=[CH:9][C:4]=1[CH2:3]2)=[O:15]
Reactant: Nc1ccccn1
Reactant: COc1cc2oc3c(c(=O)c2cc1O)C(=O)c1c(ccc2cc4c(c(O)c12)C(=O)N1CCOC1(C)C4)C3=O
Agent: CC1(O)C2CC3CC(C2)CC1C3
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc2oc3c(c(=O)c2cc1OC)C(=O)c1c(ccc2cc4c(c(O)c12)C(=O)N1CCOC1(C)C4)C3=O
Temperature: 23 °C

Procedure:
16.42 parts of the compound (II-167-a) (5-norbornene-2,3-dicariboxylic acid anhydride, Wako Pure Chemical Industries, Ltd.) and 53.29 parts of tetrahydrofuran were charged, stirred at 23° C. to dissolved. To the obtained mixture, 2.44 parts of amino pyridine was added at 23° C., and stirred. To the obtained mixture, 2.44 parts of dimethylamino pyridine was added at 23° C., and stirred for 30 minutes at 50° C. To the obtained mixture, a mixture of 16.63 parts of 2-methyl-2-adamantanol and 53.29 parts of tetrahydrofuran was added in the form of drops over 1 hour, and stirred for 10 hours at 50° C. To the obtained mixture, 30 past of ion-exchanged water and 60 parts of ethyl acetate were added to wash, and separated to collect an organic layer. To the obtained organic layer, 30 past of ion-exchanged was added to wash, and separated to collect an organic layer. This washing with water operation was repeated three times. The obtained organic layer was concentrated to obtain a concentrate. The concentrate was column-fractionated under the condition below, whereby giving 25.2 parts of the compound (II-167-b).
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14](=[S:29])[NH:15][CH2:16][C:17]1[S:18][C:19]2[C:25]([F:26])=[CH:24][C:23]([F:27])=[C:22]([F:28])[C:20]=2[N:21]=1)C.[OH-].[Na+]>C(O)C>[F:13][C:11]1[CH:10]=[CH:9][C:8]([C:14](=[S:29])[NH:15][CH2:16][C:17]2[S:18][C:19]3[C:25]([F:26])=[CH:24][C:23]([F:27])=[C:22]([F:28])[C:20]=3[N:21]=2)=[C:7]([CH:12]=1)[O:6][CH2:5][C:4]([OH:30])=[O:3]
Reactant: CCOC(=O)COc1cc(F)ccc1C(=S)NCc1nc2c(F)c(F)cc(F)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1cc(F)ccc1C(=S)NCc1nc2c(F)c(F)cc(F)c2s1
Reaction time: 2 h
Yield: 56.7 %

Procedure:
A suspension of {5-fluoro-2-[(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-thiocarbamoyl]-phenoxy}-acetic acid ethyl ester (2.0 g, 4.3 mmol) in ethanol (22 mL) and treated with aq 2 N NaOH (13 mL, 26 mmol). After stirring for 2 h, the solution was concentrated in vacuo to remove most of the ethanol and acidified to pH 1 with aq 2 N HCl. The product was extracted with ethyl acetate and washed with saturated NaCl. The organic layer was dried over MgSO4, filtered and concentrated to give {5-fluoro-2-[(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-thiocarbamoyl]-phenoxy}-acetic acid as an orange solid (1.05 g, 57%): mp 150° C.; Rf 0.50 (20% methanol in dichloromethane); 1H NMR (DMSO-d6 300 MHz) δ 13.76 (br s, 1H), 7.83 (br t, J=8.0 Hz, 1H), 7.79-7.70 (m, 1H), 7.14 (dd, J1=11.1 Hz, J2=2.4 Hz, 1H), 6.84 (dt, J1=8.4 Hz, J2=2.4 Hz, 1H), 5.37 (d, J=5.7 Hz, 2H), 4.58 (s, 2H). ESI-LC/MS m/z calcd for C17H10F4N2O3S2: 430.4; Found 429.0 (M−1)−. Anal. calcd for C17H10F4N2O3S2: C, 47.44; H, 2.34; N, 6.51; S, 14.90. Found C, 46.72; H, 2.81; N, 5.85; S, 12.02. Ethanol and water may still have been in the sample for the analytical values to be off.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39]1([CH:45]([NH2:48])[CH2:46][CH3:47])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:22])[NH:48][CH:45]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:46][CH3:47])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:37])[CH3:38])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCC(N)c1ccccc1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Product: CCC(NC(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(Nc2ncnc3nc(C(C)C)ccc23)c1)c1ccccc1
Yield: 90 %

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and (RS)-1-phenylpropylamine: yield 90%.
Reaction SMILES: [CH3:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C:9]2[C:22]3[C:21](=[O:23])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14](=[O:24])[C:13]=3[CH:12]=[CH:11][C:10]=2[NH:25][C:26](=[O:29])[CH2:27]Cl)=[O:7])=[CH:4][CH:3]=1.C[CH2:33][N:34](C(C)C)[CH:35](C)C.CNC.C(OCC)(=O)C>O1CCCC1.CCO.CCCCCC>[CH3:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C:9]2[C:22]3[C:21](=[O:23])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14](=[O:24])[C:13]=3[CH:12]=[CH:11][C:10]=2[NH:25][C:26](=[O:29])[CH2:27][N:34]([CH3:35])[CH3:33])=[O:7])=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(C(=O)Nc2c(NC(=O)CCl)ccc3c2C(=O)c2ccccc2C3=O)cc1
Agent: CNC
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCCCCC
Product: Cc1ccc(C(=O)Nc2c(NC(=O)CN(C)C)ccc3c2C(=O)c2ccccc2C3=O)cc1
Reaction time: 0.12 h
Yield: 54 %

Procedure:
Compound CC-12 (0.86 g, 2 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and to the solution was added successively with DIPEA (1 ml, 6 mmole) and dimethylamine (0.8 ml, 8 mmole) under stirring for 5 to 10 minutes. This mixture was heated under reflux for 16 hours. After the completion of the reaction, the mixture was filtered, and the filtrate was concentrated by reduced pressure concentrator (such as Vacuum Evaporator). The residue was extracted with ethyl acetate for several times. The extract was dried on magnesium sulfate, and concentrated under reduced pressure. The crude product was washed with ethyl acetate/hexane. Finally, the crude product was recrystallized in hot ethanol to obtain a yellowish-brown compound CC-35. Mol. Wt.: 441.4785 (C26H23N3O4); Rf: 0.33 (ethyl acetate:n-hexane=1:2); Yield: 54%; Mp.: 190-191° C. (EtOH); HRMS (EI) m/z: calcd [M]+, 441.1689 (C26H23N3O4+). Found, 441.1689. 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 2.11 (s, 6H, —NCH3), 2.44 (s, 3H, —CH3), 3.09 (s, 2H, —CH2N—), 7.43 (d, J=8.1 Hz, 1H, Ar—H), 7.88-7.91 (m, 2H, Ar—H), 8.11-8.19 (m, 2H, Ar—H), 8.26 (d, J=8.7 Hz, 1H, Ar—H), 8.64 (d, J=8.4 Hz, 1H, Ar—H), 10.16 (s, 1H, Ar—NH—), 10.54 (s, 1H, Ar—NH—); 13C-NMR (75 MHz, DMSO-d6) δ (ppm): 20.86, 45.16, 62.82, 125.73, 126.30, 126.47, 127.79, 127.99, 128.12, 128.89, 129.09, 129.39, 130.93, 132.32, 134.13, 134.36, 134.43, 140.34, 142.23, 166.35 (NCO), 169.14 (NCO), 181.45 (CO), 183.63 (CO).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[C:14]([NH:17][CH:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:16])[CH3:15].C[O-].[Na+]>CCO>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][CH2:15][C:14]([NH:17][CH:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:16]
Reactant: ClCc1ccc2ccccc2n1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(NC(=O)CCc1ccc2ccccc2n1)C(=O)OCC
Yield: 99 %

Procedure:
To a solution of 2(chloromethyl)quinoline monohydrochloride (5.0 g, 23.4 mmol) and diethyl acetamidomalonate (10.1 g, 46.7 mmol) in EtOH (60 mL) was added sodium methoxide (3.78 g, 70 mmol). The reaction mixture was heated at reflux for 6 h. The reaction mixture was cooled, filtered, and concentrated. The residue was dissolved in EtOAc (400 mL) and extracted with cold 4N HCl (3×150 mL). The aqueous layer was neutralized with 10N NaOH and extracted with EtOAc (3×200 mL). The combined organic extract was washed with water, dried (anhydrous MgSO4), filtered, and concentrated to give the title compound (8.3 g).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH:16]1[C:25]2[C:20](=[C:21]([CH2:26][C:27]([OH:29])=O)[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][N:17]=1.ON1C2N=CC=CC=2N=N1.[F:40][C:41]([F:52])([F:51])[O:42][C:43]1[CH:50]=[CH:49][C:46]([CH2:47][NH2:48])=[CH:45][CH:44]=1.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>ClCCl.C(N(CC)CC)C>[CH:16]1[C:25]2[C:20](=[C:21]([CH2:26][C:27]([NH:48][CH2:47][C:46]3[CH:49]=[CH:50][C:43]([O:42][C:41]([F:40])([F:51])[F:52])=[CH:44][CH:45]=3)=[O:29])[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][N:17]=1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)Cc1cccc2cnccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1cccc2cnccc12)NCc1ccc(OC(F)(F)F)cc1
Reaction time: 0.08 h

Procedure:
Polymer supported 1,3-dicyclohexylcarbodiimide (0.845 g) in dichloromethane (5 mL) was treated with 5-isoquinolinylacetic acid (0.075 g, 0.40 mmol) in dichloromethane (1 mL), 1-hydroxy-7-azabenzotriazole (0.049 g), and triethylamine (0.080 g) in dichloromethane (1 mL). After stirring for 5 minutes, the mixture was treated with 4-(trifluoromethoxy)benzylamine (0.40 mmol). After stirring for 16 hours, the mixture was treated with MP-Carbonate resin (0.310 g), stirred for 5 minutes, and filtered. The filtrate was diluted with dichloromethane (40 mL), washed with water (4×20 mL), brine (1×20 mL), dried (NasSO4), filtered, and the filtrate was concentrated under reduced pressure to provide the title compound which was purified by forming the hydrochloride salt and triturating the solid with hot ethyl acetate. MS (ESI+) m/z 361 (M+H)+; MS (ESI−) m/z 359 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 3.99 (s, 2H), 4.31 (d, J 5.7, 2H), 7.31 (d, J 8.8, 2H), 7.36 (d, J 6.4, 2H), 7.66 (m, 2H), 7.93 (d, J 6.1, 1H), 8.03 (d, J 8.2, 1H), 8.51 (d, J 6.1, 1H), 8.74 (t, J 6.1, 1H), 9.31 (s, 1H); Anal. Calcd for C19H15F3N2O2+1HCl: C, 57.51; H, 4.06; N, 7.06. Found: C, 57.42; H, 3.98; N, 6.72.
Reaction SMILES: NC1C=CC(F)=CC=1C(NC)=O.[F:13][C:14]1[C:28]([O:29][CH3:30])=[C:27]([N+:31]([O-])=O)[CH:26]=[CH:25][C:15]=1[CH2:16][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]>>[NH2:31][C:27]1[CH:26]=[CH:25][C:15]([CH2:16][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])=[C:14]([F:13])[C:28]=1[O:29][CH3:30]
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])c(OC)c1F)OCC
Agent: CNC(=O)c1cc(F)ccc1N
Product: CCOP(=O)(Cc1ccc(N)c(OC)c1F)OCC

Procedure:
The title compound was prepared using the procedure from Compound 102A (2-Amino-5-fluoro-N-methylbenzamide) with Diethyl (2-fluoro-3-methoxy-4-nitrobenzyl)phosphonate (Compound 147B). 1H NMR (CDCl3, 400 MHz): δ=1.29 (t, J=6.95 Hz, 6H), 3.13-3.21 (m, 2H), 3.93 (d, J=1.52 Hz, 3H), 4.04-4.12 (m, 4H), 6.55 (d, J=8.34 Hz, 1H), 6.83 (td, J=7.96, 2.78 Hz, 1H). MS (ES+): m/z 292.11 [MH+] (TOF, polar).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH3:20][CH:21]([CH3:34])[CH2:22][CH2:23][NH:24][C:25](=O)[O:26]C1C=CC=CC=1>CN(C)C=O>[CH3:20][CH:21]([CH3:34])[CH2:22][CH2:23][NH:24][C:25]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)=[O:26]
Reactant: Nc1cc(Oc2ccc3[nH]ccc3c2)ccn1
Reactant: CC(C)CCNC(=O)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CCNC(=O)n1ccc2cc(Oc3ccnc(N)c3)ccc21
Temperature: 25 °C
Yield: 48.3 %

Procedure:
4-(1H-5-Indolyloxy)-2-pyridinamine (2.0 g, 8.9 mmol, CAS No. 417722-11-3) which was described in WO 02/32872 was dissolved in N,N-dimethylformamide (20 ml); and sodium hydride (426 mg, 10.7 mmol) was added thereto at room temperature while stirring. The reaction mixture was cooled with ice bath after 30 minutes; phenyl N-(3-methylbutyl)carbamate (2.02 g, 9.75 mmol) was added thereto; and the reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and water; the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated; and the residue was purified by NH-silica gel column chromatography (hexane:ethyl acetate=3:1) to yield the title compound as crystals (1.45 g, 4.3 mmol, 48%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5]Br)[CH3:2].[OH:7][C:8]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:20][C:9]=1[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=[O:11]>>[CH2:1]([O:3][CH2:4][CH2:5][O:7][C:8]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([F:29])([F:27])[F:28])=[CH:20][C:9]=1[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=[O:11])[CH3:2]
Reactant: CCOCCBr
Reactant: O=C(NCc1ccccn1)c1cc(OCC(F)(F)F)ccc1O
Product: CCOCCOc1ccc(OCC(F)(F)F)cc1C(=O)NCc1ccccn1
Yield: 35.1 %

Procedure:
Using the general method of Example I Part A, 4.3 g (0.028 mole of 2-bromoethyl ethyl ether was reacted with 6.52 g (0.02 mole) of 2-hydroxy-N-(2-pyridylmethyl)-5-(2,2,2-trifluoroethoxy)benzamide to provide 2.8 g of white crystalline 2-(2-ethoxyethoxy)-N-(2-pyridylmethyl)-5-(2,2,2-trifluoroethoxy)benzamide, m.p.90°-94° C. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:4][C:3]=1[C:13]([F:16])([F:15])[F:14].Cl.[NH2:18][N:19]1[CH2:25][C:23](=[O:24])[NH:22][C:20]1=[O:21]>O=S(Cl)Cl.N1C=CC=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([NH:18][N:19]2[CH2:25][C:23](=[O:24])[NH:22][C:20]2=[O:21])=[O:10])=[CH:4][C:3]=1[C:13]([F:16])([F:15])[F:14]
Reactant: NN1CC(=O)NC1=O
Reactant: O=C(O)C=Cc1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C(C=Cc1ccc(Cl)c(C(F)(F)F)c1)NN1CC(=O)NC1=O

Procedure:
A stirred mixture of 4-chloro-3-trifluoromethylcinnamic acid (50 g, 0.2 mole) in 200 ml of SOCl2 was heated at reflux for 2 hours. The excess SOCl2 was removed in vacuo and the residue flushed with dry benzene. The residue was treated with a mixture of 1-aminohydantoin hydrochloride (30 g, 0.2 mole) in 400 ml of pyridine. The reaction mixture was heated at reflux for 3 hours; then poured into ice/HCl. The crude residue (74 g, 100%) was recrystallized from CH3NO2 (Darco) to give an analytical sample melting at 270°-273°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=[O:16])[N:11]=[N:10]2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=[O:16])[N:11]=[N:10]2)=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)O)nnn1Cc1ccc(Br)cc1
Reactant: OB(O)c1ccccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1c(C(=O)O)nnn1Cc1ccc(-c2ccccc2Cl)cc1
Temperature: 85 °C
Yield: 53.3 %

Procedure:
To a solution of 1-[(4-bromophenyl)methyl]-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (0.2 g, 0.67 mmol) in DME (10 mL) were added (2-chlorophenyl)boronic acid, (0.137 g, 0.88 mmol), Pd tetrakis (20 mg, 10% mol/mol) and a 2M solution of sodium carbonate (1.34 mL, 4 eq). The reaction was heated at 85° C. for 48 hours. After evaporation of DME, water was added and the reaction was extracted with ethyl acetate (2×40 mL). The aqueous phase was adjusted to PH=7 by addition of a 1N HCl solution and extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate and evaporated in vacuo to give the title compound as a solid (117 mg, 40%). HRMS calculated for C17H14ClN3O2(M+H)+328.0853. found: 328.0865, Rt: 2.04 min.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[CH:14]=[CH:13][C:12]([C:16]([O:18]C)=[O:17])=[CH:11][C:10]=3[N:9]3[CH2:20][CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:8]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl.O>O1CCCC1.CO>[CH:1]1([C:7]2[C:15]3[CH:14]=[CH:13][C:12]([C:16]([OH:18])=[O:17])=[CH:11][C:10]=3[N:9]3[CH2:20][CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:8]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCCc1ccccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCCc1ccccc1-3
Temperature: 50 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To a solution of methyl 13-cyclohexyl-6,7-dihydro-5H-benzo[3,4]azepino[1,2-a]indole-10-carboxylate (55 mg, 0.147 mmol) in tetrahydrofuran (2 ml) and methanol (2 ml) was added 4N aqueous sodium hydroxide solution (1 ml), and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was allowed to cool to room temperature, and 2N hydrochloric acid (2.5 ml) and water were added to the reaction mixture. The precipitated solid was collected by filtration, washed with water and dried in vacuo to give 13-cyclohexyl-6,7-dihydro-5H-benzo[3,4]azepino[1,2-a]indole-10-carboxylic acid (44 mg, yield 83%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[C:5]2=[O:19].[BH4-].[Na+].O>CO.O1CCCC1>[CH3:11][C:10]1[CH:9]=[C:8]2[C:4](=[CH:3][C:2]=1[CH3:1])[C:5](=[O:19])[N:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH:7]2[OH:12]
Reactant: Cc1cc2c(cc1C)C(=O)N(c1cccnc1)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2c(cc1C)C(O)N(c1cccnc1)C2=O
Yield: 78.7 %

Procedure:
The product of above-mentioned (7-a) (0.50 g, 2.0 mmol) was suspended in methanol (10 ml) and tetrahydrofuran (10 ml), and sodium borohydride (75 mg, 2.0 mmol) was added by portions thereto with stirring under ice cooling, followed by stirring at the same temperature for 30 minutes. To the reaction solution was added water, and the precipitated crystals were collected by filtration, washed with water, followed by drying to give 0.40 g of 5,6-dimethyl-3-hydroxy-2-(3-pyridyl)isoindolin-1-one.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C@@H:8]1[CH2:12][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C@H:10]([C:21](O)=[O:22])[CH2:9]1.[N:34]1([C:40]2[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=2[C:42]#[N:43])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[F:30][C:28]([F:29])([F:31])[C:26]1[CH:25]=[C:5]([CH:4]=[C:3]([C:2]([F:33])([F:32])[F:1])[CH:27]=1)[CH2:6][N:7]([CH3:24])[CH:8]1[CH2:12][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[CH:10]([C:21]([N:37]2[CH2:36][CH2:35][N:34]([C:40]3[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=3[C:42]#[N:43])[CH2:39][CH2:38]2)=[O:22])[CH2:9]1
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1C[C@@H](C(=O)O)N(Cc2cccc(Cl)c2)C1
Reactant: N#Cc1ccccc1N1CCNCC1
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CC(C(=O)N2CCN(c3ccccc3C#N)CC2)N(Cc2cccc(Cl)c2)C1
Yield: 111 %

Procedure:
As described for Example 64e, (2S,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-methyl-amino]-1-(3-chloro-benzyl)-pyrrolidine-2-carboxylic acid (1 mmol) was converted, using 2-piperazin-1-yl-benzonitrile instead of 2-cyclohexyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one, to the title compound (73.1 mg) in 111% yield as colorless oil.