Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]([C:27]2[S:28][C:29]([C:32]([NH:34][NH2:35])=[O:33])=[CH:30][CH:31]=2)=[O:26])[CH:19]=1>CS(C)=O>[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]([C:27]2[S:28][C:29]([C:32]([NH:34][N:35]=[C:15]([C:12]3[C:13]([OH:14])=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[S:10][CH:11]=3)[CH3:17])=[O:33])=[CH:30][CH:31]=2)=[O:26])[CH:19]=1
Reactant: NNC(=O)c1ccc(C(=O)Nc2cccnc2)s1
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Solvent: CS(C)=O
Product: CC(=NNC(=O)c1ccc(C(=O)Nc2cccnc2)s1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Temperature: 100 °C
Yield: 94 %

Procedure:
28 mg of 2-(3,4-dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene and 26 mg of 5-hydrazinocarbonylthiophene-2-carboxylic acid 3-pyridylamide were dissolved in 2 mL of dimethyl sulfoxide and heated at 100° C. for 18 hours, and the solvent was evaporated. Recrystallization from chloroform-diethyl ether gave the desired product (yield 94%).
Reaction SMILES: [F:1][C:2]([F:15])(F)[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([NH2:13])[CH3:12])=[CH:7][CH:6]=1.ClC1C=CC(C#N)=CN=1.[F:25][C:26]([F:32])(C(F)F)CO>>[F:1][C:2]([F:15])([CH:26]([F:32])[F:25])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([NH2:13])[CH3:12])=[CH:7][CH:6]=1
Reactant: OCC(F)(F)C(F)F
Reactant: CC(N)c1ccc(OCC(F)(F)F)nc1
Agent: N#Cc1ccc(Cl)nc1
Product: CC(N)c1ccc(OCC(F)(F)C(F)F)nc1

Procedure:
The title compound was synthesised according to the 2-step procedure described for the synthesis of 1-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]ethanamine starting from 6-chloronicotinonitrile and 2,2,3,3-tetrafluoropropan-1-ol.
Reaction SMILES: Br[C:2]1[CH:7]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[NH:6][CH:5]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[CH:3]=1.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.O>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].Cl[Pd]Cl>[CH:9]1([O:8][C:7]2[C:2]([C:21]3[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=3)=[CH:3][C:4]([C:14]([O:16][CH3:17])=[O:15])=[CH:5][N:6]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: OB(O)c1ccncc1
Reactant: COC(=O)C1=CNC(OC2CCCC2)C(Br)=C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cnc(OC2CCCC2)c(-c2ccncc2)c1
Temperature: 40 °C
Reaction time: 4 h
Yield: 30.8 %

Procedure:
Methyl 5-bromo-6-(cyclopentyloxy)-1,6-dihydropyridine-3-carboxylate (2.50 g, 7.94 mmol) was dissolved in DME (10 mL) and pyridin-4-ylboronic acid (813 mg, 6.61 mmol), DPPF-PdCl2 (108 mg, 0.13 mmol, Strem) and water (0.5 mL, 28 mmol) were added. The mixture was stirred at 40° C. for 4 h. The reaction mixture was cooled to RT, diluted with H1O and extracted 3× with EtOAc. The combined organic extracts were washed 1× with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (40 g pre-packed column, elution 0-30% EtOAc:hexanes) to give the title compound (608 mg, 31%). MS m/z: 299 (M+1).
Reaction SMILES: C(C1C([N+]([O-])=O)=CC(C(O)=O)=CC=1OCCCC)(=O)C1C=CC=CC=1.[C:26]([C:34]1[C:42]([N+:43]([O-])=O)=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][C:35]=1[O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[NH2:43][C:42]1[C:34]([C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:35]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=2)[CH:36]=[C:37]([CH:41]=1)[C:38]([OH:40])=[O:39]
Reactant: O=C(O)c1cc(OCc2ccccn2)c(C(=O)c2ccccc2)c([N+](=O)[O-])c1
Agent: CCCCOc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccccc1
Product: Nc1cc(C(=O)O)cc(OCc2ccccn2)c1C(=O)c1ccccc1

Procedure:
By replacing in Example 1, step C, 4-benzoyl-3-n-butoxy-5-nitrobenzoic acid with 4-benzoyl-5-nitro-3-(2-pyridylmethoxy)benzoic acid, and following the procedure described, 5-amino-4-benzoyl-3-(2-pyridylmethoxy)benzoic acid is obtained with a melting point of 212°-213° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9](CC2C=CC(OC)=CC=2OC)[C:10]([NH:12][C:13]2[S:14][CH:15]=[C:16]([CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[N:17]=2)=[O:11])[S:5][C:6]=1[Br:7].C(O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1>O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10]([NH:12][C:13]2[S:14][CH:15]=[C:16]([CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[N:17]=2)=[O:11])[S:5][C:6]=1[Br:7]
Reactant: COCCOCc1csc(NC(=O)N(Cc2cc(Br)c(Br)s2)Cc2ccc(OC)cc2OC)n1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COCCOCc1csc(NC(=O)NCc2cc(Br)c(Br)s2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Deprotection: The 1-(4,5-Dibromo-thiophen-2-ylmethyl)-1-(2,4-dimethoxy-benzyl)-3-[4-(2-methoxy-ethoxymethyl)-thiazol-2-yl]-urea was treated with TFA followed by the addition of a drop of anisole and a drop of water. Stirred overnight at ambient temperature. The volatiles were removed in vacuo and the crude material was purified by taking up in MeOH and filtering to remove insolubles. The filtrate was concentrated in vacuo, and the resulting solid titrated with ether to give the title compound. 1H NMR (400 MHz, DMSO): 10.70 (br s, 1H), 7.17 (br m, 1H), 7.00 (s, 1H), 6.88 (s, 1H), 4.42 (d, 2H), 4.37 (s, 2H), 3.55 (m, 2H), 3.45 (m, 2H), 3.24 (s, 3H). MS (ES+): M/Z 484, 486 and 488 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:21]([O:25][C:26]([N:28]([C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)[CH3:29])=[O:27])([CH3:24])([CH3:23])[CH3:22].C1(CC(O)=O)CCCC1>>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:5]2[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:34](=[O:35])[C:33]3[CH:32]=[CH:31][C:30]([N:28]([C:26]([O:25][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:27])[CH3:29])=[CH:38][CH:37]=3)[N:3]=[CH:4]2)=[CH:12][CH:13]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1ccc(Cn2cnc(N)c2C(N)=O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(C(=O)O)cc1
Agent: O=C(O)CC1CCCC1
Product: CN(C(=O)OC(C)(C)C)c1ccc(C(=O)Nc2ncn(Cc3ccc(C(C)(C)C)cc3)c2C(N)=O)cc1
Yield: 55 %

Procedure:
An amidation reaction and post-treatment were carried out under the same conditions as in Example 19, using 2.65 g (9.71 mmol) of 4-amino-1-(4-t-butylbenzyl)-5-imidazolecarboxamide which was prepared in the same manner as in Example 57 and 4-(N-t-butyloxycarbonyl-N-methylamino)benzoic acid which was prepared seperately by a conventional method instead of cyclopentyl acetic acid to obtain 2.69 g of 1-(4-t-butylbenzyl)-4-(4-(N-t-butyloxycarbonyl-N-methylamino)benzoylamino)-5-imidazolecarboxamide (yield 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23](=[O:27])[N:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+].[Br:34][CH2:35][CH2:36]Br.O>CN(C)C=O>[Br:34][CH2:35][CH2:36][O:21][C:15]1[CH:14]=[C:13]2[C:18]([C:9]([O:8][C:6]3[CH:5]=[CH:4][C:3]([NH:22][C:23](=[O:27])[N:24]([CH3:26])[CH3:25])=[C:2]([Cl:1])[CH:7]=3)=[N:10][CH:11]=[N:12]2)=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: COc1cc2c(Oc3ccc(NC(=O)N(C)C)c(Cl)c3)ncnc2cc1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(NC(=O)N(C)C)c(Cl)c3)ncnc2cc1OCCBr
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A starting compound (N′-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N,N-dimethylurea, 80 mg), potassium carbonate (138 mg), and 1,2-dibromoethane (0.085 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give an intermediate (N′-(4-{[7-(2-bromoethoxy)-6-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl)-N,N-dimethylurea). The intermediate, potassium carbonate (138 mg), and morpholine (0.043 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC by development with chloroform/methanol to give 72 mg (yield 72%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:22]([C:23]([NH2:25])=[O:24])=[C:21]([NH:26][C:27]([N:29]4[CH2:33][CH2:32][CH2:31][C:30]4=[O:34])=[O:28])[S:20][N:19]=3)=[CH:14][CH:13]=2)=[O:10])=[CH:4][CH:3]=1.Cl.[OH-:36].[Na+]>>[NH2:25][C:23]([C:22]1[C:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)=[O:10])=[CH:13][CH:14]=2)=[N:19][S:20][C:21]=1[NH:26][C:27]([NH:29][CH2:33][CH2:32][CH2:31][C:30]([OH:34])=[O:36])=[O:28])=[O:24]
Reactant: [OH-]
Reactant: Cc1ccc(NC(=O)Nc2ccc(-c3nsc(NC(=O)N4CCCC4=O)c3C(N)=O)cc2)cc1
Agent: Cl
Agent: [Na+]
Product: Cc1ccc(NC(=O)Nc2ccc(-c3nsc(NC(=O)NCCCC(=O)O)c3C(N)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[4-({[(4-methylphenyl)amino]carbonyl}amino)phenyl]-5-{[(2-oxopyrrolidin-1-yl)carbonyl]amino}isothiazole-4-carboxamide (11.8 g,) was added to 1 N sodium hydroxide (100 mL) at ambient temperature. The resulting mixture was stirred at ambient temperature for overnight (reaction mixture became clear solution). Reaction mixture acidified with 2 N HCl. The solid which formed was collected by filtration and washed with water then dried in vacuo to give the title compound as off white solid (9.1 g, 75%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.B(Br)(Br)Br>C(Cl)Cl>[O:12]1[CH2:11][CH2:10][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[OH:2])[CH2:14][CH2:13]1
Reactant: COc1ccccc1N1CCOCC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccccc1N1CCOCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 4-(2-methoxyphenyl)morpholine (200 mg, 1.02 mmol) in CH2Cl2 (20 mL) was added BBr3 (1 mL) at 0° C. The mixture was stirred for 2 h at 0° C. The mixture was then added drop wise to ice-water (50 mL) and the mixture treated with CH2Cl2 (2×20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to give the yellow solid which was used in next step without further purification (165 mg Yield 80%). LCMS (m/z): 180.1 (M+1).
Reaction SMILES: C(N)CC.[C:5]1([O:11][C:12]([N:14]2[CH:27]([C:28]#[CH:29])[C:26]3[CH2:25][CH2:24][CH2:23][CH:22]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[C:21]=3[C:20]3[CH:19]=[CH:18][C:17]([O:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=4[N+:46]([O-:48])=[O:47])=[CH:16][C:15]2=3)=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:49]1C=C[CH:52]=[CH:51][CH:50]=1>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.[Cu]I>[C:5]1([O:11][C:12]([N:14]2[CH:27]([C:28]#[C:29]/[CH:49]=[CH:50]\[C:51]#[C:52][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:26]3[CH2:25][CH2:24][CH2:23][CH:22]([O:30][Si:31]([C:34]([CH3:36])([CH3:37])[CH3:35])([CH3:33])[CH3:32])[C:21]=3[C:20]3[CH:19]=[CH:18][C:17]([O:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=4[N+:46]([O-:48])=[O:47])=[CH:16][C:15]2=3)=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C#CC1C2=C(c3ccc(OCc4ccccc4[N+](=O)[O-])cc3N1C(=O)Oc1ccccc1)C(O[Si](C)(C)C(C)(C)C)CCC2
Reactant: c1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCN
Product: CC(C)(C)[Si](C)(C)OC1CCCC2=C1c1ccc(OCc3ccccc3[N+](=O)[O-])cc1N(C(=O)Oc1ccccc1)C2C#C/C=C\C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
A mixture of Pd(PPh3)4 (1.12 g, 0.97 mmol), 1-chloro-4-(trimethylsilyl)-but-1-3n-3-yne (4.60 g, 28.98 mmol), and n-propylamine (2.38 mL, 28.98 mmol) in degassed benzene (100 mL) was stirred at 25° C. for 15 minutes. The resultant solution was added to a mixture of Compound 143b (79:21, mixture of diastereomers, 11.80 g, 19.32 mmol) and CuI (0.74 g, 3.86 mmol) in degassed benzene (300 mL) via a syringe followed by stirring at 25° C. for five hours. The reaction was quenched with saturated aqueous NH4Cl, extracted with ethyl ether (500 mL), washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. Purification of the crude product by flash column chromatography (silica gel, 20 percent ethyl ether in petroleum ether) gave Compound 232 (12.3 g, 87 percent): amorphous solid; Rf =0.51 (silica, 25 percent ethyl ether in petroleum ether); IR (CHCl3) νmax 2957, 2932, 1716, 1613, 1506, 1495, 1384, 1344, 1306, 1253, 1200, 1093, 1025, 858, 844 cm-1 ; 1H NMR (300 MHz, CDCl3) δ 8.19 (d, J=8.1 Hz, 1 H, aromatic), 7.97 (d, J=7.7 Hz, 1 H, aromatic), 7.80-7.17 (m, 9 H, H1, H4and aromatic), 6.93-6.84 (m, 1 H, H2), 5.96 (br s, 0.79 H, H6), 5.93 (br s, 0.21 H, H6), 5.88-5.77 (m, 2 H, olefinic), 5.58 (s, 2 H, benzylic), 5.03 (br s, 0.79 H, H10), 4.73 (br s, 0.21 H, H10), 2.67-2.50 (m, 1 H, H7), 2.39-2.26 (m, 1 H, H7), 2.16-1.91 (m, 3 H, H8 and H9), 1.84-1.70 (m, 1 H, H8 or H9), 1.02 (s, 1.89 H, SiC(CH3)3), 0.90 (s, 7.11 H, SiC(CH3)3), 0.27 (s, 9 H, Si(CH3)3), 0.18 (s, 3 H, SiCH3), 0.16 (s, 3 H, SiCH3); MS (FAB+) m/e (rel intensity) 865 (M+Cs, 72), 732 (42), 675 (82), 639 (28), 585 (100), 450 (34), 330 (39), 279 (52), 198 (42); HRMS for C42H48N2O6Si2Cs (M+Cs), calcd 865.2105, found 865.2111.
Reaction SMILES: [CH2:1]([N:5]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH3:29])=[CH:19][CH:18]=3)=[CH:16][C:11]=2[CH:10]=[C:9]([C:30]([O:32]C)=[O:31])[CH2:8][CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].Cl>C(O)C.C1COCC1>[CH2:1]([N:5]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH3:29])=[CH:21][CH:22]=3)=[CH:16][C:11]=2[CH:10]=[C:9]([C:30]([OH:32])=[O:31])[CH2:8][CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCCN3CC(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCCN3CC(C)C)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 82.6 %

Procedure:
To a solution of methyl 1-isobutyl-8-[4-(2-propoxyethoxy)phenyl]-1,2,3,4-tetrahydro-1-benzazocine-5-carboxylate (1.20 g) in a mixture of ethanol-THF (10-5 ml) was added an aqueous 1N sodium hydroxide solution (5.2 ml) at room temperature. The mixture was stirred at 60° C. for 16 hours and cooled to 0° C. 1N Hydrochloric acid (6 ml) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropylether to give 1-isobutyl-8-[4-(2-propoxyethoxy)phenyl]-1,2,3,4-tetrahydro-1-benzazocine-5-carboxylic acid (0.96 g) as yellow crystals.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.O.[NH2:12][NH2:13].[OH-].[K+]>C(O)C>[NH:12]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1)[NH2:13]
Reactant: NN
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NNc1ccc(C(=O)O)cn1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
5.0 g (31.7 mmol) 6-chloronicotinic acid and 30.9 ml (31.8 g, 634.7 mmol) hydrazine hydrate are initially introduced into 10 ml ethanol and the mixture is stirred at the boiling point at a bath temperature of 100° C. for 16 h. The solvent and excess hydrazine hydrate are distilled off on a rotary evaporator, the residue is taken up in water, 1.8 g (31.7 mmol) potassium hydroxide are then added and the mixture is stirred for 15 min. The solvent is removed completely on a rotary evaporator, the residue is dried in vacuo and 7.5 g of crude product, which is reacted further as such, are obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:13]2)=[O:11])[CH2:5][CH2:4]1>[Pd].CO>[CH3:33][N:2]([CH3:1])[C:3]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:8][CH2:7][CH:6]([CH2:9][C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:13]2)=[O:11])[CH2:5][CH2:4]1
Reactant: CN(C)C1(c2ccccc2)CCC(=CC(=O)N2CCCC(c3c[nH]c4ccccc34)C2)CC1
Agent: [Pd]
Solvent: CO
Product: CN(C)C1(c2ccccc2)CCC(CC(=O)N2CCCC(c3c[nH]c4ccccc34)C2)CC1
Reaction time: 24 h
Yield: 30 %

Procedure:
Palladium on carbon (5%, 60 mg) was added to a solution of 2-(4-dimethylamino-4-phenylcyclohexylidene)-1-[3-(1H-indol-3-yl)piperidine-1-yl]-ethanone (220 mg, 0.498 mmole) in abs. methanol (30 ml). The reaction mixture was hydrogenated for 24 hours at RT under a pressure of 3 bar. The catalyst was separated using Celite and the filtrate was concentrated by evaporation. After chromatographic separation of the residue (210 mg) on silica gel (20 g) with EE/methanol (2:1), 2-(4-dimethylamino-4-phenylcyclohexyl)-1-[3-(1H-indol-3-yl)piperidine-1-yl]-ethanone was isolated as a colourless oil in a yield of 30% (66 mg). The compound was obtained as a diastereoisomer mixture.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH2:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[C:12](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:13]>ClCCl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]=[C:12]=[S:13])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: Nc1n[nH]c2cc(F)ccc12
Solvent: ClCCl
Product: Fc1ccc2c(N=C=S)n[nH]c2c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
To 6-fluoro-1H-indazol-3-amine (0.32 g, 2.1 mmol) in dichloromethane (15 mL) was added 1,1′-thiocarbonyldipyridin-2(1H)-one (0.53 g, 2.30 mmol). The reaction was stirred at 50° C. for 3 hours. The reaction was cooled to room temperature and the crude product was purified by column chromatography (25% ethyl acetate/hexanes) to afford 6-fluoro-3-isothiocyanato-1H-indazole (0.30 g, 1.53 mmol, 73.0% yield) as a light yellow powder. 1H NMR (500 MHz, DMSO-D6) δ ppm 13.39 (s, 1 H), 7.78 (dd, J=8.85, 4.88 Hz, 1 H), 7.41 (dd, J=9.31, 1.68 Hz, 1 H), 7.14 (td, J=9.16, 1.83 Hz, 1 H). MS (LC/MS) R.T.=3.69; [M+H]+=194.07.
Reaction SMILES: C(S([N:6]1[CH2:11][CH2:10][CH:9](C2C3C(=C(C(N)=O)C=C(C4SC(CNCC(C)CC)=CC=4)C=3)NC=2)[CH2:8][CH2:7]1)(=O)=O)C.[CH:36]([C:38]1[S:42][C:41]([B:43]([OH:45])[OH:44])=[CH:40][CH:39]=1)=O.C(N)CCCC.[BH3-]C#N.[Na+]>>[CH2:7]([NH:6][CH2:36][C:38]1[S:42][C:41]([B:43]([OH:45])[OH:44])=[CH:40][CH:39]=1)[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: O=Cc1ccc(B(O)O)s1
Reactant: CCC(C)CNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCCCCN
Product: CCCCCNCc1ccc(B(O)O)s1

Procedure:
Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), pentylamine (29 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 45 mg of crude {5-[(pentylamino)methyl]-2-thienyl}boronic acid. The crude {5-[(pentylamino)methyl]-2-thienyl}boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) to give 20.7 mg of the title compound (20%).
Reaction SMILES: [CH2:1]([N:3]([S:18]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)(=[O:20])=[O:19])[C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([O:15]CC)=[O:14])=[CH:9]2)[CH3:2].[OH-].[Na+].O1CCCC1>CO>[CH2:1]([N:3]([S:18]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)(=[O:20])=[O:19])[C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9]2)[CH3:2]
Reactant: CCOC(=O)c1cc2cccc(N(CC)S(=O)(=O)c3cccs3)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 50 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A mixture of ethyl 7-[ethyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (0.54 g), 2N aqueous sodium hydroxide solution (2.2 mL), tetrahydrofuran (4 mL) and methanol (4 mL) was stirred at 50° C. for 1 hr. The reaction mixture was concentrated, and water was added to the residue. The mixture was acidified with 10% aqueous citric acid solution, and the resulting crystals were filtrated, washed with water, and dried to give the title compound (0.43 g, yield 86%) as colorless crystals. melting point>222° C. (decomposition).
Reaction SMILES: C1C=C(C(N)=O)C=C2C=1C=C1C3C(=CC=CC=3)CN12.Br[C:21]1[NH:22][C:23]2[C:28]([C:29]=1[CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[CH:27][CH:26]=[C:25]([C:36]([NH:38][S:39](=[O:44])(=[O:43])[N:40]([CH3:42])[CH3:41])=[O:37])[CH:24]=2.[CH:45]([C:47]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:48]=1B(O)O)=[O:46].[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+].Cl>O.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.CCO.C1(C)C=CC=CC=1>[CH:30]1([C:29]2[C:28]3[C:23](=[CH:24][C:25]([C:36]([NH:38][S:39](=[O:44])(=[O:43])[N:40]([CH3:42])[CH3:41])=[O:37])=[CH:26][CH:27]=3)[NH:22][C:21]=2[C:48]2[CH:49]=[CH:50][C:51]([O:53][CH3:54])=[CH:52][C:47]=2[CH:45]=[O:46])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: COc1ccc(B(O)O)c(C=O)c1
Reactant: CN(C)S(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: NC(=O)c1ccc2cc3n(c2c1)Cc1ccccc1-3
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2[nH]c3cc(C(=O)NS(=O)(=O)N(C)C)ccc3c2C2CCCCC2)c(C=O)c1
Temperature: 70 °C
Yield: 64.9 %

Procedure:
6H-Isoindolo[2,1-a]indole-3-carboxamide, 11-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-ethoxy-8-methoxy-. To a 5 L four necked round bottom flask equipped with a temperature controller, a condenser, a N2 inlet and a mechanical stirrer, was charged toluene (900 mL), EtOH (900 mL), 2-bromo-3-cyclohexyl-N-(N,N-dimethylsulfamoyl)-1H-indole-6-carboxamide (90 g, 0.21 mol), 2-formyl-4-methoxyphenylboronic acid (49.2 g, 0.273 mol) and LiCl (22.1 g, 0.525 mol). The resulting solution was bubbled with N2 for 15 mins. A solution of Na2CO3 (66.8 g, 0.63 mol) in H2O (675 mL) was added and the reaction mixture was bubbled with N2 for another (10 mins). Pd(PPh3)4 (7.0 g, 6.3 mmol) was added and the reaction mixture was heated to 70° C. for 20 h. After cooling to 35 ° C., a solution of 1 N HCl (1.5 L) was added slowly. The resulting mixture was transferred to a 6 L separatory funnel and extracted with EtOAc (2×1.5 L). The combined organic extracts were washed with brine (2 L), dried over MgSO4, filtered and concentrated in vacuo to give a yellow solid, which was triturated with 20% EtOAc in hexane (450 mL, 50° C. to 0° C.) to give 3-cyclohexyl-N-(N,N-dimethylsulfamoyl)-2-(2-formyl-4-methoxyphenyl)-1H-indole-6-carboxamide(65.9 g) as a yellow solid. HPLC purity, 98%.