Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:30](S(C4C=CC(C)=CC=4)(=O)=O)[C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH:22][CH:23]5[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]5)=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:41][CH3:42].[OH-].[K+]>>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[NH:30][C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH:22][CH:23]5[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]5)=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:41][CH3:42]
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(CNC4CCN(C)CC4)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(nc1OC)c(-c1cc3c(CNC4CCN(C)CC4)ccnc3[nH]1)cn2C
Yield: 92.1 %

Procedure:
The product is prepared by following the procedure described in example 34 stage (k) starting with 0.250 g of [2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]-(1-methylpiperidin-4-yl)amine instead of the cyclopropyl-[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amine used in example 34 stage (k) and 2 cm3 of 5N potassium hydroxide. After purification by flash-pack chromatography (SiO2, dichloromethane/methanol 90/10 by volume as eluents), 0.170 g of [2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]-(1-methylpiperidin-4-yl)amine is obtained with the following characteristics:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N:7]1([C:12]2[CH:40]=[CH:39][C:15]([CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4Br)[CH2:19]3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1>[Cu](Br)Br.C1(C)C=CC=CC=1>[N:7]1([C:12]2[CH:40]=[CH:39][C:15]([CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][C@@H:20]([N:23]4[C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=5[CH2:31][O:30][C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]4=5)[CH2:19]3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: Brc1ccccc1COc1ccccc1N[C@@H]1CCN(CCc2ccc(N3CCCC3)cc2)C1
Agent: Br[Cu]Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)COc1ccccc1N2[C@@H]1CCN(CCc2ccc(N3CCCC3)cc2)C1

Procedure:
Potassium carbonate (1.71 g, 12.4 mmol), copper bromide (I) (53 mg, 0.37 mmol) and toluene (30 ml) were added to (R)-N-[1-(4-pyrrolidinophenethyl)pyrrolidin-3-yl]-2-(2-bromobenzyloxy)aniline (1.4 g as mixture). The reaction mixture was heated under reflux for 53 hours and then copper bromide (I) (60 mg, 0.42 mmol) was added thereto. The reaction mixture was heated under reflux for additional 50 hours. Toluene (10 ml), potassium carbonate (1.04 g, 7.52 mmol) and copper bromide (I) (42 mg, 0.29 mmol) were added thereto. The reaction mixture was heated under reflux for 48 hours and then filtered through Celite. Water was added to the filtrate. The organic layer was taken and dried over sodium sulfate. The solvent was evaporated under reduced pressure. A part (187 mg) of the obtained residue (1.12 g) was subjected to the high performance liquid chromatography. After the elution with acetonitrile and water (gradient from 20:80 to 70:30), suitable fractions were collected and distributed into methylene chloride and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to the thin layer silica gel chromatography. After the development with hexane and ethyl acetate (1:5), silica gel was collected from proper parts and then eluted with a solvent mixture of methylene chloride and methanol (3:1). The effluents were collected, and he solvent was evaporated under reduced pressure to obtain the title compound in the form of a white solid (25.5mg, yield in 2 steps: 39%).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][C@@H:5]([CH2:7]O)[CH2:4][O:3]1.[CH3:10][S:11]([O:14][CH2:15][C@H:16]1[CH2:20][O:19][C:18]([CH3:22])([CH3:21])[O:17]1)(=[O:13])=[O:12].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC#N>[CH3:10][S:11]([O:14][CH2:15][C@H:16]1[CH2:20][O:19][C:18]([CH3:22])([CH3:21])[O:17]1)(=[O:12])=[O:13].[CH2:23]([NH:30][CH2:7][C@H:5]1[CH2:4][O:3][C:2]([CH3:1])([CH3:9])[O:6]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1ccccc1
Reactant: CC1(C)OC[C@H](CO)O1
Agent: CC1(C)OC[C@H](COS(C)(=O)=O)O1
Solvent: CC#N
Product: CC1(C)OC[C@H](CNCc2ccccc2)O1
Yield: 76 %

Procedure:
(R)-(2,2-Dimethyl-1,3-dioxolan-4-yl)methyl methanesulfonate was prepared from (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (Sigma-Aldrich, 99% ee) by a known literature procedure (H. S. Kim, D. Barak, T. K. Harden, J. L. Boyer and K. A. Jacobson, J. Med. Chem., 2001, 44, 3092). The title compound was prepared in the same way as described by M. Lemaire, F. Posada, J.-G. Gourcy and G. Jeminet, Synlett, 1995, 627. A solution of (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl methanesulfonate (3.9 g, 18.55 mmol) and benzylamine (8.10 ml, 74.2 mmol) was refluxed in CH3CN (50 ml) for 48 h. The solvent was evaporated and the residue dissolved in EtOAc and washed with aqueous sat. NaHCO3, dried and the solvent evaporated. The residue was chromatographed (EtOAc-hex, 6:4 then 8:2) to give (S)—N-benzyl-1-(2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (3.1 g, 14.01 mmol, 76% yield) as a yellow oil.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[CH:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[CH:16]([C:26]([NH:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:27])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:37].[N+]([NH:41][C:42](N)=[O:43])([O-])=O>C(O)C>[CH2:30]([O:29][NH:28][C:26]([CH:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:37])[N:8]([CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]2[NH:1][C:42](=[O:43])[NH2:41])[CH:17]1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])=[O:27])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2ccccc2)C1c1ccc(Cl)cc1Cl
Reactant: NC(=O)N[N+](=O)[O-]
Solvent: CCO
Product: NC(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2ccccc2)C1c1ccc(Cl)cc1Cl
Yield: 53.4 %

Procedure:
To a mixed liquid of 269 mg of (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 20 ml of ethanol was added 53 mg of nitrourea, followed by heating under reflux for 1 hour. The reaction solution was cooled and then concentrated, and the residue was purified by silica gel column chromatography (eluent: chloroform-methanol), then crystallized with acetonitrile, and collected by filtration to obtain 155 mg of (3RS,4RS)—N-(benzyloxy)-2-[(1SR,2SR)-2-(carbamoylamino)cyclohexyl]-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)(=O)=O)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:24](Br)[CH:25]=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:11]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)[CH2:24]/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:4][CH:3]=1
Reactant: BrCC=Cc1ccccc1
Reactant: COC(=O)c1ccc(CS(=O)(=O)c2ccc(F)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C/C=C/c2ccccc2)Sc2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 110.1 %

Procedure:
To a solution of methyl 4-{[(4-fluorophenyl)sulfonyl]methyl}benzoate (0.26 g, 0.84 mmole) in DMF at 0° C. was added NaH (25 mg, 0.74 mmole) and the reaction was stirred for 15 minutes at 0° C. Then a solution of cinnamyl bromide (0.16 g, 0.81 mmole) in THF (1 mL) was added, and the reaction was allowed to warm to room temperature. The reaction was quenched with saturated NH4Cl solution and extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered, and evaporated. The residue was chromatographed to yield 0.35 g of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([S:10][CH3:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[CH:17][C:18]=1[Cl:19].CC([O-])(C)C.[K+]>C1COCC1.CS(C)=O>[Cl:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][C:18]=1[Cl:19])[O:20][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([S:10][CH3:11])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CSc1ccc(Cl)nc1C#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CSc1ccc(Oc2ccc(Cl)c(Cl)c2)nc1C#N

Procedure:
6-Chloro-3-methylthio-2-pyridinecarbonitrile was mixed with 16.3 g of 3,4-dichlorophenol in the presence of 11.2 g of t-BuOK in 150 ml THF and 15 ml of DMSO. 13.4 g (54%) of the desired, 6-(3,4-dichlorophenoxy)-3-methylthio-2-pyridinecarbonitrile was recovered, m.p. 156°-158° C.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:25][C:26]1[N:27]=[C:28]([CH3:31])[S:29][CH:30]=1.O>CN(C)C=O>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])/[N:7]([CH2:25][C:26]2[N:27]=[C:28]([CH3:31])[S:29][CH:30]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cl)cc1C(=O)Nc1ncc(C(C)(C)C)s1
Reactant: Cc1nc(CCl)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1Cc1csc(C)n1
Reaction time: 0.25 h

Procedure:
To a solution of Example 74B (0.79 g, 2.43 mmol) in N,N-dimethylformamide (20 mL) was added sodium hydride (Aldrich, 98 mg, 2.43 mmol) and the reaction mixture was stirred for 15 min and 4-(chloromethyl)-2-methylthiazole (0.36 g, 2.43 mmol) was added. The reaction mixture was stirred at room temperature for 18 hr, poured into water (75 mL) and then extracted with EtOAc (75 mL). The organic layer was washed with water (2×75 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to provide the title compound. MS, DCI, m/z 436 (M+H)+.
Reaction SMILES: [CH2:1]([S:4][CH2:5][C:6](=[N:13][NH:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1)=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:2]#[CH:3].C([BH3-])#N.[Na+].Cl>CO>[CH2:1]([S:4][CH2:5][CH:6]([NH:13][NH:14][C:15]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][C:25]([F:28])([F:26])[F:27])=[CH:22][CH:23]=1)=[O:16])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:2]#[CH:3]
Reactant: C#CCSCC(=NNC(=O)Nc1ccc(OC(F)(F)F)cc1)c1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: C#CCSCC(NNC(=O)Nc1ccc(OC(F)(F)F)cc1)c1ccccc1

Procedure:
In 10 ml of methanol was suspended 0.50 g (1.2 mmoles) of 2-[2-(2-propynylthio)-1-phenylethylidene]-N-(4-trifluoromethoxyphenyl)hydrazinecarboxamide, and 0.37 g (4.7 mmoles) of sodium cyanoborohydride was added to the resulting suspension. The resulting mixture was adjusted to pH 4 to 6 with a methanolic solution of hydrogen chloride at room temperature and subjected to reaction.
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([Br:15])=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])C)=[O:4].[F:16][C:17]1[CH:18]=C(N)[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>C(O)(C)C>[Br:15][C:7]1[S:6][C:5]2[C:3](=[O:4])[N:12]([C:14]3[CH:20]=[CH:21][C:22]([O:23][CH2:24][CH2:25][N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[C:17]([F:16])[CH:18]=3)[CH:11]=[N:10][C:9]=2[CH:8]=1
Reactant: Nc1ccc(OCCN2CCCC2)c(F)c1
Reactant: COC(=O)c1sc(Br)cc1N=CN(C)C
Solvent: CC(C)O
Product: O=c1c2sc(Br)cc2ncn1-c1ccc(OCCN2CCCC2)c(F)c1

Procedure:
5-Bromo-3-(dimethylaminomethyleneamino)thiophene-2-carboxylic acid methyl ester was reacted with 3-fluoro-4-(2-pyrrolidin-1-ylethoxy)phenylamine by method A with addition of isopropanol in addition. The product with the molecular weight of 438.32 (C18H17BrFN3O2S) was obtained in this way; MS (ESI): 438, 440 (M+H+).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]([C:10]([NH:12][C:13]3[CH:17]=[C:16]([C:18]([NH:20][CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[O:19])[N:15]([CH3:27])[CH:14]=3)=[O:11])=[CH:8][C:7]([NH:28][C:29]([C:31]3[N:32]([CH3:39])[CH:33]=[C:34]([N+:36]([O-])=O)[CH:35]=3)=[O:30])=[CH:6]2)[CH2:3][CH2:2]1.[CH2:40]([OH:42])C>[Pd]>[CH:1]1([CH2:4][N:5]2[C:9]([C:10]([NH:12][C:13]3[CH:17]=[C:16]([C:18]([NH:20][CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[O:19])[N:15]([CH3:27])[CH:14]=3)=[O:11])=[CH:8][C:7]([NH:28][C:29]([C:31]3[N:32]([CH3:39])[CH:33]=[C:34]([NH:36][CH:40]=[O:42])[CH:35]=3)=[O:30])=[CH:6]2)[CH2:3][CH2:2]1
Reactant: CCO
Reactant: CN(C)CCCNC(=O)c1cc(NC(=O)c2cc(NC(=O)c3cc([N+](=O)[O-])cn3C)cn2CC2CC2)cn1C
Agent: [Pd]
Product: CN(C)CCCNC(=O)c1cc(NC(=O)c2cc(NC(=O)c3cc(NC=O)cn3C)cn2CC2CC2)cn1C
Reaction time: 3 h
Yield: 42 %

Procedure:
N-[1-(Cyclopropylmethyl)-5-({[5-({[3-(dimethylamino)propyl]amino}-carbonyl)-1-methyl-1H-pyrrol-3-yl]amino}carbonyl)-1H-pyrrol-3-yl]-1-methyl-4-nitro-1H-pyrrole-2-carboxamide (100 mg, 0.186 mmol; see step (iv) above) was dissolved in ethanol (25 mL) to which Pd/C-10% (78 mg) was added at 0° C. under N2 with stirring. The reaction mixture was hydrogenated for 3 h at room temperature and atmospheric pressure. The catalyst was removed over Kieselguhr. Ethyl formate was added to the ethanolic solution of the amine and the reaction mixture was heated under reflux for 48 h. Ethanol and excess ethyl formate were removed under reduced pressure and the crude product was purified by HPLC. The product was obtained as pale yellow solid (52 mg, 42% yield) after freeze drying with no distinct melting point.
Reaction SMILES: [Cl:1][C:2]([Cl:20])([F:19])[S:3][C:4]1[CH:5]=[N:6][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:8]=1N.O1CCCC1.N(OC(C)(C)C)=O>O>[Cl:20][C:2]([Cl:1])([F:19])[S:3][C:4]1[CH:5]=[N:6][N:7]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[CH:8]=1
Reactant: COc1ccc(Cn2ncc(SC(F)(Cl)Cl)c2N)cc1
Agent: CC(C)(C)ON=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc(SC(F)(Cl)Cl)cn2)cc1
Temperature: 25 °C
Yield: 94.6 %

Procedure:
1.04 g of 4-{[dichlorofluoromethyl]thio}-1-(4-methoxybenzyl)-1H-pyrazole-5-amine was dissolved to 20 ml of tetrahydrofuran. 1.55 g of t-butyl nitrite was added to the solution, followed by refluxed for 3 hours. After the reaction mixture was cooled to room temperature, water was added to the reaction mixture, and extracted with diethyl ether. The organic layer was washed with water, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.94 g of 4-{[dichlorofluoromethyl]thio}-1-(4-methoxybenzyl)-1H-pyrazole.
Reaction SMILES: [OH:1][C:2]1([C:15]2[CH:24]=[C:23]([CH2:25][OH:26])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.N1C=CC=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.C(=O)(O)[O-].[Na+]>[CH:25]([C:23]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([C:2]2([OH:1])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:4][CH2:3]2)[CH:24]=1)=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc(CO)c3ccccc3c2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cc(C=O)c3ccccc3c2)CC1

Procedure:
To a solution of 1.0 g (2.8 mmol) of tert-butyl 4-hydroxy-4-[4-(hydroxymethyl)-2-naphthyl]piperidine-1-carboxylate in 10 mL of anhydrous dichloromethane under an atmosphere of nitrogen was added 0.34 mL (4.2 mmol) of pyridine then 1.9 g (4.5 mmol) of Dess-Martin periodinane and the resulting solution was stirred at ambient temperature for 2 h. The mixture was diluted with a saturated aqueous sodium bicarbonate solution (5 mL), the layers were separated and the aqueous phase extracted with dichloromethane (3×10 mL). The combined organic layers were washed with brine (25 mL), dried over magnesium sulfate, filtered and evaporated in vacuo to yield the crude title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[C:9]([NH:12][CH2:13][CH2:14][NH2:15])(=[O:11])[CH3:10].C([O-])(O)=O.[Na+]>CN(C=O)C>[C:9]([NH:12][CH2:13][CH2:14][NH:15][C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)NCCN
Reactant: Cc1ccc(Cl)nn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)NCCNc1ccc(C)nn1
Yield: 57.7 %

Procedure:
A mixture of 3-chloro-6-methylpyridazine (1.29 g, 10 mmol), N-(acetyl)ethylenediamine (638 mg, 6.25 mmol) and NaHCO3 (1.6 g) in dry DMF (10 mL) was heated at reflux under argon for 20 h. The mixture was filtered, the filtrate concentrated, and the residue was dissolved in CH2Cl2 and purified by flash chromatography (silica gel, step gradient, 0-8% CH3OH/CH2Cl2) to yield the title compound as a yellow solid (700 mg, 44%): MS (ES) m/e 195.0 [M+H]+.
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-:12])(=O)=O)=CC=1.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH:19]=[O:20].C(=O)([O-])[O-].[K+].[K+]>CO>[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19]1[O:20][CH:12]=[N:11][CH:10]=1
Reactant: O=Cc1cccs1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: c1csc(-c2cnco2)c1
Yield: 36.7 %

Procedure:
To a solution of p-toluenesulfonylmethyl isocyanide (3.0 g, 15.36 mmol) and Thiophene-2-carboxaldehyde (1.72 g, 15.36 mmol) in methanol (45 mL) under N2 is added potassium carbonate (2.12 g, 15.36 mmol). The mixture is heated to reflux for 5 hr, then cooled and concentrated in vacuum (cold water bath). The residue is partitioned between ether (100 mL) and water (100 mL). The organic layer is washed with water (100 mL), dried over magnesium sulfate and then concentrated in vacuum. The residue is purified over 35 g silica gel, eluted with ethyl acetate: heptane (1:5) to afford 5-thiophen-2-yl-oxazole (0.852 g, 37%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1.[C:16](Cl)(=[O:18])[CH3:17]>>[C:16]([C:8]1[CH:7]=[C:6]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:4][C:3]=1[O:2][CH3:1])(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C(C)c1ccc(OC)cc1
Product: CCOC(=O)C(C)c1ccc(OC)c(C(C)=O)c1

Procedure:
This compound is prepared by a Friedel-Crafts reaction between ethyl 2-(4-methoxy-phenyl)propionate and acetyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([NH2:11])[CH:6]=[CH:5][N:4]=1.[CH3:12][C:13]([CH:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)([CH3:19])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16]>>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([NH:11][C@H:23]2[CH2:22][CH2:21][C@@H:20]([C:13]([CH3:19])([CH3:12])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:25][CH2:24]2)[CH:6]=[CH:5][N:4]=1
Reactant: CC(C)(C)CC(C)(C)C1CCC(=O)CC1
Reactant: COc1nccc(N)c1OC
Product: COc1nccc(N[C@H]2CC[C@@H](C(C)(C)CC(C)(C)C)CC2)c1OC

Procedure:
As Example 75, but using 1.54 g (10 mmol) of 2,3-dimethoxy-4-aminopyridine instead of 2-ethyl-3-bromo-4-amino-pyridine and 4.2 g (20 mmol) of 4-(1,1,3,3-tetramethylbutyl)cyclohexanone instead of 4-phenylcyclohexanone.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:31])[N:5]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:6]([CH:12]([NH:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]3[C:17]=1[N:18]=[CH:19][NH:20]3)[CH2:13]C)=[N:7]2.[Cl:32]C1C=C(C=CC=1)N.NC1C=CC=CC=1.O=C1CCC(=O)N1OC(=O)C(NC(OC(C)(C)C)=O)C.O=C1CCC(=O)N1OC(=O)C(NC(OCC1C=CC=CC=1)=O)CC.C(O)(C(F)(F)F)=O.NC1N=C2C(N=CN2)=C(NC(C2N(C3C=CC=C(C)C=3)C(=O)C3C(=CC=CC=3C)N=2)C)N=1>>[Cl:32][C:29]1[CH:30]=[C:25]([N:5]2[C:4](=[O:31])[C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[CH3:1])[N:7]=[C:6]2[CH:12]([NH:15][C:16]2[N:24]=[CH:23][N:22]=[C:21]3[C:17]=2[N:18]=[CH:19][NH:20]3)[CH3:13])[CH:26]=[CH:27][CH:28]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CCC(Nc1ncnc2[nH]cnc12)c1nc2cccc(C)c2c(=O)n1-c1ccccc1
Agent: CC(NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Agent: CCC(NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Agent: Cc1cccc(-n2c(C(C)Nc3nc(N)nc4[nH]cnc34)nc3cccc(C)c3c2=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: Nc1ccccc1
Product: Cc1cccc2nc(C(C)Nc3ncnc4[nH]cnc34)n(-c3cccc(Cl)c3)c(=O)c12

Procedure:
Compound 66 was prepared using the general procedure described above with respect to compound 14, but 3-chloroaniline was substituted for aniline in step A, 2-tert-butoxycarbonylamino-propionic acid 2,5-dioxopyrrolidin-1-yl ester was substituted for 2-benzyloxycarbonylaminobutyric acid 2,5-dioxo-pyrrolidin-1-yl ester in step B, and the alternate procedure (TFA deprotection) was used in step C. 1H NMR (dmso-d6): 8.40-8.31 (m, 2H); 7.73-7.66 (m, 1H); 7.55-7.32 (m, 6H); 5.04-4.86 (m, 1H); 2.72 (s, 3H); 1.52-1.50 (m, 3H). Compound 65 is shown below.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:25][CH3:26])=[CH:20][C:21]([CH:23]=[O:24])=[CH:22][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Br:27]Br>C(O)(=O)C>[Br:27][C:22]1[C:12]2[N:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]=2[C:19]([O:25][CH3:26])=[CH:20][C:21]=1[CH:23]=[O:24]
Reactant: BrBr
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C=O)cc(OC)c21
Solvent: CC(=O)O
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(C=O)cc(OC)c21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3.0 g (8.51 mmol) of 2-(4-Isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carbaldehyde is dissolved in 90 ml acetic acid. Bromine (437 ul, 8.51 mmol) is added dropwise and the reaction is stirred for 5 h at RT. Ice/water is added and the reaction mixture is extracted with ethyl acetate (3×). The organic layer is washed with water (3×) and brine (2×), dried (Na2SO4) and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexanes/EtOAc) to give 2:08 g of colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([OH:13])=[O:12])[S:10][C:3]=12.[CH3:14][NH:15][C:16]([N:18]1[C:26]2[C:21](=[CH:22][C:23]([NH2:27])=[CH:24][CH:25]=2)[CH:20]=[C:19]1[CH3:28])=[O:17]>CS(C)=O>[CH3:28][C:19]1[N:18]([C:16](=[O:17])[NH:15][CH3:14])[C:26]2[C:21]([CH:20]=1)=[CH:22][C:23]([NH:27][C:2]1[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]([OH:13])=[O:12])[S:10][C:3]=13)=[CH:24][CH:25]=2
Reactant: CNC(=O)n1c(C)cc2cc(N)ccc21
Reactant: O=C(O)c1cc2nccc(Cl)c2s1
Solvent: CS(C)=O
Product: CNC(=O)n1c(C)cc2cc(Nc3ccnc4cc(C(=O)O)sc34)ccc21
Temperature: 75 °C
Reaction time: 14 h
Yield: 91.9 %

Procedure:
To 0.68 g (1.23 mmol) of 7-Chloro-thieno[3,2-b]pyridine-2-carboxylic acid, prepared as described in Groton patent, was added 0.25 g (1.23 mmol) of 5-Amino-2-methyl-indole-1-carboxylic acid methylamide, prepared as described in Example 1(a) steps (i) to (iii), dissolved in 3 mL of DMSO that was degassed with Ar and warmed to 75° C. The solution was stirred for 14 h, cooled to 25° C. and filtered. The precipitate was rinsed with EtOAc (2×5 mL) and put under high vacuum for 12 h to give 0.43 g (98%) of 7-(2-Methyl-1-methylcarbamoyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridine-2-carboxylic acid as yellow solid. HPLC: Rt 3.38 min. (97.2% area). 1H NMR (CDCl3, 300 MHz) δ 9.18 (1H, bs), 8.37 (1H, d, J=5.6 Hz), 8.30 (1H, q, J=3.4 Hz), 7.94 (1H, s), 7.70 (1H, d, J=8.7 Hz), 7.46 (1H, s), 7.17 (1H, dd, J=8.8, 1.9 Hz), 6.79 (1H, d, J=5.6 Hz), 6.45 (1H, s), 2.96 (3H, s), 2.94 (3H, s). LCMS (APCI) (M+H+) m/z: 381.1