Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([OH:12])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]([C:24]1[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=1)=[O:23]>CO>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH2:21][C:22](=[O:23])[C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)[CH:5]=1
Reactant: Cc1cccc(C(=O)CBr)c1
Reactant: COC(=O)c1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1ccc(OC)c(OCC(=O)c2cccc(C)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Hydroxy-4-methoxybenzoic acid methyl ester (2.50 g, 13.7 mmol) was dissolved in methanol (20 ml), potassium carbonate (3.72 g, 27.4 mmol) and 2-bromo-1-m-tolyl-ethanone (2.92 g, 13.7 mmol) were added and the mixture was stirred overnight at room temperature. The volatiles were evaporated, the crude material was partitioned between EA and water, the aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was purified by preparative RP HPLC (water/ACN gradient) to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:9]2[CH:10]=[CH:11][C:12](=O)[NH:13][CH:14]=2)=[CH:4][CH:3]=1.N1C=CC(C)=CC=1C.P(Cl)(Cl)([Cl:33])=O.[OH-].[NH4+]>>[Cl:33][C:12]1[CH:11]=[CH:10][C:9]([CH:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:14][N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ccc(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)c[nH]1
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccnc(C)c1
Product: Clc1ccc(C(c2ccc(Cl)cc2)c2ccc(Cl)nc2)cc1
Temperature: 120 °C

Procedure:
To a mixture of 35.2 g. (0.11 mole) of 5-[bis-(4-chlorophenyl)-methyl]-2-pyridone and 11.8 g. (0.11 mole) of 2,4-lutidine, add 50.6 g. (0.33 mole) of phosphorous oxychloride (dropwise) while heating the reaction mixture at 80°. Then, heat the reaction mixture at 120° C. for six hours. Pour the reaction mixture onto ice, basify with ammonium hydroxide, extract with benzene and remove both the benzene and residual 2,4-lutidine by distillation. Distill the residue at about 195°-210° C. (0.01 mm) to obtain thereby about 30 g. of the product of this step as a yellow viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=O)[NH:7][C:6]=2[CH:17]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:7][C:6]=2[CH:17]=1
Reactant: O=C1Nc2cc(Cl)ccc2Cc2ccccc21
Reactant: C1CNCCN1
Product: Clc1ccc2c(c1)N=C(N1CCNCC1)c1ccccc1C2

Procedure:
3-Chloro-5,11-dihydro-dibenzo[b,e]azepin-6-one (189JO59) (25 mg, 0.1 mmol) and piperazine were reacted according to GP4 to give 2.2 mg of the title compound (189JO60). MS (ESI) 312 (MH+). Purity for MH+ (UV/MS) 100/100.
Reaction SMILES: C([O:3][C:4](=[O:34])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23](=[O:33])[NH:24][C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([I:32])[CH:26]=4)=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)C.C(C1C=C(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=NC=2)=O)C=CC=1)(C)(C)C.CO.CN(C=O)C>C(Cl)Cl>[I:32][C:27]1[CH:26]=[C:25]([NH:24][C:23]([C:20]2[CH:21]=[CH:22][C:17]([N:14]3[CH2:13][CH2:12][N:11]([C:8]4[CH:9]=[CH:10][C:5]([C:4]([OH:34])=[O:3])=[CH:6][CH:7]=4)[CH2:16][CH2:15]3)=[N:18][CH:19]=2)=[O:33])[CH:30]=[CH:29][C:28]=1[CH3:31]
Reactant: CCOC(=O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccc(C)c(I)c4)cn3)CC2)cc1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)nc2)c1
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)nc2)cc1I

Procedure:
4-{4-[5-(3-Iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid was prepared by the hydrolysis of 4-{4-[5-(3-iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid ethyl ester with LiOH monohydrate in manner similar to the one described in the synthesis of 4-{4-[5-(3-tert-butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid, above. The product was isolated after a silica gel column chromatography with a 0-5% MeOH in CH2Cl2 to 0-100% DMF in CH2Cl2 gradient. HRMS m/z calcd for C24H23N4O3I [M+H]+: 543.0888. Found: 543.0886.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([C:17]3[C:18]4[CH:33]=[CH:32][CH:31]=[CH:30][C:19]=4[S:20][C:21]=3[C:22]3[CH:27]=[CH:26][C:25]([O:28]C)=[CH:24][CH:23]=3)=[O:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CO>C(Cl)Cl>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([C:17]3[C:18]4[CH:33]=[CH:32][CH:31]=[CH:30][C:19]=4[S:20][C:21]=3[C:22]3[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=3)=[O:16])=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(-c2sc3ccccc3c2C(=O)c2ccc(OCCN3CCCC3)nc2)cc1
Solvent: CO
Solvent: ClCCl
Product: O=C(c1ccc(OCCN2CCCC2)nc1)c1c(-c2ccc(O)cc2)sc2ccccc12
Yield: 89 %

Procedure:
By essentially following the procedures outlined in Example 1, Part D, the title compound was prepared from 2-(4-methoxyphenyl)benzo[b]thiophen-3-yl 6-[2-(1-pyrrolidinyl)ethoxy]pyrid-3-yl ketone (Part B) in 89% yield as a yellow solid following radial chromatography (SiO2, 5% MeOH in CH2Cl2).
Reaction SMILES: Cl[C:2]1[C:3]2[S:12][CH:11]=[CH:10][C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1.C(O)C.O.[NH2:17][NH2:18].ClCCl>O>[NH:17]([C:2]1[C:3]2[S:12][CH:11]=[CH:10][C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1)[NH2:18]
Reactant: NN
Reactant: CSc1nc(Cl)c2sccc2n1
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: CSc1nc(NN)c2sccc2n1
Temperature: 25 °C
Yield: 93 %

Procedure:
4-Chloro-2-methylthiothiopheno[3,2-d]pyrimidine (15.26 g, 70.4 mmol) was mixed with 400 mL of ethanol and then 7.2 mL (148 mmol) of hydrazine hydrate was added with stirring at ambient temperature and the mixture was allowed to stir overnight. The solid materials present were recovered by filtration and the filtrate was evaporated to dryness under reduced pressure to obtain additional solid material. All of the solids were combined and mixed vigorously with a mixture of 500 mL of dichloromethane and 500 mL of water for 6 hours. The solids present were recovered by filtration and dried to obtain 13.9 g of the title compound as a slightly yellow solid melting at 242°-244° C. The proton NMR spectrum was consistent with the assigned structure.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12](=[O:13])[CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[S:8][C:7]=2[CH:18]=1.[C-:19]#[N:20].[Na+]>CN(C)C=O>[C:19]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12](=[O:13])[CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[S:8][C:7]=2[CH:18]=1)#[N:20]
Reactant: O=C1Cc2ccccc2Sc2cc(CBr)ccc21
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCc1ccc2c(c1)Sc1ccccc1CC2=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Dissolve 6.4 gm. of the bromide of Step 2 in 75 cc. of dimethylformamide and add 2.95 gm. of sodium cyanide. Stir the mixture at room temperature for 1.5 hours. Dilute with 600 cc. of water and extract three times with ether. Wash the combined organics with water, dry and strip to a solid residue. Triturate in hexane and recover the solid by filtration.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([C:28]([CH2:31][CH3:32])=[CH:29][CH:30]=3)[N:12]=[C:13]([CH3:27])[C:14]=2[CH2:15][CH2:16][CH2:17][CH2:18][NH:19]C(=O)OC(C)(C)C)[CH:6]=[CH:7][CH:8]=1)#[N:2].[ClH:33]>C(OCC)(=O)C>[ClH:33].[NH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]1[C:13]([CH3:27])=[N:12][N:11]2[C:28]([CH2:31][CH3:32])=[CH:29][CH:30]=[C:10]2[C:9]=1[C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:1]#[N:2]
Reactant: CCc1ccc2c(-c3cccc(C#N)c3)c(CCCCNC(=O)OC(C)(C)C)c(C)nn12
Agent: Cl
Solvent: CCOC(C)=O
Product: CCc1ccc2c(-c3cccc(C#N)c3)c(CCCCN)c(C)nn12
Reaction time: 1 h

Procedure:
To tert-butyl 4-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]butylcarbamate (25 mg) was added 4N hydrogen chloride in ethyl acetate (1 mL) at ambient temperature. After 1 hour, the mixture was evaporated in vacuo. The residue was triturated with isopropyl ether to give 3-[3-(4-aminobutyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl]benzonitrile hydrochloride as dark green amorphous (18 mg).
Reaction SMILES: Cl.C([O:9][CH2:10][C@@H:11]1[O:20][CH2:19][C@@:18]2([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[C@H:13]([CH2:14][S:15][C:16]([NH2:28])=[N:17]2)[CH2:12]1)C1C=CC=CC=1.[OH-].[Na+]>>[NH2:28][C:16]1[S:15][CH2:14][C@H:13]2[C@:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])([CH2:19][O:20][C@@H:11]([CH2:10][OH:9])[CH2:12]2)[N:17]=1
Reactant: NC1=N[C@@]2(c3ccccc3F)CO[C@@H](COCc3ccccc3)C[C@H]2CS1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NC1=N[C@@]2(c3ccccc3F)CO[C@@H](CO)C[C@H]2CS1
Temperature: 25 °C
Yield: 92.1 %

Procedure:
Concentrated hydrochloric acid (25.2 ml) was added to (4aR,6R,8aS)-6-benzyloxymethyl-8a-(2-fluorophenyl)-4,4a,5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-ylamine (1.26 g), and the mixture was heated under reflux for two hours. After cooling the reaction solution to room temperature, the reaction mixture was poured into ice. The mixture was neutralized with 5 N sodium hydroxide, and the aqueous layer was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residual solid was washed with a mixed solvent of heptane and ether to obtain the title compound (890 mg).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([CH2:6][S:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:3]1.Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:21]>>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:20](=[O:21])[CH2:19][N:2]2[CH2:5][CH:4]([CH2:6][S:7]([C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=3)(=[O:9])=[O:8])[CH2:3]2)=[CH:23][CH:24]=1
Reactant: N#Cc1ccc(S(=O)(=O)CC2CNC2)cc1
Reactant: O=C(CBr)c1ccc(F)cc1
Agent: Cl
Product: N#Cc1ccc(S(=O)(=O)CC2CN(CC(=O)c3ccc(F)cc3)C2)cc1
Yield: 29 %

Procedure:
Following the procedure of Example 2, 4-[(azetidin-3-ylmethyl)sulfonyl]benzonitrile hydrochloride (75 mg, 0.27 mmol) was reacted with 2-bromo-1-(4-fluorophenyl)ethanone. Crude product was purified on a 10 g bond elute silica cartridge using the personal flash master eluting with 0.5% MeOH/DCM to 2% MeOH/DCM to give the freebase as a pale yellow gum (30 mg, 29%). The freebase was dissolved in 3:1 ether/MeOH (5 ml) and 1.0M hydrogen chloride in ether (89μl) was added. The side of the flask was etched and the salt precipitated and was isolated by filtration and dried under vacuum to give the title compound as a white solid (20 mg). 1H NMR (500 MHz, CDCl3) δ 3.05–3.13 (1H, m), 3.90–3.96 (2H, m), 4.03–4.12 (2H, m), 4.23–4.30 (2H, m), 5.06 (2H, s), 7.44 (2H, t, J=8.8 Hz), 8.01 (2H, dd, J=5.4 & 8.8 Hz), 8.09 (2H, d, J=8.6 Hz), 8.21 (2H, d, J=8.6 Hz), 10.62 (1H, s). m/z (ES+) 373 (M+H)+.
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([C:20]#[N:21])=[C:18]([S:22][CH2:23][C:24]3[N:25]=[C:26]([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)[S:27][CH:28]=3)[N:17]=[C:16]([NH2:36])[C:15]=2[C:37]#[N:38])[CH2:10][CH2:9]1)=[O:7])(=O)C.[OH-].[Li+]>O1CCOCC1.O>[NH2:36][C:16]1[C:15]([C:37]#[N:38])=[C:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[CH2:5][OH:4])[CH2:9][CH2:10]2)[C:19]([C:20]#[N:21])=[C:18]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:17]=1
Reactant: CC(=O)OCC(=O)N1CCC(c2c(C#N)c(N)nc(SCc3csc(-c4ccc(Cl)cc4)n3)c2C#N)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1C1CCN(C(=O)CO)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
29 mg (0.05 mmol) of the compound from Example 25A are dissolved in a mixture of 1.5 ml of dioxane and 0.8 ml of water, and 2.4 mg (0.10 mmol) of lithium hydroxide are added. The reaction mixture is stirred at RT for two hours. After removal of the solvent on a rotary evaporator the residue is purified by preparative HPLC (column: YMC GEL ODS-AQ S-5, 15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[CH:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[N:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)([CH3:14])[CH3:13].C(N(C(C)C)CC)(C)C>C(O)(C)C>[Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:27][C:24]2[CH:25]=[N:26][C:21]([N:18]3[CH2:19][CH2:20][N:15]([CH:12]([CH3:14])[CH3:13])[CH2:16][CH2:17]3)=[CH:22][CH:23]=2)=[N:4][CH:3]=1
Reactant: CC(C)N1CCN(c2ccc(N)cn2)CC1
Reactant: Brc1ncc(Br)n2ccnc12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCN(c2ccc(Nc3ncc(Br)n4ccnc34)cn2)CC1
Temperature: 90 °C
Reaction time: 48 h
Yield: 71.3 %

Procedure:
To a solution of 5,8-dibromo-imidazo[1,2-a]pyrazine (0.85 g, 3.1 mmol) in isopropanol are added 6-(4-isopropyl-piperazin-1-yl)-pyridin-3-yl-amine (0.68 g, 3.1 mmol) and diisopropylethylamine (0.6 mL, 4.6 mmol) and the mixture is stirred at 90° C. for 48 hours. The solvent is removed in vacuo and the product taken up in DCM-10% citric acid. The organic layer is discarded and the aqueous solution basified with sat. NaHCO3 (pH 7-8) and extracted using DCM. The organic layer is dried over MgSO4, filtered and concentrated in vacuo to afford the title compound as a purple solid (0.92 g, 71%). HPLC (254 nm): Rt 3.30 min (95.8%); m/z 416/418 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:20]([NH:23][S:24](Cl)(=[O:26])=[O:25])[CH2:21][CH3:22]>>[CH2:1]([NH:19][S:24]([NH:23][CH2:20][CH2:21][CH3:22])(=[O:26])=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCNS(=O)(=O)Cl
Reactant: CCCCCCCCCCCCCCCCCCN
Product: CCCCCCCCCCCCCCCCCCNS(=O)(=O)NCCC
Yield: 31 %

Procedure:
The title compound was prepared following the method described in Example 6. The starting reactants are 0.54 g (2.0 mmol) of N-octadecylamine and 0.31 g (2.0 mmol) of N-propylsulfamoyl chloride. 0.06 g of a white solid were obtained. Yield 31%; m.p. 110-112° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([O:25][CH3:26])[C:19]=2[F:27])[CH2:8]/[C:9](=[N:12]\OS(C)(=O)=O)/[C:10]=1[Cl:11])=[O:4]>C(O)(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9]([NH2:12])[CH:8]=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([O:25][CH3:26])[C:19]=2[F:27])[N:6]=1)=[O:4]
Reactant: COC(=O)C1=C(Cl)/C(=N/OS(C)(=O)=O)CC(c2ccc(Cl)c(OC)c2F)N1
Solvent: CC(=O)O
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(N)c1Cl

Procedure:
A magnetically stirred solution of 6-(4-chloro-2-fluoro-3-methoxyphenyl)-4-[(E)-methanesulfonyloximino]-3-chloro-1,4,5,6-tetrahydropyridine-2-carboxylic acid methyl ester (29, 0.441 g (0.001 mol) in glacial acetic acid (2 mL) was warmed to 90° C. for 4 h. After removing the solvent on the rotary evaporator, the residue was dissolved in CH2Cl2 (25 mL) and was washed with saturated solutions of NaHCO3 and NaCl. After drying (MgSO4), solvent removal gave 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylic acid methyl ester (39; 0.332 g, 96%; 93% pure by GC and 1H NMR spectroscopy) as a white solid: mp 141-143° C. 1H NMR (400 MHz, CDCl3) δ 7.65 (dd, J=8.6, 7.8 Hz, 1H), 7.23 (dd, J=8.7, 1.8 Hz, 1H), 7.18 (d, J=1.7 Hz, 1H), 4.85 (s, 2H), 4.00 (s, 3H), 3.97 (d, J=0.9 Hz, 3H). HRMS-ESI (m/z): calcd for C14H11Cl2FN2O3, 344.013. found, 344.013.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[C:24]1([C:34](O)=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:34]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)=[O:35])=[O:8])[N:6]=1
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: O=C(O)c1cccc2ccccc12
Product: Nc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3ccccc23)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with Naphthalene-1-carboxylic acid. LC-MS (basic): tR=0.83 min; [M+H]+=487.4.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]([NH:27][NH2:28])=[O:26])[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:37](Cl)(Cl)=[O:38]>C(Cl)Cl.C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]4[O:26][C:37](=[O:38])[NH:28][N:27]=4)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:35])([F:36])[F:34])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C(=O)NN)cc32)cc1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(-c4n[nH]c(=O)o4)cc32)cc1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
To a solution of 6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine-8-carbohydrazide (intermediate 57, 0.040 g, 0.0771 mmol) in DCM (0.2 mL) at −78° C. was added phosgene (0.081 mL of a ˜20% solution in toluene) dropwise. After stirring at −20° C. overnight, the reaction was quenched with saturated aqueous NaHCO3, and the product was extracted with EtOAc and DCM. The combined extracts were washed with brine, dried (MgSO4) and concentrated. The residue was purified via SiO2 column chromatography, eluting with mixtures of EtOAc and hexane, to afford the title compound. LC/MS: m/e 546.1 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 7.96 (1H, d, J=6.4 Hz), 7.62 (11-1, d, J=8.4 Hz), 7.54 (1H, d, J=7.8 Hz), 7.29 (1H, d, J=5.5 Hz), 7.03-7.04 (3H, m), 6.86-6.89 (3H, m), 4.50-4.90 (2H, br), 1.14 (9H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:10](=[O:23])[CH:11]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:12][C:13]=2[O:14][CH3:15])=[C:4]([CH3:24])[CH:3]=1.[CH2:25]([Sn](CCCC)(CCCC)C#CC)[CH2:26][CH2:27]C>C1(C)C=CC=CC=1.O>[CH3:8][C:6]1[CH:7]=[C:2]([C:25]#[C:26][CH3:27])[CH:3]=[C:4]([CH3:24])[C:5]=1[C:9]1[C:10](=[O:23])[CH:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:12][C:13]=1[O:14][CH3:15]
Reactant: COC1=C(c2c(C)cc(Br)cc2C)C(=O)C(Cc2ccccn2)C1
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Solvent: O
Solvent: Cc1ccccc1
Product: CC#Cc1cc(C)c(C2=C(OC)CC(Cc3ccccn3)C2=O)c(C)c1
Temperature: 130 °C

Procedure:
To a degassed solution of rac-2-(4-bromo-2,6-dimethylphenyl)-3-methoxy-5-pyridin-2-ylmethylcyclopent-2-enone (1.0 g, 2.5 mmol) in toluene (10 ml) is added tributyl(1-propynyl)tin (1.55 ml, 5.18 mmol) and tetrakistriphenylphosphine palladium(0) (0.5 g, 0.5 mmol) under a nitrogen atmosphere. The reaction mixture is heated at 130°C. for 40 minutes under microwave irradiation, then diluted with distilled water (20 ml) and extracted with ethyl acetate (50 ml×2). The combined organic fractions are washed with distilled water, brine, dried over sodium sulfate, filtered and the filtrate concentrated in vacuo to afford rac-2-(2,6-dimethyl-4-prop-1-ynylphenyl)-3-methoxy-5-pyridin-2-ylmethylcyclopent-2-enone. This material is used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:4][C:3]=1[C:11]([OH:13])=O.CN1CCCCC1.Cl.[CH3:22][NH:23][O:24][CH3:25].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:22][N:23]([O:24][CH3:25])[C:11]([C:3]1[CH:4]=[C:5]([S:7](=[O:9])(=[O:8])[NH2:10])[S:6][C:2]=1[Cl:1])=[O:13]
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(Cl)s1
Reactant: CNOC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CN1CCCCC1
Product: CON(C)C(=O)c1cc(S(N)(=O)=O)sc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 40.4 %

Procedure:
1,1-Carbonyldiimidazole (7.70 g, 0.047 mol) was added portionwise to a solution of 5-chloro-4-carboxythiophene-2-sulfonamide (7.25 g, 0.03 mol) in DMF (60 mL). After two hours, N-methylpiperidine (6.0 mL, 0.05 mol) and N,O-dimethylhydroxylamine hydrochloride (5.2 g, 0.05 mol) were added to the reaction mixture. After an additional four hours at room temperature, the reaction mixture was poured into ice/water saturated with NaHCO3. The crude product was extracted into ethyl acetate, the extract was dried (anhydrous Na2SO4), filtered and evaporated. The crude residue was chromatographed on silica gel and eluted with 59% methanol/methylene chloride to give 3.45 g (40%) of white solid product, mp 223°-225° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[S:16])[NH:11][CH2:12][C:13](N)=[O:14].[CH2:17](I)[CH3:18]>>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]1[C:13](=[O:14])[CH2:12][N:11]=[C:10]1[S:16][CH2:17][CH3:18]
Reactant: NC(=O)CNC(=S)Nc1c(Cl)cccc1Cl
Reactant: CCI
Product: CCSC1=NCC(=O)N1c1c(Cl)cccc1Cl
Yield: 44.3 %

Procedure:
The title compound was prepared by the procedure described in Example 2 using 27.8 g of 2-[3-(2,6-dichlorophenyl)-thioureido]-acetamide and 31.2 g of ethyl iodide. 12.8 g of the title compound was obtained, m.p. 122°-124° C. Anal. Calcd. for. C11H10Cl2N2O S: C, 45.69; H, 3.49; N, 9.69. Found: C, 45.62; H, 3.33; N, 9.43. Mass spectrum (+FAB, [M+H]+) m/z 289/291/293. 1H-NMR (DMSO-d6 ; 400 MHz) δ7.72 (s, 1H), 7.70 (s, 1H), 7.58 (t, 1H), 4.50 (s, 2H), 3.10 (q, 2H), and 1.27 ppm (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](O)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.S(Cl)([Cl:36])=O.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20]([Cl:36])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)O)c3)n2)n1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
To a suspension of 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonic acid (example 345) (2.0 g, 4.25 mmol) in DMF (20 mL) at 23° C. was added thionyl chloride (1.54 mL, 21.25 mmol) and the mixture was stirred at 23° C. for 2 h, then added again SOCl2 (1.54 mL, 21.25 mmol) and the mixture was stirred at 23° C. for 1 h. Diluted with EtOAc, poured into ice cold half-sat. NaHCO3-sol., separated phases, washed organic layer with brine and dried over Na2SO4. Removal of the solvent in vacuum left the title compound as an off-white solid (2.0 g, 98%), which was used without further purification. MS (ISP) 489.2 [(M+H)+] and 491.1 [(M+2+H)+].