Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][CH:5]=[C:4]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[C:15]([OH:17])=O)[CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[F:33][C:34]([F:38])([F:37])[CH2:35][NH2:36]>ClCCl>[Cl:1][C:2]1[N:7]=[N:6][CH:5]=[C:4]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[C:15]([NH:36][CH2:35][C:34]([F:38])([F:37])[F:33])=[O:17])[CH:3]=1
Reactant: NCC(F)(F)F
Reactant: O=C(O)[C@@H]1CCCC[C@@H]1Nc1cnnc(Cl)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(NCC(F)(F)F)[C@@H]1CCCC[C@@H]1Nc1cnnc(Cl)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
(Cis)-2-[(6-chloropyridazin-4-yl)amino]cyclohexanecarboxylic acid I-22b (2.2 g, 8.60 mmol), HOBT (2.64 g, 17.21 mmol), EDC (3.30 g, 17.21 mmol) and trifluoroethyl amine hydrochloride (2.332 g, 17.21 mmol) were added to DCM (30.0 ml) followed by the addition of TEA (6.00 ml, 43.0 mmol). The slurry was allowed to stir at RT for 17 hr. The reaction was diluted with dichloromethane washed with sat. sodium bicarb., brine dried with sodium sulfate and concentrated to an oil. Purification on Biotage Normal Phase system (DCMeOH, 0-8% B) afforded the product I-22 as a solid. (1.56 g, 51.2%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH:19]([OH:22])[CH:20]=[CH2:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>N1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH:19]([O:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH2:21])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CC(O)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: C=CC(OC(=O)c1ccccc1)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 10.0 g of 1-(1-benzenesulfonyl-1H-indol-2-yl)-allyl alcohol (32 mmol) in 100 ml of pyridine were added dropwise 5,6 ml benzoyl chloride (48 mmol) at 10° C. The mixture was stirred for an additional 1 h at 20° C. Most of the pyridine was distilled off, the residue was given in portions to 300 ml of ice water. The pH was adjusted to 2-3 with conc. HCl. The water was distilled off and the residue was dissolved in 100 ml of diethyl ether. After about 1 h the product crystallized. The suspension was stirred in an ice bath for 2 h, the solid was filtered off. The crude material was recrystallized from 90 ml methanol and dried 12 h at 35° C.
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:12](Cl)(=O)=O>Cl.O.C(O)(=O)C>[Br:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[SH:12]
Reactant: Cc1cc(C(=O)O)cc(S(=O)(=O)Cl)c1Br
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(C(=O)O)cc(S)c1Br
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A solution of stannous chloride (196 g, 0.86 mol) in concentrated hydrochloric acid (250 mL) and water (55 mL) was added to a stirred suspension of compound of Example 1c (68 g, 0.217 mol) in acetic acid (580 mL) at 80° C., over a period of 20 min. The reaction mixture was stirred at 80° C. for 4 h. The reaction mixture was cooled, poured into water (500 mL) with stirring and digested at 80° C. for 30 min. The solid was filtered, washed with water till filtrate was neutral and dried to obtain the title compound. Yield: 48 g (90%); 1H NMR (DMSO-d6, 300 MHz): δ 2.40 (s, 3H, CH3), 7.70 (s, 1H, Ar), 7.84 (s, 1H, Ar); MS: m/e (ES−) 491 (M−1).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C@H:6]1[NH:14][C:15]1[C:20]([CH2:21][CH3:22])=[N:19][C:18]([C:23]2[CH:28]=[CH:27][C:26](Cl)=[CH:25][C:24]=2[Cl:30])=[C:17]([CH2:31][CH3:32])[N:16]=1)(=[O:3])[CH3:2].ClC1C=[C:38]([O:40]C)C=CC=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC>>[C:1]([O:4][C@H:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C@H:6]1[NH:14][C:15]1[C:20]([CH2:21][CH3:22])=[N:19][C:18]([C:23]2[CH:28]=[CH:27][C:26]([O:40][CH3:38])=[CH:25][C:24]=2[Cl:30])=[C:17]([CH2:31][CH3:32])[N:16]=1)(=[O:3])[CH3:2]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1OC(C)=O
Reactant: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1OC(C)=O

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-yl acetate but substituting (1R,2S)-1-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a light yellow semi-solid. IR (diffuse reflectance) 2969, 2933, 1742, 1604, 1568, 1551, 1482, 1439, 1393, 1372, 1286, 1232, 1204, 1176, 1037 cm−1; OAMS supporting ions at: ESI+ 465.2; MS (EI) m/z 465 (M+); [α]25D=79 (c 0.80, methylene chloride); Anal. Calcd for C26H28ClN3O3: C, 67.02; H, 6.06; N, 9.02. Found: C, 66.99; H, 6.18; N, 8.92.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:19])=[CH:5][C:6]2[NH:10][C:9](=[O:11])[N:8]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:7]=2[CH:18]=1.[O:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1.[BH3-]C#N.[Na+]>CO>[Cl:2][C:3]1[C:4]([F:19])=[CH:5][C:6]2[NH:10][C:9](=[O:11])[N:8]([CH:12]3[CH2:13][CH2:14][N:15]([CH:23]4[CH2:24][CH2:25][O:20][CH2:21][CH2:22]4)[CH2:16][CH2:17]3)[C:7]=2[CH:18]=1
Reactant: O=c1[nH]c2cc(F)c(Cl)cc2n1C1CCNCC1
Reactant: O=C1CCOCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=c1[nH]c2cc(F)c(Cl)cc2n1C1CCN(C2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6-Chloro-5-fluoro-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (D5) (0.286 mmol, 77 mg), Ti(iPrO)4 (2 eq., 0.572 mmol, 0.170 ml), tetrahydro-4H-pyran-4-one (2 eq., 0.572 mmol, 0.053 ml) were stirred together at room temperature for one hour; dry methanol (2 ml) followed by NaBH3CN (2 eq., 0.572 mmol, 36 mgs) were added and the mixture was stirred under argon at room temperature for 3 hours. The crude mixture was subsequently quenched with water (5 ml) and it was firstly purified by SCX followed by chromatography (methanol-NH3-dichloromethane) to yield 6-chloro-5-fluoro-1-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one, 15 mg, 13%, M++H=353, which was converted into the hydrochloride salt using 1M HCl in diethyl ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][NH:8][C:9]2[C:10]([N+:27]([O-])=O)=[C:11]([CH:24]=[CH:25][CH:26]=2)[NH:12][CH:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][C:15]([OH:17])=[O:16])=[CH:5][CH:4]=1.O.NN>C(O)C.[Ni]>[NH2:27][C:10]1[C:9]([NH:8][CH2:7][C:6]2[CH:30]=[CH:31][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:26][CH:25]=[CH:24][C:11]=1[NH:12][CH:13]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:14][C:15]([OH:17])=[O:16]
Reactant: COc1ccc(CNc2cccc(NC(CC(=O)O)c3ccccc3)c2[N+](=O)[O-])cc1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(CNc2cccc(NC(CC(=O)O)c3ccccc3)c2N)cc1
Temperature: 25 °C
Reaction time: 0.6 h

Procedure:
To a solution of 3-{3-[(4-methoxybenzyl)amino]-2-nitroanilino}-3-phenylpropanoic acid (176 mg, 418 μmol) in ethanol (6 mL) was added Raney-nickel (Aldrich22, 167-8, catalytic, ca. 5 mg) and hydrazine hydrate (200 μL, 4.12 mmol). The resulting suspension was stirred at room temperature for 0.6 hour. The suspension was filtered through Celite®, and the pad washed with ethanol. The combined filtrates were evaporated in vacuo, and the residue purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (19:1) to afford the title compound, 1H NMR: (CD3OD), 7.76-7.74 (m, 1H), 7.66-7.61 (m, 1H), 7.41-7.20 (m, 7H), 6.91-6.87 (m, 2H), 6.50-6.46 (m, 1H), 6.23-6.21 (m, 1H), 6.07-6.05 (m, 1H), 4.81 (br t, J=6.59, 1H), 4.27-4.24 (m, 3H), 3.80 (s, 3H), 2.90 (dd, J=15.38, 8.79, 1H), 2.76 (dd, J=15.38, 9.89, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C@H:7]([C:12]2[CH:17]=[CH:16][C:15]([O:18]CC3C=C(C4C=CC(C(F)(F)F)=CC=4)C=CC=3)=[CH:14][CH:13]=2)[CH2:8][C:9]([OH:11])=[O:10])=[N:5][CH:4]=[N:3]1.[CH3:36]COC(C)=O>>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([C@@H:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][N:5]=2)[CH2:8][C:9]([O:11][CH3:36])=[O:10])=[CH:13][CH:14]=1
Reactant: CCOC(C)=O
Reactant: Cn1ncnc1[C@@H](CC(=O)O)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Product: COC(=O)C[C@@H](c1ccc(O)cc1)c1ncnn1C
Reaction time: 8 h

Procedure:
Methyltriazole M13.6 (2.78 g, 5.61 mmol) was dissolved in 50 mL of EtOAc, and nitrogen was bubbled through the solution for 5 minutes. 1 g of palladium on carbon (5 wt. %, wet contains 50% water) was added, and a hydrogen balloon was attached. After 8 hours, the mixture was filtered through a plug of silica with 10% MeOH in EtOAc. The organic layer was concentrated under reduced pressure and partitioned between ACN (100 mL) and hexane (50 mL). The ACN layer was washed with hexane (4×50 mL). The ACN layer was concentrated under reduced pressure to afford (S)-methyl 3-(4-hydroxyphenyl)-3-(2-methyl-2H-1,2,4-triazol-3-yl)propanoate M13 (1.30 g, 4.99 mmol) as a colorless oil. MS ESI (pos.) m/e: 262.4 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([F:11])[C:3]=1[F:12].[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:13]([O:20][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([F:11])[C:3]=1[F:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)c(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.5 %

Procedure:
1,2,3-Trifluoro-4-nitrobenzene (30 g, 0.17 mol), benzyl alcohol (18.4 g, 0.17 mol) and K2CO3 (35 g, 0.25 mol) were combined in DMF (300 mL) and were stirred at RT for 8 h. Water (300 mL) was added, and the mixture was extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine, dried (MgSO4), concentrated in vacuo and purified by column chromatography on silica gel to give 1-benzyloxy-2,3-difluoro-4-nitrobenzene (16 g, 36% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.06 (m, 1H), 7.49-7.30 (m, 6H), 5.37 (s, 2H).
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:11][CH2:12][C:6]=2[C:5]([OH:19])=[CH:4][CH:3]=1.S(Cl)([Cl:23])(=O)=O>C1(C)C=CC=CC=1.C(NC(C)C)(C)C>[Cl:23][C:4]1[CH:3]=[C:2]([F:1])[C:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:18])[C:14]([F:16])([F:17])[F:15])[CH2:11][CH2:12][C:6]=2[C:5]=1[OH:19]
Reactant: O=C(N1CCc2c(O)ccc(F)c2CC1)C(F)(F)F
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(C)NC(C)C
Solvent: Cc1ccccc1
Product: O=C(N1CCc2c(F)cc(Cl)c(O)c2CC1)C(F)(F)F
Temperature: 60 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
Dissolve 9-fluoro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.0 g, 3.6 mmol) in toluene (36 mL) with diisopropylamine (41 μL, 0.29 mmol). Warm to 60° C. and add dropwise a solution of sulfuryl chloride (0.32 mL, 3.97 mmol) in toluene (10 mL). After 2 h, wash the mixture with brine, dry the organic layer over Na2SO4 and evaporate onto silica gel. Purify by chromatography on silica gel eluting with EtOAc/hexane (0:1 to 1:0) to obtain the desired intermediate (1.0 g, 92%). MS (ES+) m/z: 312 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]([OH:14])=O.[CH2:15]([O:17][C:18](=[O:34])[CH2:19][CH:20]([N:24]1[C:32]2[C:27](=[CH:28][C:29]([NH2:33])=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)[CH2:21][CH2:22][CH3:23])[CH3:16].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:15]([O:17][C:18](=[O:34])[CH2:19][CH:20]([N:24]1[C:32]2[C:27](=[CH:28][C:29]([NH:33][C:12](=[O:14])[CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[CH2:6][CH2:7][CH2:8][NH:9][C:10]=4[N:1]=3)=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)[CH2:21][CH2:22][CH3:23])[CH3:16]
Reactant: O=C(O)Cc1ccc2c(n1)NCCC2
Reactant: CCCC(CC(=O)OCC)n1ccc2cc(N)ccc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(CC(=O)OCC)n1ccc2cc(NC(=O)Cc3ccc4c(n3)NCCC4)ccc21
Yield: 68.6 %

Procedure:
A solution of (5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-acetic acid (0.2 g, 0.65 mmol), 3-(5-amino-indol-1-yl)-hexanoic acid ethyl ester (0.19 g, 0.71 mmol), BOP (0.35 g, 0.78 mmol), and diisopropylethylamine (0.45 mL, 2.6 mmol) in DMF (2.5 mL) was stirred for 16 h. Solvents were evaporated. The resulting residue was partitioned between H2O and EtOAc. The aqueous layer was separated and extracted once more with EtOAc. The extracts were combined, washed with H2O, brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel, eluting with EtOAc/DCM (15, 30, 50, and 80%) to give the title compound (0.20 g, 67% yield) as a brown oil. Mass spectrum (LCMS, ESI) calculated for C26H33N4O3 449.3 (M+H); found 449.3.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[S:25]1[CH:29]=[CH:28][C:27]([C:30](Cl)=[O:31])=[CH:26]1>>[S:25]1[CH:29]=[CH:28][C:27]([C:30]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:31])=[CH:26]1
Reactant: Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1
Reactant: O=C(Cl)c1ccsc1
Product: O=C(Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1)c1ccsc1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.009 mL (0.061 mMol) 3-thiophenecarbonyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:12]([OH:21])[CH:11]=2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.I[CH2:30][CH3:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:12]([O:21][CH2:30][CH3:31])[CH:11]=2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1O
Reactant: CCI
Product: CCOc1cc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)ccc1CS(C)(=O)=O
Yield: 41.2 %

Procedure:
N-(4-Chloro-3-(pyridin-2-yl)phenyl)-3-hydroxy-4-(methylsulfonylmethyl)benzamide (50 mg, 0.12 mmol) was treated with iodoethane (10 μl, 0.12 mmol) via procedure U to yield 22 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-3-ethoxy-4-(methylsulfonylmethyl)benzamide. MS (Q1) 445 (M)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][NH:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:11][N:12]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CNCCC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CCN(C)c1ccc([N+](=O)[O-])cn1

Procedure:
2-Chloro-5-nitropyridine (158 mg, 1 mmol), N-methylisoamylamine (101 mg, 1 mmol), and finely ground potassium carbonate (419 mg, 3 mmol) were heated to 80° C. in 10 mL anhydrous DMF for 3.5 hrs. The mixture was diluted with EtOAc, extracted with H2O and dried over MgSO4. The EtOAc layer was filtered, evaporated to dryness to yield 220 mg. ES-MS calcd for C11H17N3O2 (m/e) 223.28, obsd 224.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[OH:21][CH:22]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)[CH3:23]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:28][C:27]2[CH:29]=[CH:30][C:24]([CH:22]([OH:21])[CH3:23])=[CH:25][CH:26]=2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CC(O)c1ccc(N)cc1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CC(O)c1ccc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)cc1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and 4-(1-hydroxyethyl)aniline (53 mg, 0.39 mmol). The title compound was obtained as a solid (50 mg, 33% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.50 (1H, s), 9.00 (2H, s), 8.72 (1H, m), 7.56 (2H, dd), 7.32 (2H, dd), 5.10 (1H, m), 4.68 (1H, m), 1.31 (3H, s). MS m/z: 468.10, 470.10 [M+H]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[C:26]([C:27]2[CH:28]=[C:29]([CH:35]=[CH:36][CH:37]=2)[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:25][C:10]2[C:11]([C:21](=[O:24])[NH:22][CH3:23])=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[O:13][C:9]=2[CH:8]=1>N1C=CC=CC=1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[O:13][C:9]3[CH:8]=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[C:26]([C:27]4[CH:28]=[C:29]([CH:35]=[CH:36][CH:37]=4)[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:25][C:10]=3[C:11]=2[C:21](=[O:24])[NH:22][CH3:23])=[CH:15][CH:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1cccc(-c2cc3c(C(=O)NC)c(-c4ccc(F)cc4)oc3cc2N)c1
Solvent: c1ccncc1
Product: CCOC(=O)c1cccc(-c2cc3c(C(=O)NC)c(-c4ccc(F)cc4)oc3cc2NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
Methanesulfonyl chloride (303 μL, 3.88 mmol) was added to a stirring solution of ethyl 3-(6-amino-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoate (1.40 g, 3.24 mmol) in pyridine (32 mL) at 25° C. It was allowed to stir overnight at rt. The reaction was concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the titled compound (1.01 g, 61%). LC-MS retention time: 1.53 min; m/z (MH+): 511. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:10][C:9]2[S:11][CH:12]=[CH:13][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[Cl:14]N1C(=O)CCC1=O>C(O)(=O)C.C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[NH:10][C:9]2[S:11][C:12]([Cl:14])=[CH:13][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccsc2[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc2cc(Cl)sc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
Using a modified procedure by R. M. Kellogg et al. (J. Org. Chem., 33: 2902-290 (1968)), to a 0° C. solution of 6H-thieno[2,3-b]pyrrole-5-carboxylic acid ethyl ester (Eras, J.; Galvez, C.; Garcia, F., J. Heterocycl. Chem., 21: 215-217 (1984); 1.45 g, 7.44 mmol) in acetic acid (15 mL) and CHCl3 (15 mL) was added N-chlorosuccinimide (1.04 g, 7.81 mmol) over 2 h. The reaction mixture was slowly allowed to warm to room temperature over several hours, stirred overnight, concentrated to remove the chloroform, diluted with water, basified with 5 N NaOH, and extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous NaHCO3, dried over MgSO4, and concentrated. The product was purified by chromatron chromatography (radial) using 90:10 hexanes/diethyl ether and then then then the product obtained was recrystallized using hexanes/diethyl ether (90:10). Last, the product of the recrystallization was further purified by flash column chromatography using 90:10 petroleum ether/isopropyl ether. The resulting product was obtained as a white solid (824 mg, 48%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>CC(C)=O>[CH3:24][S:25]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[CH:4][CH:3]=1)(=[O:27])=[O:26]
Reactant: Nc1ccc(-c2nc(C(F)(F)F)c[nH]2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc(-c2nc(C(F)(F)F)c[nH]2)cc1
Reaction time: 20 h

Procedure:
To a solution of 2-(p-aminophenyl)-4-trifluoromethylimidazole (3.0 g.) in acetone (50 ml.) and triethylamine (2.7 g.) is added methanesulfonyl chloride (1.5 g.). After refluxing for four hours, a second portion of methanesulfonyl chloride (1.5 g.) is added. Reflux is continued 20 hours, a third portion of methanesulfonyl chloride (1.5 g.) is added and reflux continued another four hours. The reaction mixture is filtered and concentrated to an oil which, upon trituration with water, affords a solid. After chromatography on silica gel and recrystallization from a mixture of acetonitrile and water 1.3 g. of 2-(p-methylsulfonamidophenyl)-4-trifluoromethylimidazole, m.p. 253°-255° C. is obtained.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[S:10][C:9]([S:11](Cl)(=[O:13])=[O:12])=[CH:8][CH:7]=2)=[N:2]1.[NH2:15][C:16]1[CH:17]=[C:18]([C:22]2[NH:26][N:25]=[N:24][N:23]=2)[CH:19]=[CH:20][CH:21]=1.C(O)(C(F)(F)F)=O>O>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[S:10][C:9]([S:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4[NH:26][N:25]=[N:24][N:23]=4)[CH:17]=3)(=[O:13])=[O:12])=[CH:8][CH:7]=2)=[N:2]1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccon2)s1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(-c2ccon2)s1
Yield: 54 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, with 5-isoxazol-3-ylthiophene-2-sulfonyl chloride (13.7 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8.0 mg, 0.050 mmol) and with a slightly modified purification method using 0.1% TFA in water as buffet. The title compound was obtained in 54% yield (11.1 mg). MS (ESI+) calcd mass for C14H10N6O3S2 374.025580, found 374.025400.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[ClH:11].[CH2:12]([OH:14])[CH3:13]>>[ClH:11].[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7](=[NH:8])[O:14][CH2:12][CH3:13])=[CH:5][CH:4]=1
Reactant: COc1ccc(C#N)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A cold solution (0° C.) of 4-methoxybenzonitrile (1.29 g, 9.59 mmol) in ethanol (30 mL) was saturated with dry HCl(g). The mixture was then stirred at room temperature for 2 days, after which FT-IR showed complete disappearance of the nitrile. The solution was concentrated to dryness, and further dried in vacuo. The ethyl 4-methoxybenzimidate hydrochloride thus obtained was used in the synthesis of compounds 152, 153 and 154.