Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:7][C:8]([CH3:28])=[C:9]([C:24]([O:26][CH3:27])=[O:25])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[C:29](N1C=CN=C1)([N:31]1[CH:35]=[CH:34][N:33]=[CH:32]1)=[O:30].CN1CCOCC1>O1CCCC1>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:10]1[C:9]([C:24]([O:26][CH3:27])=[O:25])=[C:8]([CH3:28])[NH:7][C:6]([CH2:5][O:4][CH2:3][CH2:2][NH:1][C:29]([N:31]2[CH:35]=[CH:34][N:33]=[CH:32]2)=[O:30])=[C:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCOC(=O)C1=C(COCCNC(=O)n2ccnc2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Yield: 66.2 %

Procedure:
A solution of 2-(2-aminoethoxy)methyl-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (20.4 g), carbonyldiimidazole (8.9 g) and N-methylmorpholine (20 ml) in tetrahydrofuran (500 ml) was stirred at room temperature for 2 hours and then evaporated. The residue was partitioned between ethyl acetate and water and the organic layer washed with water, dried (Na2SO4), and evaporated. The residual solid was washed with diethyl ether and dried to give the title compound (16.6 g), m.p. 149°-151° C. Found: C,57.35; H,5.54; N,11.22. C24H27ClN4O6 requires: C,57.54; H,5.43; N,11.18%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)([O-:3])=[O:2].[I-].C[N+:16](C)(C)N.CC(C)([O-])C.[K+].[Cl-].[NH4+]>CS(C)=O>[N+:1]([C:4]1[C:5]([NH2:16])=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc2cccnc12
Reactant: C[N+](C)(C)N
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CS(C)=O
Product: Nc1ccc2cccnc2c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.9 %

Procedure:
To a solution of 8-nitroquinoline (1.88 g, 10 mmol) and 1,1,1-trimethylhydrazinium iodide (3.03 g, 15 mmol) in anhydrous dimethyl sulfoxide (DMSO) (20 mL) was added potassium tert-butoxide (3.36 g, 30 mmol) as a solid. The mixture was stirred at room temperature for 1 h. The mixture was then poured into saturated aqueous ammonium chloride and extracted with EtOAc. The organic layers were concentrated and the residue was purified by silica gel column chromatography (eluting with PE/EtOAc v/v 2:1) to give 8-nitroquinolin-7-amine as a yellow solid (300 mg, yield 18%). ESI MS: m/z 189 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 8.93 (dd, 1H, 1J=3.2 Hz, 2J=1.6 Hz), 8.00 (dd, 1H, 1J=6.4 Hz, 2J=1.6 Hz), 7.69 (d, 1H, J=6.8 Hz), 7.29 (dd, 1H, 1J=6.0 Hz, 2J=3.2 Hz), 7.00 (d, 1H, J=7.2 Hz), 5.60 (s, 2H).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>N1C=CC=CC=1>[CH3:19][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:1][CH2:2][C@@H:3]2[CH2:4][CH2:5][C:6](=[O:8])[O:7]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CC[C@@H](CO)O1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCC(=O)O2)cc1

Procedure:
A mixture of (S)-5-(hydroxymethyl)dihydrofuran-2(3H)-one, para-toluenesulfonyl chloride and pyridine were processed using the method described in Example 162A to afford the title compound MS (ESI) m/z 288 (M+18)+.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Cl)=[CH:33][CH:32]=1>>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:35][C:34]3[CH:37]=[CH:38][C:31]([O:30][CH3:29])=[CH:32][CH:33]=3)[CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CCl)cc1
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(Cl)cc2)c2cc[nH]c2c(=O)n1C
Product: COc1ccc(Cn2ccc3c(-c4ccc(Cl)cc4)c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c32)cc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 2 from methyl 2-(tert-butoxy)-2-(4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate and 4-methoxybenzyl chloride. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.57-7.64 (m, 1H) 7.43-7.49 (m, 2H) 7.37-7.43 (m, 1H) 7.24-7.29 (m, 2H) 6.99-7.06 (m, 1H) 6.83-6.90 (m, 2H) 5.93-6.00 (m, 1H) 5.70-5.83 (m, 2H) 5.30-5.36 (m, 1H) 3.79 (s, 3H) 3.68 (s, 3H) 1.01 (s, 9H); LCMS (m/z) ES+=509 (M+1).
Reaction SMILES: [I-].[I-].[CH3:3][N+:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([O:12][C:13]2[CH:30]=[CH:29][C:28]3[C@@H:27]4[C@H:18]([C@H:19]5[C@@:23]([CH2:25][CH2:26]4)([CH3:24])[C@@H:22]([O:31][C:32]([C:34]4[CH:35]=[N+:36]([CH3:40])[CH:37]=[CH:38][CH:39]=4)=[O:33])[CH2:21][CH2:20]5)[CH2:17][CH2:16][C:15]=3[CH:14]=2)=[O:11])[CH:5]=1.C1(CN2C=CC(C(N)=O)=CC2)C=CC=CC=1>C(#N)C.C(Cl)Cl>[CH3:3][N:4]1[CH:9]=[CH:8][CH2:7][C:6]([C:10]([O:12][C:13]2[CH:30]=[CH:29][C:28]3[C@@H:27]4[C@H:18]([C@H:19]5[C@@:23]([CH2:25][CH2:26]4)([CH3:24])[C@@H:22]([O:31][C:32]([C:34]4[CH2:39][CH:38]=[CH:37][N:36]([CH3:40])[CH:35]=4)=[O:33])[CH2:21][CH2:20]5)[CH2:17][CH2:16][C:15]=3[CH:14]=2)=[O:11])=[CH:5]1
Reactant: C[n+]1cccc(C(=O)Oc2ccc3c(c2)CC[C@@H]2[C@@H]3CC[C@]3(C)[C@@H](OC(=O)c4ccc[n+](C)c4)CC[C@@H]23)c1
Agent: NC(=O)C1=CCN(Cc2ccccc2)C=C1
Agent: [I-]
Solvent: CC#N
Solvent: ClCCl
Product: CN1C=CCC(C(=O)Oc2ccc3c(c2)CC[C@@H]2[C@@H]3CC[C@]3(C)[C@@H](OC(=O)C4=CN(C)C=CC4)CC[C@@H]23)=C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
One gram (1.31 mmol) of the product of Example 71 was dissolved in 100 mL of dry acetonitrile. To that solution, which was flushed with nitrogen, 0.28 g (1.31 mmol) of 1-(phenylmethyl)-4-(aminocarbonyl)-1,2-dihydropyridine was added, and the reaction mixture was stirred at 0° C. for 1 hour. Removal of the solvent under reduced pressure afforded a solid, which was suspended in methylene chloride and removed by filtration. The filtrate was chromatographed several times on a neutral alumina column prepared with methylene chloride. Purification and evaporation of the solvent in vacuo gave a solid foam. The product had the formula ##STR107## as confirmed by UV, NMR and elemental analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:17][NH:18][C:19]([NH:21][C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[C:24]([N+:32]([O-:34])=[O:33])[CH:23]=3)=[S:20])[CH3:16])[C:10]=2[OH:35])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+].Cl.O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:17][NH:18][C:19]([NH:21][C:22]3[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[C:24]([N+:32]([O-:34])=[O:33])[CH:23]=3)=[S:20])[CH3:16])[C:10]=2[OH:35])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1ccc(NC(=S)NN=C(C)c2nn(C)c(-c3ccc(Cl)c(Cl)c3)c2O)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)c([N+](=O)[O-])c1)c1nn(C)c(-c2ccc(Cl)c(Cl)c2)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.2 %

Procedure:
Methyl 4-{[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethylidene}hydrazino)-carbonothioyl]amino}-2-nitrobenzoate (100 mg, 0.19 mmol) synthesized in Synthetic Example 104 was dissolved in methanol (3 ml), and 1 M sodium hydroxide aqueous solution (0.74 ml, 0.74 mmol) was added thereto, following by stirring overnight at room temperature. After completion of the stirring, 1 M hydrochloric acid (0.74 ml, 0.74 mmol) and water were added thereto. The precipitated solid was recovered by filtration, washed with water, isopropyl alcohol, and chloroform. The obtained solid was stirred in chloroform, and then filtered to obtain 37 mg of the desired product as a yellow solid (yield 48%).
Reaction SMILES: C1(C#CC2CC3(CCNCC3)ON=2)C=CC=CC=1.[Cl:19][C:20]1[CH:21]=[C:22]([C:26]#[C:27][C:28]2[CH2:32][C:31]3([CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33]3)[O:30][N:29]=2)[CH:23]=[CH:24][CH:25]=1>>[Cl:19][C:20]1[CH:21]=[C:22]([C:26]#[C:27][C:28]2[CH2:32][C:31]3([CH2:36][CH2:35][NH:34][CH2:33]3)[O:30][N:29]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC(C#Cc3cccc(Cl)c3)=NO2)C1
Agent: C(#Cc1ccccc1)C1=NOC2(CCNCC2)C1
Product: Clc1cccc(C#CC2=NOC3(CCNC3)C2)c1

Procedure:
The title compound was synthesized following the method reported for the Compound 1c, substituting Compound 1b with Compound 27c. The crude residue was used without further purification in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:27][C:28]1([C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)[CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[OH-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:12][CH:13]([O:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:20][CH:21]=3)[CH2:14]2)=[C:6]([CH:10]=1)[C:7]([NH:27][C:28]1([C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)[CH2:30][CH2:29]1)=[O:9]
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: O=C(O)c1cc(Cl)cnc1N1CC(Oc2ccc(C(F)(F)F)cc2)C1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Oc4ccc(C(F)(F)F)cc4)C3)CC2)cc1
Temperature: 110 °C
Reaction time: 0.08 h
Yield: 48.4 %

Procedure:
To a mixture of 5-chloro-2-(3-(4-(trifluoromethyl)phenoxy)azetidin-1-yl)nicotinic acid (D104) (200 mg, 0.53 mmol), methyl 4-(1-aminocyclopropyl)benzoate (D7) (144.31 mg, 0.634 mmol) and N,N-diisopropylethylamine (0.291 ml, 1.674 mmol) in dichloromethane (8 ml), ®T3P (1-Propanephosphonic acid cyclic anhydride) (403 mg, 0.633 mmol) was added and the mixture stirred under microwave irradiation at 110° C. for 10 min (2 cycle of 5 min each). 1M NaOH (5 ml) was added and the mixture extracted with dichloromethane (3×20 ml). Collected organics, after solvent evaporation, afforded a crude material that was purified by SPE-Si cartridge (10 g) eluting with a mixture cyclohexane/ethyl acetate from 100/0 to 60/40. Collected fractions, after solvent evaporation, afforded the title compound (D148) (140 mg)
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][N:4]1[C:8]2[NH:9][C:10](=[S:14])[NH:11][C:12](=[O:13])[C:7]=2[CH:6]=[N:5]1.[CH3:21]I>C1COCC1>[OH:1][CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][N:4]1[C:8]2[N:9]=[C:10]([S:14][CH3:21])[NH:11][C:12](=[O:13])[C:7]=2[CH:6]=[N:5]1
Reactant: CI
Reactant: O=c1[nH]c(=S)[nH]c2c1cnn2CC(O)c1ccccc1
Solvent: C1CCOC1
Product: CSc1nc2c(cnn2CC(O)c2ccccc2)c(=O)[nH]1
Yield: 71.8 %

Procedure:
A solution of 7 (2.88 g, 10 mmol) and methyl iodide (7.10 g, 50 mmol) in anhydrous THF (20 mL) was refluxed for 12 h. The solvent and the excess of methyl iodide were removed by distillation under reduced pressure; the oil residue crystallized by adding CHCl3 (10 mL) and was purified by recrystallization with absolute ethanol to give 8a (2.17 g, 72%) as a white solid; mp 208-209° C. 1H NMR: δ 2.51 (s, 3H, CH3), 4.27-4.50 (m, 2H, CH2N), 5.04-5.18 (m, 1H, CHO), 5.68 (d, 1H, OH, disappears with D2O), 7.20-7.42 (m, 5H Ar), 7.97 (s, 1H, H-3). IR cm−1: 3544 (NH), 3450-3350 (OH), 1678 (CO). Anal. (C14H14N4O2S) C, H, N, S.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.Br[C:18]1[N:22]2[N:23]=[CH:24][C:25]([C:27]([OH:30])([CH3:29])[CH3:28])=[N:26][C:21]2=[N:20][CH:19]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:18]2[N:22]3[N:23]=[CH:24][C:25]([C:27]([OH:30])([CH3:28])[CH3:29])=[N:26][C:21]3=[N:20][CH:19]=2)=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(F)c(-c2ccncc2)c1
Reactant: CC(C)(O)c1cnn2c(Br)cnc2n1
Product: CC(C)(O)c1cnn2c(-c3ccc(F)c(-c4ccncc4)c3)cnc2n1

Procedure:
4-Fluoro-3-(pyridin-4-yl)benzeneboronic acid was coupled with 2-(7-bromoimidazo[1,2-b][1,2,4]triazin-3-yl)propan-2-ol in 80% yield by a similar procedure to that described in Example 3, step f, to afford the title compound as a yellow solid: mp 233-237° C. (CH2Cl2-EtOAc-MeOH); 1H NMR (400 MHz, DMSO-d6) δ 1.57 (6H, s), 5.78 (1H, s), 7.60 (1H, dd, J 11.0, 8.6 Hz), 7.68-7.70 (2H, m), 8.27 (1H, m), 8.35 (1H, dd, J 7.4, 2.3 Hz), 8.53 (1H, s), 8.73 (2H, m), 9.04 (1H, s); MS (ES+) m/z 350 [M+H]+. Anal. Found: C, 64.87; H, 4.58; N, 19.79%. Required for C19H16FN5O.0.1H2O: C, 64.98; H, 4.65; N, 19.94%.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[N:11][CH:10]=[C:9]3[S:13][C:14](/[CH:16]=[CH:17]/[C:18](O)=[O:19])=[CH:15][C:8]=23)=[CH:4][CH:3]=1.O.O[N:25]1C2C=CC=CC=2N=N1.CN1CCOCC1.[NH4+].[Cl-].C(Cl)CCl>CN(C=O)C.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[N:11][CH:10]=[C:9]3[S:13][C:14](/[CH:16]=[CH:17]/[C:18]([NH2:25])=[O:19])=[CH:15][C:8]=23)=[CH:4][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)/C=C/c1cc2c(Oc3ccc(Cl)cc3)cncc2s1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: NC(=O)/C=C/c1cc2c(Oc3ccc(Cl)cc3)cncc2s1
Temperature: 0 °C
Reaction time: 10 h

Procedure:
A solution of Example 91C (51.5 mg, 0.155 mmol), N-hydroxybenzotriazole monohydrate (34.5 mg, 0.225 mmol), 4-methylmorpholine (47 mg, 0.464 mmol) and NH4Cl (31.6 mg, 0.591 mmol) in DMF (1 mL) at 0° C. was treated with EDC (45.0 mg, 0.235 mmol), stirred at 0° C. for 4 hours and at room temperature for 10 hours, treated with chloroform (5 mL), washed sequentially with 1M NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 5% methanol/dichloromethane to provide the title compound.
Reaction SMILES: [CH2:1]([C@@:3]12[CH2:27][CH2:26][C@@:25]([C:29]([F:32])([F:31])[F:30])([OH:28])[CH2:24][C@H:4]1[CH2:5][CH2:6][CH2:7][C:8]1[C:9]2=[CH:10][C:11]2[CH:12]=[N:13][N:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=3)[C:15]=2[CH:16]=1)[CH3:2].[CH3:33][S-:34].[Na+]>CN(C)C(=O)C>[CH2:1]([C@@:3]12[CH2:27][CH2:26][C@@:25]([C:29]([F:32])([F:31])[F:30])([OH:28])[CH2:24][C@H:4]1[CH2:5][CH2:6][CH2:7][C:8]1[C:9]2=[CH:10][C:11]2[CH:12]=[N:13][N:14]([C:17]3[CH:22]=[CH:21][C:20]([S:34][CH3:33])=[CH:19][CH:18]=3)[C:15]=2[CH:16]=1)[CH3:2]
Reactant: C[S-]
Reactant: CC[C@@]12CC[C@](O)(C(F)(F)F)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC[C@@]12CC[C@](O)(C(F)(F)F)C[C@H]1CCCc1cc3c(cnn3-c3ccc(SC)cc3)cc12

Procedure:
(3R,4aR,12bR)-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol (11, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.240 g, 0.538 mmol), sodium methanethiolate (0.188 g, 2.69 mmol) and N,N-dimethylacetamide (12 mL) were heated via microwave at about 90° C. for about 1 h. The reaction mixture was purified without manipulation in two portions by preparative reverse phase HPLC using a Hypersil HS C18 column (250 mm×21.2 mm, 8 μm particle size) with a gradient of 50-100% MeCN in 0.05 N aq. ammonium acetate pH 4.5 buffer. Product fractions were concentrated under reduced pressure then basified with sat. NaHCO3 then extracted with EtOAc. The organic solution was dried over MgSO4, filtered and concentrated under reduced pressure to yield (3R,4aR,12bR)-12b-ethyl-9-(4-(methylthio)phenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol (11, R1=4-(Methylthio)phenyl, R2=Ethyl, R3=Trifluoromethyl) (0.230 g, 90%); LC/MS, method 3, Rt=2.90 min, MS m/z 475 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.24 (d, J=1.3 Hz, 1H), 7.83 (s, 1H), 7.75-7.68 (m, 2H), 7.57 (s, 1H), 7.48-7.42 (m, 2H), 5.84 (s, 1H), 3.23-3.19 (m, 1H), 2.95-2.90 (m, 1H), 2.54 (s, 3H), 2.27-2.18 (m, 1H), 2.15-1.95 (m, 4H), 1.91-1.76 (m, 2H), 1.70-1.57 (m, 5H), 1.38-1.29 (m, 1H), 0.43 (t, J=7.3 Hz, 3H).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[C:6]([C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[N:11]([CH3:14])[CH:12]=[O:13])(=[O:8])[CH3:7].O>ClCCl>[Cl:4][CH2:7][C:6]([C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[N:11]([CH3:14])[CH:12]=[O:13])=[O:8]
Reactant: CC(=O)c1ccccc1N(C)C=O
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CN(C=O)c1ccccc1C(=O)CCl
Reaction time: 2 h

Procedure:
A solution of sulphuryl chloride (119 ml) in dichloromethane (168 ml) was added dropwise to the o solution of 2'-acetyl-N-methylformanilide at 0° under a nitrogen atmosphere. The mixture was stirred for 2 hours at 0° and then cold (5°) water (488 ml) was added dropwise over a period of 1 hour. The dichloromethane layer was separated and dried over magnesium sulphate to give a solution of 2'-(2-chloroacetyl)-N-methylformanilide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([C:11]2[C:20]3[O:19][CH2:18][C:17](=[O:21])[N:16]([CH3:22])[C:15]=3[CH:14]=[CH:13][CH:12]=2)=[O:10])=[C:4]([Cl:24])[CH:3]=1.[F:25][C:26]([Si](C)(C)C)([F:28])[F:27].[F-].C[N+](C)(C)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([C:11]2[C:20]3[O:19][CH2:18][C:17](=[O:21])[N:16]([CH3:22])[C:15]=3[CH:14]=[CH:13][CH:12]=2)([OH:10])[C:26]([F:28])([F:27])[F:25])=[C:4]([Cl:24])[CH:3]=1
Reactant: CC(C(=O)c1cccc2c1OCC(=O)N2C)c1ccc(Br)cc1Cl
Reactant: C[Si](C)(C)C(F)(F)F
Agent: C[N+](C)(C)C
Agent: [F-]
Product: CC(c1ccc(Br)cc1Cl)C(O)(c1cccc2c1OCC(=O)N2C)C(F)(F)F

Procedure:
In analogy to Example 1, step 3, 8-[2-(4-bromo-2-chloro-phenyl)-propionyl]-4-methyl-4H-benzo[1,4]oxazin-3-one was reacted with (trifluoromethyl)trimethylsilane and tetramethylammonium fluoride to give the title compound as a colorless foam. MS (m/e, ISP neg. ion)=476 [M−H+].
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:19][O:20][CH2:21]Cl>ClCCl>[CH3:19][O:20][CH2:21][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: COCCl
Reactant: O=Cc1ccc(O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1ccc(C=O)cc1
Temperature: 0 °C
Yield: 105.7 %

Procedure:
A solution of 4-hydroxybenzaldehyde (118.20 g, 0.968 mol) in dichloromethane (1.1 L) was stirred mechanically and cooled to 0° C., under argon. N,N-diisopropylethylamine (337.2 ml) was added to the reaction, and the mixture was stirred until homogenous. Chloromethyl methyl ether (101.30 g, 1.94 mol) was added dropwise, maintaining reaction temperature below 10° C. After the addition, the solution was warmed to room temperature, then stirred for 1 hour. The reaction was quenched with water (500 ml), and the aqueous phase was separated from the organic phase. The organic layer was washed with water, 5% glacial acetic acid, and saturated aqueous NaCl. The solution was dried with sodium sulfate, filtered, and rotary evaporated, yielding 170 g of pure product.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].[C:6]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)(=[O:8])[CH3:7].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:6]([N:9]1[CH2:14][CH2:13][N:12]([S:1]([Cl:5])(=[O:3])=[O:2])[CH2:11][CH2:10]1)(=[O:8])[CH3:7]
Reactant: CC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(S(=O)(=O)Cl)CC1
Reaction time: 6 h

Procedure:
A solution of sulfuryl chloride (3.55 ml) in chloroform (45 ml) was added a solution of 1-acetylpiperazine (5.66 mg) and triethylamine (6.16 ml) in chloroform (15 ml) dropwise under cooling on an ice-water bath. After stirring for 6 hours, a precipitate was collected by filtration. After drying over sodium hydroxide, 1-acetylpiperazine-4-sulfonyl chloride (2.43 g) was obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[N:6][OH:7])[NH2:5].[H-].[Na+].[N+:10]([C:13]1[CH:14]=[C:15]([CH:34]=[C:35]([N+:37]([O-:39])=[O:38])[CH:36]=1)[CH2:16][N:17]1[C:29]2[CH:28]=[N:27][C:26]([C:30](OC)=O)=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)([O-:12])=[O:11]>O1CCCC1>[N+:10]([C:13]1[CH:14]=[C:15]([CH:34]=[C:35]([N+:37]([O-:39])=[O:38])[CH:36]=1)[CH2:16][N:17]1[C:29]2[CH:28]=[N:27][C:26]([C:30]3[O:7][N:6]=[C:4]([CH2:3][O:2][CH3:1])[N:5]=3)=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)([O-:12])=[O:11]
Reactant: COC(=O)c1cc2c3ccccc3n(Cc3cc([N+](=O)[O-])cc([N+](=O)[O-])c3)c2cn1
Reactant: COCC(N)=NO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1noc(-c2cc3c4ccccc4n(Cc4cc([N+](=O)[O-])cc([N+](=O)[O-])c4)c3cn2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.4 %

Procedure:
A suspension of 2-methoxyacetamidoxime (260 mg, 2.5 mmol) and 4 Å molecular sieves (1 g) in anhydrous tetrahydrofuran (15 mL) was stirred at room temperature for 0.5 hours, then treated with sodium hydride (2.75 mmol, 110 mg of 60% mineral oil suspension). The mixture was heated at reflux for 1 hour. After cooling to room temperature, a suspension of methyl 9-(3,5-dinitrobenzyl)-9H-β-carboline-3-carboxylate (205 mg, 0.5 mmol) in anhydrous tetrahydrofuran (10 mL) was added. The resulting mixture was heated at reflux for 15 hours, cooled, filtered, and the filtrate concentrated in vacuo. The residue was purified by preparative thin layer chromatography with 4% 2M NH3—CH3OH in CH2Cl2 as eluent to afford the desired product (86 mg, 38% yield) as a white solid. 1H NMR (DMSO-d6) δ9.41 (s, 1H), 9.24 (s, 1H), 8.72 (t, J=1.9 Hz, 1H), 8.59 (d, J=7.8, 1H), 8.49 (d, J=1.9 Hz, 2H), 7.94 (d, J=8.3 Hz, 1H), 7.73 (t, J=7.8Hz, 1H), 7.45 (t, J=7.5 Hz, 1H), 6.20 (s, 2H), 4.67 (s, 2H), 3.42 (s, 3H); MS (APCI; (M+H)+) m/z 461.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[N:9]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][C:11]=2[C:19]([F:22])([F:21])[F:20])[C:8]2[CH:23]=[CH:24][CH:25]=[CH:26][C:7]=2[N:6]=1)[CH3:3].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:58][C:59]1[CH:70]=[CH:69][C:62]2[NH:63][C:64]([C@@H:66]([NH2:68])[CH3:67])=[N:65][C:61]=2[CH:60]=1.ClCl>CS(C)=O.ClCCl.CO>[Cl:58][C:59]1[CH:70]=[CH:69][C:62]2[NH:63][C:64]([C@@H:66]([NH:68][C:14](=[O:16])[C:13]3[CH:17]=[CH:18][C:10]([N:9]4[C:8]5[CH:23]=[CH:24][CH:25]=[CH:26][C:7]=5[N:6]=[C:5]4[CH2:4][N:2]([CH3:3])[CH3:1])=[C:11]([C:19]([F:20])([F:22])[F:21])[CH:12]=3)[CH3:67])=[N:65][C:61]=2[CH:60]=1
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: CN(C)Cc1nc2ccccc2n1-c1ccc(C(=O)O)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)c1ccc(-n2c(CN(C)C)nc3ccccc32)c(C(F)(F)F)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 26 %

Procedure:
Prepared analogously to Example 1g from 4-(2-dimethylaminomethylbenzimidazol-1-yl)-3-trifluoromethylbenzoic acid, TBTU, diisopropylethylamine, and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in dimethylsulfoxide. Yield: 26%; Rf value: 0.25 (silica gel: dichloromethane/methanol=10:1); C27H24ClF3N6O (540.975); mass spectrum: (M+H)+=541/543 (chlorine isotope).
Reaction SMILES: C(O)C.[OH-].[K+].[CH2:6]([C:10]1[N:11]([CH2:18][C:19]2[CH:27]=[CH:26][C:25]3[C:21](=[CH:22][N:23]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([O:36]CC)=[O:35])[N:24]=3)[CH:20]=2)[C:12]([CH2:16][OH:17])=[C:13]([Cl:15])[N:14]=1)[CH2:7][CH2:8][CH3:9]>O>[CH2:6]([C:10]1[N:11]([CH2:18][C:19]2[CH:27]=[CH:26][C:25]3[C:21](=[CH:22][N:23]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([OH:36])=[O:35])[N:24]=3)[CH:20]=2)[C:12]([CH2:16][OH:17])=[C:13]([Cl:15])[N:14]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc2nn(-c3ccccc3C(=O)OCC)cc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc2nn(-c3ccccc3C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.3 %

Procedure:
Ethanol (1.5 ml), ion-exchanged water (0.3 ml), and potassium hydroxide (42 mg) were added to 2-butyl-4-chloro-1-[2-(2-ethoxycarbonylphenyl)-2H-indazol-5-yl]methyl-5-(hydroxymethyl)-1H-imidazole (116 mg, 0.248 mmol) as obtained in Example 3, and the mixture was stirred at room temperature for 1.5 hours. The mixture was concentrated in an evaporator, and partitioned by ion-exchanged water (2.5 ml) and diethyl ether (5 ml). The water layer was separated and conc. hydrochloric acid was dropwise added thereto to adjust its pH to 2. The resultant solid was filtered off and washed three times with ion-exchanged water (1 ml). The solid was dried in vacuo at 37° C. overnight to give 58 mg of 2-butyl-4-chloro-1-[2-(2-carboxyphenyl)-2H-indazol-5-yl]methyl-5-(hydroxymethyl)-1H-imidazole.