Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14][C@H:15]1[O:20][C@:16]1([CH3:19])[CH2:17][OH:18].[H][H]>CO.O.[Ni]>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14][CH2:15][C@:16]([CH3:19])([OH:20])[CH2:17][OH:18]
Reactant: COc1c(C)c(C)c(OC)c(C[C@H]2O[C@]2(C)CO)c1C
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Solvent: O
Product: COc1c(C)c(C)c(OC)c(CC[C@](C)(O)CO)c1C
Yield: 86.4 %

Procedure:
185 mg of (2R,3R)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2,3-epoxy-2-methylbutanol are dissolved in 5 ml of methanol and the solution is subsequently diluted with 5 ml of water. Thereupon, Raney-nickel is added and the mixture is heated at reflux under hydrogen for 2 hours. After the hydrogen uptake has finished the mixture is filtered, the filter residue is washed with methanol and methylene chloride and the combined filtrate and washings are concentrated on a rotary evaporator. Residual water is distilled off azeotropically by the addition of methylene chloride. The oil obtained is recrystallized from n-hexane/diethyl ether and there are obtained 161 mg of 55% (S)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-methyl-1,2-butanediol (48% yield; GC analysis of the acetonide). Data of the pure substance: M.p. 86°-87° C.; [α]D20 +2.55° (c=5.3% in CHCl3).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[Cl:27])=[CH:14][CH:15]=1)=O)C.[NH2:28][C:29]1[N:34]=[CH:33][C:32]([CH2:35][N:36]([CH3:42])[CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])=[CH:31][CH:30]=1.C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[CH3:40][N:39]([CH3:41])[CH2:38][CH2:37][N:36]([CH2:35][C:32]1[CH:31]=[CH:30][C:29]([NH:28][C:4]([C:6]2[C:7]3[N:8]=[CH:9][CH:10]=[N:11][C:12]=3[C:13]([C:16]3[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=3[Cl:27])=[CH:14][CH:15]=2)=[O:3])=[N:34][CH:33]=1)[CH3:42]
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2Cl)c2nccnc12
Reactant: CN(C)CCN(C)Cc1ccc(N)nc1
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN(C)CCN(C)C)cn3)c3nccnc23)c1F
Temperature: 80 °C
Reaction time: 5 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 144.1), N-(6-amino-pyridin-3-ylmethyl)-N,N′,N′-trimethyl-ethane-1,2-diamine (prepared as described in Example 26 but using N,N,N′-trimethyl-ethane-1,2-diamine in Step 26.2 and purified by column chromatography), 2 equiv of trimethyl aluminum, stirring the reaction mixture for 5 h at 80° C., pouring it onto a saturated aqueous solution of NaHCO3 and DCM. The title compound: ESI-MS: 553.1 [M+H]+; tR=3.43 min (System 1); TLC: Rf=0.06 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:22]([CH3:34])[CH:21]=3)([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:11]=2)[CH:6]=1)=[O:4].[OH-].[Na+]>C1COCC1.CO>[CH3:32][C:29]([CH3:30])([CH3:31])[C:28](=[O:33])[CH2:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:15]([C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:14]=[CH:13]3)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:21][C:22]=1[CH3:34]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)OC)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)O)ccc2c1
Temperature: 55 °C
Yield: 87.6 %

Procedure:
Treat a solution of 6-{1-[4-(3,3-Dimethyl-2-oxobutoxy)-3-methylphenyl]-1-ethylpropyl}-naphthalene-2-carboxylic acid methyl ester (0.53 g, 1.15 mmol) in THF (8 mL) and MeOH (16 mL) with 2N NaOH (2.9 mL, 5.8 mmol) and heat at 55° C. for 16 h. Concentrate the reaction mixture. Dilute the residue with in EtOAc (50 mL) and water (25 mL) and acidify the resulting mixture to pH 1 using 1N HCl. Discard the aqueous layer and wash the organic layer with brine, Dry the organic layer over Na2SO4, filter, and concentrate the filtrate to give the title compound as a yellow solid (0.45 g, 87%). MS (ES) m/e 447 (M+1).
Reaction SMILES: [C:1]([C:5]1[C:10]2[O:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([C:16]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>C1(C)C=CC=CC=1>[C:1]([C:5]1[C:10]2[O:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([C:16]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)=[S:32])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C(=O)c2ccco2)cc2c1OCC2(C)C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(C(=S)c2ccco2)cc2c1OCC2(C)C
Yield: 159.6 %

Procedure:
7-tert-Butyl-2,3-dihydro-3,3-dimethyl-5-(2-furoyl)benzo[b]furan (600 mg, 2 mmol) and Lawesson's reagent (404 mg, 1 mmol) in dry toluene (10 mL) is refluxed in an argon atmosphere. The mixture is cooled and the toluene evaporated. The resulting solid was purified by flash chromatography on silica gel to give 502 mg (80%) of the title compound as a yellowish crystals.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2[OH:21])=[N:5][C:6]([CH2:9]C)=[CH:7][N:8]=1)[CH3:2].Cl[C:23]1C(C2CC2)=NC=C(C)N=1>>[CH:1]1([C:3]2[C:4]([NH:11][C@@H:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:14][C@@H:13]3[OH:21])=[N:5][C:6]([CH3:9])=[CH:7][N:8]=2)[CH2:2][CH2:23]1
Reactant: Cc1cnc(C2CC2)c(Cl)n1
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: Cc1cnc(C2CC2)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3-chloro-2-cyclopropyl-5-methylpyrazine and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.92-1.01, 1.25, 1.76, 2.36, 3.08, 3.24, 4.80, 5.38, 5.59, 7.22-7.49, 7.64; MS (ESI+) for C17H19N3O m/z 282 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:25])[C:12]([S:15]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][CH:23]=2)(=[O:17])=[O:16])([CH3:14])[CH3:13])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[NH:32]1[CH2:35][CH2:34][CH2:33]1>O1CCOCC1>[N:32]1([C:21]2[N:20]=[CH:19][C:18]([S:15]([C:12]([CH3:14])([CH3:13])[C:11]([NH:10][C:7]3[S:8][CH:9]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[N:6]=3)=[O:25])(=[O:17])=[O:16])=[CH:23][CH:22]=2)[CH2:35][CH2:34][CH2:33]1
Reactant: CC(C)(C)c1csc(NC(=O)C(C)(C)S(=O)(=O)c2ccc(Cl)nc2)n1
Reactant: C1CNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)c1csc(NC(=O)C(C)(C)S(=O)(=O)c2ccc(N3CCC3)nc2)n1
Temperature: 70 °C
Yield: 79.3 %

Procedure:
To a solution of 79 mg (0.20 mmol) of N-(4-tert-butyl-thiazol-2-yl)-2-(6-chloro-pyridine-3-sulfonyl)-2-methyl-propionamide (example 265, Table 19) and 57.5 mg (0.42 mmol) of potassium carbonate in dioxane (2 mL) were added 27 μL (0.4 mmol) of azetidine. The reaction was heated in a sealed tube to 70° C. for 3 h. The solids were removed by filtration and rinsed with dioxane (5 mL). The filtrate was concentrated under reduced pressure and the residue purified by column chromatography (silica, eluent DCM, 5-10% ethyl acetate) to afford 67 mg of 2-(6-azetidin-1-yl-pyridine-3-sulfonyl)-N-(4-tert-butyl-thiazol-2-yl)-2-methyl-propionamide.
Reaction SMILES: C([O:8][C:9](=[O:25])[CH2:10][C:11]1[C:15]([NH:16][C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:24])=[CH:14][S:13][CH:12]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[Cl:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([Cl:23])[C:17]=1[NH:16][C:15]1[C:11]([CH2:10][C:9]([OH:25])=[O:8])=[CH:12][S:13][CH:14]=1
Reactant: O=C(Cc1cscc1Nc1c(Cl)cccc1Cl)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(O)Cc1cscc1Nc1c(Cl)cccc1Cl

Procedure:
393 mg (1 mmole) of 4-(2,6-dichloroanilino)-3-thiophenacetic acid benzyl ester are subjected to hydrogenolysis (in a mixture of 100 ml of ethyl acetate and 10 ml of glacial acetic acid in a circulatory hydrogenation apparatus in the presence of 50 mg of 10 percent strength palladium-on-active charcoal at room temperature and under atmospheric pressure) until the theoretical amount of hydrogen has been taken up. The catalyst is filtered off, the filtrate is concentrated in vacuo, and the residue is dissolved in 1 N sodium hydroxide solution. The aqueous solution is extracted with toluene, and the product phase is acidified with 1 N hydrochloric acid and extracted again with toluene. The organic phase is dried and concentrated. 4-(2,6-Dichloroanilino)-3-thiophenacetic acid (m. 179° to 180°) is obtained.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([NH2:10])[S:8][CH:9]=1)[CH2:2][CH2:3][CH3:4].[Cl:11][C:12]1[C:13]([CH3:22])=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1>>[CH2:1]([C:5]1[N:6]=[C:7]([NH:10][S:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([Cl:11])[C:13]=2[CH3:22])(=[O:19])=[O:20])[S:8][CH:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: CCCCc1csc(N)n1
Product: CCCCc1csc(NS(=O)(=O)c2cccc(Cl)c2C)n1
Yield: 22 %

Procedure:
The title compound was prepared from 4-butyl-1,3-thiazol-2-ylamine (METHOD H) and 3-chloro-2-methylbenzenesulfonyl chloride according to METHOD A, yellow solid, 52 mg (22% yield): HRMS Calcd (found) for C14H17ClN2O2S2 m/z 344.0420 (334.0414).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>C1(C)C=CC=CC=1>[CH:11](=[N:5][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=1[F:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccc(F)cc1F
Reactant: O=Cc1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1ccc(CN=Cc2ccccc2)c(F)c1

Procedure:
50.2 g (0.35 mol) of 2,4-difluorobenzylamine and 37.1 g (0.35 mol) of benzaldehyde are dissolved in 140 ml of toluene and heated to reflux. The water produced is separated off using a water separator. The reaction is complete (GC check) after two hours. The solution is evaporated on a vacuum rotary evaporator. 78.9 g (97% of theory) of a slightly yellow liquid are obtained.
Reaction SMILES: [C:1](PCC1C(CPC(C)(C)C)=CC=CC=1)(C)(C)C.CS(O)(=O)=O.[C:24]([O-:44])(=[O:43])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34][C@@H:35]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[OH:36]>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:43][C:24](=[O:44])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34][C@@H:35]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[OH:36]
Reactant: CC(C)(C)PCc1ccccc1CPC(C)(C)C
Reactant: CCCCCC[C@@H](O)C/C=C\CCCCCCCC(=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CS(=O)(=O)O
Product: CCCCCC[C@@H](O)C/C=C\CCCCCCCC(=O)OC
Temperature: 25 °C

Procedure:
Pd(OAc)2 (0.45 mg, 0.002 mmol) and α,α′-di-tert-butylphosphino-o-xylene (4 mg, 0.01 mmol) were dissolved in 4 mL of either one of the solvents of Table 5. Subsequently, methanesulfonic acid (1.3 μL, 0.02 mmol) and ricinoleate (1 mmol, 338 μL) were added. The reaction was allowed to proceed at the temperature and time as indicated in Table 5. The reaction mixtures were cooled down to room temperature and analyzed by means of GC. The results are summarized in Table 5.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6]([CH2:11]Cl)[CH:5]=1)[CH3:2].[P:13]([O-:22])([O:19][CH2:20][CH3:21])([S:15][CH2:16][CH2:17][CH3:18])=[S:14].[K+].[I-].[Na+]>CC(C)=O>[P:13]([S:15][CH2:16][CH2:17][CH3:18])([O:19][CH2:20][CH3:21])([S:14][CH2:11][C:6]1[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[N:9]=[C:8]([CH3:10])[N:7]=1)=[O:22]
Reactant: CCCSP([O-])(=S)OCC
Reactant: CCOc1cc(CCl)nc(C)n1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCSP(=O)(OCC)SCc1cc(OCC)nc(C)n1
Temperature: 45 °C
Reaction time: 12 h

Procedure:
8.0 g (0.043 mol) of 6-ethoxy-4-chloromethyl-2-methyl-pyrimidine and 10.8 g (0.045 mol) of potassium O-ethyl S-(n-propyl) dithiophosphate are suspended in 20 ml of acetone. After the addition of a small amount (spatula tip) of sodium iodide the mixture is stirred well at 45° C. for 12 hours. The mixture is then filtered through Celite, the filtrate is concentrated under reduced pressure and the thus-isolated solid is taken up in 100 ml of toluene. The toluene solution is washed once with 5% sodium carbonate solution and once with saturated sodium chloride solution and dried over anhydrous sodium sulphate, and the solvent is removed by evaporation at 60° C. under reduced pressure. In this manner there is obtained O-ethyl S-(6-ethoxy-2-methyl-4-pyrimidinylmethyl) S-(n-propyl) dithiophosphate as an almost colourless oil, nD20 1.5385.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH2:3][CH2:2]1.Cl[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][C:22]=1[O:30][CH3:31].C(#N)C>O>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([CH:4]2[CH2:3][CH2:2][N:1]([CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][C:22]=3[O:30][CH3:31])[CH2:6][CH2:5]2)=[N:8]1
Reactant: c1ccc2c(C3CCNCC3)n[nH]c2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Solvent: O
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(c2n[nH]c3ccccc23)CC1
Yield: 83.4 %

Procedure:
A mixture of 3-(4-piperidinyl)-1H-indazole (3.0 g, 15 mmol), K2 CO3 (1.6 g), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.3 g, 22 mmol), a few crystals of KI and acetonitrile (100 ml) was stirred and refluxed for 16 hours. The reaction was poured into water and a white solid separated from solution. The solid was collected, dried and afforded 5.1 g of product. Recrystallization from ethanol yielded 3.6 g of the compound, which upon chromatography (preparative HPLC on silica gel, eluting with methylene chloride/methanol--9:1) gave 3.0 g (49%) of an off-white solid. Recrystallization from ethanol afforded the analytically pure 1-[4-[3-[4-(1H-indazol-1 3-yl)-1-piperidinyl]-propoxy]-3-methoxyphenyl]ethanone as a white solid, m.p.=171°-173° C.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([C:9]([O:11][CH3:12])=[O:10])=[CH:6][NH:7][CH:8]=1)[CH2:2][CH3:3].[Br:13]N1C(=O)CCC1=O>N1C=CC=CC=1>[Br:13][C:8]1[NH:7][CH:6]=[C:5]([C:9]([O:11][CH3:12])=[O:10])[C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: CCCc1c[nH]cc1C(=O)OC
Reactant: O=C1CCC(=O)N1Br
Solvent: c1ccncc1
Product: CCCc1c(C(=O)OC)c[nH]c1Br
Yield: 71.8 %

Procedure:
Using methyl 4-propyl-1H-pyrrole-3-carboxylate (2.8 g), N-bromosuccinimide (3.0 g) and pyridine (0.5 mL), a procedure as in Reference Example 40 was performed to give the title compound as colorless crystals (yield 2.96 g, 72%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:18])[CH3:17])=[CH:8][N:7]=1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:27])C=1.C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:18])[CH3:17])=[CH:8][N+:7]=1[O-:27])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCOc1ccc(COC(C)=O)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OCCOc1ccc(COC(C)=O)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.74 g of the crude product from example 25A is dissolved in 3.4 ml of dry dichloromethane, and 0.74 g (3.21 mmol) of meta-chloroperbenzoic acid is added a little at a time. The reaction mixture is stirred at RT for 8 h, and 2 ml of saturated aqueous sodium bicarbonate solution are then added. With stirring, more sodium bicarbonate powder (about 0.4 g) is added until the evolution of gas has ceased. The aqueous phase is extracted twice with in each case 5 ml of dichloromethane, and the combined organic phases are dried over magnesium sulphate. After removal of the solvent on a rotary evaporator, the crude product that remains is used directly for the subsequent reaction.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.[H-].[Na+].[OH-].[Na+]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)[CH:7]=1
Reactant: Clc1cccnc1Cl
Reactant: c1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Clc1cncc(-n2cccc2)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 3.5 dichloropyridine (10.0 g, 67.6 mmol), pyrrole (5.50 g, 81.1 mmol), sodium hydride 60% (3.52 g, 87.9 mmol) and dimethyl sulfoxide (50 ml) was stirred at 70° C. for 2 h. Aqueous sodium hydroxide (200 ml, 1 M) was added and the mixture was extracted three times with diethyl ether (100 ml). The mixture was evaporated and, purified by chromatography on silica gel with dichloromethane and ethanol (4%) as solvent. Yield 6.3 g, 52%. Mp 70.5-72.0° C.
Reaction SMILES: [C:1]1([C:7]2([C:10]([OH:12])=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:15])=O>>[C:1]1([C:7]2([C:10]([Cl:15])=[O:12])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1(c2ccccc2)CC1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C1(c2ccccc2)CC1
Temperature: 80 °C

Procedure:
1-Phenyl-cyclopropanecarboxylic acid (0.5 g, 3.1 mmol), was dissolved in thionyl chloride (10 eq, 0.031 mol, 3.68 g, 2.3 ml), and refluxed at 80° C. for 1.5 hours. Then excess of thionyl chloride was evaporated on the rotary evaporator which yielded a dark-yellowish liquid (1-phenyl-cyclopropanecarbonyl chloride A), which was then cooled to 0° C., under argon.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[CH3:6][C@H:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:13]=2[O:17][CH2:18][CH2:19][CH3:20])[N:8]1[C:27](=[O:29])[CH3:28].C(N(CC)CC)C>ClCCl>[C:27]([N:8]1[C:9]2[C:14](=[C:13]([O:17][CH2:18][CH2:19][CH3:20])[C:12]([CH:21]3[CH2:26][CH2:25][N:24]([C:2]([O:4][CH3:5])=[O:3])[CH2:23][CH2:22]3)=[CH:11][CH:10]=2)[CH2:15][CH2:16][C@@H:7]1[CH3:6])(=[O:29])[CH3:28]
Reactant: CCCOc1c(C2CCNCC2)ccc2c1CC[C@H](C)N2C(C)=O
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOc1c(C2CCN(C(=O)OC)CC2)ccc2c1CC[C@H](C)N2C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
Methyl chloroformate (5 μL, 0.06 mmol) was added to a solution of (S)-1-(2-methyl-6-(piperidin-4-yl)-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone (20 mg, 0.05 mmol) and triethylamine (0.04 mL, 0.27 mmol) in dichloromethane (0.5 mL), and the reaction stirred at room temperature overnight. The reaction was quenched via the addition of water (5 mL). The organic layer was collected and further washed with water (5 mL) and brine (5 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified via column chromatography on silica gel (Biotage 10 g column, gradient elution with 10-20% methanol in ethyl acetate) to afford methyl (S)-4-(1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl)piperidine-1-carboxylate (19 mg, 89%) as a colorless oil. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.94-1.07 (m, 6H), 1.17-1.26 (m, 1H), 1.43-1.57 (m, 2H), 1.60-1.79 (m, 4H), 2.01 (s, 3H), 2.16-2.31 (m, 2H), 2.68-2.91 (m, 3H), 2.95-3.03 (m, 1H), 3.58 (s, 3H), 3.61-3.73 (m, 2H), 4.04-4.15 (m, 2H), 4.56 (br d, J=6.45 Hz, 1H), 7.05 (br s, 2H). MS (ESI, pos. ion) m/z 389 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([OH:20])=O.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][C:30]=2[C:36]([F:39])([F:38])[F:37])[CH2:24][CH2:23]1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([NH:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][N:25]2[CH2:24][CH2:23][N:22]([CH3:21])[CH2:27][CH2:26]2)=[C:30]([C:36]([F:39])([F:38])[F:37])[CH:31]=1)=[O:20]
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1Cl
Reactant: CN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(NC(=O)Cc3ccc(-n4cnc5cccnc54)cc3Cl)cc2C(F)(F)F)CC1

Procedure:
The title compound is prepared as described in Example 1 but using (2-chloro-4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid (Step 16.1) and 4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (see WO 03/099771). Title compound: ES-MS: 542.9 [M+H]+; single peak at tR=3.31 min (System 1); Rf=0.16 (CH2Cl2/MeOH+1% NH3aq, 9:1).
Reaction SMILES: C([O:9][CH2:10][C@:11]12[CH2:46][CH2:45][C@@H:44]([C:47]([CH3:49])=[CH2:48])[C@@H:12]1[C@@H:13]1[C@@:26]([CH3:29])([CH2:27][CH2:28]2)[C@@:25]2([CH3:30])[C@@H:16]([C@:17]3([CH3:43])[C@@H:22]([CH2:23][CH2:24]2)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]2[CH:37]=[C:36]([C:38]([O:40]CC)=[O:39])[NH:35][N:34]=2)=[CH:19][CH2:18]3)[CH2:15][CH2:14]1)(=O)C1C=CC=CC=1.O.O.[OH-].[Li+]>O1CCOCC1>[OH:9][CH2:10][C@:11]12[CH2:46][CH2:45][C@@H:44]([C:47]([CH3:49])=[CH2:48])[C@@H:12]1[C@@H:13]1[C@@:26]([CH3:29])([CH2:27][CH2:28]2)[C@@:25]2([CH3:30])[C@@H:16]([C@:17]3([CH3:43])[C@@H:22]([CH2:23][CH2:24]2)[C:21]([CH3:31])([CH3:32])[C:20]([C:33]2[CH:37]=[C:36]([C:38]([OH:40])=[O:39])[NH:35][N:34]=2)=[CH:19][CH2:18]3)[CH2:15][CH2:14]1
Reactant: C=C(C)[C@@H]1CC[C@]2(COC(=O)c3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6cc(C(=O)OCC)[nH]n6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6cc(C(=O)O)[nH]n6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 75 °C
Yield: 49.5 %

Procedure:
To a solution of ethyl 3-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(benzoyloxymethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1H-pyrazole-5-carboxylate (0.07 g, 0.105 mmol) in 1,4-Dioxane (4 mL) was added Water (1 mL) and lithium hydroxide monohydrate (0.085 g, 2.026 mmol). The mixture was heated to 75° C. for 18.25 h, was cooled to rt, and was quenched with 1N HCl (7 mL). The mixture was extracted with dichloromethane (4×7 mL) and the combined organic layers were dried with Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. Purification was accomplished by crystallization from dioxane and water to give 3-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(hydroxymethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1H-pyrazole-5-carboxylic acid (0.03 g, 0.052 mmol, 49.2% yield) as a white solid. LCMS: m/e 533.60 (M−H)−, 1.24 min (method 1). 1H NMR (500 MHz, Pyr) δ ppm 0.86 (t, J=7.48 Hz, 3H), 0.95 (s, 3H), 1.06 (s, 6H), 1.06-1.99 (m, 22H), 1.80 (s, 3H), 2.14-2.24 (m, 2H), 2.40-2.51 (m, 2H), 2.65 (dt, J=10.99, 5.49 Hz, 1H), 3.69 (d, J=10.68 Hz, 1H), 4.12 (d, J=10.68 Hz, 1H), 4.79 (s, 1H), 4.93 (d, J=2.14 Hz, 1H), 6.13 (br. s., 1H), 7.33 (s, 1H).