Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]=3)=[CH:10][C:9]=2[CH3:22])=[O:7])=[CH:4][CH:3]=1.CC1C=C(CC(O)=O)N(C)C=1C(C1C=CC(Cl)=CC=1)=O.CC1C=CC(C(C2N(C)C(CC(O)=O)=CC=2)=O)=CC=1.[CH3:64][N:65]([CH3:69])[C:66](Cl)=[O:67]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:66]([N:65]([CH3:69])[CH3:64])=[O:67])=[CH:17][N:16]=3)=[CH:10][C:9]=2[CH3:22])=[O:7])=[CH:23][CH:24]=1
Reactant: Cc1cc(Cc2ccc(N)cn2)n(C)c1C(=O)c1ccc(Cl)cc1
Reactant: CN(C)C(=O)Cl
Agent: Cc1cc(CC(=O)O)n(C)c1C(=O)c1ccc(Cl)cc1
Agent: Cc1ccc(C(=O)c2ccc(CC(=O)O)n2C)cc1
Solvent: c1ccncc1
Product: Cc1cc(Cc2ccc(NC(=O)N(C)C)cn2)n(C)c1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 57 %

Procedure:
{2-[5-(4-Chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl]pyridin-5-yl}amine [prepared by the method described in Example 5, but substituting the methyl ester of zomepirac for the methyl ester of tolmetin in Step (a)] (0.45 g, 1.32 mmol) and dimethylcarbamoyl chloride (0.13 ml, 1.46 mmol) were dissolved in pyridine (6.6 ml), and the mixture was stirred at room temperature for 96 h. The solvents were removed in vacuo and the residue was crystallized from chloroform-hexane mixture to give 1-{2-[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl]pyridin-5-yl }-3,3-dimethylurea (0.31 g, 57%) as a solid, mp 227.2-230.0° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[C:20]3[C:19](=O)[CH2:18][CH2:17][C:16]=3[CH:15]=[N:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].FC1C=C(B(O)[OH:34])C=CC=1C(F)(F)F>>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[C:20]3[CH2:19][CH2:18][CH:17]([OH:34])[C:16]=3[CH:15]=[N:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:10])([F:9])[F:11]
Reactant: OB(O)c1ccc(C(F)(F)F)c(F)c1
Reactant: O=C1CCc2cncc(-c3ccc(C(F)(F)F)c(F)c3)c21
Product: OC1CCc2c(-c3ccc(C(F)(F)F)c(F)c3)cncc21
Yield: 55 %

Procedure:
In analogy to the procedure described for the preparation of example 1 (rac)-4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (intermediate A-4 [C2]) was reacted with 3-fluoro-4-(trifluoromethyl)phenylboronic acid to give the title compound as grey solid in 55% yield. MS: 298.1 (M+H+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7](OC)=O)[CH2:3][CH2:2]1.[CH3:11][NH2:12].Cl.CN.[OH-].[Na+]>C1COCC1>[CH3:11][NH:12][CH2:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: CN
Reactant: COC(=O)C1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CNCC1CCOCC1
Temperature: 110 °C

Procedure:
Methyl tetrahydro-2H-pyran-4-carboxylate (5 ml, 40.0 mmol) was added to a solution of methylamine (generated by heating a mixture of methylamine hydrochloride and sodium hydroxide pellets) in THF (30 ml) and the mixture heated at 110° C. in a bomb reactor overnight. The solvents were evaporated, the residue dissolved in THF (100 ml), and LiAH4 (4.6 g, 121 mmol) added, and the mixture heated at 70° C. for 1 h. The mixture was cooled to 0° C., concentrated NaOH solution added and the THF evaporated. Chloroform (100 ml) was added to the residue and the resulting solid was filtered off and the filtrate concentrated under vacuum to give N-methyl-N-tetrahydro-2H-pyran-4-ylmethylamine as a pale brown oil. The preceding amine (Ig, 7.8 mmol) was dissolved in dichloromethane (50 ml), and triethylamine (4 ml) and [2,1,3]-benzoxadiazole-5-carbonylchloride (1.7 g, 9.3 mmol), as a solution in dichloromethane (20 ml), were added, slowly. The mixture was stirred at room temperature for 1 h, the mixture washed with 1N HCl (20 ml), and saturated sodium bicarbonate solution (20 ml), dried (MgSO4) and evaporated. The residue was purified by silica gel chromatography eluting with ethyl acetate/chloroform (3:1) to give the title compound as a pale brown oil. 1H NMR (300 MHz, CDCl3, 2-rotamers) δ 7.93 (d, J=9.3 Hz, 1H), 7.83 (br s, 1H), 7.38-7.45 (m, 1H), 4.10-3.90 (m, 2H), 3.52-3.20 (m, 4H), 3.13 and 3.05 (both s, total 3H), 2.18-1.80 (m, 1H), 1.73-1.40 ppm (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:12]=[C:11]([NH2:13])[N:10]([CH3:14])[N:9]=1.[C:15]([O:18][C:19](Cl)=[O:20])([CH3:17])=[CH2:16]>C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:12]=[C:11]([NH:13][C:19](=[O:20])[O:18][C:15]([CH3:17])=[CH2:16])[N:10]([CH3:14])[N:9]=1
Reactant: Cn1nc(-c2ccccc2F)cc1N
Reactant: C=C(C)OC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=C(C)OC(=O)Nc1cc(-c2ccccc2F)nn1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.2 %

Procedure:
To a biphasic solution of 3-(2-fluorophenyl)-1-methyl-1H-pyrazol-5-amine (1.19 g, 6.22 mmol) in ethyl acetate (30 mL) and NaHCO3 solution (30 mL) was added isopropenylchloroformate (1.28 g, 10.6 mmol) and mixture was stirred at RT for 24 h. Both layers were separated; the aqueous layer was extracted with ethyl acetate (1×30 mL) and the combined organic layers were washed with brine, dried (Na2SO4) and concentrated to afford crude product which was purified by chromatography (ethyl acetate/hexane) to afford prop-1-en-2-yl 3-(2-fluorophenyl)-1-methyl-1H-pyrazol-5-ylcarbamate (1.15 g, 82% yield) as a pasty mass. 1H NMR (400 MHz, DMSO-d6): δ 10.09 (brs, 1H), 7.90 (td, J=8.0 Hz, 1.6 Hz, 1H), 7.38-7.22 (m, 3H), 6.54 (d, J=3.6 Hz, 1H), 4.79-4.77 (m, 2H), 3.76 (s, 3H), 1.96 (s, 3H); MS (ESI) m/z: 276.0 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][N:31]=[C:30]2[CH:36]=O.N1CCCCC1>CO>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:36]/[C:30]3[C:29]4[C:33](=[CH:34][CH:35]=[C:27]([Cl:26])[CH:28]=4)[NH:32][N:31]=3)/[O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: O=Cc1n[nH]c2ccc(Cl)cc12
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2n[nH]c4ccc(Cl)cc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 51.1 %

Procedure:
A solution of tert-butyl 4-[1-(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.100 g, 0.287 mmol) in methanol (1.2 mL) was added with 5-chloro-1H-indazole-3-carbaldehyde (0.0518 g, 0.287 mmol), and piperidine (0.00244 g, 0.0287 mmol) at room temperature, and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was added with methanol (4 mL), suspended in methanol and thereby washed, and then the solid was collected by filtration to obtain tert-butyl (Z)-4-({6-hydroxy-3-oxo-2-[(5-chloro-1H-indazol-3-yl)methylene]-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0750 g, 51%).
Reaction SMILES: [C:1]([C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:16][C:17]#[N:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:19].CCOC(C)=O>[Pt]=O.CCO>[ClH:19].[CH3:15][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:9]=1[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[N:18][CH2:17][CH2:16]2
Reactant: Cc1cccc(CC#N)c1C(=O)c1ccccc1
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cccc2c1C(c1ccccc1)=NCC2
Reaction time: 5 h

Procedure:
To (2-benzoyl-3-methylphenyl)acetonitrile (3.3 g) were added EtOH (40 mL), 4 M HCl/EtOAc (5 mL), and platinum oxide (IV) (0.53 g), followed by stirring under a hydrogen atmosphere for 5 hours. The reaction liquid was filtered through celite and then concentrated. Toluene was added to the concentrate, followed by extraction with an aqueous 1 M HCl solution. A 28% aqueous ammonia solution was added to the aqueous layer, which was then extracted with toluene and dried over magnesium sulfate. The solvent was evaporated and the residue was dissolved in toluene to which 4 M HCl/EtOAc (5 mL) was then added, followed by concentration. iPrOH and diisopropyl ether were added to the resulting residue, and the precipitated solid was collected to obtain 8-methyl-1-phenyl-3,4-dihydroisoquinoline hydrochloride (1.5 g).
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@:11]3([O:25][CH2:26][O:27][CH2:28][CH3:29])[CH:12]=[CH:13][C:14]2=O)[CH2:6]1)(=O)C.[OH-].[Na+]>CO.O>[OH:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@:11]3([O:25][CH2:26][O:27][CH2:28][CH3:29])[CH:12]=[CH:13][CH2:14]2)[CH2:6]1
Reactant: CCOCO[C@]12C=CC(=O)[C@@]1(C)CC[C@H]1[C@H]2CC=C2C[C@@H](OC(C)=O)CC[C@@]21C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOCO[C@]12C=CC[C@@]1(C)CC[C@H]1[C@H]2CC=C2C[C@@H](O)CC[C@@]21C
Yield: 94.9 %

Procedure:
A solution of 6.00 g of 3β-acetoxy-14β-ethoxymethoxyandrosta-5,15-dien-17-one and 30 ml of 2 N aq. sodium hydroxide in 120 ml of methanol was kept at room temperature for 24 hrs. The mixture was then diluted with water and extracted with dichloromethane. The organic phase was dried over sodium sulfate and evaporated to dryness to give 4.90 g of the title compound (II-a) as a white solid
Reaction SMILES: COC(=O)C1C(C)=CC(C2C=CC=C(C(F)(F)F)C=2)=NC=1OC.Cl[C:25]1[N:30]=[C:29]([C:31]([N:33]2[CH2:38][CH2:37][CH:36]([N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[CH2:35][CH2:34]2)=[O:32])[C:28]([CH3:44])=[CH:27][C:26]=1[C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=1.CC1(C)C(C)(C)OB([C:63]2[CH:64]=[CH:65][C:66]([NH2:69])=[N:67][CH:68]=2)O1>>[NH2:69][C:66]1[N:67]=[CH:68][C:63]([C:25]2[C:26]([C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:52])([F:53])[F:54])[CH:46]=3)=[CH:27][C:28]([CH3:44])=[C:29]([C:31]([N:33]3[CH2:38][CH2:37][CH:36]([N:39]4[CH2:43][CH2:42][CH2:41][CH2:40]4)[CH2:35][CH2:34]3)=[O:32])[N:30]=2)=[CH:64][CH:65]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Cl)nc1C(=O)N1CCC(N2CCCC2)CC1
Agent: COC(=O)c1c(C)cc(-c2cccc(C(F)(F)F)c2)nc1OC
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(-c2ccc(N)nc2)nc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of intermediate 5C, [6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 3) was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine to give the title compound as off-white solid. MS: 510.4 (MH+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:28][CH2:29][NH2:30])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27].O>ClCCl>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:28][CH2:29][NH:30][C:15](=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(CCN)cc1OC
Reactant: O=C(O)CCCCCCCCc1ccccc1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CCNC(=O)CCCCCCCCc2ccccc2)cc1OC
Reaction time: 18 h

Procedure:
A solution of 9-phenylnonanoic acid (1.934 g) and N,N'-carbonyldiimidazole (1.34 g) in dry dichloromethane (20 ml) was stirred at 20° for one hour and a solution of 3,4-dimethoxybenzeneethanamine (1.4 ml) in dry dichloromethane (10 ml) then added. The mixture was stirred at 20° for 18 hours and water added. The organic phase was separated, washed with dilute hydrochloric acid, aqueous sodium bicarbonate and brine, dried over magnesium sulphate and evaporated to leave a solid. Crystallisation from 2-propanol gave the amide as colourless prisms (2.7 g); mp, 117°-119°.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][CH2:3][CH2:2]2.[NH:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]1[O:19][C:18](S)=[N:17][N:16]=1.C(O)CCCC>C(Cl)(Cl)Cl>[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:18]1[O:19][C:15]([C:11]3[NH:10][CH:14]=[CH:13][CH:12]=3)=[N:16][N:17]=1)[CH2:3][CH2:2]2
Reactant: C1CN2CCC(CC2)N1
Reactant: Sc1nnc(-c2ccc[nH]2)o1
Solvent: ClC(Cl)Cl
Solvent: CCCCCO
Product: c1c[nH]c(-c2nnc(N3CCN4CCC3CC4)o2)c1
Reaction time: 15 h

Procedure:
A mixture of 1,4-diazabicyclo[3.2.2]nonane (3.02 g, 23.9 mmol), 5-(1H-pyrrol-2-yl)-1,3,4-oxadiazole-2-thiol (5.0 g, 20.9 mmol) and 1-pentanol (50 ml) was stirred for 15 h. The mixture was solved in chloroform and was filtered through celite. The mixture was purified three times by silica gel chromatography, using chloroform, methanol and aqueous ammonia (89:10:1). The product was dried and evaporated. Yield 382 mg (6%). LC-ESI-HRMS of [M+H]+ shows 260.15096 Da. Calc. 260.15059 Da, dev. 1.4 ppm.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:21][C:12]2=[C:13]3[N:18]([N:19]=[C:11]2[CH2:10]1)[CH:17]=[C:16]([CH3:20])[CH:15]=[N:14]3)=O)(C)(C)C.CCO>CC(O)=O>[ClH:1].[CH3:20][C:16]1[CH:15]=[N:14][C:13]2[N:18]([N:19]=[C:11]3[CH2:10][NH:9][CH2:21][C:12]3=2)[CH:17]=1
Reactant: Cc1cnc2c3c(nn2c1)CN(C(=O)OC(C)(C)C)C3
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cnc2c3c(nn2c1)CNC3
Temperature: 25 °C
Reaction time: 28 h
Yield: 65.1 %

Procedure:
Aq. 32% HCl (1.61 mL; 16.4 mmol; 3 eq.) was added to a solution of 6-methyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carboxylic acid tert-butyl ester (1.5 g; 5.47 mmol; 1 eq.) in AcOH (7.5 mL) and the resulting mixture was stirred at room temperature for 28 hours then poured dropwise into EtOH (40 mL) under vigorous stirring. The precipitate was filtered off, washed with EtOH then MTBE and dried to afford the title compound (0.75 g, 65%) as a white solid. 1H NMR (DMSO-d6) δ 10.50 (s, 2H), 9.06-9.02 (m, 1H), 8.51 (d, J=2.1 Hz, 1H), 4.55-4.52 (m, 4H), 2.33 (s, 3H). HPLC (max plot) 100.0%; Rt 4.36 min.
Reaction SMILES: B(F)(F)F.CCOCC.C(O[CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])C.[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[O:26][C@H:27]1[CH2:32][CH2:31][C@H:30]2[C@H:33]3[C@H:43]([CH2:44][CH2:45][C@:28]12[CH3:29])[C@:41]1([CH3:42])[C@H:36]([CH2:37][C:38](=[O:46])[CH2:39][CH2:40]1)[CH2:35][CH2:34]3.C(N(C(C)C)CC)(C)C>ClCCl>[CH2:18]([O:17][CH:13]([O:14][CH2:15][CH3:16])[C@@H:39]1[CH2:40][C@@:41]2([CH3:42])[C@@H:36]([CH2:35][CH2:34][C@@H:33]3[C@@H:43]2[CH2:44][CH2:45][C@@:28]2([CH3:29])[C@H:30]3[CH2:31][CH2:32][C@@H:27]2[O:26][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][O:20]2)[CH2:37][C:38]1=[O:46])[CH3:19]
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC3CCCCO3)CC[C@@H]12
Reactant: CCOC(OCC)OCC
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(OCC)[C@@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](OC4CCCCO4)CC[C@@H]32)CC1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 49.3 %

Procedure:
Under an argon atmosphere at less than -30° C. boron trifluoride etherate (100 ml., 115.4 g., 0.704 mole) was added to a solution of triethylorthoformate (109.5 ml., 97.56 g., 0.658 mole) in dichloromethane (300 ml.). The temperature was raised to 0° C., kept there for 15 min., then lowered to -70° C. A solution of (5α,17β)-17-[(tetrahydro-2H-pyran-2-yl)oxy]androstan-3-one (0.3 mole) in dichloromethane (250 ml.+50 ml. for rinsing) was then added, followed by diisopropylethylamine (166.5 ml., 123.5 g., 0.955 mole), the latter while maintaining the temperature at less then -55° C. The temperature was lowered to -70° C. for 1 hr. The mixture was then quenched in aqueous sodium bicarbonate solution (3 1., made by dissolving 300 g. of sodium bicarbonate in 3.5 1. of water). The layers were separated. The aqueous layer was extracted with dichloromethane (250 ml.). The combined dichloromethane layers were washed twice with cold hydrochloric acid (2N, 1200 ml., 600 ml.), then with half-saturated aqueous sodium bicarbonate solution (800 ml.), dried and stripped of dichloromethane. The residue was triturated with hexane, affording (2α,5α,17β)-2-(diethoxymethyl)-17-[(tetrahydro-2H-pyran-2-yl)oxy]androstan-3-one (70.57 g., 49% yield, m.r. 165°-168° C.).
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:17]2([CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)[C:9]2=[CH:10][CH:11]=[C:12]([C:13]([F:16])([F:15])[F:14])[N:8]2[CH2:7][CH2:6]1)=[O:4].[ClH:30].O1CCOCC1>C(#N)C>[ClH:30].[CH3:1][NH:2][C:3]([N:5]1[C:17]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[C:9]2=[CH:10][CH:11]=[C:12]([C:13]([F:15])([F:16])[F:14])[N:8]2[CH2:7][CH2:6]1)=[O:4]
Reactant: CNC(=O)N1CCn2c(C(F)(F)F)ccc2C12CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: CNC(=O)N1CCn2c(C(F)(F)F)ccc2C12CCNCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To tert-butyl 2-(methylcarbamoyl)-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (0.66 g, 1.6 mmol) and acetonitrile (5 mL) was added a solution of HCl in dioxane (5.2 mL of 4.0 M, 21 mmol). The reaction mixture was stirred at room temperature for 60 minutes. The solvent was evaporated under reduced pressure to yield N-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-2-carboxamide hydrochloride as a brown solid (99%). ESI-MS m/z calc. 316.2, found 317.2 (M+1)+; Retention time: 0.77 minutes (3 min run).
Reaction SMILES: [CH2:1]([O-:3])C.[Na+].CO[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].[C:16](=[O:21])(OC)[O:17][CH3:18]>>[CH3:1][O:3][C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:8]([CH2:7][C:16]([O:17][CH3:18])=[O:21])=[O:9]
Reactant: COC(=O)OC
Reactant: COCC(=O)c1ccccc1
Reactant: CC[O-]
Agent: [Na+]
Product: COC(=O)CC(=O)c1ccccc1OC
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
58.5 g (1.08 mol) of sodium ethanolate are added to 500 ml of dimethyl carbonate. The mixture is then heated to boiling and traces of methanol are removed by distillation. 153.5 g (1.02 mol) of 2-methoxyacetophenone are allowed to drip in at 86° C. with vigorous stirring during the course of 4.5 hours. (If the reaction mixture becomes too viscous, a further addition of dimethyl carbonate is recommended.) The mixture is then subsequently stirred for a further 30 minutes and the solvent is removed by distillation under reduced pressure. After cooling to room temperature, 350 ml of water and 70 ml of glacial acetic acid are added and the mixture is stirred overnight. The oil formed is separated off and the aqueous phase is extracted by shaking with a total of 300 ml of ethyl acetate. The combined organic phases are first washed with a 6% strength sodium hydrogen carbonate solution (100 ml), then with a sodium chloride solution (the sodium chloride promotes the phase separation). After drying the ethyl acetate phase over sodium sulfate, filtration and after removing the solvent on a rotary evaporator, the remaining oil is distilled in a high vacuum.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1([F:45])[CH2:11][CH:10]1[C:12]([NH:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20](C1CCCCO1)[N:19]=[C:18]2[C:30]1[NH:34][C:33]2[CH:35]=[CH:36][C:37]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:38][C:32]=2[N:31]=1)=[O:13]>C(Cl)Cl>[F:45][C:9]1([F:8])[CH2:11][CH:10]1[C:12]([NH:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[C:18]2[C:30]1[NH:34][C:33]2[CH:35]=[CH:36][C:37]([N:39]3[CH2:40][CH2:41][O:42][CH2:43][CH2:44]3)=[CH:38][C:32]=2[N:31]=1)=[O:13]
Reactant: O=C(Nc1ccc2c(c1)c(-c1nc3cc(N4CCOCC4)ccc3[nH]1)nn2C1CCCCO1)C1CC1(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2[nH]nc(-c3nc4cc(N5CCOCC5)ccc4[nH]3)c2c1)C1CC1(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
TFA (2.212 μL, 0.029 mmol) was added to solution of 2,2-difluoro-N-(3-(5-morpholino-1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropane carboxamide (15 mg, 0.029 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred overnight at room temperature, and then the solvent was removed in vacuo. Purification by flash column chromatography (5% CH3OH/CH2Cl2) afforded the title compound (10 mg) as a yellow solid. 1H NMR: (400 MHz, CD3OD): δ 8.69 (d, 1H, J=1.2 Hz), 7.71 (d, 1H, J=9.2 Hz), 7.68 (d, 1H, J=8.8 Hz), 7.48 (dd, 1H, J=1.6 and 9.2 Hz), 7.35 (dd, 1H, J=1.6 and 9.6 Hz), 7.19 (m, 1H), 3.88 (m, 4H), 3.26 (m, 4H), 2.82-2.74 (m, 1H), 2.19-2.12 (m, 1H), 1.93-1.87 (m, 1H); ESI-MS: [M+H]+: 439.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26](=[O:27])[NH:25][C:24](C)=[N:23]2)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[C:26](=[O:27])[N:25]([C@H:12]([CH3:13])[C@:9]3([C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])[O:10][CH2:11]3)[CH:24]=[N:23]2)=[CH:20][CH:21]=1
Reactant: Cc1nn(-c2ccc(Cl)cc2)c(=O)[nH]1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1cnn(-c2ccc(Cl)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 25.1 %

Procedure:
In the same manner as in Reference Example 5, starting from 0.70 g of (1S)-1-[(2R)-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 0.62 g of 2-(4-chlorophenyl)-5-methyl-3(2H,4H)-1,2,4-triazolone, 0.28 g of 2-(4-chlorophenyl)-4[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3(2H,4H)-1,2,4-triazolone was obtained as a colorless oil.
Reaction SMILES: CN(C)C([S:5][C:6]1[C:13]([O:14][CH3:15])=[CH:12][C:11]([CH3:16])=[CH:10][C:7]=1[CH:8]=[O:9])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[OH:9][CH2:8][C:7]1[CH:10]=[C:11]([CH3:16])[CH:12]=[C:13]([O:14][CH3:15])[C:6]=1[SH:5]
Reactant: COc1cc(C)cc(C=O)c1SC(=O)N(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1cc(C)cc(CO)c1S

Procedure:
59 g (0.23 mol) of the compound from Example 14 are reduced with 11.4 g (0.3 mol) of lithium aluminium hydride analogously to Example 6.
Reaction SMILES: ClC1C=CC(C(=O)[CH2:9][NH:10][C:11](=[O:35])[CH2:12][CH:13]([CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH:21]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=3)[CH2:20]2)[C:14]([F:17])([F:16])[F:15])=CC=1.O=P(Cl)(Cl)[Cl:39].[C:42]1([CH3:48])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C>[Cl:39][C:45]1[CH:46]=[CH:47][C:42]([C:48]2[O:35][C:11]([CH2:12][CH:13]([C:14]([F:17])([F:15])[F:16])[CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH:21]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[CH:26]=4)[CH2:20]3)=[N:10][CH:9]=2)=[CH:43][CH:44]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccccc1
Reactant: O=C(CC(CN1CCCC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F)NCC(=O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cccc(C2CCCN(CC(Cc3ncc(-c4ccc(Cl)cc4)o3)C(F)(F)F)C2)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
In a 5 mL round-bottomed flask, N-(2-(4-chlorophenyl)-2-oxoethyl)-4,4,4-trifluoro-3-((3-(3-(trifluoromethyl)phenyl)piperidin-1-yl)methyl)butanamide (30 mg, 56.1 μmol) and POCl3 (51.6 mg, 336 μmol) were combined with toluene (1 ml) to give a colorless solution. The reaction mixture was heated to 100° C. and stirred for 4 h. The reaction mixture was diluted with ethyl acetate (30 ml), poured into ice-water and made basic with saturated solution of Na2CO3. The organic layer was separated and washed with brine and H2O, dried over MgSO4, filtered and concentrated in vacuo to give an oil. The resultant oil was purified by flash chromatography (silica gel, 12 g, 0% to 50% ethyl acetate in hexane gradient) to afford 1-{2-[5-(4-chloro-phenyl)-oxazol-2-ylmethyl]-3,3,3-trifluoro-propyl}-3-(3-trifluoromethyl-phenyl)-piperidine as an oil. It was dissolved in Et2O/Hexane, treated with 4N HCl in dioxane (0.1 ml) and concentrated in vacuo to afford 23 mg (76%) of 1-{2-[5-(4-chloro-phenyl)-oxazol-2-ylmethyl]-3,3,3-trifluoro-propyl}-3-(3-trifluoromethyl-phenyl)-piperidine hydrochloride as a white solid. MH+=517.