Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])[CH:3]=1.C([O-])=O.[NH4+]>C(O)C>[CH3:19][O:18][C:11]1[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][C:4]1[CH:3]=[CH:2][N:7]=[CH:6][N:5]=1
Reactant: COc1ccc(CNc2cc(Cl)ncn2)c(OC)c1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COc1ccc(CNc2ccncn2)c(OC)c1
Temperature: 80 °C
Yield: 96.7 %

Procedure:
6-Chloro-N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (Preparation 112, 3.46 g, 12.39 mmol) was dissolved in ethanol (140 mL). The solution was degassed and then 10% palladium on carbon (0.98 g) was added followed by ammonium formate (4.55 g, 72.15 mmol) and the reaction was heated at 80° C. for 2 hours. The reaction was cooled to room temperature, filtered through pad of Celite™ and the filtrate was concentrated in vacuo. The residue was partitioned between dichloromethane (30 mL) and water (15 mL). The organic layer was separated, dried over anhydrous MgSO4, filtered and evaporated to give the title compound (2.94 g, 97%) as viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=O)[NH:7][C:6]=2[CH:17]=1.[CH3:18][CH:19]1[CH2:24][NH:23][CH2:22][CH:21]([CH3:25])[NH:20]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([N:23]3[CH2:22][CH:21]([CH3:25])[NH:20][CH:19]([CH3:18])[CH2:24]3)=[N:7][C:6]=2[CH:17]=1
Reactant: CC1CNCC(C)N1
Reactant: O=C1Nc2cc(Cl)ccc2Nc2ccccc21
Product: CC1CN(C2=Nc3cc(Cl)ccc3Nc3ccccc32)CC(C)N1
Yield: 52.8 %

Procedure:
8-Chloro-5,10-dihydro-dibenzo[b,e][1,4]diazepine-11-one (25 mg, 0.1 mmol) and 2,6-dimethylpiperazine (114 mg, 1.0 mmol) were reacted according to GP4 to give 18 mg of the title compound (160FE33B). MS (ESI) 341 (MH+). Purity for MH+ (UV/MS) 100/100.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[CH:17][N:18]([CH3:30])[C:19]=2[C:20]2[S:29][C:23]3[N:24]=[CH:25][N:26]=[C:27]([NH2:28])[C:22]=3[CH:21]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O.O>C(Cl)Cl.CO>[NH2:28][C:27]1[C:22]2[CH:21]=[C:20]([C:19]3[N:18]([CH3:30])[CH:17]=[N:16][C:15]=3[C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=3)[S:29][C:23]=2[N:24]=[CH:25][N:26]=1
Reactant: Cn1cnc(-c2ccc(OCc3ccccc3)cc2)c1-c1cc2c(N)ncnc2s1
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: Cn1cnc(-c2ccc(O)cc2)c1-c1cc2c(N)ncnc2s1
Yield: 67.3 %

Procedure:
6-{4-[4-(Benzyloxy)phenyl]-1-methyl-1H-imidazol-5-yl}thieno[2,3-d]pyrimidin-4-amine (Example 53) (19 mg) was refluxed with TFA (3 mL) and water (0.05 mL) for 6 hr. The mixture was diluted with 1:1 DCM/MeOH and passed through an acidic extraction cartridge (Waters Oasis® MCX 1 g). The cartridge was washed with 1:1 DCM/MeOH, then eluted with concentrated aqueous NH3/DCM/MeOH 4:48:48. Fractions were evaporated to give the title compound as a solid (10 mg, 67%);
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]12[CH2:17][N:16]([C:18]3[C:27]([F:28])=[C:26]4[C:21]([C:22](=[O:35])[C:23]([C:32]([OH:34])=[O:33])=[CH:24][N:25]4[CH:29]4[CH2:31][CH2:30]4)=[C:20]([F:36])[C:19]=3[F:37])[CH2:15][CH:14]1[CH2:13][CH2:12][O:11]2)=O)(C)(C)C.[ClH:38]>>[ClH:38].[NH2:8][CH2:9][C:10]12[CH2:17][N:16]([C:18]3[C:27]([F:28])=[C:26]4[C:21]([C:22](=[O:35])[C:23]([C:32]([OH:34])=[O:33])=[CH:24][N:25]4[CH:29]4[CH2:31][CH2:30]4)=[C:20]([F:36])[C:19]=3[F:37])[CH2:15][CH:14]1[CH2:13][CH2:12][O:11]2
Reactant: CC(C)(C)OC(=O)NCC12CN(c3c(F)c(F)c4c(=O)c(C(=O)O)cn(C5CC5)c4c3F)CC1CCO2
Agent: Cl
Product: NCC12CN(c3c(F)c(F)c4c(=O)c(C(=O)O)cn(C5CC5)c4c3F)CC1CCO2

Procedure:
In an analogous manner to Example 1B, the product from step A is reacted with half-concentrated hydrochloric acid to give 7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride with a melting point of 175°-177° C. (with decomposition).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([CH2:15][O:16][C:17](=[O:33])[NH:18]C4C=CC(C5C=CC=CC=5)=CC=4C#N)=[CH:12][C:11]=3[CH:34]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-]=[N+]=[N-].[Na+].[Cl-].[NH4+].C(OCC)(=O)C>CN(C=O)C>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([CH2:15][O:16][C:17](=[O:33])[NH2:18])=[CH:12][C:11]=3[CH:34]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1cc(-c2ccccc2)ccc1NC(=O)OCc1cc2cc(-c3ccccc3)ccc2o1
Agent: [Cl-]
Agent: [N-]=[N+]=[N-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)OCc1cc2cc(-c3ccccc3)ccc2o1
Temperature: 90 °C

Procedure:
A mixture of (3-cyano-biphenyl-4-yl)-carbamic acid-5-phenyl-benzofuran-2-yl-methylester (0.40 g, 0.90 mmol), sodium azide (0.117 g, 1.80 mmol) and ammonium chloride (0.096 g, 1.80 mmol) in 3 mL DMF was heated to 90° C. under a nitrogen atmosphere for 20 h. The mixture was cooled to room temperature, ethyl acetate was added and the solution was washed with 1M HCl, followed by water, dried and concentrated to dryness. Purification by chromatography gave 72 mg of 3-(1H-tetrazol-5-yl)-biphenyl-4-yl]-carbamic acid 5-phenyl-benzofuran-2-ylmethyl ester 501, mp: 180-183° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7](Cl)[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][CH:4]=1.[NH2:13][CH:14]([CH2:17][OH:18])[CH2:15][OH:16]>C(O)C>[CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:13][CH:14]([CH2:17][OH:18])[CH2:15][OH:16])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][CH:4]=1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: NC(CO)CO
Solvent: CCO
Product: COc1ccc([N+](=O)[O-])c(NC(CO)CO)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
6-Methoxy-2-chloro-3-nitropyridine (36.94 g, 195.9 mmol) and 2-aminopropane-1,3-diol (35.65 g, 391.3 mmol) were stirred in ethanol (500 ml) at reflux under argon for 3 h. The mixture was allowed to cool to room temperature and left overnight. The solvent was partially removed under reduced pressure (to ca. 150 ml) and the resulting bright yellow slurry was poured into ice-water (1.5 L) with vigorous stirring. The mixture was stirred for 1 h then filtered with suction while cold. The solid was washed with ice-cold water (200 ml) and air-dried to give the title compound as a bright yellow solid (45.03 g, 94%). LCMS showed desired product (93%) plus 7% starting material. The product was used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]([OH:15])[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].I[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:37]=[CH:36][C:24]2[CH2:25][CH2:26][CH:27]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[O:28][C:23]=2[C:22]=1[CH2:38][CH2:39][CH3:40].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:1][C:2]1[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]([CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5])[O:15][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:37]=[CH:36][C:24]2[CH2:25][CH2:26][CH:27]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[O:28][C:23]=2[C:22]=1[CH2:38][CH2:39][CH3:40]
Reactant: CCCc1c(O)ccc(C(=O)NC)c1O
Reactant: CCCc1c(OCCCI)ccc2c1OC(CCC(=O)OCC)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCOc2ccc3c(c2CCC)OC(CCC(=O)OCC)CC3)ccc(C(=O)NC)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound of Example 10 (418 mg, 2.0 mmol), the compound of Example 11 (895 mg, 2.0 mmol), and potassium carbonate (552 mg, 4.0 mmol) were added to 3.0 ml DMF, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, and dried over magnesium sulfate. Evaporation of the volatiles afforded a crude oil which was purified by chromatography using 50/50 ethyl acetate/hexane as eluant to give the product as a white solid.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][N:10]=1.[C:18]1([C:24]2[O:25][C:26]([C:32]([F:35])([F:34])[F:33])=[C:27]([C:29](O)=[O:30])[N:28]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[N:10]=[CH:11][C:12]([NH:15][C:29]([C:27]2[N:28]=[C:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:25][C:26]=2[C:32]([F:34])([F:35])[F:33])=[O:30])=[CH:13][CH:14]=1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(NC2CC3CCC2C3)nc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(NC2CC3CCC2C3)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Yield: 17 %

Procedure:
Bicyclo[2.2.1]hept-2-yl-(5-nitro-pyridin-2-yl)-amine (102 mg, 0.4 mmol) was hydrogenated as above and reacted with 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (123 mg, 0.48 mmol), Et3N (281 uL, 2 mmol) and BOP (194 mg. 0.444 mmol). Following work-up as above, the crude material was purified by flash chromatography to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(bicyclo[2.2.1]hept-2-ylamino)-pyridin-3-yl]-amide as a light purple solid (30 mg). ES-MS calcd for C23H21F3N4O2 (m/e) 442.44, obsd 443.2 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[C:9]3[CH:16]=[C:15]([CH2:17][C:18]([F:21])([F:20])[F:19])[S:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:3][CH2:2]1.[OH:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.[BH3-]C#N.[Na+]>CO.C(O)(=O)C>[F:20][C:18]([F:21])([F:19])[CH2:17][C:15]1[S:14][C:10]2[N:11]=[CH:12][N:13]=[C:8]([NH:7][CH:4]3[CH2:5][CH2:6][N:1]([CH2:27][C:26]4[CH:29]=[CH:30][C:23]([OH:22])=[CH:24][CH:25]=4)[CH2:2][CH2:3]3)[C:9]=2[CH:16]=1
Reactant: FC(F)(F)Cc1cc2c(NC3CCNCC3)ncnc2s1
Reactant: O=Cc1ccc(O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Oc1ccc(CN2CCC(Nc3ncnc4sc(CC(F)(F)F)cc34)CC2)cc1

Procedure:
59 mg of N-(piperidin-4-yl)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-amine (0.19 mmol) and 21 mg of p-hydroxybenzaldehyde (0.19 mmol) were dissolved in 0.5 mL of MeOH in the presence of 10 uL of acetic acid. 19 mg of NaBH3CN (0.3 mmol) was slowly added to that mixture and solution was stirred for 24 hs. All volatiles were removed under reduced pressure and residue was partitioned between water and ethyl acetate. Organic layer was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified on silica gel column with DCM:MeOH:Et3N as eluent resulting in 62 mg of 4-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)phenol (compound 105). 1H NMR (600 MHz, CDCl3): δ 8.46 (s, 1H), 7.09 (d, 2H, J=8.4 Hz), 7.07 (s, 1H), 6.68 (d, 2H, J=8.4 Hz), 5.28 (d, 1H, J=7.7 Hz), 4.21 (m, 1H), 3.59 (q, 2H, 9.9 Hz), 3.46 (s, 2H), 2.96 (m, 2H), 2.21 (m, 2H), 2.09 (m, 2H), 1.62 (m, 2H). 13C NMR (150 MHz, CDCl3): δC 166.45, 156.08, 155.98, 154.14, 131.01, 128.23, 125.57, 118.65, 116.52, 115.62, 62.48, 52.10, 47.96, 35.50 (q, J=31.5 Hz), 31.89. ESI MS [MH+]: 423.1458. Its monohydrochloride salt was obtained by adding 1 equivalent of 1N HCl solution in diethyl ether to a solution of compound in ethanol.
Reaction SMILES: C1CO[C:3]2([CH2:8][CH2:7][CH:6]([CH3:9])[C:5]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])(S(C3C=CC=CC=3)(=O)=O)[CH2:4]2)[O:2]1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.CC(C)=O>[OH:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:5]1[CH:6]([CH3:9])[CH2:7][CH2:8][C:3](=[O:2])[CH:4]=1
Reactant: CC1CCC2(CC1(CCCCCCCCCCO)S(=O)(=O)c1ccccc1)OCCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CC1CCC(=O)C=C1CCCCCCCCCCO
Yield: 75 %

Procedure:
Paratoluenesulfonic acid (20 ml) was added to a solution of 235 mg of 1,1-(ethylenedioxy)-3-(10-hydroxydecyl)-4-methyl-3-(phenylsulfonyl)-cyclohexane in 20 ml of chloroform and 4 ml of acetone. The resulting mixture was reacted at 50° C. for 24 hours. To the reaction mixture were added 10 ml of a saturated aqueous solution of sodium bicarbonate, followed by extraction with dichloromethane. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column while using hexane-ethyl acetate, whereby 3-(10-hydroxydecyl)-4-methyl-2-cyclohexene-1-one was obtained in the form of a colorless oil. Yield: 75%, CCM: (hexane-AcOEt: 6-4) Rf=0.2
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]3[CH:26]=[C:25]([N:27]([C:32]4[CH:37]=[CH:36][C:35]([B:38]5[O:42]C(C)(C)C(C)(C)[O:39]5)=[C:34]([F:47])[CH:33]=4)[S:28]([CH3:31])(=[O:30])=[O:29])[C:24]([CH:48]4[CH2:50][CH2:49]4)=[CH:23][C:17]=3[C:18]=2[C:19]([NH:21][CH3:22])=[O:20])=[CH:10][CH:9]=1.Cl.CCOC(C)=O>C1COCC1.O>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]3[CH:26]=[C:25]([N:27]([C:32]4[CH:37]=[CH:36][C:35]([B:38]([OH:39])[OH:42])=[C:34]([F:47])[CH:33]=4)[S:28]([CH3:31])(=[O:30])=[O:29])[C:24]([CH:48]4[CH2:49][CH2:50]4)=[CH:23][C:17]=3[C:18]=2[C:19](=[O:20])[NH:21][CH3:22])=[CH:10][CH:9]=1
Reactant: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N(c3ccc(B4OC(C)(C)C(C)(C)O4)c(F)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N(c3ccc(B(O)O)c(F)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.9 %

Procedure:
Sodium periodate (549 mg, 2.57 mmol) was added to a mixture of 2-(4-chlorophenyl)-5-cyclopropyl-6-(N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide (164 mg, 0.257 mmol) in THF (6 mL) and 1N HCl (3.21 mL, 3.21 mmol). The mixture was stirred at room temperature overnight and EtOAc and water were added. The aqueous layer was extracted with EtOAc (2×) and the combined organic phases were washed with 10% aq. Na2S2O3, brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by reverse phase HPLC (MeCN/H2O with 0.1% TFA) to give the title compound as a white solid (80 mg, 56%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.52 (q, 1H) 8.23 (br. s., 1H) 8.07 (s, 1H) 7.94 (d, 2H) 7.64 (d, 2H) 7.55 (t, 1H) 7.22 (s, 1H) 7.11 (s, 1H) 7.07-7.10 (m, 1H) 3.45 (s, 4H) 2.85 (d, 3H) 2.04-2.15 (m, 1H) 1.00 (br. s., 1H) 0.82 (d, 2H) 0.54 (br. s., 1H). LCMS (m/z, ES+)=557 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[O:22])[CH:4]=1.[OH-].[K+].[CH2:25](N)[CH2:26]N.C#C>C(O)(C)(C)C.C1COCC1>[C:25]([C@@:12]1([OH:22])[CH2:11][CH2:10][C@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]12[CH3:14])[C@:18]1([CH3:21])[C:5]([CH:4]=[C:3]([O:2][CH3:1])[CH2:20][CH2:19]1)=[CH:6][CH2:7]3)#[CH:26]
Reactant: COC1=CC2=CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CC1
Reactant: NCCN
Agent: C#C
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: C#C[C@@]1(O)CC[C@H]2[C@@H]3CC=C4C=C(OC)CC[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
In an inert pressurizable vessel is placed 3-methoxyandrosta-3,5-dien-17-one (I Aa, 15 g) THF (60 ml), milled potassium hydroxide (15 g), t-butanol (1.5 ml), and ethylenediamine (10 ml). The stirred mixture is heated to 53° and a 15-pound partial pressure of acetylene is applied. These conditions are maintained for 3 hr at which time TLC indicates a mixture of ethisterone methyl enol ether and epiethisterone methyl enol ether. The reaction mixture is quenched with phosphate buffer (pH=7) and methylene chloride is used to isolate the product as an oil. The resulting oil is crystallized from toluene to give epi-ethisterone enol ether of approximately 90% purity.
Reaction SMILES: [Cl:1][C:2]1[C:11]([S:12]([NH2:15])(=[O:14])=[O:13])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C[Al](C)C.C[O:28][C:29](=O)[NH:30][C:31]1[N:36]=[C:35]([O:37][CH3:38])[N:34]=[C:33]([O:39][CH3:40])[N:32]=1>C(Cl)Cl>[Cl:1][C:2]1[C:11]([S:12]([NH:15][C:29]([NH:30][C:31]2[N:32]=[C:33]([O:39][CH3:40])[N:34]=[C:35]([O:37][CH3:38])[N:36]=2)=[O:28])(=[O:14])=[O:13])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1c(Cl)ccc2cccnc12
Reactant: COC(=O)Nc1nc(OC)nc(OC)n1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1nc(NC(=O)NS(=O)(=O)c2c(Cl)ccc3cccnc23)nc(OC)n1
Reaction time: 0.75 h
Yield: 27.5 %

Procedure:
To a stirred mixture of 7-chloro-8-quinolinesulfonamide (1.5 g) in 75 ml methylene chloride is added a 2 M toluene solution of trimethyl aluminum (4.7 ml). The resulting solution is stirred under N2 for 45 min. Solid methyl(4,6-dimethoxy-1,3,5-triazin-2-yl)carbamate (1.1 g) is added and the mixture is heated at reflux for 60 h. The reaction is quenched sequentially with acetic acid (1 ml), 6 N HCl (2.5 ml) and water (13 ml). The organic solution is retained, dried with MgSO4, and is concentrated to an oil-solid mixture. Filtration afforded 0.6 g yellow solid m.p. 169°-191° C. (dec). The infrared spectrum showed characteristic absorption bands at 3300 and 1700 cm-1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:14][NH:15][CH2:16][CH3:17])([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]=O>C(O)=O>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:14][N:15]([CH2:16][CH3:17])[CH3:18])([OH:13])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCNCC1(O)CCN(Cc2ccccc2)C1
Reactant: C=O
Solvent: O=CO
Product: CCN(C)CC1(O)CCN(Cc2ccccc2)C1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
21.8 g (93 mmol) 1-benzyl-3-ethylaminomethyl-3-hydroxy-pyrrolidine (according to example Ca) are dissolved in a mixture of 9.5 g formic acid and 8.5 g 37% proof aqueous formaldehyde solution. The mixture is stirred at 80° C. for 4 hours. The solvents are removed in vacuo, the residue is taken up in water, and the pH is adjusted alkaline with potassium carbonate. The reaction mixture is then extracted with chloroforme, and the organic phase is dried with potassium carbonate. After filtration the organic solvent is removed in vacuo and the residue is destilled.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10]1(Cl)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[N:12][NH:11]1.[CH2:21]([NH:24][CH2:25][CH:26]1[CH2:28][CH2:27]1)[CH2:22][CH3:23]>C1(C)C=CC=CC=1>[CH:26]1([CH2:25][N:24]([CH2:21][CH2:22][CH3:23])[C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([C:3]3[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][C:4]=3[CH3:9])=[N:11][N:12]=2)[CH2:28][CH2:27]1
Reactant: CCCNCC1CC1
Reactant: Cc1cc(C)c(C2(Cl)NN=Cc3ccccc32)c(C)c1
Solvent: Cc1ccccc1
Product: CCCN(CC1CC1)c1nnc(-c2c(C)cc(C)cc2C)c2ccccc12

Procedure:
A mixture of the product of step C (100 mg), N-propyl-N-cyclopropylmethylamine (0.5 mL) and in 1 mL of toluene was heated at 100 ° C. overnight. The mixture was cooled and concentrated. The residue was purified through silica gel column chromatography to give 40 mg of the title compound as an oil. 1H NMR (CDCl3): δ0.08 (q, 2H), 0.50 (q 2H), 0.95 (t, 3H), 1.20 (m, 1H), 1.76 9m, 2H), 1.92 (s, 6H), 2.36 )s, 3H), 3.45 (d, 2H), 3.68 (m, 2H), 6.90 (s, 2H), 7.36 (d, 1H), 7.64 (t, 1H), 7.74 (t, 1H), 8.19 (d, 1H)ppm.
Reaction SMILES: CN(C)C=O.[F:6][C:7]([F:16])([F:15])[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[N:35]([CH3:36])[N:34]=[C:33]([C:37]3[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:38]=3[Cl:44])[N:32]=2)=[CH:27][C:26]=1[Cl:45]>O>[Cl:44][C:38]1[CH:39]=[CH:40][CH:41]=[C:42]([F:43])[C:37]=1[C:33]1[N:32]=[C:31]([C:28]2[CH:29]=[CH:30][C:25]([CH2:24][O:14][C:11]3[CH:10]=[CH:9][C:8]([C:7]([F:15])([F:16])[F:6])=[CH:13][CH:12]=3)=[C:26]([Cl:45])[CH:27]=2)[N:35]([CH3:36])[N:34]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(CBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(COc2ccc(C(F)(F)F)cc2)c(Cl)c1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
To 30 ml of N,N-dimethylformamide are added 4-trifluoromethyl phenol (0.77 g) and potassium carbonate (0.72 g) and 5-(4-bromomethyl-3-chlorophenyl)-3(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole (1.60 g) is added thereto at room temperature with stirring, which is stirred at 120° C. for 1 hour. On completion of the reaction, the reaction solution is cooled to room temperature, poured into water and extracted with toluene. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography to give 1.50 g of desired compound (refractive index: 1.5961).
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[CH3:30][N:31]([CH3:36])[CH2:32][CH2:33][CH2:34][NH2:35]>>[F:23][C:22]1[CH:21]=[C:20]([CH3:24])[CH:19]=[C:18]([F:25])[C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:35][CH2:34][CH2:33][CH2:32][N:31]([CH3:36])[CH3:30])=[O:29])[S:14][N:13]=1
Reactant: CN(C)CCCN
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCN(C)C)c2C(N)=O)c(F)c1

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and N,N-dimethyl-propane-1,3-diamine by the procedure analogous to Example 1. MS (APCI, m/z): 428 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[N:30]=[C:31]=[O:32]>>[F:19][C:20]1[C:21]([NH:30][C:31]([NH:1][C:2]2[CH:18]=[CH:17][CH:16]=[C:4]([O:5][C:6]3[CH:11]=[CH:10][N:9]=[C:8]4[NH:12][C:13](=[O:15])[NH:14][C:7]=34)[CH:3]=2)=[O:32])=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1)Nc1cc(C(F)(F)F)ccc1F
Yield: 20 %

Procedure:
Method G was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 2-fluoro-5-trifluoromethyl-phenylisocyanate to afford the title compound (15 mg, 20%). 1H-NMR (DMSO), δ (ppm), J (Hz): 6.45 (d, 1H, HPyr, J=5.9), 6.79 (s, 1H, Harom5′, J=2.1, J=8.0), 7.20 (d, 1H, Harom 4 or 6, J=7.9), 7.21-7.41 (m, 3H, Harom 3′, Harom 2, Harom 6 or 4), 7.50 (t, 1H, Harom 5, J=10.7), 7.79 (d, 1H, HPyr), 8.55 (d, 1H, Harom 4′, J=7.2), 8.93 (s, 1H, NHurea), 9.38 (s, 1H, NHurea), 11.23 (s, 1H, NHim), 11.42 (s, 1H, NHim); MS-LC, Rf=7.64 min, (C20H13F4N5O3), m/z: 448.1 [M++1], 100.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:14][C@H:13]([O:15][C:16]2[C:21]([Cl:22])=[CH:20][C:19]([S:23]([N:26](CC3C=CC(OC)=CC=3OC)[C:27]3[CH:32]=[CH:31][N:30]=[CH:29][N:28]=3)(=[O:25])=[O:24])=[C:18]([F:44])[CH:17]=2)[C@@H:12]([C:45]2[N:49]([CH3:50])[N:48]=[CH:47][CH:46]=2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:22][C:21]1[C:16]([O:15][C@H:13]2[CH2:14][C@H:9]([OH:8])[CH2:10][CH2:11][C@@H:12]2[C:45]2[N:49]([CH3:50])[N:48]=[CH:47][CH:46]=2)=[CH:17][C:18]([F:44])=[C:19]([S:23]([NH:26][C:27]2[CH:32]=[CH:31][N:30]=[CH:29][N:28]=2)(=[O:25])=[O:24])[CH:20]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@H]3C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CC[C@@H](O)C[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1Cl
Yield: 24.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*,5R*)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide (59.0 mg, 0.0791 mmol) prepared in Example 160b, triethylsilane (0.050 mL), trifluoroacetic acid (0.50 mL) and dichloromethane (1.0 mL), to yield the title compound (9.5 mg, 25%) as a colorless solid.