Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[C:14]1(C)[CH:19]=[CH:18][C:17](S(O)(=O)=O)=[CH:16][CH:15]=1>C1C=CC=CC=1>[CH:4]1([CH:18]2[CH2:17][CH2:16][C:15]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[CH:14][CH2:19]2)[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C1COCCN1
Reactant: O=C1CCCCC1
Solvent: c1ccccc1
Product: C1=C(N2CCOCC2)CCC(C2CCCCC2)C1

Procedure:
54 g of 4-cyclohexanone are dissolved in 90 ml benzene and 39 ml morpholine are added to the fresh solution, then a few crystals of p-toluene sulphonic acid. The whole is heated under reflux for 3 days while distilling off the water-benzene mixture. The remaining benzenic solution is evaporated to dryness under reduced pressure. The dry residue weighs 76.8 g and the raw product shows a melting point of 88°- 90°. The raw enamine is ground, then dried in vacuo to constant weight. 74.3 g of 4-cyclohexyl-1-morpholyl-cyclohex-1-ene are recovered and used without further purification for the next step of the synthesis. The yield amounts to 99 %.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:20])=[C:12]3[CH:18]=[C:17](I)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN([CH:68]=[O:69])C>CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:20])=[C:12]3[CH:18]=[C:17]([C:68]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[O:69])[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(I)cc2c1O
Reactant: CN(C)C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(C(=O)N3CCOCC3)cc2c1O
Temperature: 70 °C
Reaction time: 18 h
Yield: 33 %

Procedure:
To a solution of N-(4-chlorobenzyl)-4-hydroxy-2-iodothieno[2,3-b]pyridine-5-carboxamide (2.00 g) from Example No. 2 in DMF (45 mL) are added triethylamine (1.25 mL), morpholine (15.7 mL), Pd(OAc)2 (0.101 g), and dppp (0.186 g). The reaction mixture is degassed by bubbling N2 through the solution for 15 minutes. Carbon monoxide is then bubbled through the solution, and the reaction mixture is heated to 70° C. and stirred for 18 h. The reaction mixture is allowed to cool to room temperature and water (25 mL) and 2 N HCl (75 mL) are added. The resulting green solid is filtered off and the filtrate is extracted with CH2Cl2 (4×100 mL). The combined organic layers are dried with MgSO4, filtered, and concentrated in vacuo. The resulting orange oil is purified by column chromatography (CH2Cl2; CH2Cl2/methanol, 98/2). The resulting pale yellow solid is recrystallized from acetonitrile to yield 0.648 g (33%) of the title compound as an off-white solid.
Reaction SMILES: C[C:2]1(C)[CH2:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6](O)=[CH:7][C:8]=2O)[O:3]1.C(=O)([O-])[O-].[K+].[K+].S(OC(CCCC1C=CC=CC=1)C)(=O)(=O)C>CN(C)C=O>[O:3]1[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=2[C:10](=[O:12])[CH2:11][CH2:2]1
Reactant: CC1(C)CC(=O)c2c(O)cc(O)cc2O1
Agent: CC(CCCc1ccccc1)OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCOc2ccccc21
Temperature: 25 °C

Procedure:
A mixture of 2,2-dimethyl-5,7-dihydroxy-4-chromanone (2.08 g, 10 mM), potassium carbonate (2.76 g, 20 mM), N,N-dimethylformamide (10 ml) and 5-phenyl-2-pentanol mesylate (2.64 g, 11 mM), under a nitrogen atmosphere, is heated to 80°-82° C. in an oil bath for 1.75 hours. The mixture is cooled to room temperature and then poured into ice/water (100 ml). The aqueous solution is extracted with ethyl acetate (2×25 ml) and the combined extracts washed successively with water (3×25 ml) and saturated brine (1×25 ml). The extract is then dried (MgSO4), decolorized with charcoal and evaporated to give the product as an oil which crystallizes upon seeding with pure product; m.p. 83°-84° C. Yield=quantitative.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][C@@H:8]([CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14])[O:7][C@:6]([C@@H:17]2[CH2:21][S:20][C:19](=[O:22])[N:18]2[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)([O:15][CH3:16])[CH2:5]1)=[N+]=[N-].[NH4+].[Cl-]>C(O)C.O.C(OCC)(=O)C.[Zn]>[NH2:1][C@@H:4]1[CH2:9][C@@H:8]([CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14])[O:7][C@:6]([C@@H:17]2[CH2:21][S:20][C:19](=[O:22])[N:18]2[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)([O:15][CH3:16])[CH2:5]1
Reactant: C=CCCC[C@@H]1C[C@@H](N=[N+]=[N-])C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: C=CCCC[C@@H]1C[C@@H](N)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 75 %

Procedure:
A suspension of the title compound from Example 66 (432 mg, 0.967 mmol) in ethanol (3 mL) and water (1 mL) was treated with NH4Cl (122 mg, 2.27 mmol) and zinc dust (85.4 mg, 1.30 mmol), and the mixture was stirred vigorously at room temperature. After 6 h, an additional portion of zinc (100 mg) and NH4Cl (127 mg) was added, together with additional ethanol (4.5 mL) and water (1.5 mL), and stirring was continued for 18 h. Once more portions of zinc (100 mg) and NH4Cl (124 mg) were added, and stirring was continued. After 4 h, the mixture was diluted with ethyl acetate, washed with half-concentrated NH4OH and brine, dried, and concentrated. The residue was treated with NH4Cl (200 mg) in methanol (20 mL), and this mixture was allowed to stir at room temperature for 2 days. The mixture was diluted with ethyl acetate, washed with 1/1-satd aq NaHCO3/brine and then with brine, dried, and concentrated. Chromatography of the residue on silica gel eluting with methanol/dichloromethane gave the title compound (305 mg, 75%) as an oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[NH2:47][C:48]1[CH:49]=[C:50]2[C:54](=[CH:55][CH:56]=1)[NH:53][C:52]([C:57]([CH3:61])([CH3:60])[CH2:58][OH:59])=[CH:51]2>C(#N)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:47][C:48]4[CH:49]=[C:50]5[C:54](=[CH:55][CH:56]=4)[NH:53][C:52]([C:57]([CH3:61])([CH3:60])[CH2:58][OH:59])=[CH:51]5)=[O:15])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: CC(C)(CO)c1cc2cc(N)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(CO)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (0.075 g, 0.36 mmol) in acetonitrile (1.5 mL) were added HBTU (0.138 g, 0.36 mmol) and Et3N (152 μL, 1.09 mmol) at room temperature. The mixture was stirred at room temperature for 10 minutes before a solution of 2-(5-amino-1H-indol-2-yl)-2-methylpropan-1-ol (0.074 g, 0.36 mmol) in acetonitrile (1.94 mL) was added. After addition, the reaction mixture was stirred at room temperature for 3 h. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane. The organic layer was washed with 1 N HCl (1×3 mL) and saturated aqueous NaHCO3 (1×3 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude material was purified by column chromatography on silica gel (ethyl acetate/hexane=1/1) to give 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (0.11 g, 75%). 1H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.38 (s, 1H), 7.55 (s, 1H), 7.15 (d, J=8.6 Hz, 1H), 7.04-6.90 (m, 4H), 6.06 (s, 1H), 6.03 (s, 2H), 4.79 (t, J=2.7 Hz, 1H), 3.46 (d, J=0.0 Hz, 2H), 1.41-1.39 (m, 2H), 1.26 (s, 6H), 1.05-1.02 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[C:14]2[NH:13][C:12]3[CH:11]=[C:10]([C:15]([NH2:17])=O)[CH:9]=[CH:8][C:7]=3[C:6]=2[C:5](=[O:18])[C:4]2[CH:19]=[N:20][C:21]([N:23]3[CH2:28][CH2:27][CH:26]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[CH2:25][CH2:24]3)=[CH:22][C:3]1=2.S(Cl)(Cl)=O>CN(C=O)C.O>[CH3:1][C:2]1([CH3:35])[C:14]2[NH:13][C:12]3[CH:11]=[C:10]([C:15]#[N:17])[CH:9]=[CH:8][C:7]=3[C:6]=2[C:5](=[O:18])[C:4]2[CH:19]=[N:20][C:21]([N:23]3[CH2:24][CH2:25][CH:26]([N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)[CH2:27][CH2:28]3)=[CH:22][C:3]1=2
Reactant: CC1(C)c2cc(N3CCC(N4CCOCC4)CC3)ncc2C(=O)c2c1[nH]c1cc(C(N)=O)ccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC1(C)c2cc(N3CCC(N4CCOCC4)CC3)ncc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.1 %

Procedure:
5,5-Dimethyl-3-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-pyrido[4,3-b]carbazole-8-carboxylic acid amide (54 mg) was dissolved in DMF (1 ml), added with thionyl chloride (25 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with water. The precipitated matters were collected by filtration to obtain the title compound (25 mg, 49%).
Reaction SMILES: [I:1][CH2:2][C:3]([NH2:5])=[O:4].[CH2:6]([O:9][C:10]([N:12]1[C@H:16]([CH2:17][C:18]2[S:22][C:21]3=[CH:23][N:24]=[CH:25][N:20]3[CH:19]=2)[CH2:15][C@H:14]([S:26][C:27]2[C@H:28]([CH3:44])[C@@H:29]3[C@@H:39]([C@H:40]([OH:42])[CH3:41])[C:38](=[O:43])[N:30]3[C:31]=2[C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33])[CH2:13]1)=[O:11])[CH:7]=[CH2:8]>CC(C)=O>[I-:1].[CH2:6]([O:9][C:10]([N:12]1[C@H:16]([CH2:17][C:18]2[S:22][C:21]3=[CH:23][N:24]([CH2:2][C:3](=[O:4])[NH2:5])[CH:25]=[N+:20]3[CH:19]=2)[CH2:15][C@H:14]([S:26][C:27]2[C@H:28]([CH3:44])[C@@H:29]3[C@@H:39]([C@H:40]([OH:42])[CH3:41])[C:38](=[O:43])[N:30]3[C:31]=2[C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33])[CH2:13]1)=[O:11])[CH:7]=[CH2:8]
Reactant: NC(=O)CI
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](Cc3cn4cncc4s3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Solvent: CC(C)=O
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](Cc3c[n+]4cn(CC(N)=O)cc4s3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: [I-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.9 %

Procedure:
2-Iodoacetamide (96.1 mg) is added to a solution of 33.9 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-(imidazo[5,1-b]thiazol-2-yl)methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate described in Example 23-a) in 0.5 ml of dry acetone, and the mixture is stirred in an argon atmosphere at room temperature for 20 hr. The solvent is removed by evaporation under reduced pressure, and the residue is purified by column chromatography on Sephadex LH-20 (dichloromethane:methanol=1:1) to give 34.5 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[6-(carbamoylmethyl)imidazo[5,1-b]thiazolium-2-yl]methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate iodide as a slightly yellow solid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH:11]([CH2:15][C:16](=[O:34])[N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[CH2:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[NH:25][C:24]4=[O:33])[CH2:19][CH2:18]3)[C:12](O)=[O:13])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:35][N:36]1[CH2:41][CH2:40][CH:39]([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:38][CH2:37]1>>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH:11]([CH2:15][C:16]([N:17]3[CH2:18][CH2:19][CH:20]([N:23]4[CH2:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[NH:25][C:24]4=[O:33])[CH2:21][CH2:22]3)=[O:34])[C:12]([N:45]3[CH2:46][CH2:47][CH:42]([CH:39]4[CH2:38][CH2:37][N:36]([CH3:35])[CH2:41][CH2:40]4)[CH2:43][CH2:44]3)=[O:13])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)C(CC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1)Cc1ccc2c(c1)CCC2
Reactant: CN1CCC(C2CCNCC2)CC1
Product: CN1CCC(C2CCN(C(=O)C(CC(=O)N3CCC(N4Cc5ccccc5NC4=O)CC3)Cc3ccc4c(c3)CCC4)CC2)CC1

Procedure:
Prepared analogously to Example 76e) from and 2-indan-5-ylmethyl-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic acid and 1-methyl-[4,4′]bipiperidinyl.
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:11])[CH2:10]CCCCCC1.[C:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15].[C:20](O)(=O)[CH3:21]>C1(C)C=CC=CC=1.O>[C:12]([O:11][CH2:3][CH3:10])([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)O
Reactant: O=C1CCCCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(OCC)(OCC)OCC
Temperature: 80 °C
Yield: 71 %

Procedure:
The keto-ester was prepared by the sodium hydride induced acylation of cyclooctanone (1 using diethyl carbonate). A 1-L round bottom flask was charged with NaH (60% dispersion in mineral oil, 17.0 g, 708 mmol). The NaH was washed with three portions of toluene (200 mL), diethyl carbonate (36 mL, 207 mmol) was charged to the flask, and the reaction mixture warmed to 80° C. A solution of cyclooctanone (18.76 g, 149 mmol) in toluene (50 mL) was added dropwise over 1 hr. The temperature was maintained at 80° C. for 1.5 hr after the addition of cyclooctanone. Upon cooling to room temperature, glacial acetic acid (30 mL) was added dropwise, followed by ice water (200 mL). The reaction mixture was stirred until all the solid was in solution (additional water may be necessary). The layers were separated, and the aqueous layer was extracted with toluene (3×100 mL). The organic layer was dried over MgSO4, filtered, and evaporated in vacuo to yield an oil. Purification was achieved by simple high vacuum distillation (91°-93° C. 0.5 to 0.6 mmHg) to yield 20.8 g, 71% of 6; IR (neat) 2950, 2870, 1745, 1710, 1640, 1617, 1468, 1382, 1330, 1250, 1230, 1185, 1100 cm−1; 1H NMR (CDCl3, 300 MHz) δ (keto-enol mix) 1.23 (t), 1.29 (t), 1.33 to 1.58 (m), 1.62 to 1.76 (m), 1.85 to 1.95 (m), 2.32 to 2.68 (m), 3.5 to 3.6 (m), 4.1 to 4.25 (m), 12.6 (s, enol H).
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[CH3:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28]([C:30]2[NH:31][CH:32]=[C:33]([C:35]#[N:36])[CH:34]=2)=[O:29])[CH2:11][CH2:10]1.C(OC(=O)C)(=O)C.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[C:3]([N:24]1[CH2:23][CH2:22][N:21]([C:19]2[CH:18]=[CH:17][C:16]([NH:27][C:28]([C:30]3[NH:31][CH:32]=[C:33]([C:35]#[N:36])[CH:34]=3)=[O:29])=[C:15]([N:12]3[CH2:13][CH2:14][CH:9]([CH3:8])[CH2:10][CH2:11]3)[CH:20]=2)[CH2:26][CH2:25]1)(=[O:4])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CC1CCN(c2cc(N3CCNCC3)ccc2NC(=O)c2cc(C#N)c[nH]2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCN(c2ccc(NC(=O)c3cc(C#N)c[nH]3)c(N3CCC(C)CC3)c2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 23.5 %

Procedure:
To 4-cyano-1H-pyrrole-2-carboxylic acid [2-(4-methyl-piperidin-1-yl)-4-piperazin-1-yl-phenyl]-amide trifluoroacetic acid salt (as prepared in Example 56, step (b)) (30 mg, 0.048 mmol) in dichloromethane (5 mL) was added acetic anhydride (7.0 μL, 0.072 mmol) and DIEA (31 μL, 0.18 mmol) and the mixture was stirred for 5 h at RT. The mixture was poured into saturated aq sodium bicarbonate (5 mL), extracted with dichloromethane (5 mL), and the organic layer was dried (Na2SO4). The solvents were removed in vacuo and the resulting residue was purified by silica gel preparative TLC eluting with 10% methanol in dichloromethane to yield 4.9 mg (23%) of the title compound as an off-white solid. 1H-NMR (400 MHz, CDCl3): δ 10.57 (br s, 1H), 8.99 (s, 1H), 8.27 (d, 1H, J=8.8 Hz), 7.45 (dd, 1H, J=3.1, 1.3 Hz), 6.851 (s, 1H), 6.81 (d, 1H, J=3.5 Hz), 6.73 (dd, 1H, J=8.9, 2.6 Hz), 3.79 (m, 2H), 3.64 (m, 2H), 3.17-2.96 (m, 4H), 2.74 (m, 2H), 2.70 (m, 2H), 2.15 (s, 3H), 1.87-1.84 (m, 2H), 1.58 (m, 1H), 1.44-1.34 (m, 2H), 1.08 (d, 3H, J=6.5 Hz). LC-MS (ESI, m/z): Calcd. for C24H31N6O2, 435.2 (M+H); found: 435.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:6][CH2:5]2
Reactant: C1CCNC1
Reactant: O=C1CCc2cc(Cl)ccc2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1ccc2c(c1)CCC(N1CCCC1)=C2

Procedure:
1155 g (6.4 mol) of 6-chloro-3.4-dihydro-2(1H)naphthalenone are dissolved in 5 1 of toluene, 500 g (7.0 mol) of pyrrolidine and subsequently a solution of 26 g (0.14 mol) of p-toluenesulfonic acid monohydrate in toluene are added dropwise thereto and the mixture is boiled under reflux on a water separator. When about 120 ml of water have separated, 4 l of toluene are distilled and the mixture is left to cool slowly. A solid thereby crystallizes out. Filtration and washing with acetone gives 1-(6-chloro-3,4-dihydro-2-naphthyl)-pyrrolidine with melting point 117-118°. Concentration of the mother liquor, suspension of the residue in ether, filtration and washing with acetone gives an additional portion of the above product with meltinq point 117-118°.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[CH2:13][CH:12]([C:26]([OH:28])=O)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.[F:29][C:30]1[CH:31]=[C:32]([C:36](=[N:38]O)[NH2:37])[CH:33]=[CH:34][CH:35]=1>>[F:29][C:30]1[CH:31]=[C:32]([C:36]2[N:38]=[C:26]([CH:12]3[CH2:13][CH:14]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[CH:17]=4)[CH2:15][N:10]([C:8]([N:5]4[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]4)=[O:9])[CH2:11]3)[O:28][N:37]=2)[CH:33]=[CH:34][CH:35]=1
Reactant: NC(=NO)c1cccc(F)c1
Reactant: O=C(O)C1CC(c2cccc(C(F)(F)F)c2)CN(C(=O)N2CCC(O)CC2)C1
Product: O=C(N1CCC(O)CC1)N1CC(c2cccc(C(F)(F)F)c2)CC(c2nc(-c3cccc(F)c3)no2)C1

Procedure:
75 mg (0.2 mmol) of the compound from Example 150A and 52 mg (0.3 mmol) of 3-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 2. Yield: 16 mg (18% of theory)
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:5]=[C:4]([C:17]2[CH:18]=[N:19][CH:20]=[N:21][CH:22]=2)[C:3]=1[C:23](O)=[O:24].BrC1C=CC(N2C(C)=C(C(O)=O)C(C3C=NC=NC=3)=N2)=CC=1C(F)(F)F.Cl.Cl.[NH:54]1[CH2:59][CH2:58][CH:57]([N:60]2[CH2:64][CH2:63][CH2:62][C@H:61]2[CH2:65][OH:66])[CH2:56][CH2:55]1>>[OH:66][CH2:65][C@@H:61]1[CH2:62][CH2:63][CH2:64][N:60]1[CH:57]1[CH2:58][CH2:59][N:54]([C:23]([C:3]2[C:4]([C:17]3[CH:22]=[N:21][CH:20]=[N:19][CH:18]=3)=[N:5][N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:8]=3)[C:2]=2[CH3:1])=[O:24])[CH2:55][CH2:56]1
Reactant: OC[C@@H]1CCCN1C1CCNCC1
Reactant: Cc1c(C(=O)O)c(-c2cncnc2)nn1-c1cccc(C(F)(F)F)c1
Agent: Cc1c(C(=O)O)c(-c2cncnc2)nn1-c1ccc(Br)c(C(F)(F)F)c1
Agent: Cl
Product: Cc1c(C(=O)N2CCC(N3CCC[C@H]3CO)CC2)c(-c2cncnc2)nn1-c1cccc(C(F)(F)F)c1

Procedure:
In analogy to the procedure described in Example 160E], a mixture of 5-methyl-3-pyrimidin-5-yl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carboxylic acid and 1-(4-bromo-3-trifluoromethyl-phenyl)-5-methyl-3-pyrimidin-5-yl-1H-pyrazole-4-carboxylic acid (example 173D]) and ((S)-1-piperidin-4-yl-pyrrolidin-2-yl)-methanoldihydrochloride (Example 161A]) gave a mixture of the title compound and example 176. Purification by reversed phase HPLC (MeCN:H2O) afforded [1-(4-bromo-3-trifluoromethyl-phenyl)-5-methyl-3-pyrimidin-5-yl-1H-pyrazol-4-yl]-[4-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl]-methanone (Example 176) and [4-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl]-[5-methyl-3-pyrimidin-5-yl-1-(3-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-methanone as a white solid (32%). MS: 515.5 (MH+).
Reaction SMILES: [OH:1][C@H:2]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C@@H:4]([CH2:5][CH2:6][C:7]3[C:8]4[C@:17]([CH3:25])([CH2:18][CH2:19][C:20]=32)[C@@H:11]([C@H:12]([CH3:16])[CH2:13][CH:14]=[O:15])[CH2:10][CH:9]=4)[C:3]1([CH3:27])[CH3:26].N1C=CC=CC=1.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O>[C:34]([O:1][C@H:2]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C@@H:4]([CH2:5][CH2:6][C:7]3[C:8]4[C@:17]([CH3:25])([CH2:18][CH2:19][C:20]=32)[C@@H:11]([C@H:12]([CH3:16])[CH2:13][CH:14]=[O:15])[CH2:10][CH:9]=4)[C:3]1([CH3:26])[CH3:27])(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@H](CC=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Solvent: O
Solvent: c1ccncc1
Product: C[C@H](CC=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](OC(=O)c2ccccc2)C(C)(C)[C@@H]1CC3
Temperature: 4 °C
Reaction time: 1.5 h

Procedure:
iv)—A solution of the aldehyde (12.3 g) mentioned above in dry pyridine (150 ml) was cooled to 4° C. Benzoyl chloride (8 ml) was added in 5 min. and the reaction mixture was stirred for 1.5 h at room temperature. Then it was poured into water (2 l) and the resulting mixture was stirred overnight. The product was extracted into dichloromethane and the combined organic phases were concentrated under reduced pressure to give (3β,5α,20R)-3-(benzoyloxy)-4,4,20-trimethylpregna-8,14-diene-21-carboxaldehyde (16.1 g). The product was used in the following step without further purification.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][S:15]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=3)(=[O:17])=[O:16])=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:38][P:39]([O:44][CH2:45][CH3:46])([O:41][CH2:42][CH3:43])=[O:40])(=O)=O.O>CN(C)C=O.C(OCC)(=O)C>[Cl:24][C:22]1[CH:23]=[C:18]([S:15]([N:14]([CH2:38][P:39](=[O:40])([O:44][CH2:45][CH3:46])[O:41][CH2:42][CH3:43])[C:10]2[CH:9]=[C:8]3[C:13](=[CH:12][CH:11]=2)[N:5]([C:3](=[O:4])[NH:2][CH3:1])[CH2:6][CH2:7]3)(=[O:17])=[O:16])[CH:19]=[C:20]([Cl:25])[CH:21]=1
Reactant: CCOP(=O)(COS(=O)(=O)C(F)(F)F)OCC
Reactant: CNC(=O)N1CCc2cc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOP(=O)(CN(c1ccc2c(c1)CCN2C(=O)NC)S(=O)(=O)c1cc(Cl)cc(Cl)c1)OCC
Reaction time: 3 h

Procedure:
2.2 g 5-(3,5-dichloro-phenylsulphonylamino)-2,3-dihydro-indole-1-carboxylic acid-methylamide are dissolved in 15 ml dimethylformamide. To this are added 1.67 g potassium carbonate and 1.32 ml diethoxy-phosphorylmethyl trifluoro-methanesulphonate. The mixture is left for 3 hours at ambient temperature with stirring, the solvent is eliminated in vacuo and the residue is divided between water and ethyl acetate. The aqueous phase is extracted twice from ethyl acetate and the combined organic phases are dried on magnesium sulphate. The solvents are eliminated in vacuo and the residue is extracted from diisopropylether/ethyl acetate.