Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li][CH2:2]CCC.[C:6]1([CH:12]2[CH2:15][C:14](=O)[CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CCCCCC>[CH2:2]=[C:14]1[CH2:15][CH:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:13]1
Reactant: [Li]CCCC
Reactant: O=C1CC(c2ccccc2)C1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C1CC(c2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 39.5 %

Procedure:
To a 2-3° C. suspension of methyltriphenylphosphonium bromide (0.36 g, 1 mmol) in THF (2.5 ml) was added dropwise n-BuLi (0.69 ml, 1.1 mmol, 1.6 M in hexan). After 1 hour stirring at 0° C., a solution of 3-phenyl-cyclobutanone (0.146 g, 1 mmol) in THF (1.5 ml) was added dropwise. The reaction mixture was stirred 24 hours at room temperature and then diluted with hexane. The so obtained precipitate was filtered and the filtrate was concentrated. The residue was chromatographed over silica gel (hexane-ethylacetate 9:1) to provide (3-methylene-cyclobutyl)-benzene (57 mg, 40%) as a slightly yellow oil, MS: m/e=144.1 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[CH:10]2[C:27]([O-:29])=[O:28])[CH:6]=[CH:7][CH:8]=1.[OH-].[K+]>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[CH:10]2[C:27]([OH:29])=[O:28])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)[O-])c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl (1RS, 2RS, 3SR)-1-(3-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylate (43 mg, 0.10 mmol) in EtOH (1 ml) was added 6M KOH (0.10 mL, 0.60 mmol). The resulting mixture was allowed to stir at room temperature overnight, then was partitioned between H2O and Et2O. The aqueous phase was acidified with 3M HCl and extracted several times with EtOAc. The combined EtOAc extracts were washed successively with H2O and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo to afford an oil, which was crystallized from Et2O/hexanes. The title compound was obtained as a solid; m.p. 131-133° C.
Reaction SMILES: C(#N)C.F[C:5]1[C:14]([O:15][CH3:16])=[C:13]2[C:8]([C:9](=[O:24])[C:10]([C:21]([OH:23])=[O:22])=[CH:11][N:12]2[C@@H:17]2[CH2:19][C@@H:18]2[F:20])=[CH:7][CH:6]=1.Cl.C(N(CC)CC)C.C(O)(=O)C(O)=O.[NH:39]1[CH2:43][CH2:42][C@@H:41]([C:44]2([NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])[CH2:46][CH2:45]2)[CH2:40]1>C(N(CC)CC)C>[C:50]([O:49][C:48]([NH:47][C:44]1([C@@H:41]2[CH2:42][CH2:43][N:39]([C:5]3[C:14]([O:15][CH3:16])=[C:13]4[C:8]([C:9](=[O:24])[C:10]([C:21]([OH:23])=[O:22])=[CH:11][N:12]4[C@@H:17]4[CH2:19][C@@H:18]4[F:20])=[CH:7][CH:6]=3)[CH2:40]2)[CH2:45][CH2:46]1)=[O:54])([CH3:53])([CH3:51])[CH3:52]
Reactant: COc1c(F)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reactant: CC(C)(C)OC(=O)NC1([C@@H]2CCNC2)CC1
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1c(N2CC[C@@H](C3(NC(=O)OC(C)(C)C)CC3)C2)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
An acetonitrile solution (45 mL) containing 7-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (3 g), triethylamine hydrochloride (2.8 g), and boron trifluoride-tetrahydrofuran complex (2.84 g) was stirred at room temperature for 30 minutes. tert-Butyl {1-[(3R)-pyrrolidin-3-yl]cyclopropyl}carbamate oxalic acid salt (3.54 g) and triethylamine (5.71 mL) were further added to reaction mixture, followed by stirring for 10 hours at the same temperature. The solvent was evaporated under reduced pressure, and methanol (30 mL) was added to the residue. The mixture was refluxed for 12 hours, and the solvent was evaporated under reduced pressure. 80% Hydrated methanol (20 mL) was added to the residue, and the pH of the product was adjusted to 7 by use of 5N aqueous sodium hydroxide solution, followed by stirring at 60° C. for 30 minutes and at room temperature for 16 hours. The thus-produced crystals were recovered through filtration and dried, to thereby yield 4.79 g of the title compound (yield: 94%).
Reaction SMILES: [C:1]([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@@H:12]2[C:22](=[O:30])SC2C=CC=CN=2)[CH:4]=1)#[N:2].[CH2:31]([O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([NH2:43])([CH3:42])[CH3:41])=[CH:36][CH:35]=1)[CH3:32]>>[CH2:31]([O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([NH:43][C:22]([C@H:12]2[CH2:11][CH2:10][C@H:9]3[C@H:8]4[C@H:17]([CH2:16][CH2:15][C@:13]23[CH3:14])[C@:18]2([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]2)=[CH:6][CH2:7]4)=[O:30])([CH3:42])[CH3:41])=[CH:36][CH:35]=1)[CH3:32]
Reactant: CCOc1ccc(C(C)(C)N)cc1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Product: CCOc1ccc(C(C)(C)NC(=O)[C@H]2CC[C@H]3[C@@H]4CC=C5C=C(C#N)CC[C@]5(C)[C@H]4CC[C@]23C)cc1
Yield: 91 %

Procedure:
Following a procedure similar to that described in Example 3(b), but using S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate [prepared as described in Example 3(a)] and 1-(4-ethoxyphenyl)-1-methylethylamine (prepared as described in Preparation 10g) as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 91%.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[CH:7][C:8]1[C:9]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[C:10]=2[O:11][C:12]=1[CH3:13])=[O:5])[CH3:2]>[Pd].O1CCOCC1.C(O)C>[NH2:18][C:14]1[C:10]2[O:11][C:12]([CH3:13])=[C:8]([CH2:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:9]=2[CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)C=Cc1c(C)oc2c([N+](=O)[O-])cccc12
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)CCc1c(C)oc2c(N)cccc12
Reaction time: 3 h
Yield: 103.4 %

Procedure:
10%-Palladium on carbon (30 mg) was added to a solution of 3-(2-ethoxycarbonylethenyl)-2-methyl-7-nitrobenzo[b]furan (210 mg) in a mixture of dioxane (3 ml) and ethanol (1 ml). The mixture was hydrogenated at 3 atoms for 3 hours and the catalyst was filtered off. The filtrate was concentrated in vacuo to give 7-amino-3-(2-ethoxycarbonylethyl)-2-methylbenzo[b]furan (195 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[N+:9]([O-])=O.C(OCC)(=O)C.CCCCCC>C(O)C.[Pd]>[NH2:9][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: COc1ccncc1N
Yield: 100 %

Procedure:
To a mixture of 4-Methoxy-3-nitropyridine (5.0 g, 32.44 mmole) in ethanol (100 mL) was added 10% palladium on carbon catalyst (200 mg). The resulting mixture was allowed to shake under a hydrogen atmosphere (50 psi) for 6 h. at room temperature. TLC (50% ethyl acetate/hexane) indicated complete consumption of starting material. Filtration through celite to remove the catalyst and concentration gave 3- Amino-4 methoxypyridine (4.0 g, 32.44 mmol, 100% yield) as dark red oil.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=O)=[C:9]3[N:8]=[C:7]([S:16][CH3:17])[CH:6]=2)[CH2:3][CH2:2]1.[NH:18]1[CH2:24][C:22](=[O:23])[NH:21][C:19]1=[O:20].N1CCCCC1>C(O)C>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:24]4/[C:22](=[O:23])[NH:21][C:19](=[O:20])[NH:18]/4)=[C:9]3[N:8]=[C:7]([S:16][CH3:17])[CH:6]=2)[CH2:3][CH2:2]1
Reactant: O=C1CNC(=O)N1
Reactant: CSc1cc(NC2CC2)n2ncc(C=O)c2n1
Solvent: C1CCNCC1
Solvent: CCO
Product: CSc1cc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Temperature: 80 °C
Yield: 90 %

Procedure:
The above product 7-(cyclopropylamino)-5-(methylthio) pyrazolo[1,5-a]pyrimidine-3-carbaldehyde was dissolved in 20.0 mL ethanol, added hydantoin (2.82 g, 28.17 mmol) and piperidine (2.70 mL). The reaction was heated to 80° C. for overnight. Cooled the reaction mixture and yellow precipitate was filtered, washed with ethanol, dried to yield (Z)-5-((7-(cyclopropylamino)-5-(methylthio) pyrazolo[1,5-a]pyrimidin-3-yl)methylene) imidazolidine-2,4-dione 4.18 g (90% yield). LCMS (M+1=331)
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[C:14]1([P:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Br-:1].[F:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][P+:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:8][CH:9]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Fc1ccc(OCCCCBr)cc1
Solvent: Cc1ccccc1
Product: Fc1ccc(OCCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: [Br-]
Temperature: 25 °C
Yield: 39 %

Procedure:
A solution of 1-(4-bromobutoxy)-4-fluorobenzene (2.56 g) and triphenylphosphine (2.72 g) in toluene (10 mL) was heated under reflux for 24 hours. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration and dried to obtain [4-(4-fluorophenoxy]butyl]triphenylphosphonium bromide (2.06 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([OH:9])[C:6]([O:10][CH3:11])=[CH:5]N=1.CO[CH:14]=[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N:25]3[CH:29]=[CH:28][CH:27]=[CH:26]3)[CH:23]=2)[C:18](=[O:30])[NH:17][C:16]1=[O:31].[CH3:32]N(C)C=O>>[OH:9][C:7]1[CH:8]=[C:3]([CH:32]=[CH:5][C:6]=1[O:10][CH3:11])[CH2:2][NH:1][CH:14]=[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N:25]3[CH:29]=[CH:28][CH:27]=[CH:26]3)[CH:23]=2)[C:18](=[O:30])[NH:17][C:16]1=[O:31]
Reactant: COC=C1C(=O)NC(=O)c2ccc(-n3cccc3)cc21
Reactant: CN(C)C=O
Reactant: COc1cnc(CN)cc1O
Product: COc1ccc(CNC=C2C(=O)NC(=O)c3ccc(-n4cccc4)cc32)cc1O
Reaction time: 1 h

Procedure:
A mixture of 2-aminomethyl-5-methoxy-pyridin-4-ol (123 mg, 0.80 mmole), 4 mL of N,N-dimethylformamide and 4-methoxymethylene-6-pyrrol-1-yl-4H-isoquinoline-1,3-dione (215 mg, 0.80 mmole) is added and the reaction mixture stirred for one hour. The reaction mixture is evaporated to dryness and treated with acetonitrile, the solid filtered and dried to give a white solid, 199 mg, (65%), mp 199-209° C. dec; MS (ES+): m/z 391.1 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([F:12])[CH:3]=1.[Li]CCCC.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]#[N:26])=[N:23][CH:24]=1.C[Si](Cl)(C)C.[CH:32]1([Mg]Cl)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>C1COCC1.CCOCC>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([F:12])[CH:3]=2)[NH2:26])=[N:23][CH:24]=1
Reactant: Cl[Mg]C1CCCCC1
Reactant: N#Cc1ccc(Cl)cn1
Reactant: Fc1cc(Br)cc(C(F)(F)F)c1
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: NC(c1cc(F)cc(C(F)(F)F)c1)(c1ccc(Cl)cn1)C1CCCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
A dry 200 mL flask under nitrogen was charged with 1-bromo-3-fluoro-5-(trifluoromethyl)benzene (1.22 g, 0.005 mol). Dry ether (50mL) was added and the solution was cooled to −78° C. n-BuLi (3.0 mL, 1.6 M in hexanes, 0.0048 mol) was added dropwise and the resulting solution was stirred at −78° C. for 30 min. A solution of 5-chloropicolinonitrile (0.692 g, 0.005 mol) in anhydrous THF (7 mL) was then added. The resulting solution was stirred at −78° C. for 1 hr. Redistilled TMSCl (0.65 mL, 0.00515 mol) was added dropwise. The reaction mixture was allowed to reach 0° C. and then cooled to −78° C. Cyclohexylmagnesium chloride (2.75 mL, 2.0 M, 0.0055 mol) was added dropwise. The solution was allowed to reach room temperature. The reaction was quenched by addition of water followed by aqueous ammonium chloride. The aqueous layer was extracted with ether (2×50 mL). The combined organic portions were filtered through a pad of silica and the silica was washed with 4:1 Hexanes:EtOAc. The solvents were evaporated to get the racemic (5 -chloropyridin-2-yl)(cyclohexyl)(3-fluoro-5-(trifluoromethyl)phenyl)methanamine as an oil (1.39 g, 75% yield). LCMS RT=3.28 min, [M+H] 387.14, Purity 79% (LCMS Method 6).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([O:20][C@H:21]1[CH2:41][CH2:40][C@@:39]2([CH3:42])[C:23](=[CH:24][CH:25]=[C:26]3[C@@H:38]2[CH2:37][CH2:36][C@@:35]2([CH3:43])[C@H:27]3[CH2:28][CH2:29][C@@H:30]2[C@H:31]([CH3:34])[CH2:32][OH:33])[C:22]1([CH3:45])[CH3:44])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[C:12]([O:20][C@H:21]1[CH2:41][CH2:40][C@@:39]2([CH3:42])[C:23](=[CH:24][CH:25]=[C:26]3[C@@H:38]2[CH2:37][CH2:36][C@@:35]2([CH3:43])[C@H:27]3[CH2:28][CH2:29][C@@H:30]2[C@@H:31]([CH2:32][O:33][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH3:34])[C:22]1([CH3:44])[CH3:45])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@H](CO)[C@H]1CC[C@H]2C3=CC=C4C(C)(C)[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H](C)[C@H]2CC[C@H]3C4=CC=C5C(C)(C)[C@@H](OC(=O)c6ccccc6)CC[C@]5(C)[C@H]4CC[C@]23C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
A solution of 0.573 g toluene-4-sulfonylchloride in 4 ml pyridine was added drop by drop to a solution of 0.926 g (20S)-4,4,20-trimethyl-pregna-5,7-dien-3β,21-diol 3-benzoate in 15 ml pyridine while cooling on an ice-bath. The reaction mixture was stirred for 1 h at 0-3□C. and overnight at room temperature. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic layers were combined, washed with 1N hydrochloric acid, saturated sodium hydrogencarbonate solution and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 1.0 g of (20S)-4,4-dimethyl-20-[((toluene-4-sulfonyl)oxy)methyl]-pregna-5,7-dien-3β-ol benzoate which could be further purified by crystallization from methanol.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=O.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>C(#N)C.C(OCC)(=O)C>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:9]2[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[CH:1]=[CH:13][S:10]2(=[O:12])=[O:11])=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)Nc1ccccc1C=O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccc(CN2c3ccccc3C=CS2(=O)=O)cc1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
The title compound was synthesized according to the method described in WO 2008/073956 A2. To a solution of N-(2-formylphenyl)methanesulfonamide (2.0 g, 10 mmol) in anhydrous acetonitrile (45 mL) was added cesium carbonate (6.5 g, 20 mmol) and 4-methoxybenzylchloride (2.7 mL, 20 mmol). The mixture was heated to 50° C. and stirred for 48 hours, diluted with ethyl acetate, filtered through Celite, and concentrated. The crude product was purified by silica gel column chromatography (50-100% methylene chloride in hexanes) to give the product (0.9 g, 31%). 1H NMR (CDCl3, 300 MHz) δ 7.40-7.32 (m, 2H), 7.28-7.24 (m, 3H), 7.16-7.11 (m, 2H), 6.85-6.81 (m, 3H), 5.15 (s, 2H), 3.77 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C@@H:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)C(C)C)(C)C.Cl[C:40]([O:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=1)=[O:41]>ClCCl.CCOC(C)=O>[F:49][C:46]1[CH:47]=[CH:48][C:43]([O:42][C:40](=[O:41])[N:14]([C@@H:13]2[C@@H:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:10][N:11]([C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:22][CH2:23]3)=[O:17])[CH2:12]2)[CH3:15])=[CH:44][CH:45]=1
Reactant: CN[C@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)Oc1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71 %

Procedure:
To a solution of rac-{4-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone (50 mg, 0.11 mmol) in dichloromethane (1 mL) were added N,N-diisopropyl ethyl amine (29 μl, 0.17 mmol), 4-fluorophenyl chloroformate (19 μl, 0.15 mmol) and the resulting mixture was stirred for 18 h at ambient temperature. It was diluted with EtOAc (15 mL) and washed with an aqueous solution of sodium carbonate (1M, 10 mL). The aqueous layers were extracted with dichloromethane (30 mL), dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 90:10) afforded the title compound (45 mg, 68%) as a light brown oil. MS m/e: 576.3 [M+H]+.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][C:9]=2[N+:16]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:26]([OH:28])[CH3:27].Cl.C(OCC)(=[O:32])C>[Pd]>[CH:1]1([N:7]2[C:8]3[C:9](=[CH:10][C:11]([C:14]#[N:15])=[CH:12][CH:13]=3)[NH:16][C:26](=[O:28])[C:27]2=[O:32])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Reactant: CCOC(C)=O
Reactant: CCO
Agent: [Pd]
Agent: Cl
Solvent: CCN(CC)CC
Product: N#Cc1ccc2c(c1)[nH]c(=O)c(=O)n2C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
A solution of 1.2 g (4.9 mmol) N-cyclohexyl-4-cyano-2-nitroaniline in 100 ml ethyl acetate was hydrogenated at 40 psi by using 5% Pd/C (100 mg) as a catalyst. The reaction mixture was filtered and 2.0 g (20 mmol) dry triethylamine was added. A solution of 2.7 g (20 mmol) ethyl oxalyl chloride in 20 ml ethyl acetate was added dropwise and the reaction mixture was stirred for 3 h. The reaction mixture was filtered and evaporated in vacuo to give an oil. A mixture of the oil, 20 ml ethanol and 70 ml 0.5 N hydrochloric acid was refluxed for 1 h. After cooling to 25° C. the precipitate was filtered off and washed with water to give 0.33 g (25%) 1-cyclohexyl-6-cyanoquinoxaline-2.3(1H,4H)-dione. M.p. (DSC): decomp. 1H-NMR (DMSO-d6): 12.0 (1H, broad s), 8.0-7.4 (3H, m), 4.4 (1H, m), 2.7-0.7 (10H, m). IR (KBr): 2450, 1700 cm-1.
Reaction SMILES: [N:1]([C@@H:4]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]([O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH2:7][CH2:6][C@H:5]1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[F:33])=[N+]=[N-]>C(O)C.[Pd]>[F:33][C:27]1[C:28]([F:32])=[CH:29][CH:30]=[CH:31][C:26]=1[C@@H:5]1[CH2:6][CH2:7][C@@H:8]([O:15][Si:16]([CH:20]([CH3:22])[CH3:21])([CH:23]([CH3:25])[CH3:24])[CH:17]([CH3:18])[CH3:19])[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:14]2[C@H:4]1[NH2:1]
Reactant: CC(C)[Si](O[C@@H]1CC[C@@H](c2cccc(F)c2F)[C@H](N=[N+]=[N-])c2cccnc21)(C(C)C)C(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)[Si](O[C@@H]1CC[C@@H](c2cccc(F)c2F)[C@H](N)c2cccnc21)(C(C)C)C(C)C
Reaction time: 2.5 h

Procedure:
A mixture of (5S,6S,9R)-5-azido-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine (598 mg, 1.265 mmol)(intermediate 9) and palladium (10% on activated carbon) (0.504 mg, 0.474 μmol) in ethanol (25 ml) was stirred under hydrogen (1 atm) for 2.5 h. LCMS indicated that the desired compound was formed, stirring was continued. After 5 h, the mixture was filtered, washed thoroughly with ethanol, and then concentrated to give 21 (525 mg, 93%) as a colorless oil: MS(ESI)[M+H+]=447.3.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[H-].[Na+].[C:9]1([N:15]2[C:19]3[C:20]4[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=4[S:22][CH2:23][C:18]=3[C:17]([C:28](Cl)=[O:29])=[N:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>CN(C)C=O.O1CCOCC1>[C:1]([CH:3]([C:28]([C:17]1[C:18]2[CH2:23][S:22][C:21]3[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=3[C:19]=2[N:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:16]=1)=[O:29])[C:4]([NH2:6])=[O:5])#[N:2]
Reactant: O=C(Cl)c1nn(-c2ccccc2)c2c1CSc1ccccc1-2
Reactant: N#CCC(N)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: N#CC(C(N)=O)C(=O)c1nn(-c2ccccc2)c2c1CSc1ccccc1-2
Temperature: 25 °C

Procedure:
2-Cyanoacetamide (1.85 g) is treated with 50% sodium hydride (1.28 g) in dimethylformamide (35 ml) under stirring at room temperature until the effervescence subsides. To this solution 1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazole-3-carbonyl chloride (6.53 g), prepared according to Example 15, dissolved in dioxane (35 ml) is added under stirring at room temperature. The reaction mixture is allowed to react for 2 hours, then is diluted with ice water and acidified to pH 1 with 37% HCl. The gummy precipitate is extracted with ethyl acetate and the organic solution washed with N HCl and then evaporated to dryness in vacuo. The residue is purified over SiO2 column, using chloroform/methanol 80:20 as eluent, to give 2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-propanamide, m.p. >300° C. dec., NMR (DMSO d6) δ ppm: 4.10 (s) (2H, --S--CH2 --), 6.00-7.00 (bs) (2H, CONH2), 6.60-7.80 (m) (9H, phenyl protons), 9.00 (bs) (1H, OH).
Reaction SMILES: [O:1]1[C:13]2[C:4](=[CH:5][C:6]3[NH:10][C:9]([SH:11])=[N:8][C:7]=3[CH:12]=2)[O:3][CH2:2]1.Cl.Cl[CH2:16][C:17]1[C:22]([CH3:23])=[C:21]([O:24][CH2:25][CH3:26])[C:20]([CH3:27])=[CH:19][N:18]=1.[OH-].[Na+]>C(O)C.O>[CH2:25]([O:24][C:21]1[C:20]([CH3:27])=[CH:19][N:18]=[C:17]([CH2:16][S:11][C:9]2[NH:10][C:6]3[CH:5]=[C:4]4[O:3][CH2:2][O:1][C:13]4=[CH:12][C:7]=3[N:8]=2)[C:22]=1[CH3:23])[CH3:26]
Reactant: CCOc1c(C)cnc(CCl)c1C
Reactant: Sc1nc2cc3c(cc2[nH]1)OCO3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1c(C)cnc(CSc2nc3cc4c(cc3[nH]2)OCO4)c1C

Procedure:
5.82 g of 5H-1,3-dioxolo[4,5-f]benzimidazole-6-thiol were suspended in 200 ml of ethanol and the suspension was treated with 7.1 g of 2-chloromethyl-4-ethoxy-3,5-dimethylpyridine hydrochloride while cooling with ice. Thereafter, a solution of 2.4 g of sodium hydroxide in 100 ml of water was added dropwise thereto, the mixture was left to boil at reflux overnight and subsequently evaporated to dryness in vacuo. The residue was dissolved in 500 ml of methylene chloride. The solution was washed firstly with 250 ml of 1.5N sodium hydroxide solution and then with 3×300 ml of water, dried over sodium sulfate and evaporated in vacuo. The product was purified on 150 g of silica gel using ethyl acetate/methylene choride (1:1) as the elution agent. Crystallization from acetonitrile gave 6-[[(4-ethoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-5H-1,3-dioxolo [4,5-f]benzimidazole of melting point 184°-185°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[C:3]=1[N+:17]([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(Cl)ccc1C(=O)O
Agent: O=S(=O)(O)O
Product: Cc1c(C(=O)O)ccc(Cl)c1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A round bottom flask was charged with 4-chloro-2-methylbenzoic acid (200 mg, 0.001 mol) and sulfuric acid (1 mL, 0.02 mol). Fuming nitric acid (0.05 mL, 0.001 mol) was added at −20° C. and the reaction was stirred for 1 hour at 70° C. and poured into ice cold water, whereupon the mixture of 2- and 4-nitro compounds precipitated out. The precipitate was filtered and dissolved in ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate solution and brine, and dried over sodium sulfate. The solvent was reduced to ¼ volume whereby the undesired isomer precipitated out. The precipitate was filtered and the filtrate was dried to afford a 1:1 mixture of isomers as a white solid.