Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[CH2:2][CH3:3].[C:5]1([NH:11][NH2:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(Cl)(Cl)(Cl)Cl>[C:5]1([NH:11][N:12]=[CH:1][CH2:2][CH3:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NNc1ccccc1
Reactant: CCC=O
Solvent: ClC(Cl)(Cl)Cl
Product: CCC=NNc1ccccc1

Procedure:
Following the same procedure described in Example 1, Part A, but using 100 ml. carbon tetrachloride as the solvent for 5.8 g. (0.1 mole) propionaldehyde, adding a solution of 10.8 g. (0.1 mole) phenylhydrazine in 25 ml. carbon tetrachloride, and removing the water formed by the reaction as its carbon tetrachloride azeotrope (volume of about 50 ml.), there was obtained a carbon tetrachloride solution of propionaldehyde phenylhydrazone.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]([CH3:42])([CH3:41])[C@H:9]([NH:14][C:15]([N:17]1[C:25]2[CH2:24][CH2:23][N:22]([CH2:26][C:27](OCC)=[O:28])[CH2:21][C:20]=2[C:19]([C:32]2[CH:37]=[C:36]([F:38])[C:35]([F:39])=[CH:34][C:33]=2[F:40])=[N:18]1)=[O:16])[C:10]([NH:12][CH3:13])=[O:11]>C1COCC1>[CH3:7][C:8]([CH3:42])([CH3:41])[C@H:9]([NH:14][C:15]([N:17]1[C:25]2[CH2:24][CH2:23][N:22]([CH2:26][CH2:27][OH:28])[CH2:21][C:20]=2[C:19]([C:32]2[CH:37]=[C:36]([F:38])[C:35]([F:39])=[CH:34][C:33]=2[F:40])=[N:18]1)=[O:16])[C:10]([NH:12][CH3:13])=[O:11]
Reactant: CCOC(=O)CN1CCc2c(c(-c3cc(F)c(F)cc3F)nn2C(=O)N[C@H](C(=O)NC)C(C)(C)C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(CCO)C2)C(C)(C)C
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
To a suspension of LAH powder (8 mg) in THF was added a solution of compound 83 (45 mg) in THF at 0° C. under nitrogen. After stirring for 30 min, the reaction was quenched with brine and extracted with EtOAc. The combined organic phase was dried over sodium sulfate and evaporated to dryness. The residue was dissolved in MeOH and purified with a preparative LC-MS to give compound 85 (27 mg). LCMS (+ESI) m/z=468.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1)[CH3:2].[C:23]1([OH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:21][C:5]([S:17]([CH3:20])(=[O:19])=[O:18])([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:10][CH:9]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:22]
Reactant: CCOC(=O)C(C)(CCc1ccc(B(O)O)cc1)S(C)(=O)=O
Reactant: Oc1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(C)(CCc1ccc(Oc2ccccc2)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of {4-[4-ethoxy-3-methyl-3-(methylsulfonyl)-4-oxobutyl]phenyl}boronic acid (599 mg, 1.83 mmol) in methylene chloride (3 mL) was added phenol (86 mg, 0.91 mmol), pyridine (148 uL, 1.83 mmol) and copper (II) acetate (157 mg, 0.866 mmol). The mixture was stirred at ambient temperature under open atmosphere for 2 days. Silica gel was added and the mixture was concentrated to dryness and purified via silica gel chromatography eluting with ethyl acetate/heptanes to afford ethyl 2-methyl-2-(methylsulfonyl)-4-(4-phenoxyphenyl)butanoate as an oil. 312 mg. LCMS: (M+1) 377.2
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.[C:18](Cl)(=[O:25])[O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22].CCN(C(C)C)C(C)C.O>C(Cl)Cl>[CH3:17][O:16][C:14]([C@@H:4]1[CH2:3][C@H:2]([NH:1][C:18]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:25])[CH2:6][N:5]1[C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])=[O:15]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: COC(=O)[C@@H]1C[C@H](N)CN1C(=O)OC(C)(C)C
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](NC(=O)OCC(Cl)(Cl)Cl)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2S,4S)-1-tert-butyl 2-methyl 4-aminopyrrolidine-1,2-dicarboxylate (4.6 g, 10.7 mmol) in CH2Cl2 (100 mL) were added 2,2,2-trichloroethyl carbonochloridate (1.73 mL, 12.88 mmol) and DIPEA (2.81 mL, 16.1 mmol). The reaction mixture was stirred at RT for 2 h then was poured into water. The desired compound was extracted with EtOAc (2×100 mL), the organic phases were joined, washed with 1N HCl then brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 1:1). MS (UPLC): 421 [M+H]+, 419 [M−H]−; tR (HPLC conditions f): 1.11 min.
Reaction SMILES: [N+]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1/[CH:17]=[CH:18]/[N:19](C)C)([O-])=O>[Ni].C(O)C>[F:16][C:13]([F:14])([F:15])[C:7]1[CH:6]=[C:5]2[C:4](=[CH:9][C:8]=1[NH2:10])[NH:19][CH:18]=[CH:17]2
Reactant: CN(C)/C=C/c1cc(C(F)(F)F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: Nc1cc2[nH]ccc2cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 14.5 %

Procedure:
A suspension of (E)-2-(2,4-dinitro-5-(trifluoromethyl)phenyl)-N,N-dimethylethenamine (2.1 g, 6.9 mmol) and Raney Nickel (1 g) in ethanol (80 mL) was stirred under H2 (1 atm) at room temperature for 5 h. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by column on silica gel to give 5-(trifluoromethyl)-1H-indol-6-amine (200 mg, 14%). 1H NMR (DMSO-d6) δ 10.79 (br s, 1H), 7.55 (s, 1H), 7.12 (s, 1H), 6.78 (s, 1H), 6.27 (s, 1H), 4.92 (s, 2H); MS (ESI) m/e 200.8.
Reaction SMILES: [C:1](=[O:21])([O:5][CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)[O:2][CH2:3]Cl.[I-:22].[Na+]>CC(C)=O>[C:1](=[O:21])([O:5][CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)[O:2][CH2:3][I:22]
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)N1CCC(CCOC(=O)OCCl)CC1
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCOC(=O)OCI)CC1
Temperature: 40 °C
Reaction time: 2.5 h

Procedure:
Chloromethyl 2-(1-(tert-butoxycarbonyl)-4-piperidyl)-ethyl carbonate (4.9 g) was added to a solution of sodium iodide (9 g) in acetone (20 ml). After stirring at 40° C. for 2.5 hours the reaction mixture was cooled to room temperature, filtered and evaporated in vacuo. The residue was taken up in dichloromethane, washed with aqueous sodium bicarbonate and sodium thiosulfate, dried over magnesium sulfate, filtered and evaporated in vacuo. Purification on silica gel with hexane/ethyl acetate (2:1) as eluent gave the title compound as a light yellow oil.
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8])[CH2:2][CH:3]=[CH2:4].[BH4-].[Na+]>CO>[CH2:1]([C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][OH:8])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCc1ccccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C=CCCc1ccccc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
A mixture of 2-(but-3-en-1-yl)benzaldehyde (500 mg, 3.12 mmol) in MeOH (10 mL) was added NaBH4 (118 mg, 3.12 mmol) and the mixture was stirred at rt for 1 h. It was then added water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to obtain an oil, which was then purified by biotage, eluting with 10% EtOAc/hexane to obtain (2-(but-3-en-1-yl)phenyl)methanol (320 mg, 1.973 mmol, 63.2% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.44-7.37 (m, 1H), 7.33-7.21 (m, 3H), 5.91 (ddt, J=16.9, 10.2, 6.6 Hz, 1H), 5.13-4.99 (m, 2H), 4.76 (d, J=5.9 Hz, 2H), 2.86-2.77 (m, 2H), 2.44-2.35 (m, 2H).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([N:24]1[C@H:29]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[C@@H:28]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=2)[CH2:27][C@@:26]([C@@H:45]([CH2:50][OH:51])[C:46]([O:48][CH3:49])=[O:47])([CH3:44])[C:25]1=[O:52])[CH:21]1[CH2:23][CH2:22]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:60][S:61](Cl)(=[O:63])=[O:62]>C(Cl)Cl>[Si:1]([O:18][CH2:19][C@@H:20]([N:24]1[C@H:29]([C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)[C@@H:28]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=2)[CH2:27][C@@:26]([C@@H:45]([CH2:50][O:51][S:61]([CH3:60])(=[O:63])=[O:62])[C:46]([O:48][CH3:49])=[O:47])([CH3:44])[C:25]1=[O:52])[CH:21]1[CH2:22][CH2:23]1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](CO)[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C2CC2)C1=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](COS(C)(=O)=O)[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C2CC2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-methyl 2-((3R,5R,6S)-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)-3-hydroxypropanoate (132 mg, 0.173 mmol; Example 270, Step A) and triethylamine (97 μL, 0.69 mmol) in DCM (2.2 mL) was added a solution of methanesulfonyl chloride (27 μL, 0.35 mmol) in DCM (2.2 mL) at 0° C. Then the reaction was allowed to warm to rt and stirred for 3 h. The reaction was quenched (water), extracted (2×EtOAc) and washed (brine). The combined organic layers were dried (Na2SO4) and concentrated under the reduced pressure to provide a crude mesylated compound, (S)-methyl 2-((3R,5R,6S)-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)-3-(methylsulfonyloxy)propanoate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][S:9]([C:12]2[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[C:4]([NH2:19])[N:3]=1.OO.[C:22]([O:25]C(=O)C)(=[O:24])[CH3:23]>C(O)C>[NH2:19][C:4]1[N:3]([O:25][C:22](=[O:24])[CH3:23])[C:2](=[NH:1])[N:7]=[C:6]([O:8][S:9]([C:12]2[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(N)nc(N)n2)cc1
Agent: OO
Solvent: CCO
Product: CC(=O)On1c(N)cc(OS(=O)(=O)c2ccc(C)cc2)nc1=N
Temperature: 60 °C

Procedure:
2.8 g (0.001 mole) of 2,6-diamino-4-tosyloxypyrimidine are added to 70 ml of absolute ethanol. 5 ml of a 70% aqueous hydrogen peroxide solution are added to the obtained suspension at 40° C., then 3 ml of acetic anhydride are added dropwise. The suspension is homogenised by heating to 60° C., and the solution gets slowly opalescent while standing. Tracing the reaction by thin layer chromatography it will be found that the reaction has completed and the aimed compound is accompanied by some diacetyl compound. By filtering the reaction mixture 0.35 g of a solid material is separated. If the ethyl alcohol is distilled off and the residue is allowed to stand in a refrigerator, no product separation can be observed. Of decanting the water and dissolving the residue in ethanol a crystalline product is obtained. In this way 1.95 g (54%) of the aimed compound are obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[CH3:13][C:14]([O:17][C:18](ON=C(C1C=CC=CC=1)C#N)=[O:19])([CH3:16])[CH3:15].C([O-])([O-])=O.[K+].[K+]>C1COCC1.C(Cl)(Cl)Cl>[N:1]1([C:18]([O:17][C:14]([CH3:16])([CH3:15])[CH3:13])=[O:19])[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1
Reactant: C1CC(C2CCNCC2)CCN1
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C2CCNCC2)CC1
Yield: 45.4 %

Procedure:
To 4,4′-bipiperidine (5.48 g, 32.6 mmol) in THF (160 mL) and CHCl3 (160 mL) was added BOC-On (4.01 g) in THF (90 mL) dropwise over a 8 h period. The reaction was then concentrated and purified by flash chromatography. The residue was taken up in 1M KHSO4 (250 mL) and washed with diethyl ether (three times). K2CO3 (38.0 g, 275 mmol) was added to the aqueous layer which was subsequently extracted with CHCl3 (3×), dried (MgSO4) and concentrated to provide the title compound of step A (1.98 g, 7.40 mmol, 45%). 1H NMR (400 MHz, CDCl3) δ ppm 1.06-1.18 (m, 5H), 1.42 (s, 9H), 1.58-1.69 (m, 6H), 2.50-2.61 (m, 4H), 3.06 (d, J=12.1 Hz, 2H), 4.08 (br. s., 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:14][C:15]([N:17]([CH3:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)=[O:4].[CH3:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]([N:5]([CH2:14][C:15]([N:17]([CH3:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:16])[C:3](=[O:4])[CH2:2][NH:1][C:33]([NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([CH3:25])[CH:27]=2)=[O:34])[CH:11]=[CH:10][CH:9]=1
Reactant: COc1cccc(N(CC(=O)N(C)c2ccccc2)C(=O)CN)c1
Reactant: Cc1cccc(N=C=O)c1
Product: COc1cccc(N(CC(=O)N(C)c2ccccc2)C(=O)CNC(=O)Nc2cccc(C)c2)c1
Yield: 53.3 %

Procedure:
Using a procedure similar to that described in Example 1, but starting with 2-[2-amino-N-(3-methoxyphenyl)acetamido]-N-methyl-N-phenylacetamide (1.6 g) and 3-methylphenyl isocyanate (0.67 g), and after recrystallisation in acetonitrile, 2-{N-(3-methoxyphenyl)-2-[3-(3-methylphenyl)ureido]acetamido}-N-methyl-N-phenylacetamide (1.2 g), m.p. 179° C., is obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:10](=[O:11])[CH2:9][C:7](=O)[N:6]([CH2:12][CH3:13])[C:4]1=[O:5])[CH3:2].CN(C)[CH:16]=[O:17].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:7]1[N:6]([CH2:12][CH3:13])[C:4](=[O:5])[N:3]([CH2:1][CH3:2])[C:10](=[O:11])[C:9]=1[CH:16]=[O:17]
Reactant: CN(C)C=O
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCN1C(=O)CC(=O)N(CC)C1=O
Product: CCn1c(Cl)c(C=O)c(=O)n(CC)c1=O
Temperature: 25 °C

Procedure:
To a solution of 1,3-diethylbarbituric acid (61 g) in phosphorus oxychloride (224 ml) was added dimethylformamide (35 ml) with stirring at room temperature and then the reaction solution was refluxed for 3.5 hr. The solution was concentrated to dryness to give an oil. The oil was poured into ice-water to give crystals, 6-chloro-1,3-diethyl-5-formyluracil (64 g), m.p. 88°-89° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH2:16][CH:17]1[CH2:19][CH2:18]1)[C:13](O)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH2:16][CH:17]1[CH2:18][CH2:19]1)[CH2:13][OH:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC1(CC1CC1)C(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1(CO)CC1CC1
Temperature: 25 °C
Yield: 97.6 %

Procedure:
To a solution of 2-cyclopropylmethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (4 g, see example 64 and 65) in THF (100 mL) was added borane-methylsulfide complex (8.9 mL of a 2M solution in THF) dropwise via syringe. The reaction mixture was heated for 4 hours to 80° C. and was then cooled to RT. The THF was removed in vacuo and the residue was then diluted with water and DCM. The phases were separated and the aqueous phase was extracted with further DCM (2×50 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution, brine and dried over sodium sulfate. Filtration of the drying agent and evaporation in vacuo to dryness afforded the crude 2-cyclopropylmethyl-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (3.7 g) to which was added Dess-Martin periodinane solution (32.6 mL of a 15% solution in DCM, CAS [87413-09-0]) and the reaction mixture was stirred for 5 hours at RT. The reaction was quenched with 10 mL of saturated aqueous sodium thiosulfate solution and stirred for a further 20 minutes. The phases were separated and the DCM layer was washed with saturate aqueous sodium bicarbonate solution. The aqueous layers were back extracted with further DCM and the combined DCM layers were dried over sodium sulfate, filtered and reduced to dryness in vacuo to afford the desired 2-cyclopropylmethyl-2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.59 g, MS (ES+): 254.3 (M+H), as a brown oil).
Reaction SMILES: C(OC([N:6]1[C:25]([NH2:26])=[C:9]2[CH2:10][N:11]([S:14]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)(=[O:16])=[O:15])[CH2:12][CH2:13][C:8]2=[N:7]1)=O)C.C(N(CC)CC)C>ClCCl.CO>[F:23][C:21]1[CH:22]=[C:17]([S:14]([N:11]2[CH2:12][CH2:13][C:8]3=[N:7][NH:6][C:25]([NH2:26])=[C:9]3[CH2:10]2)(=[O:16])=[O:15])[CH:18]=[C:19]([F:24])[CH:20]=1
Reactant: CCOC(=O)n1nc2c(c1N)CN(S(=O)(=O)c1cc(F)cc(F)c1)CC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: Nc1[nH]nc2c1CN(S(=O)(=O)c1cc(F)cc(F)c1)CC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 93.9 %

Procedure:
3-Amino-5-(3,5-difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-2-carboxylic acid ethyl ester (45.4 g, 117.5 mmol) was dissolved in a mixture of dichloromethane (200 mL) and methanol (900 mL) then triethylamine (200 mL) was added. The solution was stirred at room temperature for 2 days and then evaporated to dryness. The solid was treated with diethylether (1 L), stirred for 1 hour, filtered and washed with diethylether. After drying in vacuo the title compound was obtained as white solid (34.68 g, 94%).
Reaction SMILES: [CH:1]1([C:4](=[O:26])[CH2:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([CH2:15][N:16]3[C:20](=[O:21])[N:19]([CH:22]4[CH2:24][CH2:23]4)[N:18]=[N:17]3)[C:9]=2[Cl:25])=[O:7])[CH2:3][CH2:2]1.[CH:27](OCC)(OCC)[O:28][CH2:29][CH3:30]>C(OC(=O)C)(=O)C>[CH:1]1([C:4](=[O:26])[C:5](=[CH:27][O:28][CH2:29][CH3:30])[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([CH2:15][N:16]3[C:20](=[O:21])[N:19]([CH:22]4[CH2:24][CH2:23]4)[N:18]=[N:17]3)[C:9]=2[Cl:25])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(OCC)OCC
Reactant: O=C(CC(=O)C1CC1)c1ccc(Cl)c(Cn2nnn(C3CC3)c2=O)c1Cl
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)c1ccc(Cl)c(Cn2nnn(C3CC3)c2=O)c1Cl)C(=O)C1CC1
Yield: 107.1 %

Procedure:
3-Cyclopropyl-1-{3-[(4-cyclopropyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)methyl]-2,4-dichlorophenyl}propan-1,3-dione (2.64 g) was dissolved in acetic anhydride (15 ml) and the solution, after adding triethyl orthoformate (2.12 g), was refluxed for 4 hours upon heating. The solvent was distilled off under reduced pressure and the residue was treated with toluene, which was distilled off under reduced pressure to obtain crude 3-cyclopropyl-1-{3-[(4-cyclopropyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)methyl]-2,4-dichlorophenyl}-2-ethoxymethylenepropan-1,3-dione (3.23 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]3[C:20]([N:21]=[C:22]4CC[CH2:26][CH2:25][CH2:24][C:23]=24)=[CH:19][CH:18]=[N:17]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1N2C(=CC=N2)N=C2C=1CCC2.C(OC1C=CC(B(O)O)=CC=1)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:16]3[C:20](=[CH:19][CH:18]=[N:17]3)[N:21]=[C:22]3[C:23]=2[CH2:24][CH2:25][CH2:26]3)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COc2ccc(-c3c4c(nc5ccnn35)CCCCC4)cc2)cc1
Agent: Clc1c2c(nc3ccnn13)CCC2
Agent: OB(O)c1ccc(OCc2ccccc2)cc1
Product: c1ccc(COc2ccc(-c3c4c(nc5ccnn35)CCC4)cc2)cc1

Procedure:
Using the method described for the preparation of 10-(4-benzyloxy-phenyl)-6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]indene, the reaction of 8-chloro-6,7-dihydro-5H-1,4,8a-triaza-s indacene and 4-benzyloxyphenyl boronic acid provided the title compound.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([Cl:7])Cl.[C:8]1([C:14]2[N:15]=[C:16]3[CH:21]=[CH:20][CH:19]=[C:18](CO)[N:17]3[CH:24]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[ClH:3].[C:8]1([C:14]2[N:15]=[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:5][Cl:7])[N:17]3[CH:24]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: OCc1cccc2nc(-c3ccccc3)cn12
Reactant: ClCCl
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cl
Product: ClCc1cccc2nc(-c3ccccc3)cn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a mixture solution consisting of 3.7 ml (50.0 mmol) of thionyl chloride and 5.0 ml of methylene chloride was added, 2.24 g (10.0 mmol) of 2-phenyl-5-hydroxymethylimidazo[1,2-a]pyridine with small portion. The reaction mixture was stirred for one hour at room temperature, then the solvent and excess volume of thionyl chloride were distilled off under reduced pressure to leave a white solid. Toluene (20 ml) was added to the white solid, and the mixture was sufficiently blended, followed by distilling off the solvent under reduced pressure. This process was repeated twice to give 2.76 g a crude product (99.0%, white solid).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[C:15](=[O:21])[CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:22]([OH:24])=[O:23])[CH2:3]1.Cl.[CH2:26](O)[CH3:27]>>[CH2:26]([O:23][C:22]([C@H:11]1[CH2:10][CH2:9][C@H:8]2[C@H:7]3[C@H:16]([C:15](=[O:21])[CH2:14][C@:12]12[CH3:13])[C@:17]1([CH3:20])[C@H:4]([CH2:3][C@H:2]([OH:1])[CH2:19][CH2:18]1)[CH2:5][CH2:6]3)=[O:24])[CH3:27]
Reactant: CCO
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC(=O)[C@@H]12
Agent: Cl
Product: CCOC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
A solution of 3α-hydroxy-11-oxo-5α-androstane-17β-carboxylic acid (500 mg.) in dry ethanol containing 3.3%, by weight, of hydrogen chloride (100 ml.) was refluxed for 2 hours.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[CH:17]=[O:18])[CH2:6][CH2:7][CH3:8])[CH3:2].[CH2:20](O)[CH2:21][OH:22]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[CH:17]1[O:22][CH2:21][CH2:20][O:18]1)[CH2:6][CH2:7][CH3:8])[CH3:2]
Reactant: CCCC(Oc1ccc(Cl)cc1C=O)C(=O)OCC
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCC(Oc1ccc(Cl)cc1C1OCCO1)C(=O)OCC
Reaction time: 3 h
Yield: 91.8 %

Procedure:
A mixture of 2-(4-chloro-2-formyl-phenoxy)-pentanoic acid ethyl ester (15 g, 53 mmol), ethylene glycol (25 mL, 440 mmol) and p-toluenesulfonic acid (0.8 g, 4.65 mmol) in toluene (150 mL) was refluxed with a Dean-Stark trap attached. After 3 h, the reaction was cooled and washed with water, saturated NaHCO3 solution and water, and the organic layer was dried over anhydrous Na2SO4 and concentrated to give the title compound as a light yellow oil (16 g).