Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[O:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([NH2:28])[N:23]=1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[O:12])=[N:7][N:8]2[C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH2:28])[N:23]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1n[nH]c2cc(Br)ccc12)N1CCOCC1
Reactant: Nc1nccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nccc(-n2nc(C(=O)N3CCOCC3)c3ccc(Br)cc32)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-bromo-3-[(morpholin-4-yl)carbonyl]-1H-indazole (78%, 458 mg, 1.15 mmol) in DMF (8 mL) was added NaH (60% oil suspension, 73.71 mg, 1.84 mmol) at 0° C. Mixture was stirred at RT for 10 minutes before addition of 4-chloropyrimidin-2-amine (298.44 mg, 2.3 mmol). The mixture was stirred at RT for 10 minutes and then at 65° C. for 5 hr. Reaction mixture was quenched by addition of water (5 mL) and a little EtOAc (2 mL) was added. Precipitate formed was collected and dried under vacuum to give the title compound: 1H NMR (500 MHz, DMSO) delta 3.58-3.80 (6H, m), 3.87-4.13 (2H, m), 7.07 (1H, d, J=5.52 Hz), 7.59 (1H, dd, J=8.51, 1.42 Hz), 7.94 (1H, d, J=8.83 Hz), 8.35 (1H, d, J=5.52 Hz), 9.19 (1H, d, J=1.26 Hz); LC-MS: m/z=+404.8 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[O:13][C:12](=[O:14])[O:11][C:10]=1[CH2:15][O:16][C:17](=[O:30])[C@@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1C(OC(C)(C)C)=O>C1(C)C=CC=CC=1>[CH3:8][C:9]1[O:13][C:12](=[O:14])[O:11][C:10]=1[CH2:15][O:16][C:17](=[O:30])[C@@H:18]1[CH2:22][CH2:21][CH2:20][NH:19]1
Reactant: Cc1oc(=O)oc1COC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1oc(=O)oc1COC(=O)[C@@H]1CCCN1
Reaction time: 0.75 h
Yield: 196.1 %

Procedure:
Trifluoroacetic acid (2.5 ml) was added to the compound (38) (360 mg, 1.1 mmol) under ice-cooling and the resulting mixture was stood for 45 min. To the reaction mixture was added toluene and the mixture was concentrated in vacuo to give 490 mg of the compound (39). This compound was used in the next reaction without purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([OH:21])[CH:9]=2)=[O:5])[CH3:2].O[CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1.C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(O)cc2C1=O
Reactant: OCCN1CCOCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 128.4 %

Procedure:
6-Hydroxy-1-oxo-3-phenyl-1H-indene-2-carboxylate ethyl ester [compound of formula (II)] (10.90 g, 26.75 mmol) prepared in Step 4 of Example 1 was dissolved in tetrahydrofuran:benzene (270 ml:90 ml). Then, 4-(2-hydroxyethyl)morpholine (5.83 g, 44.45 mmol) and triphenylphosphine (11.66 g, 44.45 mmol) were added thereto. Diisopropylazodicarboxylate (8.99 g, 44.45 mmol) was added dropwise to the mixture at 0° C., and stirred for 2 hours at room temperature. The reaction mixture was washed with saturated sodium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, concentrated, and the resulting residue was purified by column chromatography (ethyl acetate) to obtain the title compound (14 g, yield 93%) as a red solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)=O.[NH2:20][C:21]1[CH:25]=[CH:24][NH:23][N:22]=1>C(O)(=O)C>[F:14][C:13]([F:16])([F:15])[C:9]1[CH:8]=[C:7]([C:5]2[CH:4]=[C:3]([C:2]([F:19])([F:18])[F:1])[N:22]3[N:23]=[CH:24][CH:25]=[C:21]3[N:20]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1cc[nH]n1
Reactant: O=C(CC(=O)C(F)(F)F)c1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Product: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)n3nccc3n2)c1
Yield: 95.3 %

Procedure:
A mixture of 4,4,4-trifluoro-1-(3-trifluoromethyl-phenyl)-butane-1,3-dione (10.3 g, 36.1 mmol) and commercially available 3-aminopyrazole (3.0 g, 36.1 mmol) in acetic acid (100 mL) was refluxed for 4 h and evaporated. The crude product was further purified by crystallization (ethyl acetate/hexane) to yield 5-(3-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (11.4 g, 95%) as a light yellow solid. MS (ISP) 323.3 [(M+H)+]; mp 96° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][S:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>CC(C)=O.ClCCl>[CH3:24][S:25]([O:17][C:14]1[CH:15]=[CH:16][C:11]([S:10][CH2:9][S:8][C:5]2[CH:4]=[CH:3][C:2]([O:1][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:7][CH:6]=2)=[CH:12][CH:13]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: Oc1ccc(SCSc2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccc(SCSc2ccc(OS(C)(=O)=O)cc2)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 90.4 %

Procedure:
In 200 g of acetone was dissolved 23 g (0.1 mol) of the bis(4-hydroxyphenylthio)methane crude product in Synthesis Example 1. To this were added 35 g (0.25 mol) of potassium carbonate and 28 g (0.24 mol) of methanesulfonylchloride. While refluxing in an oil bath at 70° C., the solution was ripened for 4 hours. After cooling, the inorganic salt was filtered and washed with 50 g of acetone. The filtrate and wash liquid combined was concentrated, yielding an oily product, which was dissolved in 150 g of dichloromethane. This solution was washed with 100 g of water, and concentrated again. There was yielded 38 g of a concentrated oily residue, which was used in the subsequent reaction without further purification. It is noted that this oily matter crystallized when kept at room temperature.
Reaction SMILES: [C:1]1([S:7][CH:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][O:11][C:10]3[CH:19]=[CH:20][C:21]([C:23]([O:25]C)=[O:24])=[CH:22][C:9]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O>[C:1]1([S:7][CH:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][O:11][C:10]3[CH:19]=[CH:20][C:21]([C:23]([OH:25])=[O:24])=[CH:22][C:9]2=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc2c(c1)C(Sc1ccccc1)c1ccccc1CO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2c(c1)C(Sc1ccccc1)c1ccccc1CO2

Procedure:
Dissolve 650 mg of the ester of Step A in 15 ml of methanol. Add 10 ml of 20% aqueous sodium hydroxide and reflux for 10 minutes. Dilute with 200 ml of water and extract with ether. Acidify the aqueous extract concentrated hydrochloric acid and extract into ether. Evaporate to dryness and crystalline from methanol to obtain the title product.
Reaction SMILES: [Br:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.[H][H].CCOCC>C(O)(=O)C.[Pd]>[Br:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH2:9][CH2:8]3
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CBr)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1cc2c(c3c1NC(=O)CC3)OC(CBr)C2
Yield: 78.2 %

Procedure:
2-Bromomethyl-5-methyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (4.0 g, 13.6 mmol) was dissolved in acetic acid (100 ml). To the resultant solution, 10% palladium-on-carbon (4 g) was added, followed by stirring at 70° C. for 7 hours in the stream of hydrogen. The palladium-on-carbon was filtered off, and the filtrate was condensed under reduced pressure. Ether was added to the residue, obtaining 3.15 g of the title compound as a colorless solid (78.2%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][N:5]=[CH:4][N:3]=1.[OH-].[Na+].Cl>>[CH3:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cncnc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ncncc1C(=O)O
Temperature: 25 °C
Yield: 69.4 %

Procedure:
Intermediate 52 (2.6 g, 15.64 mmol) dissolved in sodium hydroxide solution (1.88 g, 47 mmol in 4 ml water) and refluxed. The reaction mixture was cooled to rt and acidified with con HCl to obtain the solid. Solid that obtained was filtered and dried to obtain the title compound (1.5 g) as an yellow solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 13.5 (bs, 1H), 9.14 (s, 1H), 9.05 (s, 1H), 2.71 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([C:26]4[N:30](C5CCCCO5)[N:29]=[CH:28][CH:27]=4)[S:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl.CCO>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([C:26]4[CH:27]=[CH:28][NH:29][N:30]=4)[S:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(-c2ccnn2C2CCCCO2)n1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(-c2cc[nH]n2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)thiazole-4-carboxamide (13 mg, 0.025 mmol) was added into a flask under nitrogen atmosphere. 10% HCl/EtOH (0.028 ml, 0.062 mmol) was added and the reaction mixture was stirred in RT for 3 h. The reaction mixture was diluted with ethyl acetate and washed with 1M Na2CO3. The organic phase was dried, filtered and evaporated. Yield 94%. 1H-NMR (400 MHz; MeOD): δ 1.30 (d, 3H), 4.38 (dd, 1H), 4.45 (dd, 1H), 4.59 (m, 1H), 6.75 (d, 1H), 6.83 (d, 1H), 7.61 (d, 1H), 7.73 (d, 1H), 7.76 (d, 1H), 7.84 (dd, 1H), 7.95 (d, 1H), 8.06 (s, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[C:20]1(=[C:23]2[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]2)[CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCC(Cl)C.ClCCl.C(O)(=O)C>[CH3:2][O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][CH:26]2[CH2:27][CH2:28][C:23](=[C:20]3[CH2:22][CH2:21]3)[CH2:24][CH2:25]2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: O=C1CCC(=C2CC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(Cl)CCl
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CNC2CCC(=C3CC3)CC2)cc1
Yield: 35 %

Procedure:
4-Aminomethylbenzoic acid methyl ester, hydrochloride salt (2.2 g, 11 mmol) was suspended in 1,2 dichloropropane (30 mL) and an aqueous saturated solution of potassium carbonate (15 mL) was added. The next day the organic phase was isolated and dried (MgSO4). 4-Cyclopropylidenecyclohexanone (1.5 g, 11 mmol) dissolved in dichloromethane (15 mL) was added followed by addition of acetic acid (400 μL) and sodium triacetoxyborohydride (3.3 g, 16.5 mmol). After 72 hours at 20° C. the reaction mixture was diluted with dichloromethane (50 mL) and washed with aqueous saturated sodium hydrogen carbonate (2×30 mL) and water (5×30 mL). The organic phase was dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (50 g silica) using ethyl acetate and methanol (97:3) as eluent to give 1.1 g of 4-[(4-cyclopropylidenecyclohexylamino)methyl]benzoic acid methyl ester.
Reaction SMILES: Cl.[N:2]1([C:6]([C:8]2[CH:40]=[CH:39][C:11]([O:12][C:13]3[CH:14]=[C:15]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:38])[CH2:29][O:30][Si](C(C)(C)C)(C)C)[CH:26]=3)[C:16]([NH:18][C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[O:17])=[CH:10][CH:9]=2)=[O:7])[CH2:5][CH2:4][CH2:3]1.C(=O)(O)[O-].[Na+]>CO>[N:2]1([C:6]([C:8]2[CH:40]=[CH:39][C:11]([O:12][C:13]3[CH:14]=[C:15]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:38])[CH2:29][OH:30])[CH:26]=3)[C:16]([NH:18][C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[O:17])=[CH:10][CH:9]=2)=[O:7])[CH2:5][CH2:4][CH2:3]1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2)cc(C(=O)Nc2nccs2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2)cc(C(=O)Nc2nccs2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
10% Hydrochloric acid (1 mL) was added to a solution of 3-[4-(azetidin-1-ylcarbonyl)phenoxy]-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)-N-1,3-thiazol-2-ylbenzamide (284 mg, 0.5 mmol) in methanol (10 mL). The reaction was stirred at RT for 1 hour, saturated sodium bicarbonate solution added and the methanol evaporated. The aqueous residue was taken to pH 2 and extracted with ethyl acetate. The extracts were combined, washed with brine, dried (MgSO4), filtered, and evaporated in vacuo to give the crude product which was chromatographed on silica, eluting with 1% methanol in ethyl acetate, to give the desired compound (113 mg).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.S(=O)(=O)(O)O.[CH3:16]O>>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:16])=[O:9])[CH2:4][CH2:3]1
Reactant: CO
Reactant: O=C(O)C1CCC(O)CC1
Agent: O=S(=O)(O)O
Product: COC(=O)[C@H]1CC[C@H](O)CC1
Temperature: 60 °C
Reaction time: 10 h

Procedure:
A 250-mL round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was charged with 4-hydroxycyclohexane-1-carboxylic acid (15.7 g, 108.90 mmol, 1.00 equiv) in methanol (90 mL). Sulfuric acid (0.8 mL) was added to the mixture slowly. The resulting solution was stirred for 10 hr at 60° C. The reaction was then quenched by the addition of 200 mL of sodium bicarbonate (sat.). The resulting solution was extracted with 3×200 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting trans-methyl 4-hydroxycyclohexane-1-carboxylate (16.6 g, 96%) was obtained as a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:14])=[C:4]([CH:7]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:9]=1)[CH:5]=[O:6].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.CO>C(Cl)Cl>[CH2:15]([O:14][C:3]1[C:2]([Br:1])=[CH:9][C:8]([C:10]([CH3:11])([CH3:13])[CH3:12])=[CH:7][C:4]=1[CH:5]=[O:6])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)c1cc(Br)c(OCc2ccccc2)c(C=O)c1

Procedure:
step 1—Benzylation of 3-bromo-5-tert-butyl-2-hydroxy benzaldehyde (36a) with benzyl bromide is accomplished treating 36a with benzyl bromide and tetrabutylammonium hydroxide in a biphasic system comprised of MeOH and DCM to afford 2-benzyloxy-3-bromo-5-tert-butyl-benzaldehyde (36b).
Reaction SMILES: [OH:1][C@H:2]1[C:19]2[C@:14]([CH3:21])([CH2:15][CH2:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@@:5]3([OH:23])[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[CH2:3]1.O=O>C(Cl)(Cl)Cl>[OH:23][C@:5]12[C@H:4]3[C@@H:13]([C@:14]4([CH3:21])[C:19]([C:2](=[O:1])[CH2:3]3)=[CH:18][C:17](=[O:20])[CH2:16][CH2:15]4)[CH2:12][CH2:11][C@:9]1([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]2
Reactant: C[C@]12CCC(=O)C=C1[C@H](O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@]12O
Agent: O=O
Solvent: ClC(Cl)Cl
Product: C[C@]12CCC(=O)C=C1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@]12O
Reaction time: 4 h
Yield: 99 %

Procedure:
6β,14α-dihydroxy-4-androstene-3,17-dione (50 g) thus prepared in the above-mentioned manner was dissolved in 1 liter of chloroform and transferred to a glass sealable vessel; after blowing oxygen therein, the vessel was sealed and allowed to stand for 4 hours under sunlight. Thereafter, the chloroform was removed by evaporation at 40° C. After the evaporation, the resultant residue was analyzed by thin layer chromatography and a spot for 14α-hydroxy-4-androstene-3,6,17-trione only was confirmed. According to this method, 49.2 g of 14α-hydroxy-4-androstene-3,6,17-trione was obtained. The yield was 98.4%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:8]([OH:10])=O)[NH:6][CH:7]=1)#[N:2].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([N:31]3[CH2:36][CH2:35][CH:34]([CH3:37])[CH2:33][CH2:32]3)[CH:25]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:8]([C:5]3[NH:6][CH:7]=[C:3]([C:1]#[N:2])[CH:4]=3)=[O:10])=[C:26]([N:31]3[CH2:36][CH2:35][CH:34]([CH3:37])[CH2:33][CH2:32]3)[CH:25]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC1CCN(c2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2N)CC1
Reactant: N#Cc1c[nH]c(C(=O)O)c1
Product: CC1CCN(c2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2NC(=O)c2cc(C#N)c[nH]2)CC1

Procedure:
Prepared according to the procedure from Example 53 using 4-cyano-1H-pyrrole-2-carboxylic acid (as prepared in Example 2) and 4-[4-amino-3-(4-methyl-piperidin-1-yl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester as prepared in Example 15, step (c). Purification of the resulting residue by silica gel preparative TLC eluting with 20% ethyl acetate in dichloromethane afforded the title compound in 47% as an off-white solid. 1H-NMR (400 MHz, CDCl3): δ 11.13 (br s, 1H), 9.05 (s, 1H), 8.29 (d, 1H, J=8.9), 7.48 (dd, 1H, J=3.0, 1.3 Hz), 6.88 (s, 1H), 6.84 (d, 1H, J=2.6 Hz), 6.76 (dd, 1H, J=8.9, 2.2 Hz), 3.62 (m, 4H), 3.13 (m, 4H), 3.01-2.98 (m, 2H), 2.73 (m, 2H), 1.88-1.85 (m, 2H), 1.61-1.56 (m, 2H), 1.51 (s, 9H), 1.50-1.37 (m, 2H), 1.10 (d, 3H, J=6.5 Hz). LC-MS (ESI, m/z): Calcd. for C27H37N6O3, 493.3 (M+H); found: 493.1.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][N:22]4[CH2:27][CH2:26][CH:25]([C:28]5[CH:32]=[C:31]([C:33]6[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=6)[NH:30][N:29]=5)[CH2:24][CH2:23]4)=[CH:17][CH:16]=3)=[N:9][CH:10]=[C:11]([CH:14]=2)[C:12]#[N:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[NH:40][C:41]([NH2:43])=[S:42].C(=O)(O)[O-].[Na+]>C(O)(C(F)(F)F)=O>[C:1]1([C:7]2[CH:14]=[C:11]([C:12]3[S:42][C:41]([NH2:43])=[N:40][N:13]=3)[CH:10]=[N:9][C:8]=2[C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:32]=[C:31]([C:33]5[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=5)[NH:30][N:29]=4)[CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNC(N)=S
Reactant: N#Cc1cnc(-c2ccc(CN3CCC(c4cc(-c5ccncc5)[nH]n4)CC3)cc2)c(-c2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc(-c2cnc(-c3ccc(CN4CCC(c5cc(-c6ccncc6)[nH]n5)CC4)cc3)c(-c3ccccc3)c2)s1

Procedure:
A solution of 5-phenyl-6-(4-{[4-(5-pyridin-4-yl-1H-pyrazol-3-yl)piperidin-1-yl]methyl}phenyl)nicotinonitrile (4B-5; 0.030 g, 0.060 mmol) and thiosemicarbazide (0.006 g, 0.066 mmol) in TFA (1.5 mL) were heated to 60° C. for 16 hr. The reaction was then cooled, poured onto ice and basified with saturated aqueous sodium bicarbonate. The resulting precipitate (4B-6) was filtered, taken up in DMF and purified by reverse phase HPLC (5% CH3CN: 95% H2O+0.1% TFA to 95% CH3—CN: 5% H2O+0.01% TFA). 1H-NMR (500 MHz, d6 DMSO) δ 13.54 (bs, 1H), 9.64 (s, 1H), 9.07 (d, J=1.96, 1H), 8.81 (d, J=6.11, 2H), 8.21 (s, 2H), 8.10 (d, J=2.2, 1H), 7.65 (s, 2H), 7.23-7.49 (m, 9H), 7.00 (s, 1H), 4.33 (d, 2H), 3.45 (d, J=10.5, 2H), 2.95-3.15 (m, 3H), 2.21 (d, J=12.69, 2H), 1.76-1.90 (m 2H). HRMS m/z (M+H) Calcd: 571.2387, found: 571.2359.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[C:10](=O)[C:11](=[O:13])[NH:12][C:7]=3[CH:6]=[CH:5][C:4]=2[NH:3][N:2]=1.[CH:15]1[C:20]([NH:21][NH2:22])=[CH:19][CH:18]=[C:17]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:16]=1.Cl>>[O:13]=[C:11]1[NH:12][C:7]2[CH:6]=[CH:5][C:4]3[NH:3][N:2]=[CH:1][C:9]=3[C:8]=2[C:10]1=[N:22][NH:21][C:20]1[CH:19]=[CH:18][C:17]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:16][CH:15]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: O=C1Nc2ccc3[nH]ncc3c2C1=O
Agent: Cl
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc4[nH]ncc4c32)cc1
Yield: 8 %

Procedure:
The title compound was prepared from 3,6-dihydro-pyrrolo[3,2-e]indazole-7,8-dione (Cuny, et al., Chemie Berichte 1981, 114, 1624-35) and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G in 8% yield: 1H NMR (DMSO-d6): δ7.02 (d, J=8.7 Hz, 1H), 7.28 Z (s, 2H), 7.51 (d, J=8.6 Hz, 2H), 7.68 (d, J=8.8 Hz, 1H), 7.82 (d, J=8.7 Hz, 2H), 8.34 (s,1H), 10.98 (s, 1H), 12.90 (s, 1H), 13.20 (s,1H); APCI−MS m/z 356 (M)−. Anal. Calcd for C15H12N6O3S.1.46H2O.0.2EtOAc: C, 47.41, H, 4.16; N, 20.99; S, 8.01. Found C, 47.40, H, 3.70; N, 21.00; S, 7.85.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH:5]([N:21]1[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]1)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1
Reactant: Clc1ccc(C(Cl)c2cccc(Br)c2)cc1
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: CN1CCN(C(c2ccc(Cl)cc2)c2cccc(Br)c2)CC1
Temperature: 25 °C

Procedure:
The benzhydryl chloride from above (8.33 g, 26.4 mmol) in 10 mL of N-methylpiperazine was heated to 110° for 12 hours under nitrogen. After cooling to room temperature, the residue was dissolved in 75 mL of methylene chloride and washed with 40 mL of 1M sodium hydroxide and two 50 mL portions of water. After drying over sodium sulfate, the solvent was removed in vacuo to give 10.2 g of 1-(3-bromo-4'-chlorobenzhydryl)-4-methylpiperazine as a dark oil. A portion of the oil was dissolved in ether and converted to the dihydrochloride salt with ethanolic hydrogen chloride. Recrystallization from 2:1 ethanol:methanol gave white powdery crystals, m.p. 229°-231°. Calc. for C18H20BrClN2.2HCl: C, 47.76; H, 4.90; N, 6.19. Found: C, 47.55; H, 4.91; N, 6.13.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][N:11]2[C:16](=[O:17])[CH:15]=[N:14][C:13]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[N:21][C:12]2=3)[CH2:5][CH2:4]1.C[O-].[Na+].CO.[O:29]=[C:30]1[CH2:35][S:34][C:33]2[CH:36]=[CH:37][C:38]([CH:40]=O)=[N:39][C:32]=2[NH:31]1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.C(Cl)(Cl)Cl.C(O)(=O)C>[CH3:23][O:22][C:20]1[CH:19]=[CH:18][C:13]2[N:14]=[CH:15][C:16](=[O:17])[N:11]([CH2:10][CH2:9][N:6]3[CH2:5][CH2:4][CH:3]([NH:2][CH2:40][C:38]4[CH:37]=[CH:36][C:33]5[S:34][CH2:35][C:30](=[O:29])[NH:31][C:32]=5[N:39]=4)[CH2:8][CH2:7]3)[C:12]=2[N:21]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2n1
Agent: C[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4ccc5c(n4)NC(=O)CS5)CC3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.7 %

Procedure:
To a suspension of 0.21 g of 4-(2-(4-aminopiperidin-1-yl)ethyl)-6-methoxypyrido(2,3-b)pyrazin-3(4H)-one hydrochloride in 5 mL of methanol, 0.22 g of a 28% sodium methoxide/methanol solution, 0.11 g of 3-oxo-3,4-dihydro-2H-pyrido(3,2-b)(1,4)thiazine-6-carbaldehyde, 32 μL of acetic acid and 70 mg of sodium cyanoborohydride were added, and the mixture was stirred at room temperature for 3 hours. Chloroform and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by basic silica gel column chromatography using an eluent of chloroform:methanol=10:1. Diethyl ether and hexane were added to the resultant residue, and the solid was filtered off to obtain 0.13 g of 6-(((1-(2-(6-methoxy-3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidin-4-yl)amino)methyl)-2H-pyrido(3,2-b)(1,4)thiazin-3(4H)-one as a light brown solid.