Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](CCOS(C)(=O)=O)[CH:18]=2)[NH:13][C:12]=1C)=O)C1C=CC=CC=1.COC[C@H]1CCC[NH:32]1>O1CCOCC1>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[C:12]1[NH2:32]
Reactant: Cc1[nH]c2ccc(CCOS(C)(=O)=O)cc2c1C(=O)OCc1ccccc1
Reactant: COC[C@H]1CCCN1
Solvent: C1COCCO1
Product: Nc1cc2ccccc2[nH]1
Yield: 252.2 %

Procedure:
5-(2-Methanesulfonyloxy-ethyl)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (0.350 g, 0.900 mmol, 1 eq, Example 56, Step D) was suspended in dioxane (20 mL) under Ar. (R)-2-(Methoxymethyl)-pyrrolidine (0.207 g, 1.800 mmol, 2 eq) was added. The reaction mixture was stirred and heated to reflux for 18 hours. Then the reaction was quenched with saturated sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic phases were washed with brine and dried over Na2SO4. After removing the solvent, the residue was loaded on silica gel and chromatographed, eluting with ethyl acetate/methanol/triethyl amine (100/10/1). 0.300 g (82%) of the indole-amine was obtained as a white solid. This was converted to the .HCl salt. LC/MS (ESI+) 407 (M+1); Anal. Calcd for C25H30N2O3.1 HCl.1H2O: C, 65.14; H, 7.22; N, 6.08; Found: C, 65.07; H, 7.08; N, 6.19.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[C:12]([O:15][C@@H:16]1[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:20]([O:26][C:27](=[O:29])[CH3:28])[CH2:19][O:18][C@@H:17]1Br)(=[O:14])[CH3:13]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.O>[C:12]([O:15][C@@H:16]1[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:20]([O:26][C:27](=[O:29])[CH3:28])[CH2:19][O:18][C@H:17]1[O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CO[C@@H]1Br
Reactant: O=Cc1ccc(O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Oc2ccc(C=O)cc2)OC[C@H]1OC(C)=O

Procedure:
p-Hydroxybenzaldehyde (2.2 g, 18 mmol), dichloromethane (20 mL) and a 5% aqueous solution of sodium hydroxide (25 mL) were put in a 100 mL round bottom flask and stirred vigorously. At that time, the water phase turned yellow. To the resulting mixture, tetrabutylammonium bromide (1.0 g, 3.0 mmol) was added, and then, a dichloromethane (about 6 mL) solution of 2,3,4-tri-O-acetyl-α-D-xylopyranosyl bromide (4.0 g, 12 mmol) was added dropwise. The reaction vessel was protected from light. The resulting mixture was stirred vigorously at room temperature for 2 days. The separated organic phase was washed with 50 mL of a 5% aqueous solution of sodium hydroxide three times and then with 50 mL of water three times, dried over anhydrous sodium sulfate and evaporated to dryness to give the title compound. Light brown solid. Yield 1.5 g, 34%. The product was unstable at room temperature, and stored in the freezer.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12](=[O:14])[CH3:13].[H-].[Na+].C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[C:3]([NH:11][C:12](=[O:14])[CH3:13])[CH:4]=1)([O-:10])=[O:9]
Reactant: ClCCN1CCCC1
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc([N+](=O)[O-])ccc1OCCN1CCCC1
Temperature: 100 °C
Yield: 33 %

Procedure:
To a solution of N-(2-hydroxy-5-nitrophenyl)acetamide (870 mg, 4.44 mmol) in DMF (5 mL) was added NaH (196 mg, 5.32 mmol) and K2CO3 (2.11 g, 13.32 mmol), followed by 1-(2-chloroethyl)pyrrolidine hydrochloride (905 mg, 5.32 mmol). After heating at 100° C. for 20 h, the solution was poured to ice, and was extracted with EtOAc, organic layer was washed with Sat. NaHCO3, brine, dried and concentrated to give N-(5-nitro-2-(2-(pyrrolidin-1-yl)ethoxy)phenyl)acetamide (430 mg).
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:17]([O-])=O)=[CH:4][C:5]([CH3:16])=[C:6]2[C:14]=1[C:13](=[O:15])[CH:12]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11]1>[C].[Pd].C(O)C>[NH2:17][C:3]1[C:2]([OH:1])=[C:14]2[C:6]([CH:7]3[CH:12]([C:13]2=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8]3)=[C:5]([CH3:16])[CH:4]=1
Reactant: Cc1cc([N+](=O)[O-])c(O)c2c1C1CCCCC1C2=O
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N)c(O)c2c1C1CCCCC1C2=O
Yield: 79.1 %

Procedure:
To 200 ml of ethanol were added 5.0 g of 8-hydroxy-5-methyl-7-nitro-1,2,3,4,4a,9a-hexahydro-9-fluorenone and 1 g of 5% palladium carbon and catalytic reduction was carried out at room temperature and under normal pressure. The catalyst was removed by filtration and the filtrate was concentrated to obtain 3.5 g of 7-amino-8-hydroxy-5-methyl-1,2,3,4,4a,9a-hexahydro-9-fluorenone (yellow crystal).
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)=O.[H][H]>C1C(Cl)=CC=C(Cl)C=1>[CH2:2]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)[CH3:1]
Reactant: CC(=O)c1cccc2ccccc12
Reactant: [H][H]
Solvent: Clc1ccc(Cl)cc1
Product: CCc1cccc2ccccc12
Yield: 90 %

Procedure:
A 2 mL reactor was charged with 0.150 mL of a 1.00 M solution of 1-acetonaphthalene and 0.050 mL of a 0.030 M solution of [Cp*Ru(CO)2]2(μ-H)}+OTf− in dichlorobenzene. The reaction was heated at 90° C. for 12 hours at 820 psi (5.7 MPa) of hydrogen gas. The reaction was cooled, and analyzed using gas chromatography/mass spectroscopy. Analysis indicated 100% conversion of the 1-acetonaphthalene, with a greater than 90% yield of 1-ethylnaphthalene. Note that in this example, the alcohol itself (presumably initially formed from hydrogenation of the C═O double bond) undergoes a hydrogenation reaction to yield in the final product, 1-ethylnaphthalene.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]2[N:8]([CH2:28][C:29]3[C:30]([CH3:39])=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=3)[C:9](=[O:27])[C:10]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:6]2=[N:5][N:4]=1.[I-].[Na+].CC(C)=[O:44].O>[OH-].[Na+].CCOC(C)=O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]2[C:6]3[N:7]([C:3]([CH2:2][OH:44])=[N:4][N:5]=3)[N:8]([CH2:28][C:29]3[C:30]([CH3:39])=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=3)[C:9](=[O:27])[C:10]=2[C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)=[CH:13][CH:14]=1
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1c(=O)c(-c2ccc(C#N)cc2)c(-c2ccc(Cl)cc2)c2nnc(CCl)n21
Reactant: CC(C)=O
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(C(F)(F)F)ccc1Cn1c(=O)c(-c2ccc(C#N)cc2)c(-c2ccc(Cl)cc2)c2nnc(CO)n21
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
To a round bottom flask was added 4-(3-(chloromethyl)-8-(4-chlorophenyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-7-yl)benzonitrile (30 mg, 0.053 mmol), sodium iodide (40 mg, 0.264 mmol) and acetone (2 ml). The reaction was stirred at room temperature for 8 hr. After this time, water (0.3 ml) was added followed by 1 drop of 1N NaOH. The reaction was stirred at room temperature for an additional 14 hrs. The solution was then diluted with EtOAc (25 ml) and washed with water (2×15 ml) and saturated NaCl (15 ml). The organic layer was dried (MgSO4), filtered and concentrated. The crude material was purified using an ISCO automated chromatography system (4 g silica gel, 20%-50% EtOAC/CH2Cl2) to give the product 4-(8-(4-chlorophenyl)-3-(hydroxymethyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-7-yl)benzonitrile as a white solid (15 mg, 51% yield). HPLC retention time 2.990 min (Method A); LCMS (M+1)=551.0. 1HNMR (CDCl3, 500 Hz) 7.61(2H, d, J=8.25 Hz), 7.52(1H, d, J=7.7 Hz), 7.30-7.37(7H, m), 6.05(2H, s), 4.60(2H, s), 2.78(3H, s); 13CNMR (CDCl3, 500 Hz) 161.00, 158.90, 156.25, 146.20, 144.10, 137.10, 136.80, 132.80, 131.96, 131.74, 129.90, 129.09, 118.00, (m), 113.00, 100.00, 55.10, 49.10, 22.10.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][C:27]1[CH:52]=[CH:51][C:30]([O:31][CH2:32][C:33]2[O:34][C:35]3[CH2:36][N:37]([C:42]([C:44]4[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=4)=[O:43])[CH2:38][CH2:39][C:40]=3[N:41]=2)=[CH:29][CH:28]=1)(C(C)(C)C)(C)C.O>C1COCC1>[F:50][C:47]1[CH:48]=[CH:49][C:44]([C:42]([N:37]2[CH2:38][CH2:39][C:40]3[N:41]=[C:33]([CH2:32][O:31][C:30]4[CH:29]=[CH:28][C:27]([OH:26])=[CH:52][CH:51]=4)[O:34][C:35]=3[CH2:36]2)=[O:43])=[CH:45][CH:46]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(OCc2nc3c(o2)CN(C(=O)c2ccc(F)cc2)CC3)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1ccc(F)cc1)N1CCc2nc(COc3ccc(O)cc3)oc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.2 %

Procedure:
1M solution of tetra-butylammonium fluoride in THF (0.54 mL, 0.54 mmol) was added to a stirred solution of 2-[(4-{[tert-butyl(dimethyl)silyl]oxy}phenoxy)methyl]-5-[(4-fluorophenyl)carbonyl]-4,5,6,7-tetrahydro[1,3]oxazolo[5,4-c]pyridine (264 mg, 0.36 mmol) in THF (2 mL). The mixture was stirred at room temperature for 16 hours. The mixture was treated with water and extracted with AcOEt. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 100/0). The desired fractions were collected and the solvents evaporated in vacuo. The product was triturated with DIPE to yield (4-({5-[(4-fluorophenyl)carbonyl]-4,5,6,7-tetrahydro[1,3]oxazolo[5,4-c]pyridin-2-yl}methoxy)phenol (60 mg, 45% yield) as a white solid. C20H17FN2O4 1H NMR (400 MHz, CDCl3) δ ppm 2.72 (br. s., 2 H), 3.69 (br. s, 2 H), 4.78 (br.s., 2 H), 5.05 (br. s., 2 H), 5.86 (br. s., 1 H), 6.74 (d, J=8.8 Hz, 2 H), 6.86 (d, J=8.8 Hz, 2 H), 7.09-7.18 (m, 2 H), 7.43-7.51 (m, 2 H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:20](=[O:21])[C:19]3[C:18]([O:22][CH2:23][C:24]4C=CC=CC=4)=[C:17]4[CH:30]=[CH:31][CH:32]=[CH:33][C:16]4=[C:15]([O:34]CC)[C:14]=3[C:13]2=[O:37])=[C:8]([Cl:38])[CH:7]=1)[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[Cl:38][C:8]1[CH:7]=[C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:39])[CH:11]=[CH:10][C:9]=1[N:12]1[C:13](=[O:37])[C:14]2[C:15]([OH:34])=[C:16]3[CH:33]=[CH:32][CH:31]=[CH:30][C:17]3=[C:18]([O:22][CH2:23][CH3:24])[C:19]=2[C:20]1=[O:21]
Reactant: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCc4ccccc4)c4ccccc4c3OCC)C2=O)c(Cl)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC)c4ccccc4c3O)C2=O)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.2 h
Yield: 63 %

Procedure:
To a solution of ethyl(3-chloro-4-{4-(ethyloxy)-1,3-dioxo-9-[(phenylmethyl)oxy]-1,3-dihydro-2H-benzo[f]isoindol-2-yl}phenyl)acetate (1.75 g, 3.22 mmol) in DCM (40 ml), cooled to −78° C. under an atmosphere of argon, was added boron tribromide (0.31 ml, 3.22 mmol) drop wise. Stirred at −78° C. for 12 minutes. A further addition of boron tribromide (0.31 ml, 3.22 mmol) was made drop wise. The reaction mixture was quenched with water and warmed to room temperature. This was extracted twice with DCM using a hydrophobic frit. The organic phase was evaporated to an yellow solid. This was purified by chromatography on silica gel, eluting with ethyl acetate (0-60%) in hexane to give the title compound as a orange oily solid (0.920 g, 2.03 mmol). LC/MS: Rt=3.65, [MH]+ 454.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:18]([C:20]2[CH:21]=[N:22][C:23](Cl)=[N:24][CH:25]=2)=[O:19])[CH:15]2[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:27][C:28]1[NH:29][CH:30]=[CH:31][N:32]=1>>[CH:15]1([N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:18]([C:20]2[CH:25]=[N:24][C:23]([N:29]3[CH:30]=[CH:31][N:32]=[C:28]3[CH3:27])=[N:22][CH:21]=2)=[O:19])[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)c2cnc(Cl)nc2)C2CC2)CC1
Reactant: Cc1ncc[nH]1
Product: Cc1nccn1-c1ncc(C(=O)N(C2CCNCC2)C2CC2)cn1

Procedure:
The title compound is prepared from 4-[(2-chloro-pyrimidine-5-carbonyl)-cyclopropyl-amino]-piperidine-1-carboxylic acid tert-butyl ester and 2-methyl-1H-imidazole following procedures analogous to those described in Intermediate 16 and Intermediate 17. LC (method 10): tR=0.56 min; Mass spectrum (ESI+): m/z=327 [M+H]+.
Reaction SMILES: [Cl-].ClC1N(C)CC[NH+]1C.[NH2:10][C:11]1[C:12]([Cl:17])=[N:13][CH:14]=[CH:15][CH:16]=1.C(N(CC)CC)C.[CH3:25][O:26][C:27]1[C:28](=[O:51])[C:29]([CH3:50])=[C:30]([CH2:36][C:37]2[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[C:39]([O:46][C:47](=[O:49])[CH3:48])[CH:38]=2)[C:31](=[O:35])[C:32]=1[O:33][CH3:34]>C(Cl)(Cl)Cl.C(Cl)Cl>[Cl:17][C:12]1[C:11]([NH:10][C:41](=[O:42])[C:40]2[CH:44]=[CH:45][C:37]([CH2:36][C:30]3[C:31](=[O:35])[C:32]([O:33][CH3:34])=[C:27]([O:26][CH3:25])[C:28](=[O:51])[C:29]=3[CH3:50])=[CH:38][C:39]=2[O:46][C:47](=[O:49])[CH3:48])=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)O)c(OC(C)=O)c2)=C(C)C1=O
Reactant: Nc1cccnc1Cl
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)Nc3cccnc3Cl)c(OC(C)=O)c2)=C(C)C1=O
Yield: 50 %

Procedure:
2-Chloro-1,3-dimethylimidazolinium chloride (89 mg, 0.524 mmol), 3-amino-2-chloropyridine (51 mg, 0.390 mmol) and triethylamine (53 mg, 0.524 mmol) were added to a methylene chloride solution (10 ml) of 4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (98 mg, 0.120 mmol) in a nitrogen atmosphere and the resulting solution was stirred all the night through. The reaction solution was diluted with chloroform, then washed with water and dried, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (hexand:ethyl acetate=3:1) to obtain the titled compound (29 mg, 0.060 mmol, 23%).
Reaction SMILES: [F:1][CH:2]([F:15])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][C:6]=1[CH3:14].[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[F:1][CH:2]([F:15])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([NH:22][S@@:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])[CH3:12])=[CH:7][C:6]=1[CH3:14]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cnc(OCC(F)F)c(C)c1
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1OCC(F)F
Yield: 82 %

Procedure:
The title compound is prepared in 82% yield (1.22 g, colorless oil) from 1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethanone (0.99 g, 4.61 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SC)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[C:31]([O:35][C:36](=[O:44])[N:37]([CH3:43])[CH:38]1[CH2:42][CH2:41][NH:40][CH2:39]1)([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36](=[O:44])[N:37]([CH:38]1[CH2:42][CH2:41][N:40]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:25]=[CH:26][C:2]([Cl:1])=[CH:3][C:4]=3[C:27]([F:29])([F:30])[F:28])[N:8]=[CH:9]4)[C:18](=[O:24])[N:19]=2)[CH2:39]1)[CH3:43])([CH3:34])([CH3:32])[CH3:33]
Reactant: CN(C(=O)OC(C)(C)C)C1CCNC1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CN(C(=O)OC(C)(C)C)C1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C1

Procedure:
(1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-pyrrolidin-3-yl)-methyl-carbamic acid tert-butyl ester was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and methyl-pyrrolidin-3-yl-carbamic acid tert-butyl ester following General Procedure B.
Reaction SMILES: C(O[C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH2:23]OC(=O)C)[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2OC)[CH2:6]1)(=O)C>CCOCC>[CH3:16][C@:15]12[CH2:17][CH2:18][C@H:19]3[C@@H:10]([CH2:9][CH2:8][C@@H:7]4[C@:20]3([CH3:23])[CH2:21][CH2:22][CH2:5][CH2:6]4)[C@@H:11]1[CH2:12][CH2:13][CH2:14]2
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)CC[C@]4(COC(C)=O)[C@H]3CC[C@]12C
Solvent: CCOCC
Product: C[C@@]12CCC[C@H]1[C@@H]1CC[C@H]3CCCC[C@]3(C)[C@H]1CC2

Procedure:
More particularly, a zinc and acetic acid cleavage of 5α-bromo-3β-hydroxy-6β,19-oxidoandrostan-17-one results in the formation of 3β,19-dihydroxy-5-androsten-17-one diacetate. Lithium tri-t-butoxyaluminum hydride reduction then results in the preparation of 5-androstene-3β,17β,19- triol 3,19-diacetate. The 17β-hydroxy group can now be converted to an ether using standard procedures to form, for example, 17β-methoxy-5-androstene-3β,19-diol diacetate or 17β-(4'-tetrahydropyranyloxy)-5-androstene-3β,19-diol diacetate. A catalytic hydrogenation then furnishes the corresponding 5α-androstane. Basic hydrolysis subsequently cleaves the esters to form the free 17-ether diols. In this manner the compounds, 17β-methoxy-5α-androstane-3β,19- diol and 17β-(4'-tetrahydropyranyloxy)-5α-androstane-3β,19- diol can be prepared. Oxidation results in the formation of the corresponding diones. Etherification thereof furnishes the mixed triethers.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][C:16]([CH3:18])=[C:15]([C:19]([OH:21])=O)[C:14]=1[CH3:22].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[NH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[NH:59][C:60](=[O:71])[C:61]1[CH:66]=[CH:65][C:64]([NH:67][CH2:68][CH2:69][NH2:70])=[N:63][CH:62]=1>[Cl-].[Na+].O.CN(C=O)C>[NH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[NH:59][C:60](=[O:71])[C:61]1[CH:66]=[CH:65][C:64]([NH:67][CH2:68][CH2:69][NH:70][C:19]([C:15]2[C:14]([CH3:22])=[C:13](/[CH:12]=[C:5]3\[C:6](=[O:11])[NH:7][C:8]4[C:4]\3=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=4)[NH:17][C:16]=2[CH3:18])=[O:21])=[N:63][CH:62]=1
Reactant: NCCNc1ccc(C(=O)Nc2ccccc2N)cn1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(Cl)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(Cl)cc32)c(C)c1C(=O)NCCNc1ccc(C(=O)Nc2ccccc2N)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.9 %

Procedure:
5-(5-Chloro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (316 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (384 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and N-(2-aminophenyl)-6-(2-aminoethylamino)nicotinamide (284 mg, 1.05 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (444 mg, 77%) as a yellow solid. LC-MS (m/z) 570 (M+1).
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11](=[O:12])[CH:10]=[CH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl-].[Cl-].[Ce+3].[BH4-].[Na+].O>CO.C(Cl)Cl.C(O)C>[C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]([OH:12])[CH:10]=[CH:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1C=CCC1(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: OC1C=CCC1(c1ccccc1)c1ccccc1
Yield: 82.3 %

Procedure:
To a solution of 5,5-diphenyl-2-cyclopenten-1-one (1.0 g) and cerium trichloride 7 hydrate (1.59 g) in methanol (10 ml) and methylene chloride (4 ml) was added dropwise a solution of sodium borohydride (0.16 g) in ethanol (6 ml) at 0° C. to 3° C. To the reaction mixture, cerium trichloride 7 hydrate (0.80 g) and sodium borohydride (0.08 g) were added 4 times an hour. After the reaction finished, cold water (30 ml) was added, and the mixture was extracted with chloroform. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with methylene chloride as an eluent to give 5,5-diphenyl-2-cyclopenten-1-ol 0.83 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:30])[CH2:15][N:16]3[C:20]4=[N:21][CH:22]=[CH:23][CH:24]=[C:19]4[C:18]([C:25]4[NH:26][CH:27]=[CH:28][N:29]=4)=[N:17]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:31][CH3:32].[H-].[Na+].IC.[C:37](#N)C.O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:30])[CH2:15][N:16]3[C:20]4=[N:21][CH:22]=[CH:23][CH:24]=[C:19]4[C:18]([C:25]4[N:29]([CH3:37])[CH:28]=[CH:27][N:26]=4)=[N:17]3)[CH2:12][CH2:13]2)=[CH:4][C:3]=1[O:31][CH3:32]
Reactant: COc1cc(N2CCN(C(=O)Cn3nc(-c4ncc[nH]4)c4cccnc43)CC2)ccc1Cl
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(N2CCN(C(=O)Cn3nc(-c4nccn4C)c4cccnc43)CC2)ccc1Cl
Reaction time: 1 h

Procedure:
To the solution of 1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-[3-(1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]-ethanone (50 mg, 0.11 mmol, 1 eq) in THF was added 60% sodium hydride (5.7 mg, 0.14 mmol, 1.3 eq) and stirred for 1 hr, followed by the addition of iodomethane (25.8 mg, 0.16 mmol, 1.5 eq). 2 hrs later, LCMS indicated that the major peak is the desired product preparative hplc (reverse phase, acetonitrile-water gradient) gave 1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-[3-(1-methyl-1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]-ethanone. MS (ES) [M+H]+ found: 465.2.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][C@@H:25]2[OH:28])[C@:21]2([CH3:22])[C@@H:16]([CH2:17][C@@H:18]([O:29][CH2:30][CH2:31][N:32]([C:34]4[CH:39]=[CH:38][C:37]([C@H:40]5[CH2:57][C@@:55]6([CH3:56])[C@@H:51]([CH2:52][CH2:53][C@:54]6([OH:61])[C:58]#[C:59][CH3:60])[C@H:50]6[C:41]5=[C:42]5[C:47]([CH2:48][CH2:49]6)=[CH:46][C:45](=[O:62])[CH2:44][CH2:43]5)=[CH:36][CH:35]=4)[CH3:33])[CH2:19][CH2:20]2)[CH2:15][C@H:14]3[O:63][CH2:64]SC)[CH2:11][CH2:10]1)[CH3:8])[C:3]([OH:5])=[O:4].S(Cl)([Cl:70])(=O)=O>ClCCl>[CH3:1][CH:2]([CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][C@@H:25]2[OH:28])[C@:21]2([CH3:22])[C@@H:16]([CH2:17][C@@H:18]([O:29][CH2:30][CH2:31][N:32]([C:34]4[CH:39]=[CH:38][C:37]([C@H:40]5[CH2:57][C@@:55]6([CH3:56])[C@@H:51]([CH2:52][CH2:53][C@:54]6([OH:61])[C:58]#[C:59][CH3:60])[C@H:50]6[C:41]5=[C:42]5[C:47]([CH2:48][CH2:49]6)=[CH:46][C:45](=[O:62])[CH2:44][CH2:43]5)=[CH:36][CH:35]=4)[CH3:33])[CH2:19][CH2:20]2)[CH2:15][C@H:14]3[O:63][CH2:64][Cl:70])[CH2:11][CH2:10]1)[CH3:8])[C:3]([OH:5])=[O:4]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC#C[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(N(C)CCO[C@H]4CC[C@@]5(C)[C@@H](C4)C[C@@H](OCSC)[C@@H]4[C@@H]5C[C@H](O)[C@]5(C)[C@@H]([C@H](C)CC(C)C(=O)O)CC[C@@H]45)cc3)C[C@@]21C
Solvent: ClCCl
Product: CC#C[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(N(C)CCO[C@H]4CC[C@@]5(C)[C@@H](C4)C[C@@H](OCCl)[C@@H]4[C@@H]5C[C@H](O)[C@]5(C)[C@@H]([C@H](C)CC(C)C(=O)O)CC[C@@H]45)cc3)C[C@@]21C
Temperature: 25 °C

Procedure:
The compound of Example 8A is dissolved in dichloromethane; sulfuryl chloride (1.1 eq) is added, and the mixture is stirred at ambient temperature until starting material is consumed. The reaction is quenched by the addition of aqeous sodium bicarbonate; the organic layer is removed, and the aqueous phase is re-extracted with dichloromethane. The combined organic phases are dried (Na2SO4), filtered, and concentrated in vacuo. The crude material is used without further purification.