Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.C[C:18]1[NH:19][CH:20]=[CH:21][N:22]=1.[C:23]1(C)C=CC=CC=1>>[Cl-:1].[CH3:23][N+:22]1[CH:21]=[CH:20][N:19]([CH2:2][CH:3]2[CH2:7][CH2:6][CH2:5][N:4]2[C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH:18]=1
Reactant: O=[N+]([O-])c1ccc(N2CCCC2CCl)cc1
Reactant: Cc1ncc[nH]1
Reactant: Cc1ccccc1
Product: C[n+]1ccn(CC2CCCN2c2ccc([N+](=O)[O-])cc2)c1
Product: [Cl-]

Procedure:
16.8 g (0.07 mol) of 2-chloromethyl-1-(4-nitrophenyl)pyrrolidine (1), 17.2 g (0.21 mol) of methylimidazole and 70 ml of toluene were refluxed for 9 hours. The solvent was evaporated off and the product was recrystallized from isopropanol and then dried under vacuum. 3 g of yellow crystals (2) were obtained.
Reaction SMILES: [Na+].[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:16])[C:13]([O-:15])=[O:14])=[CH:8][CH:7]=1)[CH:3]([CH3:5])[CH3:4].[CH3:17][N:18]([CH2:20][CH2:21]Cl)[CH3:19]>C1C=CC=CC=1>[CH3:17][N:18]([CH2:20][CH2:21][O:14][C:13](=[O:15])[CH:12]([C:9]1[CH:8]=[CH:7][C:6]([CH2:2][CH:3]([CH3:5])[CH3:4])=[CH:11][CH:10]=1)[CH3:16])[CH3:19]
Reactant: CN(C)CCCl
Reactant: CC(C)Cc1ccc(C(C)C(=O)[O-])cc1
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(C)Cc1ccc(C(C)C(=O)OCCN(C)C)cc1
Yield: 87.3 %

Procedure:
A mixture of 3.3 g of 2-(p-isobutylphenyl)propionic acid sodium salt, 2.3 g of dimethylaminoethyl chloride and 30 ml of benzene was refluxed for 12 hours. A solid mass produced was filtered off, and the benzene was distilled away from the filtrate under reduced pressure to leave an oily residue. This redidue was distilled under reduced pressure to give 3.5 g of 2-(p-isobutylphenyl)propionic acid dimethylaminoethyl ester as a colorless oil, boiling at 133°-136° C./1 mmHg. Analysis-Calculated for C17H27NO2 : C, 73.61; H, 9.81; N, 5.05. Found: C, 73.50; H, 9.72; N, 5.02. The infrared spectrum showed strong C=O absorption at 1730 cm-1 characteristic for ester. Mass spectrum: parent ion 277 m/e.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:6]([CH2:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[C:7]([NH2:11])[CH:8]=[CH:9][CH:10]=1.Cl.[N:27]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.O>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:6]=1[C:12]([S:13]([C:16]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[N:27][NH:11]2
Reactant: Nc1cccc(OCCCl)c1CS(=O)(=O)c1cccc2ccccc12
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2cccc(OCCCl)c12
Temperature: 3 °C

Procedure:
A mixture of 3-(2-chloro-ethoxy)-2-(naphthalene-1-sulfonylmethyl)-phenyl amine (0.78 g, 2.1 mmoles) in THF (5 mL), and 4M HCl (10 mL) was stirred in a round bottom flask, under nitrogen, at 3° C. A solution of sodium nitrite (0.15 g, 2.2 mmoles) in H2O (1 mL) was added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100 mL) and extracted with EtOAc. Compound was dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (0.74 g, 1.93 mmoles).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:30][C:31]1[N:36]=[C:35]([CH3:37])[CH:34]=[CH:33][N:32]=1>C1COCC1>[CH2:17]([O:16][C:14](=[O:15])[NH:13][C:12]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5](=[O:7])[CH2:37][C:35]2[CH:34]=[CH:33][N:32]=[C:31]([Cl:30])[N:36]=2)[C:3]=1[O:2][CH3:1])[CH:18]=[CH2:19]
Reactant: C=CCOC(=O)Nc1cccc(C(=O)OC)c1OC
Reactant: Cc1ccnc(Cl)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCOC(=O)Nc1cccc(C(=O)Cc2ccnc(Cl)n2)c1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
To a solution of methyl 2-(methyloxy)-3-{[(2-propen-1-yloxy)carbonyl]amino}benzoate (123 g, 464 mmol,) in dry THF (800 mL) at −10° C., LiHMDS (1M in THF, 1440 mmol, 1440 mL) was added dropwise and the solution was allowed to stir for 1 h at 0° C. A solution of 2-chloro-4-methylpyrimidine (72 g, 560 mmol) in THF (150 mL) was then added dropwise to the solution of ester and base at 0° C. over 20 min. The solution was allowed to stir 1 h at rt. TLC showed the reaction was complete. The reaction was quenched by addition of the saturated aqueous NH4Cl (800 mL) at 0° C. The reaction mixture was extracted with EtOAc (1 L×3). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by flash column on silica gel, eluting with DCM. This solution was evaporated to obtain a solid. The orange solid was triturated with a small amount of EtOAc and filtered, rinsing with diethyl ether to give the title compound of Step E (109.9 g, 67.8% yield). 1H NMR (400 MHz, CDCl3) δ ppm 13.64-13.68 (br, 1H), 8.38 (d, J=5.3 Hz, 1H), 8.15-8.21 (m, 1H), 7.31-7.39 (m, 2H), 7.15-7.18 (m, 1H), 6.87 (d, J=5.3 Hz, 1H), 6.19 (s, 1H), 5.92-6.15 (m, 1H), 5.23-5.40 (m, 2H), 4.66-4.70 (m, 2H), 3.76 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1([C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][C:16]3[C:21]4[C:22]([CH3:26])([CH3:25])[CH2:23][O:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)=[O:7])[CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[C:35](Cl)([O:37]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:25][C:22]1([CH3:26])[C:21]2[C:16]([O:15][C:12]3[N:11]=[CH:10][C:9]([N:8]4[C:6](=[O:7])[C:2]5([CH2:5][CH2:4][CH2:3]5)[NH:1][C:35]4=[O:37])=[CH:14][CH:13]=3)=[CH:17][CH:18]=[CH:19][C:20]=2[O:24][CH2:23]1
Reactant: CC1(C)COc2cccc(Oc3ccc(NC(=O)C4(N)CCC4)cn3)c21
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)COc2cccc(Oc3ccc(N4C(=O)NC5(CCC5)C4=O)cn3)c21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1-amino-N-{6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}cyclobutanecarboxamide (Intermediate 70, 17 mg) was dissolved in dry dichloromethane (1.8 ml). The reaction mixture was cooled down in an ice bath. Triethylamine (39.48 μl, 0.283 mmol) was added at 0° C. Then 0.89 ml of a solution of triphosgene in dry dichloromethane was added dropwise (0.0135 mg, 4.00 mg). The reaction mixture was stirred under argon during 10 min at 0° C., then during 30 min at room temperature. Then an additional 0.25 equivalent of triphosgene in dichloromethane (0.26 M solution) was added at 0° C. and the reaction mixture was stirred under argon an additional 30 min at room temperature. The solvents were removed under vacuum. The residue obtained was purified by flash chromatography on silica gel (Companion system, 4 g silica cartridge) with cyclohexane/ethylacetate as eluents from 100/0 to 55/45. This afforded the title compound (12 mg).
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[C:2]#[CH:3].[Cl:12][C:13]1[C:18](I)=[C:17]([CH3:20])[N:16]=[C:15]([NH2:21])[N:14]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:21][C:15]1[N:14]=[C:13]([Cl:12])[C:18]([C:3]#[C:2][CH2:1][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])=[C:17]([CH3:20])[N:16]=1
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: Cc1nc(N)nc(Cl)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: Cc1nc(N)nc(Cl)c1C#CCNC(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 16 h
Yield: 46.9 %

Procedure:
tert-Butyl prop-2-ynylcarbamate (3.11 g), 4-chloro-5-iodo-6-methylpyrimidin-2-amine (1.8 g) and bis(triphenylphosphine)palladium(II) chloride (0.469 g) were combined in TEA (100 mL). The reaction mixture was purged with nitrogen gas for 3 min then copper(I) iodide (0.254 g) added. The resulting mixture was stirred at 70° C. for 16 h, then cooled to rt and filtered. The filtrate was washed with water and brine, dried and the solvents evaporated. The crude material was dissolved in MeOH (20 mL), acidified with acetic acid (1 mL) and purified by SCX and further purified by chromatography eluting 10% MeOH and 0.25% Ammonia (7N) in DCM to afford the subtitle compound 0.93 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21]2>>[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:21]2=[CH:7][C:6]1[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]([O:2][CH3:1])=[CH:10][CH:9]=1
Reactant: COc1ccc(C=O)cc1-c1ccccc1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Product: COc1ccc(C=C2C(=O)Nc3ccc(Cl)cc32)cc1-c1ccccc1

Procedure:
4-Methoxy-3-phenylbenzaldehyde was condensed with 5-chloro-2-oxindole to give 0.3 g of 5-chloro-3-(6-methoxybiphenyl-3-ylmethylene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[CH2:19]([O:26][C:27](ON1C(=O)CCC1=O)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCOCC1.O.C(OCC)(=O)C>[CH2:19]([O:26][C:27]([N:11]1[CH2:12][CH2:13][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10]1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 2.05 g 3-(tert-butoxycarbonylamino)pyrrolidine, 1.85 g NaHCO3 and 3.17 g N-(Benzyloxycarbonyloxy)succinimide in 10 ml dioxane/water 1:1 was stirred for 12 h at RT. The reaction mixture was diluted with ethyl acetate, the phases separated and the organic phase washed with saturated NaHCO3 and brine. The crude product obtained after evaporation of the solvent was used in the next reaction step without further purification.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][C:20]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:21]=1[CH2:22][Cl:23]>CCO>[ClH:23].[CH3:19][C:20]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:21]=1[CH2:22][S:18][C:9]1[NH:8][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Reactant: Cc1ccc(CCl)c(C)c1
Solvent: CCO
Product: Cc1ccc(CSC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)c(C)c1
Product: Cl
Temperature: 25 °C
Yield: 55.1 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 2,4-dimethylbenzyl chloride (243 mg, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 177 mg of the product 240. 1H NMR (DMSO-d6) δ 11.18 (s, 2H), 7.20-6.80 (m, 13H), 5.80 (s, 2H), 4.88 (s, 2H), 2.41(s, 3H), 2.30 (s, 3H); MS: m/z 373 (M++1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[C:11]([O:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[C:10]=1C(=O)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:36][OH:37].Cl.[CH3:39][C:40](O[Na])=O>C(O)C.C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:12]=[C:11]([O:23][C:24]2[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=2)[C:10]=1[C:40](=[N:36][OH:37])[CH3:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1c(OCc2ccccc2)cc(OCc2ccccc2)cc1Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)O[Na]
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=NO)c1c(OCc2ccccc2)cc(OCc2ccccc2)cc1Oc1ccc([N+](=O)[O-])cc1
Yield: 85.8 %

Procedure:
A stirred solution of 1-[2,4-bis(benzyloxy)-6-(4-nitrophenoxy)phenyl]ethanone (15 g, 32 mmol), NH2OH.HCl (3 g, 42 mmol) and CH3COONa (3.5 g, 42 mmol) in ethanol (150 mL) and acetic acid (250 mL) was refluxed for 5 hours. The solvent was removed and the residue taken up in ethyl acetate was thoroughly washed with 2 M NaHCO3 solution then with brine. After drying over Na2SO4, the solvent was removed and the oily residue was filtered on a small pad of silica gel eluting with hexane/ethyl acetate 6/3 to provide the title compound (13.3 g, 88% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([C:17]3[N:18]=[C:19]([NH2:22])[S:20][CH:21]=3)=[C:12]([CH3:23])[CH:11]=2)=[N:7][CH:8]=1.C(N(CC)CC)C.Cl.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([C:17]3[N:18]=[C:19]([NH:22][C:32](=[O:39])[C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)[S:20][CH:21]=3)=[C:12]([CH3:23])[CH:11]=2)=[N:7][CH:8]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: COc1ccc(Oc2cc(C)c(-c3csc(N)n3)c(C)c2)nc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Oc2cc(C)c(-c3csc(NC(=O)c4ccncc4)n3)c(C)c2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
To a solution of 4-{4-((5-methoxypyridin-2-yl)oxy)-2,6-dimethylphenyl}thiazol-2-amine (18-4, 0.10 g, 0.31 mmol) in CH2Cl2 (5.0 mL) was added triethylamine (0.50 mL, 3.6 mmol) followed by isonicotinoyl chloride hydrochloride (0.15 g, 0.80 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with water. The resultant precipitate was filtered and recrystallized in toluene to give N-(4-{4-((5-methoxypyridin-2-yl)oxy)-2,6-dimethylphenyl}thiazol-2-yl)isonicotinamide (18, 0.070 g) as light yellow solids in 52% yield: 1H NMR (500 MHz, DMSO-d6) δ 8.81 (d, J=5.5 Hz, 2 H), 7.99 (dt, J=3.1, 1.5 Hz, 2 H), 7.92 (d, J=3.1 Hz, 1 H), 7.52 (dt, J=5.7, 3.2 Hz, 1 H), 7.20 (s, 1 H), 7.00 (d, J=8.8 Hz, 1 H), 6.81 (s, 2 H), 3.81 (s, 3 H), 2.08 (s, 6 H). ESI-MS: m/z 433.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH2:10][C:11]1[CH:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:12]=1)C(=O)OC(C)(C)C.C(OCC)(=O)C.[ClH:35]>C(OCC)(=O)C.CO>[ClH:35].[ClH:35].[CH3:1][NH:2][CH2:10][C:11]1[CH:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:12]=1
Reactant: CN(Cc1cc(Nc2ccccc2)n(-c2ccccc2)n1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CNCc1cc(Nc2ccccc2)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
tert-Butyl methyl{[1-phenyl-5-(phenylamino)-1H-pyrazol-3-yl]methyl}carbamate (90 mg) was dissolved in ethyl acetate (2 mL) and methanol (1 mL), 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate and ethanol to give the title compound as colorless crystals (yield 62 mg, yield 75%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[N:22](S(C4C=CC(C)=CC=4)(=O)=O)[C:23]([CH:25]4[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26]4)=[CH:24][C:17]=23)=[N:4][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:7]=1>O1CCOCC1.[OH-].[Na+].O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[NH:22][C:23]([CH:25]4[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26]4)=[CH:24][C:17]=23)=[N:4][C:5]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(C3CCN(C(=O)OC(C)(C)C)C3)cc3c(-c4nc(NCC5CCOCC5)ccc4Cl)ccnc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2cc3c(-c4nc(NCC5CCOCC5)ccc4Cl)ccnc3[nH]2)C1

Procedure:
A solution of Example 65C (150 mg, 0.225 mmol) in dioxane (3 mL) and 10N aqueous sodium hydroxide (0.225 mL) was heated in sealed tube at 100° C. for 3 hours. The mixture was diluted with water and ethyl acetate. The organic layer was washed with water and brine (25 mL each), dried over sodium sulfate, filtered and concentrated to afford the title compound. LCMS: 512.55 (M+H)+.
Reaction SMILES: CN(C)S(C1C2N(CC(O)=O)C=NC=2C=CC=1)(=O)=O.[N+:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([S:29]([CH2:32][CH2:33][CH3:34])(=[O:31])=[O:30])[C:24]=1[NH:35][CH2:36][CH2:37][OH:38])([O-])=O>>[NH2:20][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([S:29]([CH2:32][CH2:33][CH3:34])(=[O:30])=[O:31])[C:24]=1[NH:35][CH2:36][CH2:37][OH:38]
Reactant: CCCS(=O)(=O)c1cccc([N+](=O)[O-])c1NCCO
Agent: CN(C)S(=O)(=O)c1cccc2ncn(CC(=O)O)c12
Product: CCCS(=O)(=O)c1cccc(N)c1NCCO
Yield: 52 %

Procedure:
The compound was synthesized in 52% yield according to the procedure described for the synthesis of (7-dimethylsulfamoyl-benzimidazol-1-yl)-acetic acid, part C, starting from 2-{[2-nitro-6-(propylsulfonyl)phenyl]amino}ethanol. MS (ESI) m/z 259 [M+H]. 1H NMR (400 MHz, CDCl3/CD3OD) δ ppm 1.00 (t, J=7.3 Hz, 3H), 1.82-1.72 (m, 2H), 3.15-3.11 (m, 2H), 3.29-3.27 (m, 2H), 3.80-3.77 (m, 2H), 6.92-6.90 (m, 1H), 6.96 (t, J=7.8 Hz, 1H), 7.23 (dd, J=7.7, 1.6 Hz, 1H)
Reaction SMILES: C(C1C=CC([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=CC=1)#N.[H-].C([Al+]CC(C)C)C(C)C.CO.O>C1(C)C=CC=CC=1>[C:15]([N:12]1[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)cc2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCNCC1
Temperature: 50 °C

Procedure:
To t-butyl 4-(4-cyanophenyl)piperazine-1-carboxylate (2.30 g, 8.0 mmol, prepared by reaction of the aryl-piperazine with Boc-anhydride) in toluene (20 ml) add DIBAH (diisobutylaluminum hydride) (1.0M in toluene, 12.8 ml, 12.8 mmol). Heat at 50° C. 1.5 h, allow to cool, add MeOH (10 ml) and water (10 ml). Filter and concentrate. Chromatograph the residue over silica to obtain the Boc-piperazine as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[Cs+].[Cs+].[F:16][C:17]1[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([F:16])[C:18]=1[N+:24]([O-:26])=[O:25]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1c(F)cccc1Oc1ccc(Cl)cc1Cl
Temperature: 90 °C
Reaction time: 12 h
Yield: 27.7 %

Procedure:
Under a nitrogen atmosphere, 2,4-dichlorophenol (500 mg, 3.067 mmol) was diluted in DMF (15 mL). Cesium carbonate (3 g, 9.202 mmol) was then added followed by 2,5-difluoronitro-benzene (976 mg, 6.135 mmol). The reaction was heated to 90° C. and allowed to stir for 12 hours. Then, 500 uL of water was added and was heated for an additional 4 hours. The reaction was then quenched with water (30 mL) and extracted with ethyl acetate (3×60 mL). The organic extracts were dried over sodium sulfate and concentrated. Silica gel chromatography (5%-20% EtOAc/hexanes) gave 1-(2,4-dichlorophenoxy)-3-fluoro-2-nitrobenzene (257 mg, 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([F:18])[C:12]=2[Cl:19])[CH:9]=1)[C:5]#[N:6].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:27][C:28]1[C:36]2[C:31](=[N:32][C:33]([F:37])=[CH:34][CH:35]=2)[N:30]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[N:29]=1>CN1C(=O)CCC1.CCOC(C)=O>[C:41]([O:40][C:38]([N:30]1[C:31]2=[N:32][C:33]([F:37])=[CH:34][CH:35]=[C:36]2[C:28]([CH2:27][O:17][C:15]2[CH:14]=[C:13]([F:18])[C:12]([Cl:19])=[C:11]([O:10][C:8]3[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=[C:2]([Cl:1])[CH:9]=3)[CH:16]=2)=[N:29]1)=[O:39])([CH3:44])([CH3:43])[CH3:42]
Reactant: N#Cc1cc(Cl)cc(Oc2cc(O)cc(F)c2Cl)c1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccc(F)nc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1nc(COc2cc(F)c(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2)c2ccc(F)nc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
Under a nitrogen atmosphere, 3-chloro-5-(2-chloro-3-fluoro-5-hydroxyphenoxy)benzonitrile (50-5) (150 mg, 0.503 mmol) was dissolved in NMP (4 mL, 0.1 M). Next, Cs2CO3 (164 mg, 0.503 mmol) was added and the reaction was allowed to stir at room temperature for 15 minutes. Then, tert-butyl-3-(bromomethyl)-6-fluoro-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (37-5) (166 mg, 0.503 mmol, prepared using the procedure set forth in Example 37) was added to the reaction. The reaction was stirred at room temperature for 2 hours. It was then diluted with EtOAc (4 mL). It was partitioned with water (3 mL) and then extracted with EtOAc (3×4 mL). The organic extracts were then washed with water (3×4 mL) and brine (1×4 mL), dried over sodium sulfate and concentrated. Silica gel chromatography (1%-20% EtOAc/Hexanes) gave tert-butyl3-{[4-chloro-3-(3-chloro-5-cyanophenoxy)-5-fluorophenoxy]-methyl}-6-fluoro-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (50-6) (230 mg, 85%). LCMS (ES) m/z 446.9 (M-BOC)+.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[CH:11]([C@@H:12]([OH:29])[CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[OH:28])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CS(C)=O>[Si:1]([O:8][C@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[CH:11]([C:12](=[O:29])[CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C:18]2=[O:28])[CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)C(C1)[C@@H](O)C[C@H]1[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]12
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)C(C1)C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 5.9 %

Procedure:
To a stirred suspension of 3β-tert-butyldimethylsilyloxyandrostane-6α,17β-diol (EP 0825197 A2, 6.21 g) in DMSO (160 mL), IBX (16.45 g) was added at room temperature. After 1.5 h the mixture was quenched at room temperature by addition of H2O (300 mL). After 15 min the mixture was filtered and the cake was washed with H2O. The cake was extracted with Et2O (4×). The combined organic extracts were dried over Na2SO4 and evaporated to dryness to give 3β-tert-butyldimethylsilyloxyandrostane-6,17-dione (0.36 g, 75%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS: δ 3.54 (1H, m), 2.47-1.08 (20H, m), 0.84 (9H, s), 0.77 (3H, s), 0.66 (1H, s), 0.01 (6H, s).