Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[O:6][CH2:7][C:8]1[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:11][C:12]=1[CH3:13].[CH2:23]([O:25][C:26]1[CH:31]=[C:30]([OH:32])[CH:29]=[CH:28][C:27]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:24].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:23]([O:25][C:26]1[CH:31]=[C:30]([O:32][CH2:2][C:3]2[CH:22]=[CH:21][CH:20]=[C:5]([O:6][CH2:7][C:8]3[N:9]=[C:10]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:11][C:12]=3[CH3:13])[CH:4]=2)[CH:29]=[CH:28][C:27]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:24]
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CCl)c1
Reactant: CCOC(=O)CCc1ccc(O)cc1OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(OCc2cccc(OCc3nc(-c4ccccc4)oc3C)c2)cc1OCC
Temperature: 90 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
A mixture of 4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (0.78 g), ethyl 3-(2-ethoxy-4-hydroxyphenyl)propionate (0.50 g), anhydrous potassium carbonate (0.29 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give ethyl 3-[2-ethoxy-4-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionate as a colorless oil (0.94 g, 87%) from a fraction eluted with ethyl acetate-hexane (1:6, v/v).
Reaction SMILES: C(OC1C=C([N+]([O-])=O)C=C(I)C=1O)C1C=CC=CC=1.C(C1OC1)Cl.OCC1OC2C=C([N+]([O-])=O)C=C(I)C=2OC1.C(OCC1OC2C=C([N+]([O-])=O)C=C(I)C=2OC1)C.[CH2:59]([O:61][CH2:62][CH:63]1[O:68][C:67]2[CH:69]=[C:70]([N+:77]([O-])=O)[CH:71]=[C:72]([C:73]([F:76])([F:75])[F:74])[C:66]=2[O:65][CH2:64]1)[CH3:60]>CN(C)C=O.[Cu].[Pd]>[NH2:77][C:70]1[CH:71]=[C:72]([C:73]([F:76])([F:75])[F:74])[C:66]2[O:65][CH2:64][CH:63]([CH2:62][O:61][CH2:59][CH3:60])[O:68][C:67]=2[CH:69]=1
Reactant: CCOCC1COc2c(cc([N+](=O)[O-])cc2C(F)(F)F)O1
Agent: [Cu]
Agent: [Pd]
Agent: CCOCC1COc2c(I)cc([N+](=O)[O-])cc2O1
Solvent: ClCC1CO1
Solvent: CN(C)C=O
Product: CCOCC1COc2c(cc(N)cc2C(F)(F)F)O1

Procedure:
2-benzyloxy-4-nitrophenyl was iodinated to 2-benzyloxy-6-iodo-4-nitrophenol of melting point 143°C-145°C in the manner described for an analogous compound in J.Am.Chem. Soc. 75 4290 (1953). This compound was converted with epichlorohydrine into 2-(hydroxymethyl)-5-iodo-7-nitro-1,4-benzodioxane by the method described in J.Ned. Chem. 1965 page 455 for an analogous compound. The substance obtained was ethylated to 2-(ethoxymethyl)-5-iodo-7-nitro-1,4-benzodioxane (melting point of the crude product 90°--99°C), and this was converted with CF3J and powdered copper in dimethylformamide into 2-(ethoxymethyl)-7-nitro-5-(trifluoromethyl)-1,4-benzodioxan by the method described in Tetrahedron Letters 1969 pages 4095-4096. The reaction product was hydrogenated by means of a palladium on active carbon catalyst at room temperature and under a pressure of about 1.1 atmospheres to form 7-amino-2-(ethoxymethyl)-5-(trifluoromethyl)-1,4-benzodioxan, which was immediately converted with 2-(ethoxymethylene)malonic acid diethyl ester into 2- { [2-(ethoxymethyl)-5-(trifluromethyl)-1,4-benzodioxan-7-ylamino] -methylene } malonic acid diethyl ester which had a melting point of 96°-98°C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH:13]=O)=[CH:8][CH:7]=1)[CH3:2]>C1COCC1>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH3:13])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(NC=O)cc1
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(NC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a stirred solution of (4-formylamino-phenyl)-acetic acid ethyl ester (Preparation 268, 500 mg, 2.41 mmol) in THF (10 mL) was added borane-dimethyl sulphide complex (0.3 mL, 3.13 mmol) at 0° C. and the mixture stirred at room temperature for 1 hour. The reaction mixture was quenched with MeOH (5 mL) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (gradient of hexane:EtOAc 100:0 to 75:25) to afford the title compound as an oil in 91% yield, 460 mg.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH2:13][S:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)(=[O:16])=[O:15])[CH:10]=[CH:9][C:8]=2[NH:23][C:24]([C:26]2[N:27](COCC[Si](C)(C)C)[CH:28]=[C:29]([C:31]#[N:32])[N:30]=2)=[O:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CCO>[C:1]1([C:7]2[CH:12]=[C:11]([CH2:13][S:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)(=[O:15])=[O:16])[CH:10]=[CH:9][C:8]=2[NH:23][C:24]([C:26]2[NH:27][CH:28]=[C:29]([C:31]#[N:32])[N:30]=2)=[O:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(CS(=O)(=O)N2CCOCC2)cc1C1=CCCCC1
Solvent: ClCCl
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(CS(=O)(=O)N3CCOCC3)cc2C2=CCCCC2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 95 %

Procedure:
To a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(morpholine-4-sulfonylmethyl)-phenyl]-amide (as prepared in the previous step, 33.7 mg, 0.057 mmol) in DCM (0.5 mL) and EtOH (10 μL), TFA (0.10 mL) was added. The resulting solution was stirred at RT for 6 h and concentrated in vacuo. The residue obtained was dried and purified on silica (30% EtOAc/hexane) to obtain the title compound (11 mg, 95%): 1H-NMR (CDCl3; 400 MHz): δ9.63 (s, 1H), 8.43 (d, 1H, J=8.4 Hz), 7.73 (s, 1H), 7.36 (dd, 1H, J=8.4, 1.9 Hz), 7.25 (d, 1H, J=1.9 Hz), 5.85 (br s, 1H), 4.12 (s, 2H), 3.66-3.68 (m, 4H), 3.17-3.19 (m, 4H), 2.19-2.23 (m, 4H), 1.62-1.85 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C22H25N5O4S, 456.2 (M+H). found 455.9.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14](Cl)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].[CH2:16]([O:20][C:21]1[CH:29]=[CH:28][C:24]2[O:25][CH2:26][O:27][C:23]=2[C:22]=1B1OC(C)(C)C(C)(C)O1)[CH2:17][CH2:18][CH3:19]>>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([C:22]3[C:23]4[O:27][CH2:26][O:25][C:24]=4[CH:28]=[CH:29][C:21]=3[O:20][CH2:16][CH2:17][CH2:18][CH3:19])[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2c(Cl)ncnc12
Reactant: CCCCOc1ccc2c(c1B1OC(C)(C)C(C)(C)O1)OCO2
Product: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)OCC)c[nH]c13)OCO2

Procedure:
Starting from 4-chloro-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid ethyl ester and 5-butoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzo[1,3]dioxole (example A33) the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[N+:15]([O-])([OH:17])=[O:16].[OH-].[NH4+]>>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: Clc1ccc(Cc2ccccn2)cc1
Agent: [NH4+]
Agent: [OH-]
Product: O=[N+]([O-])c1cc(Cc2ccccn2)ccc1Cl
Reaction time: 8 h

Procedure:
99 G. (0.487 mol) of 2-(p-chlorobenzyl)pyridine was added to 500 ml. of fuming nitric acid cooled to 10 ° while maintaining the temperature at <10° for 2 hours. The resulting mixture was poured into 800 ml. of ice, neutralized with ammonium hydroxide and allowed to stand overnight at room temperature. The resulting solid was collected, washed with water and air dried to give 2-(4-chloro-3-nitrobenzyl)pyridine as off-white prisms, m. 58°-60° C. (aq. ethanol).
Reaction SMILES: OC1C(=O)NC=C(CCC2C=CC=CC=2C)C=1.[F:18][C:19]1[CH:20]=[C:21]([C:25]#[C:26][C:27]2[CH:28]=[C:29]([O:35]C)[C:30]([O:33]C)=[N:31][CH:32]=2)[CH:22]=[CH:23][CH:24]=1>>[F:18][C:19]1[CH:20]=[C:21]([CH2:25][CH2:26][C:27]2[CH:28]=[C:29]([OH:35])[C:30](=[O:33])[NH:31][CH:32]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: COc1cc(C#Cc2cccc(F)c2)cnc1OC
Agent: Cc1ccccc1CCc1c[nH]c(=O)c(O)c1
Product: O=c1[nH]cc(CCc2cccc(F)c2)cc1O

Procedure:
Prepared as described for 3-hydroxy-5-(2-methylphenethyl)pyridin-2(1H)-one (Example 27) from 5-[(3-fluorophenyl)ethynyl]-2,3-dimethoxypyridine (Intermediate 37).
Reaction SMILES: C([Li])CCC.[CH2:6]([C@H:13]1[CH2:17][O:16][C:15](=[O:18])[NH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:19](Cl)(=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C1COCC1>[O:26]=[C:19]([N:14]1[C@@H:13]([CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:17][O:16][C:15]1=[O:18])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCC(=O)Cl
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
n-Butyl lithium (58 mL, 2.5M in hexanes, 142 mmol) is added to a solution of (S)-4-benzyl-2-oxazolidinone 51 (25 g, 141 mmol) in THF (250 mL) at -78° C. under argon and stirred for 15 min. Heptanoyl chloride 50 (21 g, 141 mmol) is added to the solution dropwise and stirred for 40 min, then warmed to 0° C. for 2 hours. The reaction is quenched with NH4Cl and extracted with EtOAc. The organic layer is washed with 1N HCl, aqueous NaHCO3, aqueous NACl, and dried over MgSO4. The crude product is recrystallized from hexane to give 52.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=2[F:17])[N:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[N:6]=1)=[O:4].[OH-].[K+].CO>O>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([CH:8]2[N:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH2:9]2)=[C:11]([F:17])[CH:12]=1
Reactant: COC(=O)C1=NN(c2ccccc2Cl)C(c2ccc(Br)cc2F)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1=NN(c2ccccc2Cl)C(c2ccc(Br)cc2F)C1
Temperature: 70 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
5-(4-Bromo-2-fluoro-phenyl)-1-(2-chloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid methyl ester (3.0 g, 7.0 mmol) prepared in Step 3 and a solution of potassium hydroxide (790.9 mg, 14.1 mmol) in distilled water (47.0 mL) were added to methanol (47.0 mL). The reaction mixture was stirred at 70° C. for 2 hours and then concentrated under reduced pressure to discard methanol. The resulting residue was washed with diethyl ether, acidified by a 1N hydrochloric acid solution, and then extracted with ethyl acetate. The extract was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 2.5 g of the titled compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([N:11]2[CH2:15][CH2:14][C:13]([C:16]3[CH:21]=[C:20]([Br:22])[C:19]([O:23]CC4C=CC(OC)=CC=4)=[C:18]([Br:33])[CH:17]=3)=[N:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([N:11]2[CH2:15][CH2:14][C:13]([C:16]3[CH:21]=[C:20]([Br:22])[C:19]([OH:23])=[C:18]([Br:33])[CH:17]=3)=[N:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(COc2c(Br)cc(C3=NN(C(=O)c4ccc(Cl)c(Br)c4)CC3)cc2Br)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(Cl)c(Br)c1)N1CCC(c2cc(Br)c(O)c(Br)c2)=N1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 66.6 %

Procedure:
To a stirred solution of (3-bromo-4-chlorophenyl)(3-(3,5-dibromo-4-(4-methoxybenzyloxy)phenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (F) (51.8 mg, 0.0788 mmol) in anhydrous dichloromethane (5 ml) under nitrogen was added trifluoroacetic acid (0.1 mL) and the solution was stirred at room temperature for 1 h 40 min. The solvent was evaporated and more dichloromethane was added to the residue and evaporated. The residue was then recrystallised from EtOAc-CH2Cl2 and the resulting solid was collected by filtration, washed with 50% EtOAc/pet. ether and dried at 55° C. under vacuum to leave 28.2 mg (67%) of the title compound as a light-brown solid. 1H NMR δ (ppm) (DMSO-d6): 4.13 (2 H, t, J=9.8 Hz), 7.81 (1 H, d, J=8.4 Hz), 7.86 (2 H, s), 7.86-7.93 (1 H, m), 8.24 (1 H, d, J=2.0 Hz), 10.62 (1 H, br s). LCMS (10 cm_apci_formic) Rt 4.29 min; m/z 535/537/539/541/543 [M+H].
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[O:15]1[C:19]2[C:20]([CH:24]=O)=[CH:21][CH:22]=[CH:23][C:18]=2[CH2:17][CH2:16]1.[BH4-].[Na+].Cl>C1(C)C=CC=CC=1>[O:15]1[C:19]2[C:20]([CH2:24][NH:14][C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[O:7][C:4]3[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=3)=[CH:21][CH:22]=[CH:23][C:18]=2[CH2:17][CH2:16]1
Reactant: O=Cc1cccc2c1OCC2
Reactant: Nc1ccccc1Oc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: c1ccc(Oc2ccccc2NCc2cccc3c2OCC3)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Aminodiphenyl ether (1 g, 5.4 mmol) was treated with 2,3-Dihydro-benzofuran-7-carbaldehyde (1 g, 7.02 mmol) and toluene (10 ml) and heated at reflux for 4 h under an atmosphere of nitrogen with vigorous stirring. The solution became yellow and homogeneous. The reaction was then concentrated in vacuum to remove the toluene, cooled to 0° C., diluted with methanol (15 ml), and treated with sodium borohydride (612 mg 16 mmol) in portions over a period of 20 min. The reaction was then allowed to warm to room temperature and stirred for a further 30 min. 2N hydrochloric acid (5 ml) was added and the reaction stirred for a further 30 min. The reaction was then concentrated in vacuum to a gum and 10% aq potassium carbonate (50 ml) added. The product was then recovered by extraction into ethyl acetate (50 ml), the extract was dried over magnesium sulphate and concentrated in vacuum to a gum. The gum was chromatographed on a 120 g silica column in a gradient of 10-30% ethyl acetate in petrol. The main fast running fraction, N-(2,3-Dihydro-benzofuran-7-ylmethyl)-N-(2-phenoxyphenyl)-amine was collected as a gum (1.2824 g, 4.04 mmole, 74.9%) that crystallized on standing.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:10]([OH:20])[CH2:11][CH2:12][NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:21]([C:23]([OH:30])([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])#[CH:22]>>[F:16][C:15]([F:18])([F:17])[C:14]([NH:13][CH2:12][CH2:11][CH:10]([OH:20])[C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([C:22]#[C:21][C:23]([OH:30])([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])[CH:3]=1)=[O:19]
Reactant: C#CC(O)(CCC)CCC
Reactant: COc1ccc(C(O)CCNC(=O)C(F)(F)F)cc1Br
Product: CCCC(O)(C#Cc1cc(C(O)CCNC(=O)C(F)(F)F)ccc1OC)CCC

Procedure:
N-(3-(3-bromo-4-methoxyphenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide was coupled with alkynol 20 following the procedure described in Example 10 to give 2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-hydroxy-3-propylhex-1-ynyl)-4-methoxyphenyl)propyl)acetamide as a yellow oil. Yield (0.92 g, 55%): 1H NMR (400 MHz, DMSO-d6) δ 9.31 (t, J=5.0 Hz, 1H), 7.24-7.21 (m, 2H), 6.95 (d, J=9.2 Hz, 1H), 5.25 (d, J=4.8 Hz, 1H), 5.05 (s, 1H), 4.51-4.47 (m, 1H), 3.75 (s, 3H), 3.24-3.17 (m, 2H), 1.77-1.72 (m, 2H), 1.61-1.42 (m, 8H), 0.89 (t, J=7.0 Hz, 6H).
Reaction SMILES: [OH:1][CH:2]([C@H:7]1[CH2:15][CH2:14][C@H:13]2[C@H:16]3[C@H:26]([CH2:27][CH2:28][C@:8]12[CH2:9][C:10]([OH:12])=[O:11])[C@:24]1([CH3:25])[C:19](=[CH:20][C:21](=[O:29])[CH2:22][CH2:23]1)[N:18]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:17]3)[CH2:3][CH:4]([CH3:6])[CH3:5].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>CN(C=O)C>[O:1]=[C:2]([C@H:7]1[CH2:15][CH2:14][C@H:13]2[C@H:16]3[C@H:26]([CH2:27][CH2:28][C@:8]12[CH2:9][C:10]([OH:12])=[O:11])[C@:24]1([CH3:25])[C:19](=[CH:20][C:21](=[O:29])[CH2:22][CH2:23]1)[N:18]([C:30]([CH3:31])([CH3:32])[CH3:33])[CH2:17]3)[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)CC(O)[C@H]1CC[C@H]2[C@@H]3CN(C(C)(C)C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12CC(=O)O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CC(=O)[C@H]1CC[C@H]2[C@@H]3CN(C(C)(C)C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12CC(=O)O

Procedure:
A solution of 17β-(1-hydroxy-3-methylbutyl)-6-t-butylcarboxy-6-azaandrost-4-en-3-one (160 mg, 0.349 mmol) prepared in part C above, in DMF (10 mL) is treated with pyridinium dichromate (656 mg, 1.74 mmol) at room temperature. After 10 hrs the reaction is poured into water, extracted with ethyl acetate (2×50 mL), the extracts are dried over MgSO4, concentrated and chromatographed on silica gel (40% ethyl acetate/hexanes) to give crude 17β-(1 -oxo-3-methylbutyl)-6-t-butylcarboxy-6-azaandrost-4-en-3-one; yield: 135 mg (85%). A portion of this material (81 mg, 0.18 mmol) is treated with trifluoroacetic acid as described in Example 4 above to give, after recrystallization from diethyl ether/hexanes 17β-(1-oxo-3-methylbutyl)-6-azaandrost-4-en-3-one as a white crystalline solid; yield: 58 mg (92%); m.p. 169°-171° C. Anal. Calcd. for C23H35NO2 ·1/4H2O; C, 76.30; H, 9.88; N, 3.87. Found: C, 76.48; h, 9.93; N, 3.89.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH2:22])=[O:21])[CH:15]=2)[C:8](=[O:13])[CH:9]=[C:10]([OH:12])[CH:11]=1)(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[F:29][C:30]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:31]=1[CH2:32]Br>CN(C)C=O>[C:1]([O:4][CH2:5][C:6]1[N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH2:22])=[O:21])[CH:15]=2)[C:8](=[O:13])[CH:9]=[C:10]([O:12][CH2:32][C:31]2[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:30]=2[F:29])[CH:11]=1)(=[O:3])[CH3:2]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: CC(=O)OCc1cc(O)cc(=O)n1-c1cccc(C(N)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1cc(OCc2ccc(F)cc2F)cc(=O)n1-c1cccc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 32.1 %

Procedure:
{1-[3-(aminocarbonyl)phenyl]-4-hydroxy-6-oxo-1,6-dihydropyridin-2-yl}methyl acetate (crude from step 1) (3.61 g, 11.94 mmol) was dissolved in N,N-dimethylformamide (40 mL). K2CO3 (3.80 g, 27.46 mmol) was added followed by 2,4-difluorobenzyl bromide (5.44 g, 26.27 mmol). The reaction mixture was stirred for 48 hours at room temperature. The reaction mixture was then partially concentrated and the residue taken up in dichloromethane/tetrahydrofuran 1:1 and filtered. The filtrate was collected, concentrated and the residue tritrated with dichloromethane to afford a tan solid (1.64 g, 32%). 1H NMR (400 MHz, DMF-d6) δ 8.19 (br s, 1H), 8.07 (app dt, J=1.35, 7.66 Hz, 1H), 7.91 (app t, J=1.81 Hz, 1H), 7.76 (app dt, J=6.58, 8.59 Hz, 1H) 7.62 (t, J=7.79 Hz, 1H), 7.55 (ddd, J=1.21, 2.01, 7.79 Hz, 1H), 7.46 (br s, 1H), 7.34 (ddd, J=2.55, 9.40, 10.47 Hz, 1H), 7.23-7.18 (m, 1H), 6.26 (d, J=2.55 Hz, 1H), 6.11 (d, J=2.69 Hz, 1H), 5.23 (s, 2H), 4.62 (AB q, JAB=14.97 Hz, 2H), 1.96 (s, 3H). ES-HRMS m/z 429.1280 (M+H calcd for C22H18F2N2O5 requires 429.1257).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:13]([O:15]CC)=O)=[N:10][NH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25]>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:13]([NH:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:15])=[N:10][NH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1n[nH]cc1-c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)NCCN
Product: CC(C)(C)OC(=O)NCCNC(=O)c1n[nH]cc1-c1cccc(F)c1
Yield: 64.6 %

Procedure:
4.6 q (19.64 mmol) of ethyl 4-(3-fluorophenyl)-3-pyrazolecarboxylate were reacted with t-butyl (2-aminoethyl)carbamate in an analoqous manner to that described in Example 16. Chromatoqraphy of the crude product and recrystallization from ethyl acetate/hexane yielded 4.4 g (64.6%) of t-butyl [2-(4-(3-fluorophenyl)-3-pyrazolecarboxamido)ethyl]carbamate as white crystals, melting point 175°-176°.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23]3=[C:24]([NH:26][C:27](=[S:28])[N:22]3[CH2:21][CH2:20][CH2:19]2)[CH:25]=1.[OH-].[Na+]>CCO>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23]3=[C:24]([N:26]=[C:27]([S:28][CH2:3][C:4]4[CH:13]=[CH:12][C:11]5[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=5)[N:5]=4)[N:22]3[CH2:21][CH2:20][CH2:19]2)[CH:25]=1
Reactant: COc1cc2c3c(c1)[nH]c(=S)n3CCC2
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc2c3c(c1)nc(SCc1ccc4ccccc4n1)n3CCC2
Temperature: 25 °C
Yield: 61.2 %

Procedure:
2-Chloromethylquinoline hydrochloride (0.845 g, 4.0 mmol) was added to a solution of 5,6-dihydro-8-methoxy-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione (0.871 g, 4.0 mmol) in 1 N-NaOH (8 ml) and EtOH (8 ml). The mixture was heated to reflux, cooled to room temperature, concentrated in vacuo, and the aqueous residue extracted with CH2Cl2 (50 ml). The extract was washed with 1NNaOH (2×30 ml), and brine (20 ml), dried (MgSO4), and evaporated in vacuo to give an oil which was purified by chromatography (SiO2, Et2O) and trituration with Et2O-petrol ether to give the title compound (0.885 g, 62%) as yellow crystals, mp 89°-91° C. (Found: C,70.1; H,5.4; N,11.4; C21H19N3OS requires C,69.8; H,5.3; N,11.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([OH:22])[C@@H:9]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH2:36]([O:38][C:39](=[O:43])[CH2:40][CH2:41][NH2:42])[CH3:37]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([OH:22])[C@@H:9]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:42][CH2:41][CH2:40][C:39]([O:38][CH2:36][CH3:37])=[O:43])=[O:18])=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCN
Reactant: CCC[C@H](c1ccc(C(=O)O)cc1)[C@@H](O)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC[C@H](c1ccc(C(=O)NCCC(=O)OCC)cc1)[C@@H](O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product of Step C (5.00 g, 15.7 mmol) in THF (100 mL) was added CDI (3.05 g, 18.82 mmol). After stirring at room temperature for one hour, β-alanine ethyl ester hydrochloride (3.61 mg, 23.53 mmol) was added, then the mixture was stirred at room temperature for two days. The mixture was diluted with EtOAc then washed with 1N NaOH, then water, then brine. The organic layer was dried over MgSO4, filtered, then concentrated to provide the title compound which was used without further purification. 1H NMR (499 MHz, CDCl3): δ 7.74 (d, J=7.9 Hz, 2H); 7.32 (d, =8.2 Hz, 2H); 7.28 (t, J=4.0 Hz, 2H); 7.25-7.15 (m, 2H); 6.88 (brs, 1H); 4.77 (d, 0.1=7.7 Hz, 1H); 4.20 (q, J=7.1 Hz, 2H); 3.75 (q, J=5.9 Hz, 2H); 2.89 (ddd, J=11.1, 7.7, 4.1 Hz, 1H); 2.66 (1, J=5.8 Hz, 2H); 1.47-1.37 (m, 2H); 1.30 (t, J=7.1 Hz, 3H); 1.11 (m, 2H); 0.76 (t, J=7.3 Hz, 3H). LC-MS: LC1 1.14 min. (M+H)+ 418.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C:11]2([NH:14][C:15]([C:17]3[C:18]4[CH:19]=[N:20][N:21]([C:27]5[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=5)[C:22]=4[CH:23]=[C:24](Br)[CH:25]=3)=[O:16])[CH2:13][CH2:12]2)[CH:8]=[CH:7][N:6]=1)(=[O:4])=[O:3].[CH3:34][S:35](C1C=C(C2(NC(C3C4C=NN(C5C=CC(F)=CC=5)C=4C=C(I)C=3)=O)CC2)C=CN=1)(=[O:37])=[O:36]>>[CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C:11]2([NH:14][C:15]([C:17]3[C:18]4[CH:19]=[N:20][N:21]([C:27]5[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=5)[C:22]=4[CH:23]=[C:24]([S:35]([CH3:34])(=[O:37])=[O:36])[CH:25]=3)=[O:16])[CH2:13][CH2:12]2)[CH:8]=[CH:7][N:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cc(C2(NC(=O)c3cc(I)cc4c3cnn4-c3ccc(F)cc3)CC2)ccn1
Reactant: CS(=O)(=O)c1cc(C2(NC(=O)c3cc(Br)cc4c3cnn4-c3ccc(F)cc3)CC2)ccn1
Product: CS(=O)(=O)c1cc(C(=O)NC2(c3ccnc(S(C)(=O)=O)c3)CC2)c2cnn(-c3ccc(F)cc3)c2c1

Procedure:
The title compound is synthesized according to the coupling procedure described in Example 18 from a mixture of 6-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid [1-(2-methanesulfonyl-pyridin-4-yl)-cyclopropyl]-amide, and 1-(4-fluoro-phenyl)-6-iodo-1H-indazole-4-carboxylic acid [1-(2-methanesulfonyl-pyridin-4-yl)-cyclopropyl]-amide (100 mg).