Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:20][CH:19]=1.I[CH2:32][CH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:36].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:32][CH2:33][CH2:34][C:35](=[O:36])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:8][CH2:7]2)[N:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:4][N:3]1[C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N2CN(c3ccccc3)C3(CCNCC3)C2=O)cc1
Reactant: O=C(CCCI)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(N2CN(c3ccccc3)C3(CCN(CCCC(=O)c4ccccc4)CC3)C2=O)cc1
Yield: 80.6 %

Procedure:
tert-Butyl 4-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)benzoate (0.274 g, 0.672 mmol), 4-iodobutyrophenone (0.18 g, 0.672 mmol), and potassium carbonate (0.14 g, 1.01 mmol) in N,N-dimethylformamide (5 mL) were heated at 65° C. for 3 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried (MgSO4), and evaporated. The residue was purified by PTLC (5% methanol/dichloromethane) to give product as an oil (0.30 g, 80%); MS for C34H39N3O4 m/z 554 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:10]=[CH:11][C:12]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][C:13]=3[N:14]=2)[CH:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O>>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:10]=[CH:11][C:12]3[CH2:18][CH2:17][NH:16][CH2:15][C:13]=3[N:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(Nc2ncc3c(n2)CN(C(=O)OC(C)(C)C)CC3)ccn1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2ncc3c(n2)CNCC3)ccn1

Procedure:
A solution of 188 (136 mg, 0.398 mmol) and TFA (2 mL) was stirred for 15 min. The reaction was concentrated to afford N-(2-methylpyridin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine (190) which was used without additional purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[C:10]([O:15]C(C)=O)=[CH:11][CH2:12][CH2:13][CH3:14])=[CH:4][CH:3]=1.Cl.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[C:10](=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14])=[CH:4][CH:3]=1
Reactant: CCCC=C(OC(C)=O)C(=Cc1ccc(Cl)cc1)n1cncn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCC(=O)C(=Cc1ccc(Cl)cc1)n1cncn1
Temperature: 50 °C

Procedure:
To the resulting 1-(4-chlorophenyl)-2-(1,2,4-triazole-1-yl)-3-acetoxyl-1,3-heptadiene (9 g) was added conc. hydrochloric acid (100 ml), and the mixture was heated to 50° C. for 2 hours and poured into ice water (500 ml). The aqueous liquor was neutralized with potassium carbonate and extracted with ethyl acetate (300 ml). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation. The crystalline residue was recrystallized from a carbon tetrachloride/n-hexane (1:1) mixture to obtain 6 g of the II-B isomer of 1-(4-chlorophenyl)-2-(1,2,4-triazole-1-yl)-1-heptene-3-one.
Reaction SMILES: [CH2:1]([N:4]([CH2:15][CH2:16][CH3:17])[CH2:5][CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH3:3].C([O-])(=O)C([O-])=[O:20]>>[CH2:15]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:20])[CH:13]=2)[CH2:8][CH2:7]1)[CH2:16][CH3:17]
Reactant: O=C([O-])C(=O)[O-]
Reactant: CCCN(CCC)CC1CCc2ccccc21
Product: CCCN(CCC)CC1CCc2ccc(O)cc21

Procedure:
N,N-Dipropyl-1-indanmethylamine, oxalate. M.P 99°-102° C. (Lu 21-091)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[C:12]2[CH2:17][OH:18].O1C[CH2:22][CH2:21][CH2:20]1.[H-].[Na+].C(Br)C=C>O>[CH2:22]([O:18][CH2:17][C:12]1[C:13]2[C:8](=[C:7]([C:2]3[N:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:10][CH:11]=1)[CH:21]=[CH2:20]
Reactant: OCc1cccc2c(-c3ncccn3)cccc12
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C=CCBr
Product: C=CCOCc1cccc2c(-c3ncccn3)cccc12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a 250 ml single neck round bottom flask equipped with a reflux condensor and an argon inlet is added 2.35 gm of the 5-pyrimidyl-1-naphthylcarbinol and 100 ml of anhydrous tetrahydrofuran. The system is cooled to 0° C. and after cooling 0.26 gm sodium hydride is added. The system is stirred for an additional 20 minutes and 1.1 ml of allyl bromide is added. The system is allowed to come to room temperature over 1/2-hour and is stirred there for an additional 2 hours. Afterwards, the system is heated at reflux for 17 hours. At this time, water is added to the system and the product extracted with methylene chloride. The methylene chloride is then washed with water and dried over sodium sulfate. The methylene chloride is removed by stripping to give the 5-pyrimidyl-1-naphthylcarbinol allylether.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[C:8]([OH:10])=[O:9].[CH2:18](Br)[CH:19]=[CH2:20]>>[CH2:20]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[C:8]([OH:10])=[O:9])[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: COc1cc(C(=O)O)cc(CCCO)c1OC
Product: C=CCOCCCc1cc(C(=O)O)cc(OC)c1OC

Procedure:
3-(3-Allyloxypropyl)-4,5-dimethoxybenzoic acid was prepared from 3-(3-hydroxypropyl)-4,5-dimethoxybenzoic acid (Example 10, Step 1) and allyl bromide in quantitative yield by following Method I and used without further purification.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]([OH:12])=O)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(Cl)(=O)C([Cl:16])=O.CN(C=O)C>C(Cl)Cl>[N:1]1[CH:2]=[C:3]([C:10]([Cl:16])=[O:12])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cnc2ccccn12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cnc2ccccn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of imidazo[1,2-a]pyridine-3-carboxylic acid (5.270 g, 32.5 mmol) in DCM (200 ml) was treated with oxalyl chloride (3.13 ml, 35.8 mmol) followed by the addition of DMF (0.252 ml, 3.25 mmol). The reaction mixture was stirred at RT overnight. The solvent was removed in vacuo to afford the title compound as a hydrochloride salt;
Reaction SMILES: [N:1]1[O:2][C:3]2[CH2:4][CH2:5][CH2:6][C:7]3[C:16]=2[C:15]=1[C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:8]=3.C([BH3-])#N.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[N:1]1[O:2][C:3]2[CH2:4][CH2:5][CH2:6][CH:7]3[C:16]=2[C:15]=1[C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:8]3
Reactant: c1ccc2c(c1)nc1c3c(onc32)CCC1
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: c1ccc2c(c1)NC1CCCc3onc-2c31
Reaction time: 0.5 h
Yield: 58 %

Procedure:
In 100 ml glacial acetic acid was dissolved 4.75 g 4,5-dihydro-3H-isoxazolo[5,4,3-kl]acridine. To the mechanically stirred solution under nitrogen was added 2.84 g of sodium cyanoborohydride. The reaction was complete after 0.5 hour at room temperature. The reaction mixture was neutralized with excess aqueous sodium carbonate and extracted with dichloromethane (DCM). The DCM was dried over MgSO4, filtered and concentrated to a solid. The solid was purified by flash chromatography and recrystallized from 1:1 DCM/hexanes to yield 2.78 g of powder, m.p. 152°-154° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[C:21](O)=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:24][CH2:25][C:26](=[O:28])[CH3:27].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClCCl.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:13][C@H:12]1[C:21](=[O:22])[NH:24][CH2:25][C:26](=[O:28])[CH3:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Reactant: CC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)CNC(=O)[C@@H]1C[C@@H](OC(C)(C)C)CN1C(=O)OCc1ccccc1
Reaction time: 24 h
Yield: 55.4 %

Procedure:
To a stirred solution of (2S,4R)-4-tert-butoxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester (10.78 g, 33.54 mmol) and 1-amino-propan-2-one (2.45 g, crude, 33.54 mmol) in dichlormethane (56 mL) were added EDC.HCl (6.405 g, 33.54 mmol), HOBt (5.128 g, 33.54 mmol) and triethylamine (12.67 mL, 100.62 mmol). The mixture was stirred at room temp. for 24 h. The reaction mixture was then diluted with water, extracted with dichloromethane and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude was then purified by column chromatography to give (2S,4R)-4-tert-butoxy-2-(2-oxo-propylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester (7 g, 55.4% yield) as a light brown liquid. MS calcd. for C20H29N2O5 [(M+H)+] 377.0, obsd. 377.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][CH2:23]O)[N:21]=1)=[CH:5]2.[CH3:25][S:26]([O-])(=[O:28])=[O:27].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][CH2:23][S:26]([CH3:25])(=[O:28])=[O:27])[N:21]=1)=[CH:5]2
Reactant: CS(=O)(=O)[O-]
Reactant: OCC[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)CC[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.5 %

Procedure:
2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethanol (50 mg, 0.11 mmol) prepared in Example 5 was dissolved in N,N-dimethylformamide (2 mL). Sodium methanesulfonate (54 mg, 0.55 mmol) was added thereto, and the mixture was stirred for 8 h at room temperature. The reaction was quenched by water. The reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound (19 mg, Yield 45%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][C:15]1([CH3:19])[CH2:18][O:17][CH2:16]1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FB(F)F.C(OCC)C.C(N(CC)CC)C.C(OCC)C>ClCCl>[CH2:1]([O:8][CH2:9][CH2:10][C:11]12[O:12][CH2:16][C:15]([CH3:19])([CH2:14][O:13]1)[CH2:18][O:17]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(COC(=O)CCOCc2ccccc2)COC1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC12COC(CCOCc3ccccc3)(OC1)OC2
Temperature: -15 °C
Reaction time: 5 h
Yield: 73.9 %

Procedure:
3-Methyl-3-oxetanylmethyl 3-benzyloxypropionate (521 mg) was dissolved in dichloromethane under an argon atmosphere, and trifluoroborane-diethylether was added thereto at -15° C. The mixture was stirred for 5 hours at -15° C. Triethylamine (280 μl) was added to the reaction mixture, and stirring was continued for 15 minutes. Subsequently, diethylether (3 ml) was added. The precipitating crystals were removed from the reaction mixture by filtration, then the mother liquid was concentrated under reduced pressure. The residue was purified by alumina column chromatography (ethyl acetatehexane 1:3), to give 385 mg of 1-(2-benzyloxyethyl)-4-methyl-2,6,7-trioxabicyclo-[2.2.2]octane as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:28]4[CH:29]=[CH:30][C:25]([C:24]([F:35])([F:34])[F:23])=[CH:26][CH:27]=4)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccc(C(F)(F)F)cc4)c3O2)cc1
Yield: 74.3 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 4-(trifluoromethyl)phenylboronic acid (0.372 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.435 g (74%) of (±)-{7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate as a light yellow solid. mp 116-118° C.; Anal. calcd. for C23H19F3O4S: C, 61.6; H, 4.27. Found: C, 61.37; H, 4.36.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:32]=[CH:31][C:7]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([CH:18]([NH:20][C:21](=[O:29])[CH2:22][CH2:23][CH2:24][C:25]([O:27]C)=[O:26])[CH3:19])=[CH:15][C:14]=3[CH:30]=2)=[CH:6][CH:5]=1)[CH3:2].[OH-].[Na+]>CO>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([CH:18]([NH:20][C:21](=[O:29])[CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH3:19])=[CH:15][C:14]=3[CH:30]=2)=[CH:31][CH:32]=1)[CH3:2]
Reactant: CCOc1ccc(COc2ccc3oc(C(C)NC(=O)CCCC(=O)OC)cc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOc1ccc(COc2ccc3oc(C(C)NC(=O)CCCC(=O)O)cc3c2)cc1
Yield: 4.9 %

Procedure:
Using methyl 5-[(1-{5-[(4-ethoxybenzyl)oxy]-1-benzofuran-2-yl}ethyl)amino]-5-oxopentanoate (214 mg, 0.489 mmol) obtained in Example 97, methanol (2.0 mL) and 8N aqueous sodium hydroxide solution (0.10 mL, 0.82 mmol), an operation in the same manner as in Example 35 was performed to give the title compound (10.2 mg, yield 30%) as a white solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][N+:7]=1[O-:13].[OH-].[Na+]>S(=O)(=O)(O)O>[CH3:5][C:6]1[CH:11]=[C:10]([N+:1]([O-:4])=[O:2])[C:9]([CH3:12])=[CH:8][N+:7]=1[O-:13]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(C)[n+]([O-])c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1c[n+]([O-])c(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
260 ml of fuming nitric acid (d=1.5) were added dropwise to 840 ml of concentrated sulphuric acid while cooling. 348.2 g of 2,5-dimethylpyridine 1-oxide were subsequently added portionwise at 0°-5°. The mixture was stirred at room temperature for 1 hour, then heated to 90° within 3 hours, left at this temperature overnight and, after cooling, poured on to 6 kg of ice. The mixture was adjusted to pH 3 with concentrated sodium hydroxide solution and extracted three times with 2 l of methylene chloride. The combined organic phases were washed with 4 l of water, dried over sodium sulfate and evaporated in vacuo. The residue was crystallized from methylene chloride/petroleum ether and there was obtained 2,5-dimethyl-4-nitropyridine 1-oxide of melting point 142°-144°.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:7](S(C)(=O)=O)[N:6]=1)(=[O:4])=[O:3].[OH:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1.C([Li])CCC>C1COCC1>[CH3:1][S:2]([C:5]1[N:6]=[C:7]([O:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[C:8]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[N:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c(S(C)(=O)=O)n1
Reactant: Oc1cccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CS(=O)(=O)c1nc(Oc2cccnc2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Temperature: 0 °C

Procedure:
To a 50 mL round bottom flask fitted with a magnetic stirrer bar and rubber septum was added 20 mL anhydrous THF (Aldrich) and 2,4-bis(methyl-sulfonyl)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (Reference Example 5) (1.0 g, 2 mmol). The flask was flushed with nitrogen and cooled to 0° C. In a separate flask, also fitted with a magnetic stirrer bar and rubber septum, was added 10 mL anhydrous THF and 3-hydroxypyridine (213 mg, 2.24 mmol), This flask was flushed with nitrogen and cooled to 0° C. Then n-butyl lithium (1.12 mL, 2.24 mmol) (Aldrich-2M solution in hexane) was added via syringe and the solution stirred for several minutes. The lithium alkoxide solution was then withdrawn by syringe and slowly added to the first reaction flask. The solution was stirred at 0° C. for 1 h, quenched with saturated sodium bicarbonate and the reaction products extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO4, filtered and the solvent removed under reduced pressure. Flash column chromatography on silica gel (eluted with 35/65 hexanes/ethyl acetate) afforded 2-methylsulfonyl-4-(3-pyridyloxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine: 1H-NMR 500 MHz (CDCl3): δ 3.20 (s, 3H), 7.20-7.25 (m, 4H), 7.30-7.38 (m, 3H), 7.41 (m, 1H), 7.63-7.65 (m, 1H), 8.53-8.55 (m, 2H).
Reaction SMILES: [CH3:1][C@@:2]12[C:10]([OH:13])([C:11]#[N:12])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:14][CH2:15][C:16]3[C@@:22]([CH3:23])([C:5]1(O)[CH2:4][CH2:3]2)[CH2:21][CH2:20][C:18](=[O:19])[CH:17]=3.S(=O)(=O)(O)O>O>[C:11]([C@@:10]1([OH:13])[CH2:9][CH2:8][C@H:7]2[C@H:6]3[C:5](=[CH:4][CH2:3][C@:2]12[CH3:1])[C@:22]1([CH3:23])[C:16](=[CH:17][C:18](=[O:19])[CH2:20][CH2:21]1)[CH2:15][CH2:14]3)#[N:12]
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(O)(C#N)[C@@]3(C)CCC12O
Agent: O=S(=O)(O)O
Solvent: O
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@@]2(C)[C@H]1CC[C@]2(O)C#N

Procedure:
17β-Cyano-9α,17α-dihydroxyandrost-4-en-3-one (I, EXAMPLE 85, 313 mg) is added to sulfuric acid (57%, 5 ml) at 2° and is stirred at 2°-5° for several hr and then overnight at 22°; solids formed. Water (10 ml) is added at 10°, the mixture stirred for 15 min, the solids collected and air dried to give the title compound, NMR (CDCl3 /DMSO-d6 ; 5/1) 5.7, 5.6, 1.4 and 0.9 δ.
Reaction SMILES: [F:1][S:2]([C:5]1[CH:6]=[C:7]([CH:25]=[CH:26][CH:27]=1)[C:8]([NH:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][C:15]([C:22](O)=[O:23])=[C:16]2[OH:21])=[O:9])(=[O:4])=[O:3].CN(C)C=O.S(Cl)([Cl:35])=O>ClCCl>[F:1][S:2]([C:5]1[CH:6]=[C:7]([CH:25]=[CH:26][CH:27]=1)[C:8]([NH:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][C:15]([C:22]([Cl:35])=[O:23])=[C:16]2[OH:21])=[O:9])(=[O:4])=[O:3]
Reactant: O=S(Cl)Cl
Reactant: O=C(Nc1cccc2c(O)c(C(=O)O)ccc12)c1cccc(S(=O)(=O)F)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Nc1cccc2c(O)c(C(=O)Cl)ccc12)c1cccc(S(=O)(=O)F)c1
Temperature: 5 °C

Procedure:
5-(3-Fluorosulphonylbenzamido)-1-hydroxy-2-naphthoic acid (11) (10 g, 26 m.mole) was suspended in dry dichloromethane (200 ml), containing dimethylformamide (0.5 ml) and thionyl chloride (10.8 g, 91 m.mole). The mixture was heated under reflux with stirring for 2.5 hours, during which time the required acid chloride had crystallized as a pale yellow solid. After cooling to 5° C., the acid chloride was removed by filtration and washed with a little cold, dry dichloromethane.
Reaction SMILES: C([N:8]1[C:12]([NH:13][CH:14]2[CH2:19][CH2:18][CH:17]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:16][CH2:15]2)=[CH:11][CH:10]=[N:9]1)C1C=CC=CC=1.C(O)(=O)C.C([O-])=O.[NH4+].C(OCC)(=O)C>C(O)C.[OH-].[Pd+2].[OH-]>[Si:21]([O:20][CH:17]1[CH2:18][CH2:19][CH:14]([NH:13][C:12]2[NH:8][N:9]=[CH:10][CH:11]=2)[CH2:15][CH2:16]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:22])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(Nc2ccnn2Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OC1CCC(Nc2ccn[nH]2)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 68.3 %

Procedure:
To a suspension of 1-benzyl-N-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-pyrazol-5-amine (1.3 g) and palladium hydroxide (10 wt %, 1.27 g) in ethanol (6 mL)-acetic acid (0.6 mL) was added ammonium formate (0.62 g) by small portions at 80° C. After stirring at 80° C. for 2 hr, the mixture was allowed to cool, ethyl acetate was added, and the insoluble material was filtered off. Saturated aqueous sodium hydrogen carbonate was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.68 g, 69%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].Cl.ClCC1C=C(C=CC=1)O[CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1ccc(OCc2ccc3ccccc3n2)cc1O
Temperature: 50 °C

Procedure:
2′,4′-Dihydroxy-acetophenone (912 mg, 6 mmol) and 2-chloromethyl-quinoline hydrochloride (856 mg, 4.0 mmol, example 49) are dissolved in acetonitrile (20 mL). K2CO3 (1.12 g, 8.0 mmol) is added and the contents are heated to 50° C. for 16 hrs. The reaction is cooled to room temperature, and the solvent is removed by rotary evaporation. The contents are partitioned between ethyl acetate (100 mL) and water (100 mL), the aqueous layer is acidified with 2 N HCl to ˜pH 2 and further extracted with ethyl acetate (2×50 mL). All organic fractions are combined and washed with brine (3×150 mL), dried over MgSO4 and concentrated. The crude material is preadsorbed onto silica gel and purified by flash chromatography (silica, 15% ethyl acetate in hexanes) to give the title compound; MS (ion spray) 294 (M+H)+.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:19]([C:20]([O:22]C)=[O:21])=[C:18]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[O:17][C:14]2=[CH:15][N:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1COCC1.CO.C(OCC)(=O)C>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:19]([C:20]([OH:22])=[O:21])=[C:18]([C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[O:17][C:14]2=[CH:15][N:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)oc2cnc(OCc3ccccc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1c(-c2ccc(F)cc2)oc2cnc(OCc3ccccc3)cc12
Yield: 100 %

Procedure:
NaOH (27.8 mL, 27.8 mmol, 1M aq.) was added to a stirring solution of methyl 5-(benzyloxy)-2-(4-fluorophenyl)furo[2,3-c]pyridine-3-carboxylate (2.62 g, 6.94 mmol) in THF (174 mL) and MeOH (174 mL) at 60° C. for 2 hours. The mixture was diluted with ethyl acetate and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give the expected product 5-(benzyloxy)-2-(4-fluorophenyl)furo[2,3-c]pyridine-3-carboxylic acid (2.52 g, 6.94 mmol, 100% yield) consistent by LCMS. LC-MS retention time: 2.19 min; m/z (MH+): 364. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.