Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH4+:1].[OH-].[Br-].[CH2:4]([N+:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9]C=1)[CH:5]=[CH2:6].O>C(O)C>[CH2:6]([NH:1][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[S:9][S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:7][CH2:4][CH:5]=[CH2:6])[CH:5]=[CH2:4]
Reactant: C=CC[n+]1csc2ccccc21
Reactant: [NH4+]
Agent: [Br-]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCNc1ccccc1SSc1ccccc1NCC=C
Reaction time: 96 h

Procedure:
NH4OH (28° Be, 100 ml) was added to N-allylbenzothiazolium bromide (10 g, 0.04 mole) in ethanol (100 ml). The resulting solution was held four days at room temperature, then poured into cold water (500 ml) and extracted twice with ethyl ether (2×100 ml). The organic solution was dried over anhydrous Na2SO4, then evaporated to dryness. The oily residue was purified by column chromatography silica gel, eptane:CH2Cl2 1:1) to give the product (yield 5 g).
Reaction SMILES: O.[CH2:2]([C:4]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([C:18]#[N:19])[CH:13]=[C:14]([CH:17]=2)[C:15]#[N:16])=[C:7]([CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([S:29][CH3:30])=[CH:25][CH:24]=2)[NH:6][N:5]=1)[CH3:3].[OH:31]OS([O-])=O.[K+]>ClCCl>[CH2:2]([C:4]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([C:18]#[N:19])[CH:13]=[C:14]([CH:17]=2)[C:15]#[N:16])=[C:7]([CH2:20][CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([S:29]([CH3:30])=[O:31])=[CH:27][CH:28]=2)[NH:6][N:5]=1)[CH3:3]
Reactant: O=S([O-])OO
Reactant: CCc1n[nH]c(CCOc2ccc(SC)cc2)c1Oc1cc(C#N)cc(C#N)c1
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCc1n[nH]c(CCOc2ccc(S(C)=O)cc2)c1Oc1cc(C#N)cc(C#N)c1
Yield: 37.2 %

Procedure:
Wet alumina was prepared by adding water (1 ml) to Brockman grade I alumina (5 g). A sample of this material (160 mg) was added to a stirred solution of the sulfide from Example 1 (106 mg, 0.16 mmol) in dichloromethane (1 ml), followed by oxone (98 mg, 0.16 mmol). The reaction mixture was heated at reflux for 45 minutes, before being filtered. The solids were washed with dichloromethane (10 ml) and the combined organics were concentrated under reduced pressure. The crude product mixture was purified by flash chromatography on silica gel eluting with dichloromethane:methanol (100:0, 98:2 and 96:4, by volume) to give the title compound as a colourless oil (25 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([CH3:13])[C:11]([S:14][CH3:15])=[N:10][N:9]=1.ClC1C=C(C=CC=1)C(OO)=[O:21]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([CH3:13])[C:11]([S:14]([CH3:15])=[O:21])=[N:10][N:9]=1
Reactant: CSc1nnc(-c2ccccc2F)n1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1c(-c2ccccc2F)nnc1S(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred, 0° C., solution of 3-(2-fluorophenyl)-4-methyl-5-methylthio-4H-1,2,4-triazole (5.0 g, 2.2×10-2 mole) and CH2Cl2 (125 ml) was added portionwise m-chloroperoxybenzoic acid (4.83 g, 2.24×10-2 mole, 80% active MCPBA). After stirring overnight at room temperature, the reaction was diluted with CH2Cl2 until homogeneous and was then washed in turn twice with saturated aqueous NaHCO3 and once with saturated aqueous NaCl. After drying over anhydrous Na2SO4, the CH2Cl2 was evaporated leaving an oil which slowly crystallized. Crystallization from EtOAc/hexane gave a colorless solid: Mp 95°-97° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].Br[CH2:13][C:14](OCC)=[O:15].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[N+:8]([C:7]1[C:2]2[NH:1][C:14](=[O:15])[CH2:13][O:11][C:3]=2[CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: CCOC(=O)CBr
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1COc2cccc([N+](=O)[O-])c2N1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 2-amino-3-nitrophenol (1.54 g, 10 mmol), ethyl bromoacetate (1.67 g, 10 mmol), potassium carbonate (1.54 g, 11 mmol) and DMF (5.0 mL) was stirred at room temperature for 20 h. Reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL×3). Combined ethyl acetate layers were washed with water (50 mL×2), dried (brine, sodium sulphate), concentrated and dried on high vacuum to give 5-Nitro-4H-benzo[1,4]oxazin-3-one, K-64 (1.6 g).
Reaction SMILES: Cl[CH:2]([CH2:12][C:13]([Cl:16])([Cl:15])Cl)[C:3]([CH3:11])([CH3:10])[CH:4]([C:8]#[N:9])C(O)=O.C([O-])(=O)C.[Na+]>CN(C)C=O>[Cl:16][C:13]([Cl:15])=[CH:12][CH:2]1[C:3]([CH3:10])([CH3:11])[CH:4]1[C:8]#[N:9]
Reactant: CC(C)(C(Cl)CC(Cl)(Cl)Cl)C(C#N)C(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)C(C#N)C1C=C(Cl)Cl
Temperature: 145 °C
Reaction time: 12 h
Yield: 97.3 %

Procedure:
4-Chloro-2-cyano-3,3-dimethyl-6,6,6-trichlorohexanoic acid (3.07 g) and sodium acetate (2.05 g; water-free) were dissolved in dimethyl formamide (8.0 ml). The solution was then stirred at 145° C. for 12 hours. The working-up procedure was the same as indicated in Example III and yielded 1.85 g of Compound A with purity 90%. Yield 86%.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[C:20]([F:32])([F:33])[F:19])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1ccccc1C(F)(F)F
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)/C=C/c3ccccc3C(F)(F)F)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(2-trifluoromethyl-phenyl)-acrylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][C:18]1[NH:22][N:21]=[C:20]([CH:23]=O)[CH:19]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][NH:16][CH2:23][C:20]3[CH:19]=[C:18]([CH3:17])[NH:22][N:21]=3)[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C=O)n[nH]1
Reactant: NCCN1CCN(c2cccc(Cl)c2)CC1
Product: Cc1cc(CNCCN2CCN(c3cccc(Cl)c3)CC2)n[nH]1
Yield: 60.4 %

Procedure:
Compound 73 was prepared using the same method as that of Example 1 except that 4-(3-chlorophenyl)piperazin-1-ylethylamine and 5-methylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [C:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1Cl)=[CH:15][CH:14]=[CH:13][C:12]=2[O:19][CH3:20])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:21][C:22]1[C:23]([CH3:28])=[CH:24][CH:25]=[CH:26][CH:27]=1>O1CCOCC1>[C:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])=[CH:15][CH:14]=[CH:13][C:12]=2[O:19][CH3:20])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: Cc1ccccc1N
Solvent: C1COCCO1
Product: CCCCCC(=O)c1cnc2c(OC)cccc2c1Nc1ccccc1C
Yield: 36.7 %

Procedure:
3-hexanoyl-4-chloro-8-methoxyquinoline (5 g, 0.071 mol) and o-toluidine (2 ml, 0.019 mol) were heated under reflux in 1,4-dioxan (50 ml) for 1 hour. The solvent was evaporated and the residue was taken up in dichloromethane, washed with 10% hydrochloric acid, water, sodium hydrogen carbonate solution and brine, dried and evaporated. Trituration with ethyl acetate/ether and recrystallisation from methanol-water gave 3-hexanoyl-4-(2-methylphenylamino)-8-methoxyquinoline as yellow needles (2.53 g, 45.3%), mp 94°-6° C.
Reaction SMILES: [O:1]1[C@H:3]2[C:4](=[O:29])[CH:5]=[C:6]3[C@:26]([CH3:27])([C@@H:2]12)[C@@H:25]1[C@H:9]([C@H:10]2[C@:22]([CH3:28])([CH2:23][CH2:24]1)[C@@H:13]([C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:12][CH2:11]2)[CH:8]=[CH:7]3.[Cl-].[NH4+]>[Li].N>[OH:1][C@@H:2]1[C@@:26]2([CH3:27])[C:6](=[CH:7][CH2:8][C@@H:9]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:28])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:5][C@@H:4]([OH:29])[CH2:3]1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: N
Agent: [Cl-]
Agent: [Li]
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C

Procedure:
One modification of this procedure consists of reducing 1α,2α-epoxycholesta-4,6-dien-3--one in lithium/ammonia prior to protonation of the reaction intermediate enolate with externally added solid ammonium chloride. Our determination that this externally supplied proton source must be added as rapidly as possible led to the present invention. More exactly, when the solid ammonium chloride was added slowly (40-150 minutes) to the reduction reaction mixture, very little of the desired 1α,3β-dihydroxycholest-5-ene could be isolated. When the proton source was added rapidly (less than one minute), the desired product was isolated in high yield. This procedure proved successful for small-scale reactions (5 g or less), but failed completely when attempted on a scaled-up batch (15 g). It was further determined that the addition of the solid ammonium chloride to the larger-scale reaction resulted in uncontrollable foaming, presumably due to heat generation within the reaction flask. As a result, it was necessary to add the solid ammonium chloride to the reduction mixture was slowly (40 to 55 minutes) than had been determined conducive to the production of high yields of the desired reduction product, 1α ,3β-dihydroxycholest-5-ene.
Reaction SMILES: [NH:1]([C:5]1[CH:11]=[CH:10][C:8]([OH:9])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].C([O-])([O-])=O.[K+].[K+].[I-].[Na+].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27]>CC(C)=O>[CH3:29][O:28][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][O:9][C:8]1[CH:10]=[CH:11][C:5]([NH:1][C:2](=[O:3])[CH3:4])=[CH:6][CH:7]=1
Reactant: COC(=O)CCCCCBr
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)CCCCCOc1ccc(NC(C)=O)cc1
Yield: 42.2 %

Procedure:
To a mixture of Paracetamol (250 g, 1.654 mol), anhydrous K2CO3 (800 g, 5.789 mol) and sodium iodide (17 g, 113 mmol) in anhydrous acetone (5 liters) was added methyl 6-bromohexanoate (470 g, 2.25 mol) and refluxed for 60 hours. Acetone was distilled off and water (3 liter) was added. Crude 19 was filtered, dried and recrystallised from a mixture of chloroform:hexane (1:5) to give pure 19 (195 g, 66%) as a white powder. The melting point was found to be 96.4-98.8° C. The product was tested by HPLC and found to be 99%+ pure. The structure was confirmed with NMR.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:38][CH3:39])([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]4([OH:36])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[C:24]([CH3:37])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:40])=[CH:9][CH:8]=1>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([OH:41])=[O:4])=[CH:8][CH:9]=2)=[C:14]([CH3:40])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]2([OH:36])[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)=[C:24]([CH3:37])[CH:23]=1)[CH2:38][CH3:39])[CH3:21]
Reactant: CCC(CC)(c1ccc(C#CC2(O)CCOCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)(c1ccc(C#CC2(O)CCOCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)O)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.197 mL, 0.197 mmol) was added to a solution of (4′-{1-ethyl-1-[4-(4-hydroxy-tetrahydro-pyran-4-ylethynyl)-3-methyl-phenyl]-propyl}-2′-methyl-biphenyl-4-yl)-acetic acid methyl ester (Example 130-(6); 34.4 mg, 0.066 mmol) in methanol-tetrahydrofuran (1:1, 2 mL), and the mixture was stirred at room temperature overnight. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate:methanol:water=4:1:0.3) to give the target compound as a colorless oil (32.1 mg, 95%).
Reaction SMILES: C([O:4][CH:5]1[CH:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[C:11]2Br)[CH2:8][CH:7]([CH2:22][O:23]C(=O)C)[CH:6]1[O:27]C(=O)C)(=O)C.[CH:31]1([NH2:34])[CH2:33][CH2:32]1.[OH-].[Na+]>C(O)C>[Cl:19][C:17]1[C:16]([Cl:20])=[CH:15][C:14]2[N:10]([CH:9]3[CH:5]([OH:4])[CH:6]([OH:27])[CH:7]([CH2:22][OH:23])[CH2:8]3)[C:11]([NH:34][CH:31]3[CH2:33][CH2:32]3)=[N:12][C:13]=2[CH:18]=1
Reactant: NC1CC1
Reactant: CC(=O)OCC1CC(n2c(Br)nc3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCC1CC(n2c(NC3CC3)nc3cc(Cl)c(Cl)cc32)C(O)C1O
Yield: 25.9 %

Procedure:
(±)(1R*, 2S*, 3R*, 5R*)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (Example 39, 1.00 g, 1.87 mmol), cyclopropylamine (Aldrich, 1.7 mL, 24 mmol) and absolute ethanol (10 mL) were refluxed under nitrogen for 48 hours. The reaction was cooled and 1 N sodium hydroxide (1.2 mL) was added. Volatiles were evaporated in vacuo and the residual oily solid was chromatographed on silica gel. Elution with 5% methanol--ethyl acetate gave fractions containing white powder (200 mg). Recrystallization from 1:1 water-ethanol gave (±)-(1R*, 2S*, 3R*, 5R*)-5-[5,6-dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol as white crystals (180 mg, 40%); m.p. >250° C.; 1H-NMR(DMSO-d6)δ 7.70 (m, 1, NH), 7.62 and 7.39 (both s, 1 each, 2 benzimidazole CH), 5.77 (br s, 1, OH), 5.13 (d, J=5.3 Hz, 1, OH), 4.95-4.80 (m, 1, CHN), 4.48 (t, J=4.7 Hz, 1, CH2OH), 4.2-4.0 (m, 2, 2 OCH), 3.7-4.0 (m, 2, OCH2), 2.9-2.65 (m, 1, OCH), 2.2-1.8 (m, 3, CH2 and CH); mass spectrum (CI): 372(M+1). [See Examples 10-14]
Reaction SMILES: C([CH:3]1[CH2:11][C:10]2[C:5](=[C:6](O)[CH:7]=[CH:8][C:9]=2C)[C:4]1=[O:14])C.CC1C2C(=C(C)C=CC=2C)C(=O)C1>C(O)C>[C:4]1(=[O:14])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:11][CH2:3]1
Reactant: CCC1Cc2c(C)ccc(O)c2C1=O
Agent: Cc1ccc(C)c2c1C(=O)CC2C
Solvent: CCO
Product: O=C1CCc2ccccc21

Procedure:
The above aromatic composition of the present process is added in an amount of 1 ppm to the material plan oil of margarin, and margarin is prepared therefrom. A 5 % ethanol solution of the mixture (in the ratio 12:5) of 2-ethyl-4-methyl-7-hydroxyindan-1-one and 3,4,7-trimethylindan-1-one is added to the material oil in an amount to give 10 ppm by weight of said indanone compounds mixture thereto, and margarin is prepared therefrom.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20](O)=[O:21])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH2:23]([C:26]1[S:27][CH:28]=[C:29]([CH2:31][NH2:32])[N:30]=1)[CH2:24][CH3:25]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])=[N:12][CH:11]=[C:10]([CH:9]=2)[C:20]([NH:32][CH2:31][C:29]2[N:30]=[C:26]([CH2:23][CH2:24][CH3:25])[S:27][CH:28]=2)=[O:21])=[CH:6][CH:7]=1
Reactant: CCCc1nc(CN)cs1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: CCCc1nc(CNC(=O)c2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)cs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAS Registry No. 1018782-82-5) and 2-propyl-4-thiazolemethanamine as starting materials, LC-MS (UV peak area/ESI) 99%, 470.090 (M+H)+.
Reaction SMILES: CS[C:3]1[NH:12][C:11](=[O:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.[C:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=[O:16])[CH3:15]>C(O)CC(C)C>[C:14]([N:17]1[CH2:22][CH2:21][N:20]([C:3]2[NH:12][C:11](=[O:13])[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[N:4]=2)[CH2:19][CH2:18]1)(=[O:16])[CH3:15]
Reactant: CC(=O)N1CCNCC1
Reactant: CSc1nc2c(c(=O)[nH]1)CCCC2
Solvent: CC(C)CCO
Product: CC(=O)N1CCN(c2nc3c(c(=O)[nH]2)CCCC3)CC1

Procedure:
2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51 mmol) and N-acetylpiperazine (98 mg; 0.76 mmol) are reacted in isoamyl alcohol (1 ml) in accordance with the procedure for Example 1 (reaction time 8 h) and worked up. The crude product obtained in this way is purified by column chromatography; yield: 12 mg (8%), crystals;
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[S:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[F:12][C:2]([F:11])([F:1])[S:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][Br:13])=[CH:8][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(SC(F)(F)F)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)Sc1ccc(CBr)cc1
Reaction time: 4 h

Procedure:
A mixture of 4-trifluoromethylthiotoluene (1.5 g.), N-bromosuccinimide (1.53 g.) and benzoyl peroxide (0.05 g.) in dry carbon tetrachloride (30 ml.) was refluxed, with stirring for 4 hours. The mixture was cooled and filtered. The filtrates were evaporated in vacuo and 4-trifluoromethylthiobenzyl bromide was obtained as a crystalline solid (2.5 g.).
Reaction SMILES: O=[C:2]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[O:17][C:4]2([CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)[CH2:3]1.[NH2:24][OH:25].O>CO.C(OCC)(=O)C>[OH:25]/[N:24]=[C:2]1\[CH2:3][C:4]2([O:17][C:18]3[C:23]\1=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1ccccc1O2
Reactant: NO
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)C/C(=N\O)c1ccccc1O2
Reaction time: 24 h
Yield: 98 %

Procedure:
tert-Butyl 4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (450 mg, 1.41 mmol) and hydroxylamine 50 wt % in water (940 μL of 50% w/v, 14 mmol) were combined in methanol (9.0 mL) and heated at reflux. After 24 hours, the reaction mixture was diluted with ethyl acetate and was washed with water. The organics were dried over MgSO4, filtered and evaporated to dryness to yield (E)-tert-butyl 4-(hydroxyimino)spiro[chroman-2,4′-piperidine]-1′-carboxylate (450 mg, 98%). ESI-MS m/z calc. 332.4, found 333.3 (M+1)+; Retention time: 1.68 minutes (3 min run).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:18]3[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24].O1CCOCC1>ClCCl.C(OC(C)C)(C)C>[ClH:24].[F:23][C:20]1[CH:21]=[CH:22][C:17]2[O:16][N:15]=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:18]=2[CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2noc3ccc(F)cc23)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CC(C)OC(C)C
Product: Fc1ccc2onc(N3CCNCC3)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(5-Fluoro-benzo[d]isoxazol-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (22.7 g, 70.6 mmol) was dissolved in 40 ml dichloromethane and 4N HCl in dioxane (264 ml, 1.06 mol) was added. The white suspension was stirred for 16 hours at room temperature, diluted with diisopropylether and filtered. The crystals were washed with diisopropylether and dried for 1 hour at 50° C. and <20 mbar, to get the desired salt as a white solid (18.2 g, quant.) [MS: m/e=222.3 (M+H+)].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[Br:11][CH2:12][CH2:13][CH2:14]Br.[OH-].[Na+]>O>[Br:11][CH2:12][CH2:13][CH2:14][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9]
Reactant: BrCCCBr
Reactant: CC(=O)c1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)c1ccccc1OCCCBr

Procedure:
To a stirred and refluxing mixture of 136 parts of 1-(2-hydroxyphenyl)ethanone and 222 parts of 1,3-dibromopropane in 500 parts of water was added dropwise a solution of 40 parts of sodium hydroxide in 140 parts of water. Upon completion, stirring was continued at reflux temperature overnight. The organic layer was separated, dried and distilled, yielding 80 parts of 1-[2-(3-bromopropoxy)phenyl]ethanone; bp. 135° C. at 0.05 mm. pressure (intermediate 77).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4].[CH2:20](Br)[CH:21]=[CH:22][CH3:23].CCCCCC>C1COCC1>[CH2:20]([CH:13]([C:12](=[O:19])[C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:21]=[CH:22][CH3:23]
Reactant: CC=CCBr
Reactant: CCOC(=O)CC(=O)c1cccc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC=CCC(C(=O)OCC)C(=O)c1cccc([N+](=O)[O-])c1
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
A 60% dispersion of NaH in mineral oil (917 mg, 22.9 mmol) was added over 20 min to a solution of ethyl 3-nitro-β-oxobenzenepropanoate (5.00 g, 21.1 mmol) in THF (50 mL) at such a rate to maintain a gentle reflux. The mixture was stirred at 25° for 30 min and a solution of crotyl bromide (2.95 g, 21.9 mmol) in THF (15 mL) was added over 50 min. The reaction mixture was stirred at 25° for 45 min and then heated at reflux for 16 h. Hexane (100 mL) was added to the cooled mixture. The resulting suspension was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc and the resulting solution was washed with aqueous 10% citric acid (2×), aqueous saturated NaHCO3 (2×) and brine then was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (40-63μ silica gel, hexane:EtOAc, 9:1) to afford ethyl α-(2-butenyl)-3-nitro-β-oxobenzenepropanoate (4.60 g, 75% yield):
Reaction SMILES: [Cl:1][S:2]([C:5]1[C:15]([CH3:16])=[CH:14][C:8]([O:9][CH2:10][C:11](O)=[O:12])=[CH:7][C:6]=1[CH3:17])(=[O:4])=[O:3].O=S(Cl)[Cl:20]>>[Cl:1][S:2]([C:5]1[C:15]([CH3:16])=[CH:14][C:8]([O:9][CH2:10][C:11]([Cl:20])=[O:12])=[CH:7][C:6]=1[CH3:17])(=[O:4])=[O:3]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(OCC(=O)O)cc(C)c1S(=O)(=O)Cl
Product: Cc1cc(OCC(=O)Cl)cc(C)c1S(=O)(=O)Cl

Procedure:
Referring to FIG. 37, 2-(4-(Chlorosulfonyl)-3,5-dimethylphenoxy)acetic acid (6 g, 21.6 mmol) was dissolved in SOCl2 (50 mL) and the reaction mixture was refluxed overnight. Proton NMR analysis on a sample from the reaction mixture exhibited the conversion went completion. Concentration of the mixture under reduced pressure gave product as a white solid (6.4 g, quantitative); 1H NMR (CDCl3, 300 MHz): δ 6.71 (s, 2H), 5.03 (s, 2H), 2.80 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C([Li])(C)(C)C.CCCCC.[B:25](OC)([O:28]C)[O:26]C>O1CCCC1>[CH2:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:25]([OH:28])[OH:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCc1ccccc1Br
Reactant: COB(OC)OC
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCCCCCCc1ccccc1B(O)O

Procedure:
Following General Procedure A and using 1-bromo-2-heptyl-benzene (Intermediate 67, 0.4 g, 1.56 mmol), 4 mL of anhydrous tetrahydrofuran, 1.7M solution of t-butyllithium in n-pentane (1.84 mL, 3.1 mmol) and trimethyl borate (0.45 mL, 3.1 mmol), the title compound was obtained (0.27 g, 50%).
Reaction SMILES: [C:1]([CH:9]1[C:26](=[O:27])[CH2:25][CH2:24][C@@:23]2([CH3:28])[C@H:10]1[CH2:11][CH2:12][C@@H:13]1[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@H:14]1[CH2:15][CH2:16][C@@H:17]2[OH:29])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCOCC>C(Cl)Cl>[C:1]([CH:9]1[C:26](=[O:27])[CH2:25][CH2:24][C@@:23]2([CH3:28])[C@H:10]1[CH2:11][CH2:12][C@@H:13]1[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@H:14]1[CH2:15][CH2:16][C:17]2=[O:29])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@]12CCC(=O)C(C(=O)c3ccccc3)[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@]12CCC(=O)C(C(=O)c3ccccc3)[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 2 h

Procedure:
4-Benzoyl-17β-hydroxy-5α-androstan-3-one made as in Example 1 (788 mg, 2 mmole) in 2 ml of CH2Cl2 is added to pyridinium chlorochromate (650 mg, 3 mmole) suspended in CH2Cl2 (2 ml) at 25° C. After 2 hours, ether is added and the solvent decanted. This is then filtered through Florisil, the eluate evaporated and the residue recrystallized from chloroform-heptane.