Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:11]1([CH:18]=CC=[C:14](O)[CH:13]=1)[OH:12]>S(=O)(=O)(O)O>[Cl:1][CH2:2][C:3]1[C:9]2[C:8](=[CH:18][C:11]([OH:12])=[CH:13][CH:14]=2)[O:7][C:5](=[O:6])[CH:4]=1
Reactant: Oc1cccc(O)c1
Reactant: CCOC(=O)CC(=O)CCl
Agent: O=S(=O)(O)O
Product: O=c1cc(CCl)c2ccc(O)cc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
Under ice-cooling, ethyl 4-chloroacetoacetate (14.0 g, 85.0 mmol) was dissolved in concentrated sulfuric acid (30 mL), resorcinol (8.81 g, 80.0 mmol) was added by small portions, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into ice water, and the precipitated solid was collected by filtration, washed with water, and air-dried to give the title compound (14.1 g, yield 84%) as a beige powder.
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[N:6][CH:5]=[CH:4][N:3]=1.[NH2:9][NH2:10]>C(O)C>[Cl:1][C:2]1[C:7]([NH:9][NH2:10])=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccnc1Cl
Reactant: NN
Solvent: CCO
Product: NNc1nccnc1Cl
Yield: 75.6 %

Procedure:
2,3-Dichloropyrazine (2 mL, 13 mmol) was dissolved in 95% ethanol (4 mL) and to this was added, dropwise and with stiffing, hydrazine anhydrous (2 mL, 67 mmol). During the addition of the hydrazine the solution became warm and yellowish. Following cooling of this mixture in an ice bath, the resulting material was isolated by filtration, washed with cold aqueous 95% ethanol to riled 1-(3-chloropyrazin-2-yl)hydrazine (1.42 g, 73% yield) as white crystals. No further purification was done. MS m/z: 145.0 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:34]=[CH:33][C:7]([C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([O:24][CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])[CH2:20][CH2:19]2)=[O:17])=[O:9])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2]>ClCCl.FC(F)(F)C(O)=O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:20][CH2:19]2)=[O:17])=[O:9])=[CH:33][CH:34]=1)(=[NH:2])[NH2:3]
Reactant: CC(C)(C)OC(=O)COC1CCN(C(=O)C2CCCCN2C(=O)c2ccc(C(=N)N)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)c1ccc(C(=O)N2CCCCC2C(=O)N2CCC(OCC(=O)O)CC2)cc1

Procedure:
A solution of 700 mg of t-butyl [[1-[[1-(p-amidinobenzoyl)-2-piperidinyl]carbonyl]-4-piperidinyl]oxy]acetate in 20ml of dichloromethane and 20 ml of trifluoroacetic acid is stirred at room temperature for 3 hours and evaporated. The residue is dissolved in ethanol and treated with ether. Suction filtration and drying of the precipitate and chromatography on silica gel (RP-18, water/THF 9:1) gives 111 mg of [[1-[[1-(p-amidinobenzoyl)-2-piperidinyl]carbonyl]-4-piperidinyl]oxyacetic acid. M.p. 233°-234° C.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[C:7]([Si:9]([CH3:12])([CH3:11])[CH3:10])#[CH:8]>>[CH3:10][Si:9]([CH3:12])([CH3:11])[C:7]#[C:8][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1
Reactant: Brc1cccs1
Reactant: C#C[Si](C)(C)C
Product: C[Si](C)(C)C#Cc1cccs1
Yield: 81 %

Procedure:
Use a method similar to the General Procedure 8 to couple 2-bromo-thiophene (0.97 mL, 10 mmol) with ethynyl-trimethylsilane (2.82 mL, 20 mmol). Purify by chromatography on silica gel eluting with isohexane to give the desired intermediate (1.46 g, 81%). GC-MS m/z 180 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[F:12].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH2:27]([C@@H:34]1[CH2:38][O:37][C:36](=[O:39])[NH:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[Li]CCCC>C1COCC1>[CH2:27]([C@@H:34]1[CH2:38][O:37][C:36](=[O:39])[N:35]1[C:9](=[O:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:12])[CH:4]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(O)Cc1ccc(Cl)c(F)c1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Cc1ccc(Cl)c(F)c1)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.5 %

Procedure:
2-(4-Chloro-3-fluorophenyl)acetic acid (1.00 g, 5.30 mmol) was dissolved in THF (14 mL) at 0° C. and treated with triethylamine (0.81 mL, 5.8 mmol). Pivaloyl chloride (0.69 mL, 5.6 mmol) was then added to the solution, and the mixture was allowed to stir for one hour at 0° C. In a separate flask, (R)-4-benzyloxazolidin-2-one (0.987 g, 5.57 mmol) was dissolved in THF (14 mL) at −78° C. and treated with n-BuLi (2.54 mL, 5.83 mmol). The above anion solution was stirred for 20 minutes and then cannulated into the anhydride at −78° C. The reaction was then allowed to stir for one hour at −78° C., and then warmed to 0° C. for two hours. The mixture was quenched with the addition of saturated NH4Cl solution (20 mL) and concentrated in vacuo. The resulting residue was then partitioned between ethyl acetate and water. The aqueous layer was extracted once with ethyl acetate, and the organic fractions were combined, washed with brine, separated, dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography (3:1 hexanes:ethyl acetate) to give (R)-4-benzyl-3-(2-(4-chloro-3-fluorophenyl)acetyl)oxazolidin-2-one (0.95 g, 51%) as an oil, which solidified upon standing.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1.[CH3:14][NH2:15].C(O)C>O>[CH3:14][NH:15][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1
Reactant: CN
Reactant: CCOC(=S)c1cnc(C)nc1Cl
Solvent: O
Solvent: CCO
Product: CCOC(=S)c1cnc(C)nc1NC
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate (Aldrich, 20 g, 86 mmol) in 250 mL of dichworomethane at 0° C. was added slowly solution of methylamine in ethanol (33%, 35 mL 281 mmol). After stirring for 30 minutes, water (150 mL) was added and the phases were separated. The organic phase was dried (MgSO4) and filtered. The filtrate was evaporated under reduced pressure to give 19 g of the ethyl 4-methylamino-2-methylthiopyrimidine-5-carboxylate as a white solid.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[Br:12][C:13]1[CH:18]=[CH:17][C:16](F)=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1>CN(C=O)C>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1
Reactant: COC(=O)CC(=O)OC
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
Dimethyl malonate (40.34 g, 0.305 mol) in N,N′-dimethylformamide (45 mL) was added dropwise to a stirred suspension of sodium hydride (60% dispersion in mineral oil, 16.2 g, 405 mmol) in N,N′-dimethylformamide (500 mL) at 10° C. The mixture was stirred for 1 hour at room temperature then 4-bromo-1-fluoro-2-nitrobenzene (44.38 g, 202 mmol) in N,N′-dimethylformamide (45 mL) was added dropwise to the reaction mixture. The mixture was stirred 75 minutes at room temperature and then was warmed to 65° C. After 1 hour, the solvent was removed under reduced pressure, the residue was taken up in a mixture of ethyl acetate and water and 2M aqueous hydrochloric acid was added until the mixture became pale yellow in colour. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The crude product was recrystallized from diisopropyl ether to give the title compound (55.0 g, 83%) as a pale yellow solid.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].[N:18](OCCC(C)C)=[O:19]>C(OCC)C.C(O)(C)(C)C>[C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[N:18][OH:19]
Reactant: O=C1CCCc2ccccc21
Reactant: CC(C)CCON=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: O=C1C(=NO)CCc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.9 %

Procedure:
Tetralone (25 g, 171 mmol) was added to a solution of potassium tert-butoxide (22 g, 196 mol) and isoamyl nitrite (26 g, 222 mmol) in diethyl ether (200 ml) and tert-butanol (200 ml). The solution was stirred at room temperature for 4 hours and then filtered to collect the potassium salt of the oxime. The solid was dissolved with 1 N aqueous hydrochloric acid (200 ml) and extracted with chloroform and dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was washed with ethyl acetate, and dried to give 3,4-dihydro-[1,2]naphthoquinone 2-oxime (21.5 g, 123 mmol, 72%) as brown crystals.
Reaction SMILES: [C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:8][N:9]([CH3:20])[C:10](=[O:19])[CH:11](O)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[NH2:40][CH2:41][CH2:42][C:43]1[N:47]=[CH:46][NH:45][CH:44]=1>O1CCCC1.CO>[C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:8][N:9]([CH3:20])[C:10](=[O:19])[CH:11]([NH:40][CH2:41][CH2:42][C:43]2[N:47]=[CH:46][NH:45][CH:44]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(CC(c1ccccc1)c1ccccc1)C(=O)C(O)c1ccccc1
Reactant: NCCc1c[nH]cn1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CN(CC(c1ccccc1)c1ccccc1)C(=O)C(NCCc1c[nH]cn1)c1ccccc1
Reaction time: 2 h
Yield: 56.7 %

Procedure:
To stirred solution of the product of step 1 (1.50 g, 4.34 mmol) in tetrahydrofuran (15 mL) was added a 60% dispersion of sodium hydride in mineral oil (0.210 g, 5.25 mmol). After gas evolution ceased, p-toluenesulfonyl chloride (0.990 g, 5.20 mmol) was added and the mixture was stirred for 2 hours. At this time, histamine (1.93 g, 17.4 mmol) was added followed by methanol (10 mL). The reaction was stirred overnight and concentrated. The residue was partitioned between ethyl acetate and aqueous sodium carbonate solution. The organic layer was dried (sodium sulfate) and concentrated to afford a pasty white solid. Flash chromatography over silica (methylene chloride/methanolic ammonia solution) provided 1.08 g (57%) of product as a colorless tacky foam: 1H NMR (CDCl3) δ 7.52-7.43 (m, 1H), 7.40-7.00 (m, 15H), 6.78-6.69 (m, 1H), 4.36-3.97 (m, 4H), 2.92-2.20 (m, 7H) ppm.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[N+:8]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)([O-:10])=[O:9].C([O-])(=O)C.[NH4+].C(O)(=O)C>C(O)CCC>[N+:8]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[C:7]2[NH:1][C:2](=[O:3])[NH:4][C:5]2=[O:6])=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C1CNC(=O)N1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CCCCO
Product: O=C1NC(=O)C(=Cc2ccc([N+](=O)[O-])cc2)N1
Reaction time: 3 h
Yield: 93.9 %

Procedure:
A mixture of 100 grams (1.0 mole) of hydantoin, 151 grams (1.0 mole) of 4-nitrobenzaldehyde, 77 grams (1.0 mole) of ammonium acetate, 120 grams (2.0 moles) of acetic acid, and 200 ml of n-butanol were held for 3 hours at reflux temperature. After the cooling, there were obtained 219 grams of 5-(4'-nitrobenzylidene)-hydantoin, corresponding to 94% of the theory based on hydantoin. The product had a melting point of 253°-254° C. and homogeneous by thin layer chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)(=[O:27])=[O:26])[CH2:23][CH2:22]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:12]2[CH2:11][CH2:10][N:9]([CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:14][CH2:13]2)(=[O:27])=[O:26])[CH2:23][CH2:22]1
Reactant: O=S(=O)(CCCCCCBr)NC1CC1
Reactant: Clc1cccc(C(c2ccccc2)N2CCNCC2)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=S(=O)(CCCCCCN1CCN(C(c2ccccc2)c2cccc(Cl)c2)CC1)NC1CC1
Yield: 67 %

Procedure:
1-[(3-Chlorophenyl)phenylmethyl]piperazine (435.2 mg, 1.52 mmol) and N-cyclopropyl-6-bromohexanesulfonamide (474.5 mg, 1.67 mmol) were refluxed in toluene (15 ml) in the presence of triethylamine (169 mg, 1.67 mmol) for 42 hours. The reaction mixture was washed with water, and the organic layer was dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulfonamide (499.0 mg) as an oil (yield based on 1-[(3-chlorophenyl)phenylmethyl]piperazine: 67.1%).
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12].[C:18](Cl)(=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22]>O>[C:18]([NH:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])(=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCC(=O)Cl
Reactant: COC(=O)c1cccc(N)c1
Solvent: O
Solvent: c1ccncc1
Product: CCCCC(=O)Nc1cccc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To anhydrous pyridine (120 ml), methyl 3-aminobenzoate (5.00 g) was dissolved, and valeryl chloride (4.13 ml) was added while cooling on ice. The mixture was stirred at room temperature for 4 hours. Distilled water was added to the solution. The whole was extracted with ethyl acetate, washed with 5% sodium hydrogencarbonate aqueous solution and water, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (Kieselgel 60=170 g, hexane/ethyl acetate=3/1) to obtain the above-captioned compound ([6]-(62)-90) (7.70 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:12]2[C:13]3[C:5]([CH:6]=[CH:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.[C:14]1([C:20]2O[C:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:23]3[C:28]=2[CH:27]=[CH:26][CH:25]=[CH:24]3)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[C:12]2[C:13]3[C:5]([C:6]4[C:20]([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)=[C:28]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]5=[C:22]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:7]=4[C:8]=3[CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1
Reactant: c1ccc(-c2oc(-c3ccccc3)c3ccccc23)cc1
Reactant: Brc1ccc2c3c(cccc13)C=C2
Solvent: Cc1ccccc1C
Product: Brc1ccc2c3c(cccc13)-c1c-2c(-c2ccccc2)c2ccccc2c1-c1ccccc1
Temperature: 25 °C
Yield: 52.7 %

Procedure:
200 ml of xylene were added to 5-bromoacenaphthylene (14.5 g, 62.8 mmol) and diphenylisobenzofuran (17.1 g, 63.3 mmol) and the mixture was stirred under reflux of xylene for 5 hours. After the mixture was cooled to room temperature, the solvent was distilled off. Then, 26 ml of trifluoroacetic anhydride and 260 ml of chloroform were added thereto, followed by stirring under reflux for 1 hour. After the mixture was cooled to room temperature, the solvent was distilled off. The obtained residue was purified by silica gel chromatography (mobile phase; toluene:heptane=1:3), whereby 16 g of 4-bromo-7,12-diphenylbenzo[k]fluoranthene were obtained as a yellow solid.
Reaction SMILES: [C:1]([CH2:9][C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C)C.[CH3:22][NH:23][NH2:24]>O>[CH3:22][N:23]1[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:24]1
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Reactant: CNN
Solvent: O
Solvent: CC(C)O
Product: Cn1nc(-c2ccccc2)cc1-c1ccccc1
Temperature: 85 °C

Procedure:
5.0 Grams of dibenzoylmethane in 40 ml. of isopropanol is heated to 50° C. The temperature of the reaction mixture is then raised to about 85° C. and 10.5 grams of methyl hydrazine in 10 ml. of isopropanol added thereto. The mixture is heated at this temperature for 30 minutes, then cooled and cold water added thereto. A white solid precipitate forms and is filtered, washed and dried to yield 5.22 grams of product having a melting point of 59.5° C. to 60° C., 99+% yield.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[CH3:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1>C1C=CC=CC=1>[C:1]([NH:5][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][C:7]([CH3:6])=[CH:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: c1ccccc1
Product: Cc1ccc(C(=O)NC(C)(C)C)cc1
Yield: 89 %

Procedure:
The preparation of Example 1 was repeated with the changes that the starting reactants were tert-butyl amine (4.72 g, 0.065 mole) and 4-methylbenzoyl chloride (5.02 g, 0.0325 mole), the reaction was carried out in benzene and the reaction produced 5.54 g of crystals of the desired product (89% yield), mp 114°-116° C. Proton nuclear magnetic resonance (89.55 MHz) showed absorptions at 7.615 ppm (d, 8 Hz, 2H; 2,6-aryl H); 7.193 ppm (d, 8 Hz, 2H; 3.5-aryl H); 5.970 ppm (bs, 1H; N-H); 2.377 ppm (s, 3H; 4-CH3); 1.461 ppm (s, 9H; tert-butyl H).
Reaction SMILES: [Na].Br[C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][N:4]=1.[CH3:10][OH:11]>>[Br:9][C:6]1[CH:7]=[CH:8][C:3]([O:11][CH3:10])=[N:4][CH:5]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CO
Agent: [Na]
Product: COc1ccc(Br)cn1
Yield: 83 %

Procedure:
After sodium (10 g, 0.435 mol) was dissolved in methanol (500 ml), 2,5-dibromopyridine (50 g, 0.211 mol) was added thereto and the mixture was heated for 2 days under reflux. The reaction solution was cooled as it was, and then concentrated. Then, the residue was diluted with ethyl acetate and an aqueous saturated solution of ammonium chloride. The organic layer was washed with an aqueous saturated solution of ammonium chloride and brine, and then dried over anhydrous sodium sulfate and concentrated, to give the title compound (33 g, 83%) as a pale brown oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH3:13])[C:8]([OH:10])=[O:9])[N:6]=1.[Cl:14]N1C(=O)CCC1=O>C(O)(=O)C>[NH2:1][C:2]1[S:3][C:4]([Cl:14])=[C:5]([C:7](=[N:11][O:12][CH3:13])[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CON=C(C(=O)O)c1csc(N)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: CON=C(C(=O)O)c1nc(N)sc1Cl
Temperature: 70 °C
Reaction time: 0.75 h

Procedure:
To 500 mL of acetic acid were added 40.0 g (0.20 mol) of 2-amino-α-(methoxyimino)-4-thiazoleacetic acid (Aldrich Chemical Company, Milwaukee, Wis.) and 27.9 g (0.21 mol) N-chlorosuccinimide. The mixture was heated in a 70° C. bath. The solids dissolved within 30 minutes, and after 45 minutes the reaction was complete by MS. The dark solution was allowed to cool to room temperature and concentrated under vacuum to give a dark solid, which was used without purification.
Reaction SMILES: [NH2:1][OH:2].[C:3]([O:12][CH2:13][CH3:14])(=[O:11])/[CH:4]=[CH:5]\[C:6]([O:8][CH2:9][CH3:10])=[O:7]>ClCCl>[OH:2][NH:1][C@H:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:4][C:3]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)/C=C\C(=O)OCC
Reactant: NO
Solvent: ClCCl
Product: CCOC(=O)C[C@H](NO)C(=O)OCC
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
Hydroxylamine free base (50% aqueous solution, 45.0 g, 0.68 mol) was added dropwise to diethyl maleate (100.0 g, 0.56 mol) under nitrogen. The reaction temperature was maintained below 55° C. with an ice bath. The mixture was stirred for 30 minutes. Dichloromethane (100 ml) was added to the reaction mixture and the organic layer was collected. The organic layer was concentrated under reduced pressure to give crude diethyl N-hydroxyaspartate (103 g, 89% yield). The product was analyzed by NMR spectroscopy and found to be greater than 95% pure.
Reaction SMILES: Br[CH2:2][C:3](=[O:24])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C@@H:11]([CH2:12][C@H:13]([OH:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[OH:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1>C(N(CC)CC)C>[OH:23][C@@H:13]1[CH2:14][CH2:15][C@@:16]2([CH3:17])[C@H:11]([CH2:10][CH2:9][C@@H:8]3[C@@H:18]2[CH2:19][CH2:20][C@@:21]2([CH3:22])[C@H:7]3[CH2:6][CH2:5][C@@H:4]2[C:3](=[O:24])[CH2:2][O:25][C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH2:12]1
Reactant: C[C@]12CC[C@@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)CBr)CC[C@@H]12
Reactant: Oc1ccncc1
Solvent: CCN(CC)CC
Product: C[C@]12CC[C@@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)COc3ccncc3)CC[C@@H]12
Temperature: 25 °C
Yield: 7.7 %

Procedure:
A solution of 21-bromo-3α-hydroxy-5β-pregnan-20-one (500 mg, 1.26 mmol), 4-hydroxypyridine (144 mg, 1.51 mmol), and triethyl amine (200 μL) in 10 mL of TBIF was heated under reflux for 4 h. The mixture was cooled to room temperature and partitioned between EtOAc and water. The organic layer was washed with sat. aq. NaCl, dried with MgSO4 and concentrated in vacuo. The crude residue was subjected to flash column chromatography. Elution with 50% acetone in CH2Cl2 yielded 3α-hydroxy-21-(pyrid-4-yloxy)-5β-pregnan-20-one (40 mg) as an oily solid; TLC Rf (acetone:CH2Cl2 1:1)=0.28.
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]#[N:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N.[H][H]>C(O)C>[NH3:9].[NH2:20][CH2:19][C:17]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)=[C:10]([NH:9][CH2:8][CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:18]=1
Reactant: [H][H]
Reactant: N#Cc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Agent: N
Solvent: CCO
Product: NCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 30 h
Yield: 153.7 %

Procedure:
A solution of 6-[(2,2-diphenylethyl)amino]-9-tetrahydro-2H-pyran-2-yl-9H-purine-2-carbonitrile (5.70 g, 13.18 mmol) (Preparation 5) in ethanol (200 ml) saturated with ammonia gas was treated with Pearlmann's catalyst (1.00 g), pressurised to 60 psi with hydrogen in a sealed vessel and stirred at room temperature for 30 hours. The mixture was filtered through a pad of Arbocel (trade mark) and the solvent was removed under reduced pressure. The residue was azeotroped from dichloromethane (×2) and then purified by column chromatography on silica gel eluting with dichloromethane:methanol (95:5 by volume) gradually changing to dichloromethane:methanol:0.88 ammonia (90:10:0.5 by volume) to afford the title compound (4.34 g).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[C:17]1([S:23]([N:4]2[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:10]3[C:2]([Br:1])=[CH:3]2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Brc1c[nH]c2ncccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=S(=O)(c1ccccc1)n1cc(Br)c2cccnc21

Procedure:
3-Bromo-1H-pyrrolo[2,3-b]pyridine (3, 280 mg, 1.4 mmol) was dissolved in acetone (15 mL) and potassium carbonate (220 mg, 1.6 mmol) was added, followed by benzenesulfonyl chloride (0.2 mL, 1.6 mmol). The reaction mixture was heated to reflux overnight, filtered and concentrated under reduced pressure. The resulting solid was purified by flash chromatography (5%-20% ethyl acetate:hexanes) to provide the desired product, 4, (300 mg, 47%). MS(ESI) [M+H+]+=455.0.