Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.[N:11]1([CH2:17][CH2:18]O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:18][CH2:17][N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[N:9]=[CH:10][C:3]=12
Reactant: OCCN1CCCCC1
Reactant: Clc1ncnc2[nH]ncc12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ncnc2c1cnn2CCN1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 4263.6 %

Procedure:
To a stirred solution of 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (0.2 g, 1.29 mmol) in anh THF (10 mL), 2-(piperidin-1-yl)ethanol (0.258 mL, 1.94 mmol) and triphenylphosphine (0.51 g, 1.94 mmol) were sequentially added. The reaction mixture was cooled to 0° C. and diisopropylazodicarboxylate (0.38 mL, 1.94 mmol) was added dropwise. The mixture was stirred for 30 min. at 0° C. and kept overnight at 4° C. The solvent was removed at reduced pressure and the residue was dissolved in DCM and washed with diluted HCl 1N. The aqueous phase was separated, basified and extracted with DCM. The organic phase was separated, dried and the solvent was removed under reduced pressure to give a residue that was purified by flash chromatography eluting with (EtOAc/Petroleum ether, 8:2) to yield 4-chloro-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine (146 mg, 55 mmol, 42%) as an oil that solidifies “on standing”.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([C:18]#[N:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N:24]=[N+:25]=[N-:26])(C)C.C([Sn](=O)CCCC)CCC.CO>C1(C)C=CC=CC=1.ClCCl>[CH:1]([N:14]1[CH2:17][CH:16]([C:18]2[N:24]=[N:25][NH:26][N:19]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#CC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: c1ccc(C(c2ccccc2)N2CC(c3nn[nH]n3)C2)cc1
Temperature: 25 °C

Procedure:
1-Benzhydrylazetidine-3-carbonitrile (2.48 g, 10 mmol), trimethylsilyl azide (2.30 g, 20 mmol) and dibutyltin oxide (498 mg, 2.0 mmol) were dissolved in toluene (20 mL) and heated to reflux for 32 h. The reaction mixture was then cooled to room temperature and applied directly to ISCO system with 10% methanol in dichloromethane to give the product. 1H NMR (400 MHz, CDCl3) δ 7.54 (m, 4H), 7.31 (m, 6H), 5.11 (s, 1H), 4.47 (m, 1H), 4.05 (t, J=7.2 Hz, 2H), 3.91 (t, J=7.2 Hz, 2H). MS (ESI) m/z: Calculated: 291.15; Observed: 291.90 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[O:13])=[CH:5][CH:4]=1.[Br:14]Br>CCOCC>[Br:14][CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]1=[O:13]
Reactant: COc1ccc2c(c1)C(=O)CCC2
Reactant: BrBr
Solvent: CCOCC
Product: COc1ccc2c(c1)C(=O)C(Br)CC2
Yield: 87.2 %

Procedure:
To a 10° C. solution of 25 g (0.142 mol) of 7-methoxy-3,4-dihydro-1 (2H)-naphthalenone in 1 liter ether was added dropwise (maintaining reaction temperature at about 10° C.) 37.9 g (0.237 mol) of bromine. The reaction solution was concentrated on a rotating evaporator and the residue crystallized from ether to give 31.6 g (87%) of present title compound, m.p. 79-80° C.
Reaction SMILES: [Mg].[CH2:2]([O:9][C:10]([CH:12]1[NH:24][CH2:23][C:21]2=[C:22]3[C:17](=[C:18]([C:25]4[C:26](=[O:40])[NH:27][C:28](=[O:39])[C:29]=4[C:30]4[C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[NH:32][CH:31]=4)[CH:19]=[CH:20]2)[CH:16]=[CH:15][N:14]3[CH2:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(OCC)(=O)C>CO>[CH2:2]([O:9][C:10]([CH:12]1[NH:24][CH2:23][C:21]2=[C:22]3[C:17](=[C:18]([C@H:25]4[C@H:29]([C:30]5[C:38]6[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=6)[NH:32][CH:31]=5)[C:28](=[O:39])[NH:27][C:26]4=[O:40])[CH:19]=[CH:20]2)[CH:16]=[CH:15][N:14]3[CH2:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1NC(=O)C(c2ccc3c4c2ccn4CC(C(=O)OCc2ccccc2)NC3)=C1c1c[nH]c2ccccc12
Agent: [Mg]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)C1Cn2ccc3c([C@@H]4C(=O)NC(=O)[C@H]4c4c[nH]c5ccccc45)ccc(c32)CN1
Temperature: 25 °C

Procedure:
Magnesium turnings (195 mg, 8.0 mmol) were added to a solution of 7-[4-(1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-3,4-dihydro-1H-[1,4]diazepino[6,7,1-hi]indole-2-carboxylic acid benzyl ester (230 mg, 0.44 mmol) in anhydrous methanol (20 ml) and heated to reflux under an atmosphere of nitrogen for 1.5 hours. After cooling to room temperature the mixture was poured into ethyl acetate (200 ml) and washed with 1 M hydrochloric acid (100 ml). The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was then purified by silica gel chromatography using 50-60% ethyl acetate in hexanes to yield (±)-trans-7-[4-(1H-indol-3-yl)-2,5-dioxo-pyrrolidin-3-yl]-3,4-dihydro-1H-[1,4]diazepino[6,7,1-hi]indole-2-carboxylic acid benzyl ester as an off white solid (205 mg). 1H NMR (DMSO-d6) 400 MHz δ: 11.56 (s, 1H), 11.03 (d, 1H, J=2 Hz), 7.21-7.43 (m, 10H), 7.09 (t, 1H, J=7.2 Hz), 6.92-7.00 (m, 2H), 6.82-6.89 (m, 3H), 5.04 (s, 2H), 4.87 (d, 2H, J=7.6 Hz), 4.54 (dd, 2H, J=7.6 and 28.8 Hz), 4.30 (m, 2H), 3.92 (m, 2H).
Reaction SMILES: C([O:4][C:5]1[C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][S:8][C:9]=1[CH3:10])(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:4][C:5]1[C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][S:8][C:9]=1[CH3:10]
Reactant: COC(=O)c1csc(C)c1OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)c1csc(C)c1O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To methyl 4-acetoxy-5-methyl-3-thiophenecarboxylate (214 g) in methanol (250 ml) was added p-toluenesulphonic acid (2 g), and the solution stirred at room temperature for three days.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]#[N:24].[F-].[Cs+].[Cl-].[Na+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:13][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]#[N:24])=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCCCCCCBr
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: [Cl-]
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: N#CCCCCCCNc1ccc(OCc2ccccc2)cc1
Temperature: 100 °C
Yield: 82.7 %

Procedure:
A 20 g portion of 4-benzyloxyaniline hydrochloride was dissolved in chloroform-methanol and made basic with a solution of 70 mL of 1.25N sodium hydroxide and 70 mL of water. The layers were separated, the aqueous phase extracted with chloroform, the chloroform extracts washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was evaporated to yield 17 g of 4-benzyloxyaniline. A solution of 2 g (0.01 mol) of 4-benzyloxyaniline, 2.26 ml (0.015 mol) of 7-bromoheptanenitrile and 7.6 g (0.05 mol) of cesium fluoride in 20 mL of DMF was stirred and heated at 100° C. for two hours. The reaction was cooled and poured into saturated sodium chloride solution and extracted with ether. The ether extracts were washed three times with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to 2.9 g of oil. The oil was chromatographed on 100 g of silica gel using a gradient from 10-30% ethyl acetate in hexane. There was obtained 2.55 g (85%) of 7-[(4-benzyloxyphenyl)amino]heptanenitrile. The benzyloxy compound was treated with eight parts of 48% HBr at room temperature for 5 hours to yield impure 7-[(4-hydroxyphenyl)amino]heptanenitrile.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[C:17]12([S:27][CH2:28][C:29](O)=[O:30])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2>>[C:17]12([S:27][CH2:28][C:29]([NH:1][N:2]3[N:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]3=[O:16])=[O:30])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2
Reactant: O=C(O)CSC12CC3CC(CC(C3)C1)C2
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Product: O=C(CSC12CC3CC(CC(C3)C1)C2)Nn1nc(C(F)(F)F)c2ccccc2c1=O

Procedure:
The product from Example 11B and 2-(adamantan-1-ylthio)acetic acid were treated using a method similar to that described in Example 17C to give the title compound 1H NMR (400 MHz, DMSO-d6) δ ppm 11.68-11.85 (bs, 1H), 8.43 (ddd, J=8.0, 1.4, 0.7 Hz, 1H), 8.13 (ddd, J=8.0, 7.4, 1.4 Hz, 1H), 8.03-8.08 (m, 1H), 8.00-8.05 (m, 1H), 3.44 (s, 2H), 2.01-2.04 (m, 3H), 1.86-1.89 (m, 6H), 1.65-1.69 (m, 6H); MS (APCI+) M/Z 438 (M+H)+.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[CH:12]=[C:11]([N:13](C)[CH2:14]C2C=CC=CC=2)[CH:10]=[C:9]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[N:8]=1)=[O:6])([CH3:3])[CH3:2].CO.[H][H]>[Pd].C(O)(=O)C>[CH:1]([NH:4][C:5]([C:7]1[CH:12]=[C:11]([NH:13][CH3:14])[CH:10]=[C:9]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=2)[N:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1cc(N(C)Cc2ccccc2)cc(Oc2cccc(C(F)(F)F)c2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CNc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NC(C)C)c1

Procedure:
1.12 g (0.0012 mol) of N-(i-propyl)-4-(methyl(phenylmethyl)amino}-6-{3-(trifluoromethyl)phenoxy}-2-pyridine carboxamide were mixed with methanol and then with a small amount of 10% palladium/carbon and acetic acid. The obtained mixture was stirred at room temperature for about 16 hours in a hydrogen atmosphere. The obtained reaction solution was filtered using Hyflo Super Cell and then concentrated. The concentrate was purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1)(=O)=O.Cl.[CH2:27]([O:29][C:30](=[O:34])[CH2:31][CH2:32][NH2:33])[CH3:28].C(N(CC)CC)C>ClCCl>[CH2:27]([O:29][C:30]([CH2:31][CH2:32][NH:33][C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1)=[O:34])[CH3:28]
Reactant: CCOC(=O)CCN
Reactant: CCCOc1ccccc1-c1nc2nc(S(C)(=O)=O)ncc2c(=O)[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOc1ccccc1-c1nc2nc(NCCC(=O)OCC)ncc2c(=O)[nH]1

Procedure:
A solution of 7-methylsulphonyl-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (1.0 g), β-alanine ethyl ester hydrochloride (1.10 g) and triethylamine (0.73 g) in dichloromethane (20 ml) was stirred at ambient temperature for 2.5 hours. The reaction mixture was extracted with dilute hydrochloric acid (20 ml) then water (10 ml), and the extracts back washed with dichloromethane (10 ml). The combined organic extracts were dried (magnesium sulphate) and evaporated under reduced pressure to yield a crude product which was recrystallized from ethanol:water to yield the title compound, 0.83 g, m.p. 142-3° C.
Reaction SMILES: O=[C:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:16][C@H:17]([C:19]([N:21]1[CH2:28][C@@H:27]([S:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][C@H:22]1[C:23]([OH:25])=[O:24])=[O:20])[CH3:18].C([BH3-])#N.[Na+]>C(O)C.O>[CH2:6]([O:5][C:3]([C@@H:2]([NH:16][C@H:17]([C:19]([N:21]1[CH2:28][C@@H:27]([S:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][C@H:22]1[C:23]([OH:25])=[O:24])=[O:20])[CH3:18])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4])[CH3:7]
Reactant: C[C@H](N)C(=O)N1C[C@@H](Sc2ccccc2)C[C@H]1C(=O)O
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1C[C@@H](Sc2ccccc2)C[C@H]1C(=O)O

Procedure:
Ethyl 2-oxo-4-phenylbutyrate (1.03 gram) and 1-(L-alanyl)-4-(S)-(phenylthio)-L-proline (0.19 gram) are dissolved in a 1:1 ethanol-water solvent. A solution of sodium cyanoborohydride (0.19 gram) in ethanol-water is added dropwise at room temperature over the course of two hours. When the reaction is completed, the product is absorbed in strong acid ion exchange resin and eluted with 2% pyridine water. The product rich cuts are freeze dried and the desired isomer is separated chromatographically to yield 1-[N-(1-(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl]-4-(S)-(phenylthio)-L-proline.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([NH2:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O-])([O-])=O.[K+].[K+].ClC(OCC)=O.B>C1COCC1.O>[CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C@H:10]([NH:21][CH3:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: B
Agent: CCOC(=O)Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 51.5 %

Procedure:
To a solution of rac-(3S,4R)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylamine (0.54 g, 1.68 mmol) in THF (5 ml) was added a solution of K2CO3 (0.46 g, 3.36 mmol) in H2O (3 ml). After 10 minutes, ethyl chloroformate (0.18 ml, 1.85 mmol) was added and stirring was continued at RT for an additional 2 h. The intermediate carbamate was then extracted with Et2O, dried over Na2SO4 and concentrated under vacuo to give viscous oil. The oil was taken up in THF (5 ml) and a solution of borane in THF (1M) was added (6.7 ml). The reaction mixture was then heated at 65° C. over night, cooled to RT and carefully quenched with conc. HCl (5 ml). The mixture was then heated at 80° C. for 2 h, cooled to RT, concentrated under vacuo, diluted with Et2O (20 ml) and neutralized with an aqueous solution of NaHCO3. The organic phases were dried over Na2SO4 and the product purified by flash chromatography (SiO2, CH2Cl2/MeOH 9:1) to afford 0.29 g (51%) of rac-[(3S,4R)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-amine as a colorless oil. ES-MS m/e: 335.3 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([NH:18]C(=O)OC(C)(C)C)=[CH:15][CH:16]=3)[O:11][C:10]([CH3:27])([CH3:26])[CH:9]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>Cl.O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([NH2:18])=[CH:15][CH:16]=3)[O:11][C:10]([CH3:27])([CH3:26])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)OC(C)(C)C=C2c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)C=C(c2ccc(F)cc2)c2ccc(N)cc2O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the compound obtained in (4) described above (170 mg) in 4N hydrogen chloride/dioxane solution (3 mL) was stirred at room temperature for one hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine, filtered through a column of porous diatomite (Chem Elut) and the filtrate was concentrated in vacuo to give the titled compound (115 mg) as a crude product (pale brown powder).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14](Cl)=[O:15])[C:5]([CH2:11][O:12][CH3:13])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH3:17]>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]([NH2:17])=[O:15])[C:5]([CH2:11][O:12][CH3:13])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: COCc1cc([N+](=O)[O-])c(Cl)cc1C(=O)Cl
Reactant: N
Solvent: CCOCC
Product: COCc1cc([N+](=O)[O-])c(Cl)cc1C(N)=O
Reaction time: 0.25 h

Procedure:
A sample of 4-chloro-α-methoxy-5-nitro-o-toluoyl chloride (1.5 g.) is added to 100 ml of ether saturated with ammonia. During the addition and for 15 minutes thereafter, the reaction temperature is kept below 20°. The precipitate solid is collected and washed well with water. The crude product (0.9) has an infrared compatible with the desired structure.
Reaction SMILES: N[C:2]1[S:3][C:4]2[C:9]([NH:10][C:11]([CH3:16])([CH2:14][OH:15])[CH2:12][OH:13])=[N:8][C:7]([S:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])=[N:6][C:5]=2[N:27]=1.[ClH:28].N([O-])=O.[Na+].N>O.C(#N)C>[Cl:28][C:2]1[S:3][C:4]2[C:9]([NH:10][C:11]([CH3:16])([CH2:14][OH:15])[CH2:12][OH:13])=[N:8][C:7]([S:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])=[N:6][C:5]=2[N:27]=1
Reactant: Cl
Reactant: CC(CO)(CO)Nc1nc(SCc2cccc(F)c2F)nc2nc(N)sc12
Agent: N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(CO)(CO)Nc1nc(SCc2cccc(F)c2F)nc2nc(Cl)sc12
Temperature: 5 °C
Yield: 67 %

Procedure:
The product from step (e) (0.485 g) was suspended in conc.HCl (18 ml) which was then cooled to 15° C. A mixture of water (15 ml) and acetonitrile (25 ml) added to give a solution. Cooled to 5° C. and a solution of sodium nitrite (0.162 g) in water (1 ml) added drop-wise. Stirred at 5° C. for several hours then allowed to warm overnight. Solution cooled to −10° C. and neutralized with ammonia, then concentrated in vacuo. The yellow precipitate was collected by filtration and washed with water. Dried in vacuo to give 0.339 g of product. 67% yield.
Reaction SMILES: FC1C=C(C2CCC3C(=CC=C(O)C=3)O2)C=CC=1.[CH2:19]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]2[CH2:36][CH:35](O)[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([OH:38])[CH:33]=3)[O:28]2)=[CH:23][CH:22]=1)[CH3:20]>>[CH2:19]([C:21]1[CH:22]=[CH:23][C:24]([CH:27]2[CH2:36][CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[C:32]([OH:38])[CH:33]=3)[O:28]2)=[CH:25][CH:26]=1)[CH3:20]
Reactant: CCc1ccc(C2CC(O)c3cc(O)ccc3O2)cc1
Agent: Oc1ccc2c(c1)CCC(c1cccc(F)c1)O2
Product: CCc1ccc(C2CCc3cc(O)ccc3O2)cc1

Procedure:
2-(4-Ethylphenyl)chroman-6-ol was prepared as described for 2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from 425 mg of 2-(4-ethyl-phenyl)chroman-4,6-diol. The product was purified using heptane-ethyl acetate (3:1) as an eluant. 1H NMR (400 MHz, CD3OD) δ: 7.26 (d, 2H, J 8.2 Hz), 7.13 (d, 2H, J 8.2 Hz), 6.65 (d, 1H, J 8.6 Hz), 6.55 (dd, 1H, J 8.6, 2.8 Hz), 6.51 (d, 1H, J 2.8 Hz), 4.83 (dd, 1H, J 10.1, 2.3 Hz), 2.84 (m, 1H), 2.62 (m, 1H), 2.59 (q, 2H, J 7.6 Hz), 2.03 (m, 1H), 1.93 (m, 1H), 1.19 (t, 3H, J 7.6 Hz).
Reaction SMILES: OC1C=C(O)C=CC=1C([C:16]([CH:18]([C:25]1C=CC(O)=CC=1O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17])C1C=CC=CC=1.N1[CH2:38][CH2:37][O:36]CC1>C([O-])([O-])OCC.CN(C)C=O>[OH:17][C:16]1[CH:38]=[C:37]2[C:20]([C:16](=[O:17])[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:25][O:36]2)=[CH:19][CH:18]=1
Reactant: C1COCCN1
Reactant: O=C(C(c1ccccc1)c1ccc(O)cc1O)C(c1ccccc1)c1ccc(O)cc1O
Agent: CCOC([O-])[O-]
Solvent: CN(C)C=O
Product: O=c1c(-c2ccccc2)coc2cc(O)ccc12

Procedure:
reacting 2,4-dihydroxy-phenyl-benzyl-ketone of formula (II) ##STR7## with ethyl orthoformate in dimethylformamide as solvent and in the presence of a catalyst consisting of morpholine, to yield 7-hydroxyisoflavone of formula (III) ##STR8## b) separating of product (III) from the reaction residue, c) alkylating of product (III) from step b) with isopropyl halide to obtain ipriflavone, wherein:
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][P:6]([Cl:8])Cl)#[N:2].C[Si](C)(C)[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C(Cl)Cl>[Cl:8][P:6]([O:5][CH2:4][CH2:3][C:1]#[N:2])[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: N#CCCOP(Cl)Cl
Reactant: C[Si](C)(C)N1CCOCC1
Solvent: ClCCl
Product: N#CCCOP(Cl)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a solution of 2-Cyanoethyldichlorophosphite (3.0 g, 17.5 mmol, 2.2 mL) in CH2Cl2 (45 mL) was added dropwise 4-(trimethylsilyl)morpholine (3.1 mL, 2.8 g, 17.5 mmol) at 0° C. The resulting mixture was stirred for 2 h at room temperature. The solvent was removed under reduced pressure to give a pale yellow oil (3.87 g, 86%) as a product.
Reaction SMILES: C([S:4][CH2:5][CH2:6][S:7]([N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12]([OH:14])=[O:13])(=[O:9])=[O:8])(=O)C.N.Cl>O>[SH:4][CH2:5][CH2:6][S:7]([N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12]([OH:14])=[O:13])(=[O:8])=[O:9]
Reactant: CC(=O)SCCS(=O)(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Agent: N
Solvent: O
Product: O=C(O)[C@@H]1CCCN1S(=O)(=O)CCS
Yield: 79.9 %

Procedure:
N-[[2-(Acetylthio)ethyl]sulfonyl]-L-proline (640 mg, 0.0023 mole) is dissolved in 5 ml of water and 5 mg of concentrated ammonia and stirred 1 hour under nitrogen. The solution is acidified with concentrated hydrochloric acid, extracted with ethyl acetate, and the extracts are washed with brine, dried (MgSO4) and evaporated to an oily residue which is applied to a 75 ml silica gel column. Elution with 10% acetic acid/benzene affords a main fraction which is crystallized from chloroform/hexane, to obtain 440 mg (81%) of 1-[(2-mercaptoethyl)sulfonyl]-L-proline, m.p. 99°-101°.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.[CH3:14][C:15]1([CH3:22])[CH2:20][C:19](=[O:21])[CH2:18][CH2:17][O:16]1>C1COCC1>[CH3:14][C:15]1([CH3:22])[CH2:20][C:19]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)([OH:21])[CH2:18][CH2:17][O:16]1
Reactant: CC1(C)CC(=O)CCO1
Reactant: Cc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C2(O)CCOC(C)(C)C2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-BuLi (26.3 ml, 1.6 M in hexane, 42 mmol) was added dropwise to a solution of 4-bromo-toluene (7.70 g, 45 mmol) in THF (100 ml) at −78° C. under N2. The resulting mixture was stirred at −78° C. for 30 min and a solution of tetrahydro-2,2-dimethyl-4H-pyran-4-one (3.84 g, 30 mmol) in THF (20 ml) was added. The resulting mixture was stirred at −78° C. for another 20 min and quenched by adding MeOH (10 ml). The reaction was concentrated under vacuum and the resulting residue was diluted with EtOAc (500 ml) and washed with sat. NH4Cl (250 ml), brine (250 ml), dried and concentrated to give 2,2-dimethyl-4-(4-methylphenyl)oxan-4-ol as a white solid, which was used without further purification (5.41 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([CH:19]=1)[C:7]([NH:9][C:10]1[S:11][C:12]2[O:18][CH2:17][CH2:16][CH2:15][C:13]=2[N:14]=1)=[O:8].CC(C)([O-])C.[K+].Br[CH2:29][CH2:30][CH2:31][CH3:32]>CN(C)C=O.O1CCCC1>[CH2:29]([N:14]1[C:13]2[CH2:15][CH2:16][CH2:17][O:18][C:12]=2[S:11]/[C:10]/1=[N:9]\[C:7](=[O:8])[C:6]1[CH:19]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[O:20][CH3:21])[CH2:30][CH2:31][CH3:32]
Reactant: COc1ccc(Cl)cc1C(=O)Nc1nc2c(s1)OCCC2
Reactant: CCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCn1c2c(s/c1=N\C(=O)c1cc(Cl)ccc1OC)OCCC2
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of the product from Example 26B (mixture) in 10 mL of N,N-dimethylformamide and tetrahydrofuran (1:4) were added potassium t-butoxide (21 mg, 0.18 mmol) and 1-bromobutane (25 mg, 0.18 mmol). After stirring at 80° C. for 16 h, the reaction mixture was cooled to room temperature and quenched with saturated aqueous NaHCO3 (10 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280 ™ (SiO2, 0-50% ethyl acetate in methylene chloride) to afford 3 mg of the title compound as a single regioisomer. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.94 (t, J=7.3 Hz, 3H), 1.28-1.42 (m, 2H), 1.73 (t, 2H), 2.06 (t, 2H), 2.67 (t, J=6.3 Hz, 2H), 3.79 (s, 3H), 4.06-4.13 (m, 2H), 4.18-4.25 (m, 2H), 7.11 (d, J=8.8 Hz, 1H), 7.45 (dd, J=8.8, 3.1 Hz, 1H), 7.71 (d, J=3.1 Hz, 1H); MS (ESI+) m/z 381 (M+H)+.