Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:15][CH:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]4[N:26]([CH3:34])[C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:24])=[C:18]([O:35][CH3:36])[CH:17]=3)[C:4]=2[C:5](/[N:8]=C/N(C)C)=[N:6][CH:7]=1.ClC(OC)=S.CS[C:44](=[O:46])[NH2:45].Cl.CNOC.C(N(CC)C(C)C)(C)C.[OH:61][CH2:62][CH2:63][N:64]1[CH2:69][CH2:68]N[CH2:66][CH2:65]1>N1C=CC=CC=1>[NH2:8][C:5]1[C:4]2[C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]4[N:26]([CH3:34])[C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:24])=[C:18]([O:35][CH3:36])[CH:17]=3)=[CH:14][S:15][C:3]=2[C:2]([NH:1][C:44]([N:45]2[CH2:68][CH2:69][N:64]([CH2:63][CH2:62][OH:61])[CH2:65][CH2:66]2)=[O:46])=[CH:7][N:6]=1
Reactant: CSC(N)=O
Reactant: OCCN1CCNCC1
Reactant: COc1cc(-c2csc3c(N)cnc(/N=C/N(C)C)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: CNOC
Agent: COC(=S)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2csc3c(NC(=O)N4CCN(CCO)CC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N-[4-(7-Amino-4-{[(1E)-(dimethylamino)methylene]amino}thieno[3,2-c]pyridin-3-yl)-2-methoxyphenyl]-1-methyl-1H-indole-2-carboxamide (0.108 g, 0.217 mmol) was dissolved in pyridine (3 mL). Methyl chlorothioformate (0.020 mL, 0.233 mmol) was added, and the solution was stirred at ambient temperature for 1.5 hours, at which point LCMS analysis indicated that a clean conversion of the 7-amino group to the thiocarbamic acid S-methyl ester had occurred. N,O-Dimethylhydroxylamine hydrochloride (0.106 g, 1.09 mmol) was added, and the solution was stirred at 50° C. for 4 h, at which point LCMS analysis indicated that the 4-(dimethylaminomethyleneamino) group had been cleaved. The reaction mixture was cooled to ambient temperature, and N,N-diisopropylethylamine (0.264 mL, 1.30 mmol) and 1-(2-hydroxyethyl)piperazine (0.057 mL, 1.52 mmol) were added. The mixture was stirred at 70° C. for 12 h, then was cooled to ambient temperature and concentrated. The residue was diluted with aqueous sodium carbonate (0.5 M, 10 mL), and the mixture was extracted with dichloromethane (3×20 mL). The organic fractions were combined, dried over magnesium sulfate, and concentrated. Purification of the residue on silica gel which had been deactivated with triethylamine (10% by volume of silica gel used) afforded the title compound as an off-white powder: 1H NMR (DMSO-d6, 400 MHz) δ 9.51 (s, 1H), 8.48 (s, 1H), 7.99 (d, 1H), 7.71 (d, 1H), 7.64 (s, 1H), 7.59 (d, 1H), 7.50 (s, 1H), 7.35 (s, 1H), 7.33 (t, 1H), 7.20 (s, 1H), 7.15 (t, 1H), 7.08 (d, 1H), 5.40 (br, 2H), 4.47 (br, 1H), 4.04 (s, 3H), 3.91 (s, 3H), 3.55 (m, 2H), 3.46 (m, 4H), 2.45 (m, 6H); MS: (MI)+600.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Li]C(C)(C)C.[CH3:16][S:17]SC>C1COCC1>[CH3:16][S:17][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: CSSC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CSc1ccc2cc[nH]c2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
To a solution of 6-bromo-1H-indole (5 g, 25.50 mmol) in anhydrous THF (60 mL) at 0° C. was added KH (6.80 g, 51.00 mmol, 30% wt in mineral oil). After stirring for 30 min and cooling to −78° C., t-BuLi (39.23 mL, 51.0 mmol, 1.3 M) was added to the formed mixture under nitrogen. After 30 min, 1,2-dimethyldisulfane (4.80 g, 51.0 mmol) was added to the formed mixture. The reaction mixture was stirred at −78° C. for 1 h. The mixture was quenched with sat. NH4Cl (30 mL) at −78° C. slowly (Caution: flame), adjusted pH=7 with 1 N aqueous phosphoric acid and extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography on silica gel eluted with PE/EtOAc 10:1 to give 6-(methylthio)-1H-indole (3.9 g, 93.67% yield) as a grey solid. LC-MS MS (ESI) m/z 164.1 [M+H]+. 1H NMR (CDCl3 400 MHz): δ 8.14 (brs, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.37 (s, 1H), 7.18-7.11 (m, 1H), 6.56-6.51 (m, 1H), 2.52 (s, 3H).
Reaction SMILES: F[C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=1[N:4]([CH2:10][C:11]([F:14])([F:13])[F:12])[C@H:5]([CH2:8][CH3:9])[CH2:6][OH:7].[H-].[Na+].CO>C1COCC1>[CH2:8]([C@H:5]1[N:4]([CH2:10][C:11]([F:14])([F:13])[F:12])[C:3]2[CH:15]=[CH:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][C:2]=2[O:7][CH2:6]1)[CH3:9]
Reactant: CC[C@H](CO)N(CC(F)(F)F)c1ccc([N+](=O)[O-])cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC[C@@H]1COc2cc([N+](=O)[O-])ccc2N1CC(F)(F)F
Temperature: 25 °C

Procedure:
A solution of 190 g (0.612 mole) of the crude (2R)-2-[2-fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-1-butanol in 1 Liter of dry THF was added dropwise to a stirred suspension of 36.77 g (0.919 mole, 1.5 eq) of sodium hydride in 1.5 L of dry THF under nitrogen atmosphere. After complete addition, the reaction mixture was refluxed for 3 h when TLC of the reaction mixture indicated complete conversion. After cooling to room temperature, 400 mL of methanol was added to destroy excess sodium hydride. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The organic portions were combined, washed with brine and dried over MgSO4. After filtration, the solvents were evaporated under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography (ethyl acetate:hexanes 1:9) to obtain (+)-(3R)-3-ethyl-3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine as a yellow crystalline solid. Yield 71 g (40%). [α]D=+56.6 (CHCl3, c 7.8); 1H NMR (CDCl3) δ 7.80 (1H, dd, J=2.56, 8.98), 7.71 (1H, d, J=2.57), 6.72 (1H, d, J=9.07), 4.34 (1H, dd, J=1.44, 11.02), 4.12 (1H, m), 4.06 (1H, dd, J=2.12, 11.04), 3.79 (1H, m), 3.37 (1H, m), 1.68 (2H, m), 1.00 (3H, t, J=7.54). 13C NMR: ppm 142.6, 139.1, 138.6, 126.1, 118.6, 112.6, 110.8, 64.9, 58.9, 50.6, 22.5 and 10.3.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[N:18]=[CH:19][N:20]([CH3:22])[CH:21]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23]>CO.ClCCl.C(OCC)C>[ClH:23].[CH3:22][N:20]1[CH:21]=[C:17]([S:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)(=[O:15])=[O:16])[N:18]=[CH:19]1
Reactant: Cn1cnc(S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: Cn1cnc(S(=O)(=O)N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(1-Methylimidazole-4-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (730 mg) was dissolved in methanol (10 ml) and dichloromethane (5 ml), 2M HCl in diethyl ether (11 ml) was added and the reaction mixture was stirred at room temperature overnight. Volatiles were removed in vacuo to yield 4-(1-methylimidazole-4-sulfonyl)-piperazine hydrochloride salt (704 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[Cl-].[NH4+].O.C(OCC)(=O)C>C(O)C.[Fe]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH2:13])[CH:10]=[N:9]2)=[CH:16][CH:17]=1
Reactant: COc1ccc(Cn2cc([N+](=O)[O-])cn2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(Cn2cc(N)cn2)cc1
Yield: 93.6 %

Procedure:
1-(4-Methoxybenzyl)-4-nitro-1H-pyrazole (2.17 g, 9.30 mmol) was dissolved in ethanol (20 ml). Ammonium chloride (50 mg, 0.93 mmol) and iron (powder, 2.60 g, 46.56 mmol) were added and the mixture was refluxed for 1 h. The reaction mixture was filtered through Celite® and the solvent was evaporated to dryness under reduced pressure. Usual work-up with water and ethyl acetate afforded 1.77 g (94% yield) of the title compound as an oil, which was used in the next synthetic step without further purification.
Reaction SMILES: [CH3:1][NH:2][C:3]([O:5][CH:6]([CH2:9][O:10][C:11](=[O:31])[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7][NH2:8])=[O:4].C(SCC(OC(=O)NC)COC(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CCCCCCCCCCCCCCC.[Cl:77][CH2:78][CH2:79][CH2:80][S:81](NCC(OC)CSCCCCCCCCCCCCCCCC)(=[O:83])=[O:82]>>[Cl:77][CH2:78][CH2:79][CH2:80][S:81]([NH:8][CH2:7][CH:6]([O:5][C:3](=[O:4])[NH:2][CH3:1])[CH2:9][O:10][C:11](=[O:31])[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])(=[O:83])=[O:82]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)OC(=O)NC
Agent: CCCCCCCCCCCCCCCCSCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC(=O)NC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)OC(=O)NC

Procedure:
2-Methylcarbamoyloxy-3-octadecylcarbamoyloxypropylamine IV c2 is allowed to react and worked up by the same procedure as described in (4). m.p. 102°-104° C. The summary of the experimental condition and the physical data of the product are listed in the Table 7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[C:12]3[NH:13][CH:14]=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16](=O)[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.O=P(Cl)(Cl)[Cl:27]>>[Cl:27][C:16]1[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:23]=[CH:24][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:9]=[CH:10][C:11]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c[nH]c2c(cnn2Cc2ccc(OC)cc2)c1=O
Product: CCOC(=O)c1cnc2c(cnn2Cc2ccc(OC)cc2)c1Cl

Procedure:
Ethyl 1-(4-methoxybenzyl)-4-oxo-4,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 2 and POCl3 were heated at 80° C. in a sealed tube for 3 hours. Reaction mixture was concentrated in vacuo, diluted with diethylether, washed with water, dried over sodium sulfate and concentrated in vacuo to afford product 3 as off white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:14][C:15]([OH:17])=[O:16])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(C=O)cc1OC
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1ccc(C=CC(=O)O)cc1OC
Reaction time: 7 h
Yield: 88.5 %

Procedure:
To a solution of 1000 g (6.024 mol) of 3,4-dimethoxybenzaldehyde in 3 L pyridine, 1378.3 g (13.25 mol) of malonic acid and 100 mL of piperidine were added. The resulting mixture was stirred at 105° C. to 110° C. for 6-8 h. After completion of the reaction, the reaction mixture was cooled to 25° C. to 30° C. and slowly quenched the reaction mixture into 10 L of 5% sodium hydroxide solution at 25° C. to 30° C. (pH: 9-10). The reaction mixture was washed with ethyl acetate (2×5 L) and the organic layer separated was washed with 2 L of 5% sodium hydroxide solution. The aqueous layers were combined and cooled to 15° C. to 20° C. The aqueous layer was acidified slowly with 2.5 L of 50% sulphuric acid below 20° C. (pH: 1-2). After an additional 30-45 min stirring at 15° C. to 20° C., the solid obtained was collected by filtration, washed with 10 L of water followed by 4 L of n-hexane. The partially dried compound was unloaded into trays and dried at 55° C. to 60° C. for 8-10 h to give 1110 g of the title compound.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([N:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:18])[C:11]=2[N+:15]([O-:17])=[O:16])[C:6]1=[O:19])[CH3:4].N1C=CC=CC=1.[C:26](OC(=O)C)(=[O:28])[CH3:27].C(Cl)Cl>>[C:26]([O:1][CH2:2][C@H:3]([N:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:18])[C:11]=2[N+:15]([O-:17])=[O:16])[C:6]1=[O:19])[CH3:4])(=[O:28])[CH3:27]
Reactant: Cc1ccc2c(=O)n([C@H](C)CO)ccc2c1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC[C@@H](C)n1ccc2c([N+](=O)[O-])c(C)ccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-2-(1-hydroxypropan-2-yl)-6-methyl-5-nitroisoquinolin-1(2H)-one (100.0 mg, 0.0003813 mol), pyridine (0.062 mL, 0.00076 mol), acetic anhydride (0.0432 mL, 0.000458 mol) and methylene chloride (5 mL, 0.08 mol) was stirred at room temperature overnight. The reaction went to completion and the solvent was removed under reduced pressure, and the resulting product was dried in vacuum (yellow oil) and was used in the next reaction without any purification. MS m/z=305.4 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH:4]([CH:5]=[C:6]([Cl:8])[Cl:7])[C:3]1(C(OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10].N12CCCC1=NCCC2>CC1C=CC=CC=1C>[CH2:12]([O:11][C:9]([CH:3]1[CH:4]([CH:5]=[C:6]([Cl:7])[Cl:8])[C:2]1([CH3:1])[CH3:19])=[O:10])[CH3:13]
Reactant: CCOC(=O)C1(C(=O)OCC)C(C=C(Cl)Cl)C1(C)C
Agent: C1CN=C2CCCN2C1
Solvent: Cc1ccccc1C
Product: CCOC(=O)C1C(C=C(Cl)Cl)C1(C)C
Yield: 47.1 %

Procedure:
13 g of diethyl 2,2-dimethyl-3-(2',2'-dichlorovinyl)-cyclopropane-1,1-dicarboxylate were dissolved in 50 g of o-xylene and 20 g of 1,5-diaza-bicyclo[4.3.0]non-5-ene were added. The mixture was then heated to the boil for 8 hours. After cooling, ice-cold dilute hydrochloric acid was added, so that a neutral or weakly acid pH value resulted. The organic phase was separated off and dried with Na2SO4 and the xylene was distilled off in vacuo (boiling point = 35° - 40° C./12 mm Hg). The residue weighed 12.5 g. Fractional distillation gave 4.7 g of 2,2-dimethyl-3-(2',2'-dichlorovinyl)-cyclopropane-1-carboxylic acid ethyl ester, of which 30% was in the cis form and 70% was in the trans form. The boiling point was 65° - 72° C./0.3 mm Hg. The nuclear magnetic resonance spectrum agreed with that given in the literature. 6.5 g of the starting material were recovered. The yield was thus 92%.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)[CH3:8].Cl.[NH2:20][C:21]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:23][CH2:22]1.C(N(CC)CC)C.Cl>ClCCl.CN(C)C=O>[CH2:7]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:20][C:21]2([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:23][CH2:22]2)=[O:16])=[CH:17][CH:18]=1)[CH3:8]
Reactant: CCOc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)C1(N)CC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C1(NC(=O)c2ccc(OCC)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
Add oxalyl chloride (189 mL, 2.17 mol) to 4-ethoxybenzoic acid (334.5 g, 1.99 mol) and N,N-dimethylformamide (1 mL) in dichloromethane (3 L). After 1 hr at 25-26° C., concentrate the mixture under reduced pressure until a constant weight is achieved. Stir ethyl 1-aminocyclopropanecarboxylate hydrochloride (300 g, 1.81 mol) and dichloromethane (2.5 L) in an ice water bath. Add triethylamine (631 mL, 4.53 mol) and then add a solution of the acid chloride (ca 380 g) in dichloromethane (500 mL). Stir the reaction mixture for approximately 16 hours at ambient temperature. Dilute the reaction with aqueous 1N hydrochloric acid (1 L). Extract the aqueous layer with dichloromethane (1 L). Wash the organic layer with water (2 L) and brine (2 L). Dry the solution over sodium sulfate, filter, and concentrate under reduced pressure. Slurry the residue in hexanes and filter to give the title compound (478 g, 95%) as an ivory powder: MS (mass spectrometry) (m/z): 278 (M+1).
Reaction SMILES: C(=O)(OC(Cl)(Cl)Cl)[O:2][C:3]([Cl:6])(Cl)Cl.[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][NH:14]1>C(Cl)Cl.C(N(CC)CC)C>[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][N:14]1[C:3]([Cl:6])=[O:2]
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cl)N1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 282.7 %

Procedure:
A solution of 1.47 g of bis(trichloromethyl) carbonate in 10 ml of methylene chloride was added dropwise within 20 min. to a solution of 2 g of 1,2,3,4-tetrahydro-isoquinoline in 30 ml of methylene chloride and 2.5 ml of triethylamine under argon at 0° C. The reaction mixture was stirred at room temperature for 2 h., then diluted with 50 ml of methylene chloride and washed with 50 ml of water, 50 ml of a 5% hydrochloric acid solution, 50 ml of a saturated sodium hydrogen carbonate solution and 50 ml of a saturated sodium chloride solution. The organic phases were dried over magnesium sulfate, concentrated, and the residue was dried at room temperature and about 12 mbar. 2.74 g (94%) of 3,4-dihydro-1H-isoquinoline-2-carbonyl chloride were obtained as a pale orange oil. MS (EI): 195M30 .
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1>>[N:11]1([CH2:2][C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=2)[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: c1nc[nH]n1
Reactant: N#Cc1ccc(CBr)cc1
Product: N#Cc1ccc(Cn2cncn2)cc1

Procedure:
U.S. Pat. No. 4,978,672 discloses 4-[alpha-(4-cyanophenyl)-1-(1,2,4-triazolyl)-methyl]benzonitrile and a process for its preparation comprising reacting 4-bromomethyl benzonitrile with 1,2,4-triazole to yield 4-[1-(1,2,4-triazol-1-yl)methyl]benzonitrile. 4-[1-(1,2,4-triazol-1-yl)methyl]benzonitrile is then reacted with 4-fluorobenzonitrile to give 4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile (letrozole).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:15]([OH:17])=[O:16])[CH2:13]Cl)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[OH-].[Na+].[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>O>[C:1]([NH:11][C@H:12]([C:15]([OH:17])=[O:16])[CH2:13][S:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(N[C@@H](CCl)C(=O)O)OCc1ccccc1
Reactant: Sc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(N[C@@H](CSc1ccccc1)C(=O)O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 60.4 %

Procedure:
N-Carbobenzyloxy-β-chloro-L-alanine (0.137 g, 0.53 mmol) was dissolved in 0.68 ml of water and, then, 0.58 ml of 2 N aqueous sodium hydroxide was added. Thereafter, 0.069 g (0.63 mmol) of thiophenol was added dropwise at room temperature in a nitrogen gas atmosphere. After 2 hours of stirring at 60° C., the reaction mixture was cooled with ice and acidified with 1 N hydrochloric acid, and then extracted with ethyl acetate. The solvent was distilled off and the residue was purified by column chromatography to give 0.107 g (0.32 mmol, 61%) of N-carbobenzyloxy-S-phenyl-L-cysteine. The product obtained had an optical purity of not less than 98% e.e. as determined by HPLC analysis in the same manner as in Example 13.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl.CC(=O)OCC>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (2000.00 mg; 10.68 mmol; 1.00 eq.) in DCM 10 ml added ethyl-diisopropyl-amine (2.49 ml; 13.89 mmol; 1.30 eq.), then added dropwise methanesulfonyl chloride (0.89 ml; 11.22 mmol; 1.05 eq.) at 0° C., the reaction mixture was stirred for overnight at RT. TLC (EA/HEX=7:3) showed staring material converted to desired completed. Diluted the reaction solution with EA, washed with brine, organic layer was dried, filtered through silica gel 10 g, most color material was absorbed on silica gel, the filtrate was evaporated off solvent, got residue as title compound directly using for the next step reaction, TLC was clean.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C(N(CC)CC)C.[S:21](Cl)([CH3:24])(=[O:23])=[O:22].O>C(Cl)Cl>[CH3:24][S:21]([O:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.6 %

Procedure:
To a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (Aldrich; 7.42 g, 39.6 mmol), in DCM (20 mL) was added, at 0° C., triethylamine (8.44 mL; 48.5 mmol) and then mesylchloride (3.13 mL; 40 mmol). The mixture was stirred for 18 hours at RT and then water was added and the product was extracted with DCM (3×20 mL). The combined organic fractions were dried (MgSO4), filtered and the solvent removed in vacuo to give tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate (8.26 g; 77%) as a brown oil. 1H NMR: (CDCl3, 400 MHz) δ 5.27-5.20 (1 H, m), 3.70-3.49 (4 H, m), 3.04 (3 H, s), 2.90-2.05 (2 H, m), 1.46 (9 H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Cl:10][S:11](O)(=[O:13])=[O:12]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([S:11]([Cl:10])(=[O:13])=[O:12])[CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: COc1ccccc1Cl
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(S(=O)(=O)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A stirred solution of 2-chloroanisole (8.90 mL, 70.1 mmol) in chloroform (100 mL) was cooled to 0° C., and treated drop-wise with chlorosulfonic acid (9.3 mL, 140 mmol). After stirring at room temperature for 14 hours, the reaction mixture was poured into ice-water (250 mL) and the separated, aqueous phase extracted with chloroform (2×50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a viscous oil which crystallized upon standing (8.58 g, 52%), m.p. 78° C.;
Reaction SMILES: [CH3:1][N:2]([CH:4]([CH:7]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1)[C:5]#N)[CH3:3].C1COCC1.[S:22]1C=[CH:25][CH:24]=[C:23]1[Mg]Br.[Cl-].[NH4+]>C(OCC)C.O>[O:14]1[C:10]2([CH2:15][CH2:16][CH:7]([CH:4]([N:2]([CH3:3])[CH3:1])[C:5]3[S:22][CH:23]=[CH:24][CH:25]=3)[CH2:8][CH2:9]2)[O:11][CH2:12][CH2:13]1
Reactant: CN(C)C(C#N)C1CCC2(CC1)OCCO2
Reactant: Br[Mg]c1cccs1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)C(c1cccs1)C1CCC2(CC1)OCCO2
Reaction time: 20 h

Procedure:
A solution of the aminonitrile 3 (2.24 g, 10 mmol) in abs. THF (10 ml) was added dropwise, under argon and while cooling with ice, to a 1M solution of thiophen-2-yl-magnesium bromide in THF (20 ml, 20 mmol), and stirring was carried out for 20 h at RT. For working up the reaction mixture, saturated ammonium chloride solution (10 ml) and water (10 ml) were added, while cooling with ice, and extraction with diethyl ether (3×10 ml) was carried out. The organic phase was washed with water and saturated sodium chloride solution, dried and concentrated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([CH3:13])=[CH:6][C:4]=1N.N([O-])=O.[Na+].[BrH:18]>O>[Br:18][C:4]1[CH:6]=[C:7]([CH3:13])[C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:3]=1[O:2][CH3:1]
Reactant: Br
Reactant: COc1cc([N+](=O)[O-])c(C)cc1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc([N+](=O)[O-])c(C)cc1Br
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
a mixture of 2-methoxy-5-methyl-4-nitroaniline (20 g, 110 mmol) in 140 mL of water was heated under reflux and 48% hydrobromic acid (56 mL) was added dropwise and the mixture was heated for 20 minutes. The resulting suspension was cooled to 0° C. and treated with 40 mL of aqueous sodium nitrite (7.6 g, 110 mmol) dropwise keeping the temperature at 0° C. The suspension was added carefully dropwise to a 0° C. solution of cuprous bromide (18.1 g, 126 mmol) in 96 mL of water and 38 mL of 48% HBr. The mixture was stirred at 0° C. for 30 minutes and at room temperature for 1 hour and finally on a steam bath for 20 minutes to complete the reaction. The solid precipitate was suction filtered and dissolved in methylene chloride, washed with 400 mL of 10% sodium hydroxide, 5% sodium bisulfite, and water. The organic layer was dried, filtered, and evaporated in vacuo to give 24.9 g of dark brown solid. This was recrystallized from hexane to give 13.4 g of bromo compound.