Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:32]([C:34]1[O:38][C:37]([CH2:39][CH2:40][CH2:41][OH:42])=[CH:36][CH:35]=1)[CH3:33].[CH3:43][N:44]1[N:48]=[N:47][C:46]([C:49]2[CH:54]=[C:53]([CH3:55])[C:52](O)=[C:51]([CH3:57])[CH:50]=2)=[N:45]1>O>[CH2:32]([C:34]1[O:38][C:37]([CH2:39][CH2:40][CH2:41][O:42][C:52]2[C:51]([CH3:57])=[CH:50][C:49]([C:46]3[N:47]=[N:48][N:44]([CH3:43])[N:45]=3)=[CH:54][C:53]=2[CH3:55])=[CH:36][CH:35]=1)[CH3:33]
Reactant: CCc1ccc(CCCO)o1
Reactant: Cc1cc(-c2nnn(C)n2)cc(C)c1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: CCc1ccc(CCCOc2c(C)cc(-c3nnn(C)n3)cc2C)o1
Temperature: 25 °C
Yield: 65.4 %

Procedure:
Diethyl azodicarboxylate (DEAD, 4.84 g; 27.8 mmol) was added under nitrogen to a stirred and cooled (-20° C.) solution of triphenylphosphine (7.37 g; 27.8 mmol), 5-ethyl-2-(3-hydroxypropyl)furan (Intermediate 1c) (3.9 g; 25.3 mmol), and 4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenol (5.69 g; 27.8 mmol). The mixture was stirred at -20° C. for 1/2 h, and then was allowed to warm to room temperature overnight. Water (50 mL) was added to the mixture and the layers were separated. The aqueous layer was extracted with ether (3×50 mL), the organic layer was washed with 10% NaOH solution (3×50 mL), water, and dried over magnesium sulfate. The solvent was concentrated in vacuo to yield a residue and purified by MPLC column chromatography (ethyl acetate/hexane, 3:7) to afford 5.63 g (65%) of 5-ethyl-2-[3-[2,6-dimethyl-4-(2-methyl-tetrazol-5-yl)-phenoxy]-propyl]furan (Formula II; R3 =5-ethyl, R4 =hydrogen, R1, R2 =3,5-dimethyl, R5 =2-methyltetrazol-5-yl, Y=1,3-propylene).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1[C:14]([O:16][CH3:17])=[S:15].[C:18](OC(=O)C)(=[O:20])[CH3:19]>C(O)(=O)C>[C:18]([NH:1][C:2]1[NH:6][N:5]=[C:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1[C:14]([O:16][CH3:17])=[S:15])(=[O:20])[CH3:19]
Reactant: COC(=S)c1c(Cc2ccccc2)n[nH]c1N
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COC(=S)c1c(Cc2ccccc2)n[nH]c1NC(C)=O

Procedure:
70.5 g (0.27 mol) Methyl 5-amino-3-benzylthiopyrazole-4-carboxylate was dissolved at 80° C. in 135 ml glacial acetic acid and treated with 27.75 g (0.27 mol) acetic anhydride. The solution was heated under reflux for 7 hours and concentrated. The residue was recrystallised from ether, the crystals suction filtered, washed with ether and dried.
Reaction SMILES: O.[O:2]1[C:11]2[CH:10]=[C:9]([CH2:12][N:13]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[N:8]=[CH:7][C:6]=2[O:5][CH2:4][CH2:3]1.O.Cl.[F:29][C:30]1[CH:39]=[C:38]2[C:33]([CH:34]=[CH:35][C:36](=[O:43])[N:37]2[CH2:40][CH:41]=O)=[N:32][CH:31]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>CN1CCCC1=O.O>[O:2]1[C:11]2[CH:10]=[C:9]([CH2:12][N:13]([CH:21]3[CH2:26][CH2:25][N:24]([CH2:41][CH2:40][N:37]4[C:38]5[C:33](=[N:32][CH:31]=[C:30]([F:29])[CH:39]=5)[CH:34]=[CH:35][C:36]4=[O:43])[CH2:23][CH2:22]3)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[N:8]=[CH:7][C:6]=2[O:5][CH2:4][CH2:3]1
Reactant: O=CCn1c(=O)ccc2ncc(F)cc21
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CCn2c(=O)ccc3ncc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
To a solution of 5.0 g of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(piperidin-4-yl)carbamate monohydrate in 40 mL of N-methyl-2-pyrrolidone, 3.5 g of (7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde hydrochloride monohydrate was added, and the mixture was stirred for 1 hour at room temperature. To the mixture, 4.3 g of sodium triacetoxyborohydride was added dividedly in 5 portions over the period of 80 minutes under ice cooling, and the mixture was stirred for 1 hour and 40 minutes under ice cooling. After heating to room temperature, the mixture was added with 20 mL of water and adjusted to pH 11.5 with an aqueous solution of 20% sodium hydroxide. To the mixture, 20 mL of N-methyl-2-pyrrolidone was added at 70 to 80° C., and the mixture was stirred for 2 hours and 30 minutes at the same temperature. The reaction mixture was cooled to room temperature and the solid product was obtained by filtration and washed with water to give 6.5 g of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a light brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])[CH2:8][CH2:7][CH2:6][C:5]2=1.C(NCC)C.[ClH:29]>CO>[ClH:29].[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C@@H:9]([NH:15][C@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: C[C@H](NC1CCCc2c1[nH]c1ccc(Br)cc21)c1ccccc1
Agent: Cl
Solvent: CCNCC
Solvent: CO
Product: C[C@H](N[C@H]1CCCc2c1[nH]c1ccc(Br)cc21)c1ccccc1

Procedure:
(1S)-6-Bromo-N-[(1S)-1-phenylethyl]-2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride salt was prepared by separation of diastereomeric 6-bromo-N-[(1S)-1-phenylethyl]-2,3,4,9-tetrahydro-1H-carbazol-1-amine by SFC (Berger Amino, Chiral Technologies, 10% methanol, (2% diethyl amine/10% chloroform) 1500 psi, 50° C., 2 mL/min, retention time: 17.5 min.) The oil obtained was converted to the HCl salt to give a white solid. 1H-NMR (DMSO-d6): δ 11.6 (s, 1H), 9.85 (s, 1H), 9.30 (s, 1H), 7.80 (d, J=6.8 Hz, 1H), 7.70 (d, J=1.8 Hz, 1H), 7.52-7.45 (m, 3H), 7.43 (d, J=8.6 Hz, 1H), 7.29 (dd, J=6.8 Hz, J=1.8 Hz, 1H), 4.78 (m, J=6.4 Hz, 1H), 4.60 (m, 1H), 2.77-2.65 (m, 2H), 2.20-2.05 (m, 1H), 2.05-1.95 (m, 2H), 1.88-1.80 (m, 1H), 1.71 (d, J=6.8 Hz, 3H); MS m/z 367, 369 (M−1); Anal. Calcd. For C20H22BrN2Cl: C, 59.20; H, 5.46; N, 6.90. Found: C, 59.36; H, 5.58; N, 6.97.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[N:6][C:5]=1[F:20].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:20][C:5]1[C:4]([CH2:3][OH:2])=[CH:9][CH:8]=[C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:6]=1
Reactant: COC(=O)c1ccc(NCc2ccc(OC)cc2)nc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CNc2ccc(CO)c(F)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To 2-fluoro-6-(4-methoxy-benzylamino)-nicotinic acid methyl ester (63, 70 g, 241 mmol) in 350 mL of tetrahydrofuran, lithium aluminum hydride (362 mL, 1 M in tetrahydrofuran, 362 mmol) was added dropwise while cooling. The reaction was stirred at room temperature for 2 hours, then quenched with dropwise addition of 14 mL of water, 14 mL of 15% aqueous sodium hydroxide, and 42 mL of water, sequentially. Methyl tert-butyl ether (500 mL) was added and the solids removed by filtration. The filtrate was concentrated under vacuum and the resulting solid was dissolved in dichloromethane, passed through a plug of silica gel and eluted with 50-100% ethyl acetate in heptane. The solvent was removed under vacuum to provide the desired compound as an off-white solid (64, 63 g, 240 mmol, 100% yield).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])=[CH:4][C:3]=1[S:21][CH2:22][C:23]([O:25]CC)=[O:24].Cl>O1CCOCC1.C(OCC)(=O)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])=[CH:4][C:3]=1[S:21][CH2:22][C:23]([OH:25])=[O:24]
Reactant: CCOC(=O)CSc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(O)CSc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 80.3 %

Procedure:
8 mg Ethyl 2-(1-hydroxy-4-(thiophene-2-sulfonamido)naphthalen-2-ylthio)acetate (9a) was dissolved in 0.5 ml dioxane, to which was added 0.5 ml HCl solution (4 N). The reaction mixture was heated at 100° C. with M.W. for 10 min and diluted to 20 ml with ethyl acetate. Washed with water and brine, the organic solution was dried over Na2SO4 and filtered. The filtrate was concentrated to dryness affording title compound 6 mg (80%) as a pale yellow solid, m.p.: 175-177° C.
Reaction SMILES: [I-:1].[Na+].C(Cl)(=O)C.Cl[C:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH3:19])[N:11]=[C:10]2[S:20][C:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:9]=12>C(#N)C>[I:1][C:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH3:19])[N:11]=[C:10]2[S:20][C:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:9]=12
Reactant: [I-]
Reactant: CCOC(=O)c1c(C)nc2sc3c(c2c1Cl)CCCC3
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: CC#N
Product: CCOC(=O)c1c(C)nc2sc3c(c2c1I)CCCC3
Temperature: 25 °C
Reaction time: 30 h
Yield: 78.1 %

Procedure:
Sodium iodide (994.0 g, 6.63 Mol) was added over 5 minutes to a stirred solution of acetyl chloride (177 mL, 2.48 Mol) and ethyl (4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridine-3-yl)carboxylate (Preparation 4, 257 g, 0.83 Mol) in acetonitrile (2.0 L) at room temperature. The resulting mixture was heated to reflux and stirred for 30 hours. The mixture was allowed to cool to room temperature and stood for 72 hours. The solids were collected by filtration and washed with cold acetonitrile (500 mL). The solids were partitioned between dichloromethane (1.5 L) and water (0.75 L). The aqueous layer was basified to pH 9 by addition of 2 M sodium hydroxide solution and the two layers were separated. The organic layer was washed with 2 M sodium thiosulphate solution (800 mL), brine (800 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to give the title compound (260.0 g, 78%) as a beige solid. This material was determined by 1H NMR spectroscopy to be a 13:1 mixture of ethyl (4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridine-3-yl)carboxylate and ethyl (4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridine-3-yl)carboxylate respectively.
Reaction SMILES: [CH:1]1([CH:7]([CH2:19][C:20]([C:22]2[O:23][CH:24]=[CH:25][CH:26]=2)=O)[CH2:8][C:9]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[OH:18])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(O)=O.C[N:32](C)C=O>>[CH:1]1([C:7]2[CH:19]=[C:20]([C:22]3[O:23][CH:24]=[CH:25][CH:26]=3)[N:32]=[C:9]([C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=3[OH:18])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C=O
Reactant: O=C(CC(CC(=O)c1cc(F)ccc1O)C1CCCCC1)c1ccco1
Solvent: CC(=O)O
Product: Oc1ccc(F)cc1-c1cc(C2CCCCC2)cc(-c2ccco2)n1
Temperature: 100 °C

Procedure:
A mixture of 3-cyclohexyl-1-(2-hydroxy-5-fluorophenyl)-5-(furan-2-yl)-1,5-pentanedione on Wang resin (3.2 g, 1.9 mmol), NH4OAc (1.8 g), and AcOH (1.8 mL) in dimethylformamide (45 mL) was heated at 100° C. for 18 h. The resin was filtered, and washed with dimethylformamide (×2) and alternating MeOH and CH2Cl2 (×5), and dried under high vacuum overnight. The dried resin was treated with 50% TFA/CH2Cl2 (15 mL) for 1 h. After filtration of the reaction mixture, the filtrate was concentrated to dryness. The residue was repeatedly dissolved in CH2Cl2 (10 mL) and concentrated to remove traces of TFA. Purification by flash chromatography gave 2-(4-cyclohexyl-6-furan-2-yl-pyridin-2-yl)-4-fluoro-phenol; 1H NMR (DMSO-d6) d 1.35 (m, 4H), 1.61 (m, 2H), 1.76 (m, 4H), 2.68 (m, 1H), 6.74 (dd, J=3.4, 1.8 Hz, 1H), 6.94 (dd, J=9.0, 5.1 Hz, 1H), 7.18 (m, 1H), 7.26 (d, J=3.4 Hz, 1H), 7.72 (s, 1H), 7.94 (s, 1H), 8.04 (m, 2H), 14.22 (s, 1H); IR (KBr) 1617 cm−1; MS [M+H]+ m/z 338. Anal. calcd for C21H20FNO2.0.2MCF3CO2H: C, 71.29; H, 5.61; N, 3.89; Found: C, 71.24; H, 5.74; N, 3.76.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[S:25]1(=[O:31])(=[O:30])[CH2:29][CH2:28][CH2:27][NH:26]1>>[O:30]=[S:25]1(=[O:31])[CH2:29][CH2:28][CH2:27][N:26]1[C:20]1[CH:21]=[CH:22][C:17]([C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:6]3[C:5]([CH3:24])=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=3)[CH2:10][CH2:11]2)=[O:16])=[CH:18][CH:19]=1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Reactant: O=S1(=O)CCCN1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3)CC2)c(C)c1
Yield: 72.4 %

Procedure:
Using [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (435 mg) described in Preparation Example 133 and isothiazolidine 1,1-dioxide (158 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (310 mg) was obtained.
Reaction SMILES: C(OC([C:8]1[S:12][C:11]2[CH:13]=[C:14]([OH:18])[C:15]([OH:17])=[CH:16][C:10]=2[C:9]=1[OH:19])=O)CCC.[OH-].[Na+]>>[OH:19][C:9]1[C:10]2[CH:16]=[C:15]([OH:17])[C:14]([OH:18])=[CH:13][C:11]=2[S:12][CH:8]=1
Reactant: CCCCOC(=O)c1sc2cc(O)c(O)cc2c1O
Agent: [Na+]
Agent: [OH-]
Product: Oc1cc2scc(O)c2cc1O
Yield: 86 %

Procedure:
2.82 g (10 mmol) XIV and 6.00 g (150 mmol) NaOH were heated under reflux for 3.5 h in 300 ml degassed water. The still hot solution was then acidified with concentrated HCl to pH 1. The compound XV precipitating on cooling in an ice bath was removed and washed with a little diethylether. A yield of 1.57 g XV (8.6 mmol, 86%) was obtained.
Reaction SMILES: [NH2:1][C:2]([C:27]#[N:28])([CH3:26])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=1[Cl:25])[C:8]#[N:9].C(NC(C)C)(C)C.[F:36][C:37]([F:49])([F:48])[S:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1>ClCCl>[C:27]([C:2]([NH:1][C:43](=[O:44])[C:42]1[CH:46]=[CH:47][C:39]([S:38][C:37]([F:49])([F:36])[F:48])=[CH:40][CH:41]=1)([CH3:26])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:8]#[N:9])[CH:10]=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:24])[F:22])=[CH:16][C:15]=1[Cl:25])#[N:28]
Reactant: O=C(Cl)c1ccc(SC(F)(F)F)cc1
Reactant: CC(N)(C#N)COc1cc(C#N)ccc1Oc1ccc(OC(F)(F)F)cc1Cl
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CC(C#N)(COc1cc(C#N)ccc1Oc1ccc(OC(F)(F)F)cc1Cl)NC(=O)c1ccc(SC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
21.5 g of 3-(2-amino-2-cyano-2-methyl-ethoxy)-4-(2-chloro-4-trifluoromethoxy-phenoxy)-benzonitrile (described in example 1 step d)) and 11.4 ml of N, N-diisopropylamine are dissolved in 250 ml of dichloromethane and 14.5 g of 4-(trifluoromethylthio)-benzoylchloride are slowly added. The reaction mixture is stirred at room temperature for 20 hours and washed with water, a saturated aqueous solution of sodium bicarbonate and water. The organic phase is dried with magnesium sulfate and evaporated under vacuum. The residue is purified by recrystallization from diethylether/hexanes to yield N-[1-cyano-1-methyl-2-(5-cyano-2-{2-chloro-4-trifluoromethoxy-phenoxy}-phenoxy)-ethyl]-4-trifluoromethylsulfanyl-benzamide as a colorless solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C1(=O)[NH:11]C(=O)C2=CC=CC=C12.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21]([CH2:28]Cl)[C:20]=1[Cl:30]>>[Cl:30][C:20]1[C:19]([Cl:18])=[CH:24][CH:23]=[C:22]([N+:25]([O-:27])=[O:26])[C:21]=1[CH2:28][NH2:11]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NCc1c([N+](=O)[O-])ccc(Cl)c1Cl
Yield: 75 %

Procedure:
Potassium carbonate and 2 equivalents of phthalimide are ground together and heated to reflux with 2 equivalents of 1,2-dichloro-3-chloromethyl-4-nitrobenzene for three hours. Upon cooling, the substituted benzylphthalimide crystallizes and is filtered in 60-80% yield. 2,3-Dichloro-6-nitrobenzylamine is obtained in a 75-95% yield with acid hydrolysis using hydrochloric acid from the substituted benzylphthalimide.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[N+:7]([O-:9])[C:6]([CH3:10])=[CH:5][N:4]=1.S(Cl)(Cl)=O.[Na].[CH:16]1C=CC=CC=1>CO.[Cl-].[Cl-].[Zn+2]>[CH3:16][O:1][CH2:2][C:3]1[CH:8]=[N+:7]([O-:9])[C:6]([CH3:10])=[CH:5][N:4]=1
Reactant: c1ccccc1
Reactant: Cc1cnc(CO)c[n+]1[O-]
Agent: [Cl-]
Agent: [Na]
Agent: [Zn+2]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COCc1c[n+]([O-])c(C)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 152 %

Procedure:
2-Hydroxymethyl-5-methylpyrazine-4-oxide (3.5 g) was dissolved under stirring in a solution of 8 ml of thionyl chloride in 20 ml of dry benzene containing 0.5 g of ZnCl2, keeping the temperature below 30° C. The reaction mixture was cautiously warmed 3 hours at 60° C., then cooled to room temperature, and filtered. The solvent was evaporated under reduced pressure. The oily residue was dissolved in a solution of sodium methoxide in methyl alcohol, previously prepared dissolving 0.6 of sodium in 30 ml of methyl alcohol. After refluxing 4 hours, the reaction solution was cooled at room temperature, filtered and evaporated to dryness. The residue was taken up with water and repeatedly extracted with ethyl ether. The organic phase was washed with water, dried and the solvent was evaporated to dryness; the residue treated with pentane gave 2-methoxymethyl-5-methylpyrazine-4-oxide (1.5 g), m.p. 69°-72° C.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:9])[CH:4]([CH3:8])[O:5][C:6]=1[CH3:7].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.O>N1C=CC=CC=1.ClCCl>[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([O:9][C:3]2[C:2](=[O:1])[CH:6]([CH3:7])[O:5][C:4]=2[CH3:8])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1=C(O)C(=O)C(C)O1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1=C(OS(=O)(=O)c2ccc(C)cc2)C(=O)C(C)O1
Temperature: -10 °C
Reaction time: 3 h
Yield: 75.5 %

Procedure:
12.8 grams (0.1 m) of 4-hydroxy-2,5-dimethyl-2,3-dihydrofuran-3-one were dissolved in 70 ml of dry pyridine. The solution was stirred and cooled to -10° C. in an ice-salt bath. With stirring a cold solution of 22.9 grams (0.12 m) of p-toluene sulfonylchloride in 50 ml of dry dichloromethane was added dropwise (temp. below -5° C.). After completion of the addition (1 hour), stirring at 0° C. was continued for 3 hours, and water (10 ml) was added in portions at intervals of 5 min., with stirring and cooling, so that the temperature did not rise above 5° C. The solution was then poured into 250 ml of ice-water. The mixture was extracted four times with dichloromethane, and the combined extracts were successively washed with portions of ice-cold dilute sulphuric acid, water, sodium hydrogen carbonate solution and water. The dichloromethane solution was then dried with anhydrous sodium sulphate and evaporated to dryness. Crystallization from ethanol yielded 21.3 grams = 75.5% of the pure 4-p-toluenesulfonyloxy-2,5-dimethyl-2,3-dihydrofuran-3-one with m.p. 70°-72° C. 3.5 grams (12.4 mmol) of the tosylate thus obtained were dissolved in a mixture of 15 ml of ethanol and 5 ml of water at 40° C. To this solution was added a solution of 1.68 grams (30 mmol) of sodium hydrogen sulphide in 20 ml of ethanol, while a gentle stream of hydrogen sulphide was passed through the reaction mixture. After completion of the addition, which took one hour, stirring and passing of H2S into the solution were continued for 6 hours at 40° C. and the reaction mixture was diluted with 200 ml of water, acidified with aqueous dilute hydrochloric acid (pH 5.5) and continuously extracted with ether for 18 hours. The extract was dried over anhydrous sodium sulphate and evaporated to dryness. From the residue the title compound was isolated in a quantity of 3 grams by preparative gaschromatography, using a column of 600 × 0.4 cm, a support of Diatoport S (a silanated silicagel) ex Hewlett Packard, loaded with 1% Carbowax 20 M (a polyethylene glycol ether with a molecular weight above 20,000) ex Hewlett Packard and 10% Apiezon (a mixture of stable alkanes) ex Shell Comp. Nitrogen was used as a carrier gas at a velocity of 40 ml per minute. The temperature was programmed; starting temperature 60° C.; increase in temperature 4° per minute. The retention time found for 4-mercapto-2,5-dimethyl-2,3-dihydrothiophene-3-one was 40.1 minutes.
Reaction SMILES: C([C:8]([NH2:12])([OH:11])[CH2:9][CH3:10])(OC(C)(C)C)=O.[OH:13][C:14]([CH:16]([C:18]1[CH:31]=[CH:30][CH:29]=[C:20]([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:22])[CH:19]=1)[CH3:17])=[O:15].[ClH:32].C(OCC)(=O)C>>[NH2:12][CH:8]([OH:11])[CH2:9][CH3:10].[ClH:32].[OH:15][C:14]([CH:16]([C:18]1[CH:31]=[CH:30][CH:29]=[C:20]([C:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:22])[CH:19]=1)[CH3:17])=[O:13]
Reactant: CCC(N)(O)C(=O)OC(C)(C)C
Agent: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCC(N)O
Temperature: 25 °C

Procedure:
Under ice-cooling, 20 ml of 4 M hydrochloric acid/ethyl acetate was added to 5.330 g (12.95 mmol) of the Boc-aminopropanol-ketoprofen obtained above, followed by stirring under ice-cooling for 15 minutes and at room temperature for 2 hours. After confirming disappearance of Boc-aminopropanol-ketoprofen by TLC, the solvent was evaporated under reduced pressure, and the residue was subjected twice to decantation with diethyl ether. Thereafter, the residue was dried under reduced pressure to quantitatively give the titled substance at a yield of 4.569 g. The structure was identified by 1H-NMR (CDCl3).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([N:7]1[CH2:21][CH2:20][C:19]2[C:10](=[N:11][C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([N+:23]([O-])=O)[C:17]=3[C:18]=2[CH3:22])[CH2:9][CH2:8]1)=[O:6])[CH3:3]>Cl>[CH2:2]([O:4][C:5]([N:7]1[CH2:21][CH2:20][C:19]2[C:10](=[N:11][C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([NH2:23])[C:17]=3[C:18]=2[CH3:22])[CH2:9][CH2:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)N1CCc2nc3cccc([N+](=O)[O-])c3c(C)c2CC1
Agent: Cl
Product: CCOC(=O)N1CCc2nc3cccc(N)c3c(C)c2CC1
Yield: 26 %

Procedure:
10-Amino-1,2,4,5-tetrahydro-11-methyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester was prepared by reducing the corresponding 10-nitro compound (see Example 91) with tin-II-chloride in concentrated hydrochloric acid.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:15])[CH:11]=2)[N:6]=[C:5]1Cl.[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][NH2:21].C(O)C>CC(N(C)C)=O>[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][N:21]1[C:5]2=[N:6][C:7]3[C:12]([C:13](=[O:14])[N:4]2[CH2:3][CH2:2]1)=[CH:11][C:10]([Cl:15])=[CH:9][CH:8]=3
Reactant: O=c1c2cc(Cl)ccc2nc(Cl)n1CCCl
Reactant: NCc1ccccc1Cl
Solvent: CCO
Solvent: CC(=O)N(C)C
Product: O=c1c2cc(Cl)ccc2nc2n1CCN2Cc1ccccc1Cl

Procedure:
A solution of 1.0 g. of 3-(2-chloroethyl)-2,6-dichloro-3,4-dihydroquinazolin-4-one and 1.5 g. of 2-chlorobenzylamine in 50 ml. of ethanol and 1.0 ml of dimethylacetamide is stirred and heated at reflux for 12 hours. The solvent is removed by evaporation in vacuo and the residue dissolved in methylene chloride, washed with water, treated with charcoal, filtered and concentrated in vacuo to obtain a solid which is recrystallized from methylene chloride/pentane and filtered to obtain 1-(o-chlorobenzyl)-7-chloro-2,3-dihydro-imidazo[2,1-b]quinazolin-5(1H)-one, m.p. 173°-174° C.