Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2/[C:13](=[CH:16]/[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)/[C:14]#[N:15])([O-])=O.[Cl-].[NH4+].C(OCC)C.CCCCCCC>C(O)C.[Zn]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2/[C:13](=[CH:16]/[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)/[C:14]#[N:15]
Reactant: N#C/C(=C\c1cccnc1)c1c[nH]c2ccc([N+](=O)[O-])cc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCCCCCC
Solvent: CCO
Solvent: CCOCC
Product: N#C/C(=C\c1cccnc1)c1c[nH]c2ccc(N)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of (Z)-2-(5-nitro-1H-indol-3-yl)-3-pyridin-3-yl-acrylonitrile (370 mg, 1.27 mmol, 1.0 eq.) in ethanol (40 mL) were added zinc powder (667 mg, 10.2 mmol, 8.0 eq.) and then, ammonium chloride (679 mg, 12.7 mmol, 10.0 eq.). The reaction mixture was stirred at room temperature for 30 minutes and filtered through a celite pad. The filtrate was concentrated under reduced pressure and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and evaporated. The residue was purified by silica gel flash-column chromatography (eluent: CH2Cl2/EtOH, 96/4 to 94/6) to afford, after trituration with diethyl ether, the compound (40) as a orange solid (80 mg, 24%). IR νmax (cm−1): 2216 (νCN), 3340 (νN—H); 1H NMR (DMSO, 500 MHz) δ (ppm): 4.72 (2H, s, aniline H), 6.63 (1H, dd, J6′-7′=8.9 Hz, J6′-4′=2.4 Hz, H6′), 7.19 (1H, d, J7′-6′=8.9 Hz, H7′), 7.22 (1H, d, J4′-6′=2.4 Hz, H4′), 7.54 (1H, dd, J5″-4″=7.9 Hz, J5″-6″=4.8 Hz, H5″), 7.59 (1H, s, H3), 7.61 (1H, s, H2′), 8.29 (1H, d, J4″-5″=7.9 Hz, H4″), 8.57 (1H, d, J6″-5″=4.8 Hz, H6″), 8.93 (1H, s, H2″), 11.37 (1H, s, indolic H); 13C NMR (DMSO, 75.5 MHz) δ (ppm): 103.0 (C4′), 109.3 (C2), 109.9 (C3′), 113.2 (C6′), 113.4 (C7′), 118.5 (C1), 124.2 (C5″), 125.1 (C3a′), 127.1 (C2′), 130.9 (C3), 131.1 (C3″), 131.5 (C7a′), 134.7 (C4″), 143.7 (C5′), 149.8 (C6″), 150.2 (C2″); ESI-MS: m/z 261.1 ([M+H]+); HRESI-MS: m/z 261.1153 (calcd for C16H13N4+, 261.1140).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[C:13]2[C:14](=[O:30])[N:15]([CH2:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)[CH:16]=[CH:17][C:12]=2[S:11][CH:10]=1.B(Br)(Br)Br.[OH-].[Na+].C(Cl)[Cl:38]>>[ClH:38].[OH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[C:13]2[C:14](=[O:30])[N:15]([CH2:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)[CH:16]=[CH:17][C:12]=2[S:11][CH:10]=1
Reactant: COc1cnccc1-c1csc2ccn(CCc3ccc4ccccc4n3)c(=O)c12
Reactant: ClCCl
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Product: Cl
Product: O=c1c2c(-c3ccncc3O)csc2ccn1CCc1ccc2ccccc2n1
Reaction time: 2 h

Procedure:
To 3-(3-methoxypyridin-4-yl)-5-[2-(quinolin-2-yl)ethyl]thieno[3,2-c]pyridin-4(5H)-one (50.0 mg, 0.121 mmol) in DCM (20 mL) was added 1M BBr3 in DCM (0.363 mmol, 91 mg). The reaction mixture was stirred for 2 h under nitrogen. The reaction mixture was poured onto water and basified with 1N NaOH, extracted with DCM and dried. The organic phase was concentrated to dryness and the residue was purified by column chromatography (normal phase) on silica using DCM/methanol to give the title compound (13 mg, 0.030 mmol).
Reaction SMILES: C(N(CC)CC)C.[NH:8]=[C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:11]=[CH:10]1.[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23].O>C(Cl)Cl>[C:21]([N:8]=[C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:11]=[CH:10]1)(=[O:25])[C:22]([CH3:24])=[CH2:23]
Reactant: N=c1ccn(-c2ccccc2)nc1
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C=C(C)C(=O)N=c1ccn(-c2ccccc2)nc1
Reaction time: 2 h
Yield: 21 %

Procedure:
24.0 g (237 millimoles) of triethylamine were added dropwise to 15.0 g (72.2 millimoles) of 1,4-dihydro-4-imino-1-phenylpyridazine hydrochloricde and 12.8 g (~98 millimols) of ~80% strength methacryloyl chloride in 200 ml of methylene chloride at room temperature, while stirring. After the addition was complete, stirring was continued for a further 2 hours at room temperature, after which water was added to the reaction mixture. The organic phase was separated off, washed with water and evaporated down. The residue was recrystallized three times from toluene. 3.6 g (21% of theory) of 1,4-dihydro-4-methacryloylimino-1-phenylpyridazine were isolated as yellow crystals of melting point 136° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7]O.[H-].[Na+].[CH3:11][O:12][C:13]([C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][N:16]1[C:21](Cl)=[O:22])=[O:14].C1C[O:27]CC1>>[CH3:11][O:12][C:13]([C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][N:16]1[C:21]([O:22][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:27])=[O:14]
Reactant: OCc1ccccn1
Reactant: COC(=O)[C@@H]1CCCCN1C(=O)Cl
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)[C@@H]1CCCCN1C(=O)OCc1ccccn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
To a solution of 2-pyridylcarbinol (209 □L, 2.17 mmol) and dry THF (10 mL) at 0° C. under an atmosphere of nitrogen was added NaH (60% dispersion in mineral oil, 87 mg, 2.17 mmol), and the reaction mixture was stirred at 0° C. for 30 mins. This mixture was then added dropwise to a solution of (S)-1-(chlorocarbonyl)-2-piperidinecarboxylic acid methyl ester (EP 75737) (425 mg, 2.06 mmol) and dry THF (10 mL) at 0° C. The reaction mixture was allowed to stir for 1.5 h while warming to room temperature, then poured onto aq.KHSO3 (25 mL ) and extracted with EtOAc (2×50 mL). The combined organic phases were washed with aq.NaHCO3, followed by brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (30% ethyl acetate in hexane) to give the title compound as a colorless oil (340 mg, 59%): 1H NMR (400 MHz, CDCl3) δ 1.3–1.8 (5H, m), 2.3 (1H, bs), 3.0 (0.5H, t, J 12.0 Hz), 3.1 (0.5H, t, J 12.0 Hz), 3.9 (3H, s), 4.2 (1H, m), 5.0 (1H, m), 5.3 (2H, dd, J 14.0 Hz), 7.2–7.4 (2H, m), 7.7 (1H, m), 8.6 (1H, m)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]([NH2:11])[S:9][C:8]2=[CH:12][CH:13]=[CH:14][C:7]=12)=[O:5])[CH3:2].N1C=CC=CC=1.CO[C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1OC)[C:26](Cl)=[O:27].[CH2:34]([Cl:36])Cl>>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH2:14][CH2:13][CH2:12][C:8]=2[S:9][C:10]=1[NH:11][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[C:23]([CH2:34][Cl:36])[CH:24]=1)=[O:5])[CH3:2]
Reactant: ClCCl
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: CCOC(=O)C1=C2C=CC=C2SC1N
Solvent: c1ccncc1
Product: CCOC(=O)c1c(NC(=O)c2cccc(CCl)c2)sc2c1CCC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethyl-2-aminocyclopenta(B)thiophene-3-carboxylate (compound A) (1.0 g) was dissolved in anhydrous methylene chloride (20.0 ml). Subsequently, pyridine (760 μl) and 3-(chloromethyl)benzoyl chloride (compound B) (880 μl) were added to the solution at 0° C., and the mixture was stirred at 0° C. for one hr. After the completion of the reaction, distilled water was added thereto, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated to give 2-(3-chloromethyl-benzoylamino)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylic acid ethyl ester as a useful intermediate (800 mg, crude yield 100%).
Reaction SMILES: [CH2:1]([N:8]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:32][NH:33][O:34][CH3:35].N1C2C(=NC=CC=2)N(O)N=1.C1(N=C=NC2CCCCC2)CCCCC1>CCOCC.CCCCCC.CN(C=O)C>[CH2:1]([N:8]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=1)[C:10]([N:33]([O:34][CH3:35])[CH3:32])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNOC
Reactant: O=C(O)[C@H](Cc1ccc(C(F)(F)F)cc1)N(Cc1ccccc1)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CON(C)C(=O)[C@H](Cc1ccc(C(F)(F)F)cc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.3 %

Procedure:
To a 250 mL round bottom flask was added crude (S)-2-(dibenzylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid, DMF (700 mL), N,O-dimethylhydroxylamine hydrochloride (25.3 g, 259 mmol), TEA (36.0 mL, 259 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (17.6 g, 130 mmol), and 1,3-dicyclohexylcarbodiimide (26.7 g, 130 mmol) at 0° C. The mixture was allowed to warm to room temperature. After 18 hours, the mixture was diluted with 1 L ether, and the precipitate was filtered through a coarse scintered glass funnel washing with ether. The filtrate was washed with brine (4×200 mL) and the organic layer was again passed through a coarse scintered glass funnel. The aqueous layer was extracted with ether (200 mL), and the combined ether layers were washed with brine (100 mL) and passed through a coarse scintered glass funnel. The organic layers were dried over sodium sulfate and evaporated providing a cloudy yellow oil. The oil was passed through a medium scintered glass funnel washing with ether, and the filtrate was evaporated to provide a clear yellow oil. The crude product was loaded onto a 1.5 kg silica gel column in hexane and eluted at 400 mL/minute 0% to 70% EtOAc in hexane to provide (S)-2-(dibenzylamino)-N-methoxy-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide (26.52 g, 67.3% yield) as a light yellow oil. LCMS (ES+) m/z=457.3 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.50 (dt, J=3.67, 1.79 Hz, 3H) 3.09-3.19 (m, 3H) 3.31 (s, 3H) 3.68-3.76 (m, 2H) 3.77-3.85 (m, 2H) 7.16-7.34 (m, 12H) 7.63 (d, J=8.22 Hz, 2H).
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.[N+:24]([C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30]Cl)([O-:26])=[O:25].[K+].[Br-]>>[OH:1][CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[N:15]([CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([N+:24]([O-:26])=[O:25])[CH:28]=2)[C:14]2[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:13]=2[O:12]1
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Reactant: COc1ccc2c(c1)OC(CCO[Si](C)(C)C(C)(C)C)C(=O)N2
Agent: [Br-]
Agent: [K+]
Product: COc1ccc2c(c1)OC(CCO)C(=O)N2Cc1cccc([N+](=O)[O-])c1
Yield: 30 %

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-7-methoxy-3-oxo-2H-1,4-benzoxazine by methods F and I, alkylating with 3-nitrobenzyl chloride, in 30% yield, mp 116°-118° C.; MS (Cl) MH+ 359; IR (KBr) 3306, 3086, 2926, 2872, 1628, 1595, 1476, 1309, 1290, 1255, 1087, 999, 713, 458 cm-1 ; 1H NMR (DMSO-d6) δ 8.14 (s, 1H), 8.11 (s, 1H), 7.63 (m, 2H), 6.97 (d, 1H, J=8.93 Hz), 6.66 (d, 1H, J=2.42 Hz), 6.53 (d, 1H, J=8.87 Hz), 5.26 (s, 2H), 4.87 (dd, 1H, J=8.98, 3.78 Hz), 4.72 (t, 1H, J=5.23 Hz), 3.68 (s, 3H), 3.61 (m, 2H), 2.01 (m, 1H), 1.90 (m, 1H). Anal. Calc'd for C18H18N2O6 : C 60.33 H 5.06, N 7.82. Found: C 59.96, H 5.08, N 7.62.
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[N+:29]([C:32]1[CH:37]=[CH:36][C:35]([N:38]2[C:42]([C:43]([F:46])([F:45])[F:44])=[C:41]([C:47](Cl)=[O:48])[CH:40]=[N:39]2)=[CH:34][CH:33]=1)([O-:31])=[O:30]>>[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@H:2]([NH:1][C:47]([C:41]3[CH:40]=[N:39][N:38]([C:35]4[CH:36]=[CH:37][C:32]([N+:29]([O-:31])=[O:30])=[CH:33][CH:34]=4)[C:42]=3[C:43]([F:44])([F:45])[F:46])=[O:48])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=1)(=[O:22])[CH:19]([CH3:21])[CH3:20]
Reactant: O=C(Cl)c1cnn(-c2ccc([N+](=O)[O-])cc2)c1C(F)(F)F
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)c3cnn(-c4ccc([N+](=O)[O-])cc4)c3C(F)(F)F)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-(4-nitrophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride: ESMS m/e: 663.2 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8](O)=[O:9])([CH3:4])([CH3:3])[CH3:2].ClCCl.S(Cl)(Cl)=O.[CH3:26][NH:27][CH3:28]>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([N:27]([CH3:28])[CH3:26])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: CNC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 3 h

Procedure:
To a stirred solution of 25 g. (0.1 mole) of 3,5-di(t-butyl)-4-hydroxybenzoic acid in 200 ml. of dichloromethane is added 1 ml. of N,N-dimethylformamide and 0.11 mole of thionyl chloride. The mixture is heated at its reflux temperature for 40 minutes, then 0.1 mole of aqueous dimethylamine is added dropwise. The mixture is stirred for three hours and extracted twice with dichloromethane. The dichloromethane extracts are dried then evaporated to provide a residue which is recrystallized from a benzene-hexane mixture. The while solid is dissolved in dichloromethane, washed twice with 10 percent sodium hydroxide solution, then the dichloromethane layer is evaporated under vacuum. The product is recrystallized twice from a benzene-hexane mixture to provide 3,5-di(t-butyl)-4-hydroxy-N,N-dimethylbenzamide, m.p. 173°-174.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:11][OH:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:13](Cl)(=[O:15])[CH3:14].C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:11][O:12][C:13](=[O:15])[CH3:14])[CH3:10])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H](C)NC(=O)OC(C)(C)C
Yield: 70 %

Procedure:
N-(tert-Butoxycarbonyl)-L-alaninol (438 mg, 2.5 mmol) was dissolved in 5 mL of methylene chloride in an ice bath and acetyl chloride (0.294 mL, 3.75 mmol), followed by triethylamine (0.7 mL, 5 mmol) were added. It was then reacted at 0° C. for 1 hour and at room temperature for 2 days. The mixture was diluted with 25 mL of ethyl acetate and the organic layer was washed with 10%-sodium hydrogen carbonate (3x), brine (2x), dried over magnesium sulfate anhydrous, and then evaporated to dryness to yield 380 mg of N-(tert-butoxycarbonyl)-O-acetyl-L-alaninol.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=O.[NH2:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1.C(Cl)CCl>C1(C)C(C)=CC=CC=1>[OH:11][C:10]1[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7](=[O:21])(=[O:20])[N:6]([CH3:22])[C:5]=1[C:3]([NH:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1)=[O:2])=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Reactant: Nc1nccs1
Solvent: Cc1ccccc1C
Solvent: ClCCCl
Product: CN1C(C(=O)Nc2nccs2)=C(O)c2ccc3ccccc3c2S1(=O)=O
Yield: 56.2 %

Procedure:
19.8 gm (0.062 mol) of 4-hydroxy-2-methyl-2H-naphtho [2,1-e]-1,2-thiazine-3-carboxylic acid methyl ester-1,1-dioxide were reacted with 9.3 gm (0.093 mol) of 2-amino-thiazole in 500 ml of xylene analogous to Example 1 and yielded 13.5 gm (56% of theory) of 4-hydroxy-2-methyl-N-(2thiazolyl)-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide, m.p. 248°-249° C (decomp.; from ethylene chloride).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[N:17]1[S:18][CH:19]=[C:20]2[C:25]([CH:26]=O)=[CH:24][CH:23]=[CH:22][C:21]=12.O>O1CCCC1>[N:17]1[S:18][CH:19]=[C:20]2[C:25](/[CH:26]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:24][CH:23]=[CH:22][C:21]=12
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1cccc2nscc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1cccc2nscc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 380.3 %

Procedure:
Under nitrogen atmosphere, to a suspension of sodium hydride (60%, 1.16 g, 26.6 mmol) in tetrahydrofuran (30 mL) was added a solution of ethyl diethylphosphonoacetate (4.83 mL, 5.41 mmol) in tetrahydrofuran (10 mL) at 0° C., and the mixture was stirred for 20 min. To the reaction mixture was added a solution of 2,1-benzisothiazole-4-carbaldehyde (3.94 g, 24.1 mmol) in tetrahydrofuran (8.3 mL), and the mixture was warmed to room temperature over 4 hr. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80) to give the title compound (4.80 g, yield 85%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([CH3:24])[N:18]([C:25]1[C:26]([CH3:31])=[N:27][CH:28]=[CH:29][CH:30]=1)[C:17]2=[O:32].[C:33]([C:35]1[CH:44]=[CH:43][CH:42]=[CH:41][C:36]=1[C:37]([O:39][CH3:40])=[O:38])#[N:34]>O1CCCC1>[C:33]([C:35]1[CH:44]=[CH:43][CH:42]=[CH:41][C:36]=1[C:37]([O:39][CH3:40])=[O:38])#[N:34].[F:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([CH:24]=[C:37]([C:36]1[CH:41]=[CH:42][CH:43]=[CH:44][C:35]=1[C:33]#[N:34])[OH:38])[N:18]([C:25]1[C:26]([CH3:31])=[N:27][CH:28]=[CH:29][CH:30]=1)[C:17]2=[O:32]
Reactant: Cc1ncccc1-n1c(C)nc2ccc(F)cc2c1=O
Agent: COC(=O)c1ccccc1C#N
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1ncccc1-n1c(C=C(O)c2ccccc2C#N)nc2ccc(F)cc2c1=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 10 %

Procedure:
A solution of diisopropylamine (0.046 mL, 0.47 mmol) in tetrahydrofuran (2.7 mL) was chilled to -78° C. and butyllithium (0.13 mL, 0.32 mmol, 2.5 N in hexanes) was added dropwise. The solution was stirred 10 minutes and then a solution 6-fluoro-2-methyl-3-(2-methyl-pyridin-3-yl)-3H-quinazolin-4-one (0.10 g, 0.37 mmol) in tetrahydrofuran (0.7 mL) was added dropwise. The solution became intense red and was stirred 30 minutes. In a separate vessel a solution of methyl 2-cyanobenzoate (0.50 g, 3.1 mmol) in tetrahydrofuran (10 mL) was prepared and chilled to -78° C. The cold red anion solution was added to the cold methyl 2-cyanobenzoate solution via canula over 30 seconds. The resulting mixture was stirred 30 minutes at -78° C. and then quenched with saturated aqueous bicarbonate and warmed to ambient temperature. The mixture was diluted with water and repeatedly extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over magnesium sulfate and concentrated. The residue was flash chromatographed on silica gel (20×100 mm) with elution proceeding as follows: 10% ethyl acetate/hexane (50 mL), nil; 20% ethyl acetate/hexane (50 mL), unweighedrecovered 3-(2-methyl-pyridin-3-yl)-6-fluoro-2-methyl-3H-quinazolin-4-one; 30% ethyl acetate/hexane (50 mL), nil; 40% ethyl acetate/hexane (50 mL), unweighed recovered methyl 2-cyanobenzoate; 50% ethyl acetate/hexane (50 mL), unweighed impurity; 60% ethyl acetate/hexane (50 mL), mixture of impurity and desired product; 70% ethyl acetate/hexane (50 mL), product. The product containing fractions were combined and concentrated. The residue was triturated with 1% ethyl acetate/ether and the yellow solid which formed was collected and dried to yield 0.017 g (10%) of 2-{2-[6-fluoro-3-(2-methyl-pyridin-3-yl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-1-hydroxy-vinyl}-benzonitrile which had: mp 213-215° C.; 1H NMR δ8.70 (d, J=4 Hz, 1 H), 7.85 (dd, J=3, 8 Hz, 1 H), 7.67 (d, J=7 Hz, 1 H), 7.60 (d, J=9 Hz, 1 H), 7.58-7.38 (m, 6 H), 4.94 (s, 1 H), 2.44 (s, 3 H). Analysis calculated for C23H15FN4O2.0.25 H2O: C, 68.57; H, 3.88; N, 13.91. Found: C, 68.52, 68,91; H, 4.13, 4.21; N, 13.25, 13.28.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[O:25][CH2:26][CH2:27][S:28][CH3:29])(=[O:5])[CH2:2][CH2:3][CH3:4].[OH2:30].Cl[O-].[Na+]>C(Cl)Cl>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[O:25][CH2:26][CH2:27][S:28]([CH3:29])=[O:30])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O
Reactant: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1ccccc1OC
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: CCCC(=O)c1cnc2c(OCCS(C)=O)cccc2c1Nc1ccccc1OC
Reaction time: 2 h
Yield: 88 %

Procedure:
3-butyryl-4-(2-methoxyphenylamino)-8-(2-methylthioethoxy)quinoline (0.35 g, 0.85 mmol) was dissolved in methylene chloride (4 ml). Water (2 ml) and sodium hypochlorite (5% in water) (1.42 ml) were added and the mixture was stirred for 2 h. Another portion of sodium hypochlorite (0.5 ml) was added and the stirring was continued for 2 h. The organic layer was dried over sodium sulfate and evaporated. The residue crystallized from a mixture of ethyl acetate and isopropyl ether and 0.32 g (88%) of the title compound was obtained.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[NH:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([CH2:26][CH3:27])[C:15]3[C:20]([C:21]=2[C:22]#[N:23])=[CH:19][CH:18]=[C:17]([O:24][CH3:25])[CH:16]=3)=[CH:9][CH:8]=1.[C:29](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.O>[CH2:26]([N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[C:17]([O:24][CH3:25])[CH:16]=2)[C:21]([C:22]#[N:23])=[C:13]1[C:10]1[CH:9]=[CH:8][C:7]([N:3]2[CH2:4][CH2:5][N:6]([CH3:29])[S:2]2(=[O:1])=[O:28])=[CH:12][CH:11]=1)[CH3:27]
Reactant: CCn1c(-c2ccc(N3CCNS3(=O)=O)cc2)c(C#N)c2ccc(OC)cc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(-c2ccc(N3CCN(C)S3(=O)=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-[4-(1,1-dioxo-1λ6-[1,2,5]thiadiazolidin-2-yl)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (34 mg, 0.086 mmol) in anhydrous DMF (1.0 mL) is added potassium carbonate (25 mg, 0.18 mmol) and iodomethane (20.4 mg, 0.144 mmol). The mixture is stirred at room temperature for 2 h and then diluted with water (6.0 mL) to give a precipitate. The precipitate is filtered, washed with water and dried to give 1-ethyl-6-methoxy-2-[4-(5-methyl-1,1-dioxo-1λ6-[1,2,5]thiadiazolidin-2-yl)-phenyl]-1H-indole-3-carbonitrile, compound 726, as a white solid (35 mg, 98% yield).
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11][C:12]#[N:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)[Cl:15].ClCl.[ClH:20]>N1C=CC=CC=1.P(Cl)(Cl)Cl.O>[Cl:20][C:11](=[C:10]([Cl:15])[S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:8])=[O:9])[C:12]#[N:13]
Reactant: Cl
Reactant: N#CCCS(=O)(=O)c1ccccc1
Reactant: ClP(Cl)Cl
Agent: ClCl
Solvent: c1ccncc1
Solvent: O
Product: N#CC(Cl)=C(Cl)S(=O)(=O)c1ccccc1
Reaction time: 5 h
Yield: 87 %

Procedure:
195 g (1 mol) of 3-phenylsulphonyl-propionitrile were melted at 100° C. in a 500 ml four-necked flask and 14 g of PCl3 and 4.2 g of pyridine were added as catalysts. 150 g (2.1 mols) of chlorine at 100° to 90° C. were then introduced during the course of 9 hours. 7 g of PCl3 and 2 g of pyridine were then added once more, and 160 g (2.25 mols) of chlorine was again introduced at 80° C. during the course of 12 hours, a part of the chlorine being entrained with the escaping HCl gas. 200 ml of water were now added dropwise at 20° C., whilst cooling. The phases were separated at 90° C. and the washing operation was repeated with 200 ml of water. In order to eliminate benzenesulphonyl chloride, the mixture was now boiled for 5 hours with 200 ml of water, and the organic phase was separated off and dried in vacuo. 227 g (87%) of a dark brown crude oil was obtained, which solidified on standing overnight. After warming the solid and dissolving it in 50 ml of ethanol, cooling the solution with ice and filtering off the precipitate under suction, 135 g (51%) of pale crystals, melting point 72° C., were obtained.