Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:4]([NH2:7])(=[O:6])=[O:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:19]([O:18][C:16](=[O:17])[NH:7][S:4]([CH:1]1[CH2:3][CH2:2]1)(=[O:6])=[O:5])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NS(=O)(=O)C1CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NS(=O)(=O)C1CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of cyclopropanesulfonamide (6.51 g, triethylamine (40 mL) and DMAP (0.656 g) in DCM (150 mL) was slowly added benzyl chloroformate (12 mL). The mixture was stirred at room temperature for 18 hours. The mixture was washed with 1 N HCl. The aqueous layer (pH 1) was extracted with EtOAc (×2). The combined organics were washed with brine, dried over anhydrous MgSO4 and concentrated. The resulting residue was purified by flash chromatography (ISCO, 0-10% methanol in dichloromethane) to afford the desired product (7.8 g). 1H NMR (400 MHz, CDCl3): δ (ppm) 7.56-7.44 (m, 1H), 7.38 (s, 5H), 5.22 (s, 2H), 2.92-2.84 (m, 1H), 1.40-1.35 (m, 2H), 1.12-1.06 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25][CH:26]=[C:27]([CH3:32])[C:28](=[O:31])[CH:29]=[CH2:30].B(F)(F)F.CCOCC>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25][C:26]1[CH2:30][CH2:29][C:28](=[O:31])[C:27]=1[CH3:32]
Reactant: C=CC(=O)C(C)=CCc1c(OC)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2
Agent: FB(F)F
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: ClCCl
Product: COc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1CC1=C(C)C(=O)CC1)C(=O)OC2
Reaction time: 0.5 h

Procedure:
The solid product prepared in Example ZC-1C, 6-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy-5-isobenzofuranyl)-4-methylhexa-1,4-dien-3-one was dissolved in methylene chloride (15 mL) and treated with boron trifluoride etherate (0.5 mL). After 0.5 hours, the reaction was diluted with ethyl acetate and washed with brine, then dried over magnesium sulfate. Filtration, solvent removal and chromatography (silica gel, hexanes/methylene chloride/ether, 4/4/2) gave the product, 3-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy-5 -isobenzofuranylmethyl)-2-methylcyclopent-2-en-1-one (0.18 g) as a colorless solid m.p. 65.4-66.8
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[C:10]([CH3:14])[NH:11]2)=[CH:7][CH:6]=1)=[O:4].[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:13]=2)[CH:9]=[C:10]1[CH3:14]
Reactant: Clc1ccccc1CBr
Reactant: COC(=O)c1ccc2cc(C)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2cc(C)n(Cc3ccccc3Cl)c2c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 44.7 %

Procedure:
A mixture of 6-methoxycarbonyl-2-methylindole (0.89 g), 2-chlorobenzyl bromide (1.45 g), potassium carbonate (0.780 g) and N,N-dimethylformamide (2 ml) is stirred at 80° C. for 18 hours. The solvent is evaporated away under reduced pressure, and the resulting residue is purified through silica gel column chromatography (eluent: hexane/chloroform=3/1) to obtain 1-(2-chlorobenzyl)-6-methoxycarbonyl-2-methylindole (30) (0.660 g).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[CH3:10].[C:11](=O)=[O:12].CC(C)=O.C([Li])CCC.CN(C=O)C>C1COCC1>[Cl:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([CH:11]=[O:12])=[C:3]([CH3:10])[CH:4]=1
Reactant: O=C=O
Reactant: Cc1cc(Cl)cc(C)c1Br
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: Cc1cc(Cl)cc(C)c1C=O
Reaction time: 2 h

Procedure:
Dissolve 4-bromo-3,5-dimethyl chlorobenzene (6.5 g) in 50 mL anhydrous THF and cool to −78° C. (dry ice/acetone) under N2. Dropwise over 5 min add a solution of butyllithium (12.50 mL, 2.5M in hexanes) to the stirring solution of aryl bromide at −78° C. After 2 h, dropwise add anhydrous DMF (5.0 mL) to the orange/red reaction solution and allow to warn to ambient temperature overnight while stirring under N2. Evaporate the yellow solution down to a yellow oil and partition between H2O (100 mL) and CH2Cl2 (100 mL). Extract the aqueous layer once with CH2Cl2, then pool the organic layers and dry over Na2SO4, filter and evaporate down to 5.0 g of yellow oil. Use without further purification. LCMS=169.6 (MH+).
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)[CH3:3].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([Mg]Br)=[CH:15][CH:14]=1>C1COCC1>[NH2:9][CH:8]([C:16]1[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=1)[C:7]1[CH:10]=[CH:11][C:4]([CH:2]([OH:1])[CH3:3])=[CH:5][CH:6]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CC(O)c1ccc(C#N)cc1
Solvent: C1CCOC1
Product: CC(O)c1ccc(C(N)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The product of Step A (1.47 g, 10 mmol) was dissolved in THF (20 mL), cooled in an ice-bath and 4-chlorophenylmagnesium bromide (21.00 mL, 21.00 mmol, 1 M in THF) was added. The reaction aged at 50° C. for 4 h and then cooled to rt overnight. The solvent had evaporated overnight and the product was taken up in 2-methyltetrhydrofuran (20 mL) and an additional 1 eq of 4-chlorophenylmagnesium bromide was added. The reaction aged at rt for 3 h and was concentrated. The reaction was diluted with 15 mL MeOH. NaBH (378 mg, 10.00 mmol) was added and the reaction aged for 1 h. The reaction was concentrated, diluted with 2M HCl (aq) and extracted with EtOAc. The organic layer was collected, dried with Na2SO4, filtered and concentrated. The residue was purified somewhat by flash chromatography on silica gel gradient eluted with 0-10% MeOH/EtOAc affording title compound. HPLC/MS: 244.9 (M—NH2)+; Rt=2.09 min
Reaction SMILES: [Na].[CH2:2]([O:4][C:5](=[O:13])[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:3].[CH2:14]([O:16]C=O)C.O>C(OCC)C>[CH2:2]([O:4][C:5](=[O:13])[CH:6]([CH:14]=[O:16])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:3]
Reactant: CCOC(=O)CCC(=O)OCC
Reactant: CCOC=O
Agent: [Na]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)CC(C=O)C(=O)OCC
Temperature: 40 °C
Reaction time: 5 h
Yield: 107.2 %

Procedure:
To a suspension of sodium (333 mg, 14 mmol, 1.2 eq) in diethyl ether (7 mL) were added succinic acid diethyl ester (2.1 g, 12 mmol, 1 eq) and formic acid ethyl ester (1.7 mL, 20 mmol, 1.7 eq). The mixture was stirred at 40° C. for 5 h. Water (10 mL) was added and the aqueous layer was washed with diethyl ether (2×10 mL). The aqueous layer was then acidified with a 6N solution of hydrochloric acid and extracted with diethyl ether (3×10 mL). The organic layers were dried over magnesium sulfate, filtered and evaporated in vacuo to afford the expected compound as orange oil (2.6 g, quant. yield).
Reaction SMILES: [C:1]1([C:7]([NH:9][CH:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][N:12]([C:26](OC3C=CC([N+]([O-])=O)=CC=3)=[O:27])[CH2:11]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:38]1[CH2:43][CH2:42][CH:41]([OH:44])[CH2:40][CH2:39]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:44][CH:41]1[CH2:42][CH2:43][N:38]([C:26]([N:12]2[CH2:13][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:20][CH:21]=3)[CH2:15][CH:10]([NH:9][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:8])[CH2:11]2)=[O:27])[CH2:39][CH2:40]1
Reactant: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1)c1ccccc1

Procedure:
80 mg (0.16 mmol) of 4-nitrophenyl 3-[(phenylcarbonyl)amino]-5-[4-(trifluoromethyl)phenyl]piperidine-1-carboxylate were initially charged in 1.7 ml of DMF, and 47 mg (0.47 mmol) of piperidin-4-ol and 22 mg (0.16 mmol) of potassium carbonate were added. The mixture was reacted in a microwave (Emrys Optimizer) at 150° C. for 15 min. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 62 mg (83% of theory)
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[F:17][C:18]([F:32])([F:31])[C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([N+:28]([O-:30])=[O:29])[CH:22]=1)=O.O>C1COCC1.CN(C=O)C>[F:32][C:18]([F:17])([F:31])[C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([N+:28]([O-:30])=[O:29])[CH:22]=1)=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C=C(c1ccc(F)c([N+](=O)[O-])c1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
10.9 g (48.5 mmol) of ethyl diethylphosphonoacetate were slowly added dropwise to an ice-cooled suspension of 1.86 g (60% in mineral oil, 46.4 mmol) of sodium hydride in a mixture of 70 ml of THF and 20 ml of DMF. After the addition had ended, the mixture was stirred at 0° C. for another 30 min, and 10.0 g (42.2 mmol) of 2,2,2-trifluoro-1-(4-fluoro-3-nitrophenyl) ethanone were then added. The reaction mixture was stirred at RT overnight and then added to water. The mixture was extracted three times with ethyl acetate, and the combined organic phases were concentrated under reduced pressure. The crude product gave, after chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 20:1 to 10:1), 9.23 g of the target product (71.2% of theory).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[O:6][C@H:5]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([N+:18]([O-])=O)=[C:14]([F:17])[CH:15]=3)[CH:10]=[C:9]2[C:21]([CH3:25])([CH3:24])[CH2:22][OH:23])[CH2:4][O:3]1>C(O)C>[NH2:18][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][C:14]=1[F:17])[N:8]([CH2:7][C@@H:5]1[CH2:4][O:3][C:2]([CH3:1])([CH3:26])[O:6]1)[C:9]([C:21]([CH3:25])([CH3:24])[CH2:22][OH:23])=[CH:10]2
Reactant: CC1(C)OC[C@@H](Cn2c(C(C)(C)CO)cc3cc([N+](=O)[O-])c(F)cc32)O1
Solvent: CCO
Product: CC1(C)OC[C@@H](Cn2c(C(C)(C)CO)cc3cc(N)c(F)cc32)O1
Reaction time: 2.5 h
Yield: 79.3 %

Procedure:
(R)-2-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropan-1-ol (2.5 g, 6.82 mmol) was dissolved ethanol (70 mL) and the reaction was flushed with N2. Then Pd—C (250 mg, 5% wt) was added. The reaction was flushed with nitrogen again and then stirred under H2 (atm). After 2.5 hours only partial conversion to the product was observed by LCMS. The reaction was filtered through Celite and concentrated. The residue was re-subjected to the conditions above. After 2 hours LCMS indicated complete conversion to product. The reaction mixture was filtered through Celite. The filtrate was concentrated to yield the product as a black solid (1.82 g, 79%). ESI-MS m/z calc. 336.2. found 337.5 (M+1)+. Retention time 0.86 minutes. 1H NMR (400 MHz, DMSO-d6) δ 7.17 (d, J=12.6 Hz, 1H), 6.76 (d, J=9.0 Hz, 1H), 6.03 (s, 1H), 4.79-4.76 (m, 1H), 4.46 (s, 2H), 4.37-4.31 (m, 3H), 4.06 (dd, J=6.1, 8.3 Hz, 1H), 3.70-3.67 (m, 1H), 3.55-3.52 (m, 2H), 1.41 (s, 3H), 1.32 (s, 6H) and 1.21 (s, 3H) ppm.
Reaction SMILES: [C:1]([NH:9][C@@H:10]([CH:45]([CH3:47])[CH3:46])[C:11]([N:13]([CH2:38][C:39]1[CH:44]=C[CH:42]=[CH:41][CH:40]=1)[CH2:14][C:15]([NH:17][C@H:18]([C:23]([C:25]1[O:26]C=C(C2C(Cl)=CC=CC=2Cl)[N:29]=1)=[O:24])[CH2:19][C:20]([OH:22])=[O:21])=[O:16])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:48]1C=CC=C(C=O)C=1.C(OC(=O)CNCC1C=CC=CC=1)C.C(OC(=O)C(N)[C@H](C(OCC=C)=O)C(C1O[C:82]2[CH:88]=[C:87]([Cl:89])[CH:86]=[C:85]([Cl:90])[C:83]=2N=1)O)(C)(C)C.C(OC(=O)C[C@H](NC(=O)CN(C(=O)[C@@H](NC(=O)C1C=CC=CC=1)C(C)C)CC1C=CC=CC=1)C(C1OC=C(C2C(Cl)=CC=CC=2Cl)N=1)O)(C)(C)C>>[C:1]([NH:9][C@@H:10]([CH:45]([CH3:46])[CH3:47])[C:11]([N:13]([CH2:38][C:39]1[CH:44]=[N:48][CH:42]=[CH:41][CH:40]=1)[CH2:14][C:15]([NH:17][C@H:18]([C:23]([C:25]1[O:26][C:82]2[CH:88]=[C:87]([Cl:89])[CH:86]=[C:85]([Cl:90])[C:83]=2[N:29]=1)=[O:24])[CH2:19][C:20]([OH:22])=[O:21])=[O:16])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)N[C@@H](CC(=O)O)C(=O)c1nc(-c2c(Cl)cccc2Cl)co1)Cc1ccccc1
Reactant: O=Cc1cccnc1
Reactant: C=CCOC(=O)[C@@H](C(N)C(=O)OC(C)(C)C)C(O)c1nc2c(Cl)cc(Cl)cc2o1
Agent: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)N[C@@H](CC(=O)OC(C)(C)C)C(O)c1nc(-c2c(Cl)cccc2Cl)co1)Cc1ccccc1
Agent: CCOC(=O)CNCc1ccccc1
Product: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)N[C@@H](CC(=O)O)C(=O)c1nc2c(Cl)cc(Cl)cc2o1)Cc1cccnc1

Procedure:
Compound 720 was prepared by a method similar to the method used to prepare compound 710, except replacing benzaldehyde with 3-pyridinecarboxaldehyde in the preparation of 701 and replacing compound 707 with compound 718 in the preparation of 708: 1H NMR (500 MHz, CD3OD) δ 8.88-8.44 (m), 8.42-8.20 (m), 7.91-7.58 (m), 7.55-7.30 (m), 5.51 (m), 4.72-4.11 (m), 3.92-3.52 (m), 3.26-2.92 (m), 2.72-2.51 (m), 2.32-1.91 (m), 1.46-1.21 (m), 1.11-0.68 (m). ##STR99##
Reaction SMILES: [C:1]([C:3]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[C:12]([C:21]([NH:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[O:22])[C:13](=[O:20])[N:14]3[C:19]=2[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH2:5][CH2:4]1)#[N:2].C(N(CC)CC)C.Cl[C:44]([O:46][CH3:47])=[O:45]>ClCCl>[C:1]([C:3]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[C:12]([C:21]([NH:23][CH:24]3[CH2:29][CH2:28][N:27]([C:44]([O:46][CH3:47])=[O:45])[CH2:26][CH2:25]3)=[O:22])[C:13](=[O:20])[N:14]3[C:19]=2[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(c2ccccn2)CCN(Cc2cc(C(=O)NC3CCNCC3)c(=O)n3ccccc23)CC1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CCC(NC(=O)c2cc(CN3CCC(C#N)(c4ccccn4)CC3)c3ccccn3c2=O)CC1
Reaction time: 1 h

Procedure:
To a solution of 1-[(4-cyano-4-pyridin-2-ylpiperidin-1-yl)methyl]-4-oxo-N-piperidin-4-yl-4H-quinolizine-3-carboxamide (0.027 g, 0.057 mmol) in 2 mL of dichloromethane was added triethylamine (0.3 mL, 2.1 mmol) followed by methyl chloroformate (0.10 mL, 1.3 mmol). After 1 h, the mixture was washed with 0.5 N aqueous sodium hydroxide and brine, dried over sodium sulfate, filtered, and concentrated in vacuo to provide the title compound that gave a proton NMR spectra consistent with theory: 1H NMR (400 MHz, CDCl3) δ 9.80 (d, J=7.7 Hz, 1H), 9.40 (d, J=7.3 Hz, 1H), 8.65 (s, 1H), 8.60-8.58 (m, 1H), 8.19 (d, J=8.9 Hz, 1H), 7.76-7.66 (m, 2H), 7.62-7.59 (m, 1H), 7.32-7.23 (m, 2H), 4.24-4.21 (m, 1H), 4.03 (br s, 1H), 3.82 (s, 2H), 3.71 (s, 3H), 3.69-3.61 (m, 2H), 3.15-3.09 (m, 1H), 3.02-2.98 (m, 1H), 2.60-2.57 (m, 1H), 2.55-2.50 (m, 2H), 2.32-2.25 (m, 1H), 2.09-2.02 (m, 2H), 1.93 (br s, 1H), 1.59-1.52 (m, 1H), 1.40-1.37 (m, 2H), 1.06-1.01 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](O)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].CN(C)C=O.S(O[CH2:23][CH3:24])(OCC)=O.S(Cl)([Cl:27])=O>>[Cl:27][C:5]1[N:4]=[CH:3][C:2]([Cl:1])=[CH:10][C:6]=1[C:7]([O:9][CH2:23][CH3:24])=[O:8]
Reactant: O=C(O)c1cc(Cl)cnc1O
Reactant: CCOS(=O)OCC
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Cl)cnc1Cl

Procedure:
5-Chloro-2-hydroxynicotinic acid [11.95 g; Synthetic Comm. (1989), 19, 553] was suspended in thionyl chloride (52 mL) and anhydrous dimethylformamide (2 mL) was added. The suspension was refluxed 3 h, then concentrated under a nitrogen stream to remove the bulk of excess thionyl chloride before adding anhydrous ethanol (30 mL) giving a mixture of the desired ester and diethyl sulfite. The resulting mixture was concentrated in vacuo to remove the ethanol yielding a suspension. The solids were then filtered off and washed with anhydrous diethyl ether (2×10 mL). The combined filtrates were concentrated in vacuo yielding crude product. Purification by silica gel chromatography (ethyl acetate:hexanes 8:92) gave pure title compound (4.75 g).
Reaction SMILES: [N+:1]([C:4]1[O:5][C:6]2[CH:21]=[CH:20][CH:19]=[CH:18][C:7]=2[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][CH:10]=1)([O-:3])=[O:2].[CH2:22]([NH2:25])[CH2:23][CH3:24]>>[CH2:22]([NH:25][C:16]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]2[C:7]3[CH:18]=[CH:19][CH:20]=[CH:21][C:6]=3[O:5][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:10][CH:11]=1)=[O:17])[CH2:23][CH3:24]
Reactant: O=C=Nc1ccc(-c2c([N+](=O)[O-])oc3ccccc23)cc1
Reactant: CCCN
Product: CCCNC(=O)Nc1ccc(-c2c([N+](=O)[O-])oc3ccccc23)cc1

Procedure:
Using the method of Example 5, 4-(2-nitro-3-benzofuranyl)phenyl isocyanate (the product of Example 2) is reacted with n-propylamine to provide 1-(1-propyl)-3-[4-(2-nitro-3-benzofuranyl)phenyl]urea having the structure ##STR11##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[CH2:12][CH2:13][S:14][CH2:15][CH2:16][OH:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:34])C=1>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[CH2:12][CH2:13][S:14]([CH2:15][CH2:16][OH:17])=[O:34])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(CCSCCO)c1cc(F)ccc1F
Solvent: ClCCl
Product: O=S(CCO)CCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 75 %

Procedure:
The 2-[3-[(4-chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propylthio]ethanol (65 mg, 0.16 mmol) obtained in Example 250 was dissolved in dichloromethane (5 ml), followed by the addition of 3-chloroperbenzoic acid (33 mg, 0.19 mmol) under ice cooling. The resulting mixture was stirred at room temperature for 14 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was subjected to flash silica gel chromatography, and the fraction obtained from the dichloromethane:methanol=30:1 eluate was concentrated under reduced pressure to give a white solid. The white solid was washed with diethyl ether, whereby the title, compound (50 mg, 0.12 mmol, 74%) was obtained as a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:19][C@H:18]2[NH:28]C(=O)OCC[Si](C)(C)C)[C:13]1=[O:38])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:28][C@@H:18]1[CH2:19][C@H:20]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:21][CH2:22][C@@H:17]1[N:14]1[CH2:15][CH2:16][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:13]1=[O:38]
Reactant: CC(C)(C)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](NC(=O)OCC[Si](C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](N)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
A stirring solution of 2-(trimethylsilyl)ethyl (1R,2S,5R)-2-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-5-(tert-butylamino)cyclohexylcarbamate (100 mg, 0.183 mmol) in dichloromethane (3 mL) was charged with trifluoroacetic acid (2 mL). The reaction was stirred for 2 h at room temperature and concentrated in vacuo. The residue was dissolved in dichloromethane (50 mL) and washed with saturated NaHCO3 (20 mL). The aqueous layer was extracted with dichloromethane (3×30 mL). The dichloromethane layers were combined and dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give benzyl (S)-1-((1S,2R,4R)-2-amino-4-(tert-butylamino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (66 mg, 90%). LC/MS found [M+H]=403.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[F:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].O>C(O)(=O)C>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([N+:13]([O-:15])=[O:14])=[C:2]2[NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[F:16]
Reactant: O=[N+]([O-])c1cnc2ccc(F)cc2c1Cl
Reactant: Nc1ccccc1F
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cnc2ccc(F)cc2c1Nc1ccccc1F

Procedure:
0.4 g (1.8 mmol) of 4-chloro-6-fluoro-3-nitro-quinoline (Example 19c) and 0.17 ml (1.98 mmol) 2-fluoroaniline in 5 ml acetic acid are stirred overnight at rt. Crystals are formed. The mixture is poured into water, the solid material is filtered off and washed with water. The residue is dissolved in CH2Cl2 and washed twice with water. The organic phase is dried over MgSO4 and most of the solvent is evaporated. The title compound is obtained from this solution as yellow crystals by adding hexane. The compound is filtered off, washed with hexane and dried (70° C., high-vacuum). mp: 161-162° C.; MS: 302 (M++1); HPLC: tret=10.24 min (Grad 1).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Cl:27])=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=O)(C)(C)C.C([O:32]C(N[C@H]1CCN(S(C2C3C(Br)=CN=CC=3C=CC=2)(=O)=O)C1)=O)(C)(C)C>>[NH2:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Cl:27])=[CH:20][N:21]=[C:22]([OH:32])[C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1.[ClH:27]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3cncc(Cl)c23)C1
Product: Cl
Product: N[C@H]1CCN(S(=O)(=O)c2cccc3c(O)ncc(Cl)c23)C1

Procedure:
Intermediate 16a was used in the method of Example 6-1, Step A instead of Intermediate 1a, then the resultant was used in the method of Step B in a similar manner, and then the title compound was obtained as hydrochloride according to the method described in Example 7-1.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[N+:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=O)=[CH:27][CH:26]=1)([O-:24])=[O:23].CCN(C(C)C)C(C)C.[NH:43]1[CH2:48][CH2:47][NH:46][CH2:45][C:44]1=[O:49]>CN(C=O)C.O>[N+:22]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([N:46]2[CH2:47][CH2:48][NH:43][C:44](=[O:49])[CH2:45]2)=[O:31])=[CH:32][CH:33]=1)([O-:24])=[O:23]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C1CNCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CN(C(=O)c2ccc([N+](=O)[O-])cc2)CCN1
Reaction time: 6 h

Procedure:
EDCI (0.394 gm, 2.05 mmol) and HOBT (0.276 gm, 2.05 mmol) were added to a stirred solution of the 4-nitrobenzoic acid (LX, 0.253 gm, 2.05 mmol) in anhydrous DMF. The temperature of the mixture was reduced to 0° C., at which time DIPEA (1.14 ml, 6.15 mmol) was added under nitrogen atmosphere and the resultant solution (or suspension) was stirred at room temperature for 30 min. 2-Piperazinone (LIX, 2.05 mmol) was then added at 0° C. The reaction mixture was then brought to room temperature and stirred for 6 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (3×25 ml). The organic layer was washed with water (3×10 ml), dried over anhydrous sodium sulfate, filtered and concentrated over the rotary evaporator to get the crude product. The crude product was purified by column chromatography (60-120 silica gel, ethyl acetate:hexane, 4:6) to afford pure product LXI (0.3 gm, 60%) as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C([O:14][CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O)(=O)C.[ClH:24]>C(OCC)(=O)C>[Cl-:24].[OH:14][C:15]1[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O+:1][C:2]2[C:3]([CH:4]=1)=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=2
Reactant: Cl
Reactant: O=Cc1ccc(O)cc1O
Reactant: CC(=O)OCC(=O)c1ccccc1
Solvent: CCOC(C)=O
Product: Oc1ccc2cc(O)c(-c3ccccc3)[o+]c2c1
Product: [Cl-]
Reaction time: 24 h

Procedure:
79 g of 2,4-dihydroxybenzaldehyde were dissolved at room temperature in 800 ml of anhydrous ethyl acetate and 106 g of omega-acetoxyacetophenone were added to the solution. The reaction mixture was brought to 0° C. under agitation and gaseous hydrochloric acid added to saturation. After standing for 24 hours at room temperature, crystallisation of the product began and it was filtered and dried at 40° C. in the presence of NaOH. There were obtained 95 g of 3,7-dihydroxyflavilium chloride.