Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH:12]=[CH:11][C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=1.C1C2C=CC3C(=CC([CH:38]=[O:39])=C4C=3C=CC=C4)C=2C=CC=1.C(Cl)Cl>CCOC(C)=O>[Cl:1][C:2]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:4](=[C:5]3[C:10](=[C:11]([CH:38]=[O:39])[CH:12]=2)[CH:9]=[CH:8][CH:7]=[CH:6]3)[CH:3]=1
Reactant: Clc1cc2c3ccccc3ccc2c2ccccc12
Reactant: O=Cc1cc2c3ccccc3ccc2c2ccccc12
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=Cc1cc2c3ccccc3c(Cl)cc2c2ccccc12

Procedure:
6-Chlorochrysene (Cambridge Chemical, Inc., 70 g, 0.266 mol) was formylated according to the procedure outlined in 1A, except that CH2Cl2 (2.5 L) was used as the reaction solvent. Chromatography on a plug of SiO2 (1 kg) using EtOAc as the eluting solvent afforded after removal of solvent and drying 19.1 g (25%) of 12-chloro-6-chrysenecarbaldehyde mp 255°-257°, (EtOAc).
Reaction SMILES: [Br:1][CH:2]1[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]([NH:7][C:8](=[O:9])[CH:3]12)=[O:6].N1C=CC=CC=1.[Cl:20][C:21]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>C1C=CC=CC=1>[Cl:20][C:21]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:22]=1[C:23]([N:7]1[C:8](=[O:9])[CH:3]2[CH:2]([Br:1])[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]1=[O:6])=[O:24]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: O=C1NC(=O)C2C1CCC(Br)C2Br
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(c1ccc(Cl)cc1Cl)N1C(=O)C2CCC(Br)C(Br)C2C1=O
Temperature: 25 °C

Procedure:
3,4-Dibromohexahydrophthalimide (0.10 mole), benzene (300 ml) and pyridine (0.11 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,4-Dichlorobenzoyl chloride (0.10 mole) is then added dropwise to the flask with stirring at room temperature. After the addition is completed the reaction mixture is heated at reflux with continued stirring for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed filtrate is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,4-dichlorobenzoyl)-3,4-dibromohexahydrophthalimide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[CH:13]=[C:12]([C:14]2[CH:15]=[C:16]([NH:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:17]=[CH:18][CH:19]=2)[O:11][N:10]=1.C(N(CC)CC)C.[Cl:38][CH:39]([Cl:43])[C:40](Cl)=[O:41]>ClCCl>[Cl:38][CH:39]([Cl:43])[C:40]([N:20]([CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:12]2[O:11][N:10]=[C:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:13]=2)[CH:15]=1)=[O:41]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CC(C)(C)OC(=O)NCCNc1cccc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCN(C(=O)C(Cl)Cl)c1cccc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 2-(3-(3-(2,6-dichlorophenyl)isoxazol-5-yl)phenylamino)ethylcarbamate (230 mg, 0.51 mmol) was dissolved in anhydrous dichloromethane with triethylamine (120 μL, 0.82 mmol). The mixture was cooled in an ice-bath under nitrogen, then a solution of dichloroacetyl chloride (120 mg, 0.82 mmol) was added dropwise. After the addition was completed the ice-bath was removed and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and then washed successively with water, 10% hydrochloric acid and saturated sodium bicarbonate solution. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography, on silica gel, eluting with 95:5 hexanes:ethyl acetate to yield tert-butyl 2-(2,2-dichloro-N-(3-(3-(2,6-dichlorophenyl)isoxazol-5-yl)phenyl)acetamido)ethylcarbamate. 1H NMR (CDCl3): 7.99 (d, 1H), 7.82 (br s, 1H), 7.62 (m, 1H), 7.48-7.30 (m, 4H), 6.78 (s, 1H), 5.82 (s, 1H), 4.95 (m, 1H), 3.95 (m, 2H), 3.43 (m, 2H), 1.42 ppm (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH3:12].[N+:13]([O-])([OH:15])=[O:14]>>[CH3:12][O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:13]([O-:15])=[O:14])=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH3:1]
Reactant: COc1cccc([N+](=O)[O-])c1C
Reactant: O=[N+]([O-])O
Product: COc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To cooled (0° C.) fuming nitric acid (100 mL) was added slowly 2-methyl-3-nitroanisole (13.0 g, 77.8 mmol) in ten times. After the addition, the mixture was warmed to r.t. and stirred for 4 h, then poured into ice-water (500 g). The resulting mixture was extracted with EtOAc (3×500 mL). The combined organic layers were washed with water, saturated NaHCO3, brine, dried over Na2SO4, and concentrated to dryness. The residue was purified by silica column chromatography (petroleum ether/EtOAc=20:1) to obtain the pure product 1-methoxy-2-methyl-3,4-dinitrobenzene.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:3]=1.[CH3:18][C:19]1[CH:31]=[C:30]([CH2:32][NH:33][CH2:34][CH2:35][CH3:36])[CH:29]=[CH:28][C:20]=1[O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].C(N(CC1C=CC(OCC(OCC)=O)=C(C)C=1)C1C=NC=C(C2C=CC(Cl)=CC=2)N=1)CCC>>[CH3:18][C:19]1[CH:31]=[C:30]([CH2:32][N:33]([CH2:34][CH2:35][CH3:36])[C:2]2[CH:7]=[N:6][CH:5]=[C:4]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[N:3]=2)[CH:29]=[CH:28][C:20]=1[O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: FC(F)(F)c1ccc(-c2cncc(Cl)n2)cc1
Reactant: CCCNCc1ccc(OCC(=O)OCC)c(C)c1
Agent: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cncc(-c2ccc(Cl)cc2)n1
Product: CCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cncc(-c2ccc(C(F)(F)F)cc2)n1
Yield: 11.5 %

Procedure:
Using 2-chloro-6-(4-(trifluoromethyl)phenyl]pyrazine (0.303 g, 1 mmol) and ethyl {2-methyl-4-[(propylamino)methyl]phenoxy}acetate (0.4 g, 1.5 mmol) and the synthetic procedure described for Intermediate 77. Purification by Biotage™ chromatography (Si, 40 g) eluting 9:1–7:3 cyclohexane:EtOAc afforded the title compound as a pale yellow oil (56 mg).
Reaction SMILES: [CH2:1]=O.[CH:3]([NH:6][CH:7]([CH3:9])[CH3:8])([CH3:5])[CH3:4].[CH2:10]([OH:15])[CH2:11][CH2:12][C:13]#[CH:14].[OH-].[K+]>O1CCOCC1>[CH:3]([N:6]([CH:7]([CH3:9])[CH3:8])[CH2:1][C:14]#[C:13][CH2:12][CH2:11][CH2:10][OH:15])([CH3:5])[CH3:4]
Reactant: CC(C)NC(C)C
Reactant: C#CCCCO
Reactant: C=O
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)N(CC#CCCCO)C(C)C
Temperature: 60 °C
Yield: 35.9 %

Procedure:
A mixture of paraformaldehyde (7.14 g, 238 mmol), diisopropylamine (19.1 ml, 262 mmol) and cupric acetate monohydrate (1 g) in dioxane (40 ml) was heated in an oil bath of 60° C. for 1 hour. When the solid material disapeared, pent-4-yn-1-ol (20.02 g, 238 mmol) was added and the heating at 95° C. was continued until the greenish suspension had been completely replaced by a thin brown precipitate (approximately 3 hours). After cooling to 20° C., the reaction mixture was poured into 10% aqueous KOH (40 ml). The precipitate was filtered off and washed with ether (100 ml). The organic phase was washed with water (5 times 50 ml), dried (K2CO3) and evaporated to dryness to give the crude product. The isolated product was distilled to yield 16.88 g (36%) of 6-diisopropylaminohex-4-yn-1-ol: bp 116°-9° C. (0.05 mm Hg); 1H NMR (CDCl3) δ1.08(d, 12H), 1.40-1.98(m, 2H), 2.02-2.60(m, 2H), 2.83-3.44(m, 4H), 3.46-3.83(t, 2H), 4.09(s, 1H).
Reaction SMILES: [F:1][CH:2]([F:36])[O:3][C:4]1[CH:9]=[C:8](OC(C2SC(C3C=CC(C(F)(F)F)=CC=3)=NC=2C)CC)[CH:7]=[CH:6][C:5]=1[C:30]1NC(=O)O[N:31]=1.NO.[F:39]C(F)OC1C=C([O:48][C@@H:49]([C:52]2[S:56][C:55]([C:57]3[CH:62]=[CH:61][C:60]([C:63]([F:66])([F:65])[F:64])=[CH:59][CH:58]=3)=[N:54][C:53]=2[CH2:67][N:68]2[CH2:73][CH2:72][CH:71]([C:74]([F:77])([F:76])[F:75])[CH2:70][CH2:69]2)[CH2:50][CH3:51])C=CC=1C1NC(=O)ON=1>>[F:66][C:63]([F:64])([F:65])[C:60]1[CH:61]=[CH:62][C:57]([C:55]2[S:56][C:52]([C@H:49]([OH:48])[CH2:50][CH3:51])=[C:53]([CH2:67][N:68]3[CH2:73][CH2:72][CH:71]([C:74]([F:76])([F:75])[F:77])[CH2:70][CH2:69]3)[N:54]=2)=[CH:58][CH:59]=1.[F:1][CH:2]([F:36])[O:3][C:4]1[CH:9]=[C:8]([F:39])[CH:7]=[CH:6][C:5]=1[C:30]#[N:31]
Reactant: CCC(Oc1ccc(-c2noc(=O)[nH]2)c(OC(F)F)c1)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Reactant: CC[C@@H](Oc1ccc(-c2noc(=O)[nH]2)c(OC(F)F)c1)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CN1CCC(C(F)(F)F)CC1
Agent: NO
Product: CC[C@@H](O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CN1CCC(C(F)(F)F)CC1
Product: N#Cc1ccc(F)cc1OC(F)F

Procedure:
According to the method described for 3-(2-difluoromethoxy-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-phenyl)-4H-1,2,4-oxadiazol-5-one (except for the hydroxylamine addition step which was performed under microwave irradiation at 100° C. for 2 h), (+)-3-(2-difluoromethoxy-4-{(R)-1-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-yl]-propoxy}-phenyl)-4H-1,2,4-oxadiazol-5-one was obtained from (R)-1-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-yl]-propan-1-ol and 2-difluoromethoxy-4-fluoro-benzonitrile.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27](O)[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:61])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([O:51][Si](C(C)(C)C)(C)C)[CH:47]([O:59][CH3:60])[CH2:46]2)[CH:7]([CH3:62])[CH:6]([O:63][Si](C(C)(C)C)(C)C)[CH2:5][C:4]1=[O:71])[CH3:2].C(N(S(F)(F)[F:78])CC)C.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(Cl)Cl>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([F:78])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:61])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:59][CH3:60])[CH2:46]2)[CH:7]([CH3:62])[CH:6]([OH:63])[CH2:5][C:4]1=[O:71])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCC1C=C(C)C(O)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C)(C)C(C)(C)C)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC1C=C(C)C(F)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
To a stirred solution of 17-Ethyl-1,20-di-hydroxy-12-[2'-(4"-t-butyldimethylsilyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-14-t-butyldimethylsilyloxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone in methylene chloride cooled to -78° C. was added diethylaminosulfur trifluoride. After 3 min., saturated sodium bicarbonate solution was added followed by ethyl acetate and the reaction mixture was allowed to warm to room temperature. The reaction mixture was extracted with ethyl acetate, the organic extracts were dried over magnesium sulfate, filtered and evaporated in vacuo. The product was purified by chromatography (silica, ethyl acetate:hexanes 1:2+1% methanol. To a solution of this material (10 mg) in THF (0.6 ml) in a polypropylene vial was added 40 μL of HF-pyridine solution in THF. After stirring for 28 hours at rt, the mixture was added to a saturated solution of sodium bicarbonate. This mixture was extracted with ethyl acetate and the organic extracts were dried over magnesium sulfate, filtered and evaporated in vacuo. The product was purified by chromatography (silica, ethyl acetate:hexanes 2:1+1% methanol) to give the title compound. Mass Spectrum (FAB): 832 (M+Na)
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[CH2:9]([NH:16][CH2:17][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[CH:19]([OH:22])[CH2:20][OH:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.O>C1COCC1>[CH2:9]([NH:16][CH2:17][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[CH:19]([OH:22])[CH2:20][O:21][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC(O)C(CNCc1ccccc1)c1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCC(O)C(CNCc1ccccc1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.1 %

Procedure:
A solution of tert-butyldimethylchlorosilane (3.65 g) in THF (10 mL) was added dropwise to a solution of (2RS,3RS)-4-(benzylamino)-3-(3,4-dichlorophenyl)butane-1,2-diol (7.50 g) and triethylamine (9.22 mL) in THF (35 ml) at 0° C. Under nitrogen purging, the mixture was stirred at room temperature for 3 hr, water was added at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate (0%-100%)) to give the title compound (6.42 g) as a pale-yellow oil.
Reaction SMILES: N[CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[O:12])=[C:6]([O:9][CH3:10])[CH2:7][S:8][C@H:3]12.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=[O:29].Cl>C(N(CC)CC)C>[O:29]=[C:2]1[C:24](=[O:25])[N:4]2[C:5]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[O:12])=[C:6]([O:9][CH3:10])[CH2:7][S:8][C@H:3]12
Reactant: COC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(N)[C@H]2SC1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Product: COC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(=O)[C@H]2SC1

Procedure:
4-Nitrobenzyl 7-amino-3-methoxy-3-cephem-4-carboxylate, trifluoromethanesulfonic anhydride, triethylamine and hydrochloric acid were reacted in the same manners as those of Examples 1-4 to give 4-nitrobenzyl 7-oxo-3-methoxy-3-cephem-4-carboxylate (monohydrate). Mp. 115°-120° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[S:17][CH2:16][CH2:15][C:14]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24](O)=[CH:23][C:22]=4C)=[O:19])=[CH:13][C:12]=3[CH:29]=2)=[CH:4][CH:3]=1.CN([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)C.[CH3:39]S(Cl)(=O)=O.N1CCCCC1>O1CCCC1.C(N(CC)CC)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[S:17][CH2:16][CH2:15][C:14]([C:18]([NH:20][C:21]4[CH:22]=[CH:23][C:24]([CH2:39][N:34]5[CH2:35][CH2:36][CH2:37][CH2:38][CH2:33]5)=[CH:25][CH:26]=4)=[O:19])=[CH:13][C:12]=3[CH:29]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(O)cc2C)CCS3)cc1
Reactant: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN4CCCCC4)cc2)CCS3)cc1
Reaction time: 0.17 h

Procedure:
To a solution of 7-(4-methylphenyl)-N-(4-hydroxy-methylphenyl)-2,3-dihydro-1-benzothiepine-4-carboxamide (0.2 g), triethylamine (0.21 ml) and dimethylaminopyridine (catalytic amount) in tetrahydrofuran (10 ml) was dropwise added methane-sulfonylchloride (0.06 ml) under ice-cooling, and the mixture was stirred for 10 minutes. To the mixture was added piperidine (0.15 ml), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (methanol/triethylamine/ethyl acetate) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 7-(4-methylphenyl)-N-(4-piperidinomethylphenyl)-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 93) (0.19 g) as colorless crystals.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[CH:11][N:10]=1)[CH3:8].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[N:1]1([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[CH:11][N:10]=2)[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(Br)c1ccc(-c2ccc([N+](=O)[O-])cc2)cn1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(c1ccc(-c2ccc([N+](=O)[O-])cc2)cn1)n1ccnc1
Temperature: 50 °C

Procedure:
To a stirred solution of 1H-imidazole (13 mg, 0.19 mmol) in DMF (2 mL) was added 2-(1-bromoethyl)-5-(4-nitrophenyl)pyridine (50 mg, 0.1 mmol) and K2CO3. The reaction was heated at 50° C. for about 1 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine solution (10 mL), organic layer was dried over Na2SO4 and concentrated under vacuum to obtain crude product. The crude product was purified by flash chromatography (silica gel, 100-200μ) using 2% methanol in DCM eluent to afford 2-(1-(1H-imidazol-1-yl)ethyl)-5-(4-nitrophenyl)pyridine as off white solid (50 mg, 58% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.97 (s, 1H), 8.31 (d, 2H), 8.22 (dd, 1H), 8.01 (d, 2H), 7.82 (s, 1H), 7.30 (t, 2H), 6.91 (s, 1H), 5.71-5.65 (m, 1H), 1.84 (d, 3H), LC-MS m/z calcd for [M+H]+ 295.11. found 295.4.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][S:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]O)=[CH:21][CH:20]=1.[H+].[B-:28]([F:32])([F:31])([F:30])[F:29]>C(OCC)C.C(Cl)Cl>[F:29][B-:28]([F:32])([F:31])[F:30].[CH3:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][S+:7]([CH2:18][C:19]2[CH:26]=[CH:25][C:22]([CH3:23])=[CH:21][CH:20]=2)[CH2:6][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:17][CH:16]=2)=[CH:14][CH:13]=1
Reactant: Cc1ccc(CO)cc1
Reactant: Cc1ccc(CSCc2ccc(C)cc2)cc1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc(C[S+](Cc2ccc(C)cc2)Cc2ccc(C)cc2)cc1
Reaction time: 1 h

Procedure:
85.1 g (0.351 mol) of di-(p-methylbenzyl) sulfide and 51.5 g (0.421 mol) of p-methylbenzyl alcohol are initially introduced into 250 ml of methylene chloride under an N2 atmosphere in a reaction vessel (750 ml) provided with a stirrer and thermometer. 142.7 g of an approximately 54% by weight HBF4 solution in diethyl ether is added dropwise at an internal temperature of 20°-30° C. in the course of 40 min, while stirring. The reaction mixture is stirred at RT for 2 h. The reaction mixture is diluted with methylene chloride and extracted 4 times by shaking with deionized water (pH 5-6). The organic phase is dried with MgSO4 and the methylene chloride is removed on a rotary evaporator. The product, which has not been completely freed from methylene chloride, is stirred in 250 ml of toluene at RT for about 1 h and then at 0°-5° C. for 1 h. The crystals which have now precipitated are filtered off with suction and washed with a little toluene. The product is dried under a high vacuum at room temperature for 19 h. 118.6 g of tris-(p-methylbenzyl)-sulfonium tetrafluoroborate are obtained as white crystals of melting point 168°-170° C.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][O:25][CH:26]([CH3:28])[CH3:27])=[CH:18][CH:17]=3)=[CH:15][C:10]=2[CH:9]=[C:8]([C:29](O)=[O:30])[CH2:7][CH2:6]1)(=[O:4])=[O:3].S(Cl)(Cl)=O.[CH3:36][N:37]([CH:39]=O)[CH3:38]>>[CH3:1][S:2]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][O:25][CH:26]([CH3:28])[CH3:27])=[CH:20][CH:21]=3)=[CH:15][C:10]=2[CH:9]=[C:8]([C:29]([NH:5][C:11]2[CH:12]=[CH:13][C:14]([CH2:39][N:37]([CH3:36])[CH:38]3[CH2:24][CH2:23][O:22][CH2:19][CH2:18]3)=[CH:15][CH:10]=2)=[O:30])[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CN(C)C=O
Reactant: CC(C)OCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3S(C)(=O)=O)cc1
Solvent: O=S(Cl)Cl
Product: CC(C)OCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
In DMF (6.5 ml) was dissolved 1-methylsulfonyl-7-[4-(2-propoxy)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (296 mg). To the solution was added thionyl chloride (0.12 ml), and the mixture was stirred at room temperature for 30 minutes. Under reduced pressure, the solvent was evaporated, and to the residue was added THF (15.0 ml). On the other hand, to 4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]aniline dihydrochloride (234 mg) was added THF (10.0 ml), and then was added triethylamine (0.69 ml). To the obtained mixture was added dropwise at 0° C. the previously prepared acid chloride suspension, and the mixture was stirred at room temperature for 3 hour. To the mixture was added ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (25 g, ethyl acetate→ethyl acetate:ethanol:triethylamine=100:10:1) and recrystallized from ethanol to give 1-methylsulfonyl N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-7-[4-(2-propoxy)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 15) (248 mg, 58%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C)C=O>[CH2:23]([NH:30][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([Cl:1])[C:11]=1[N+:12]([O-:14])=[O:13])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=[N+]([O-])c1c(Cl)nc2ccccc2c1NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.7 %

Procedure:
A solution of 2,4-dichloro-3-nitroquinoline (25 g, 0.10 mol) in N,N-dimethylformamide (DMF) (130 mL) was cooled to 0° C. Triethylamine (17.2 mL, 0.123 mol) and benzylamine (11.2 mL, 0.10 mol) were sequentially added, and the reaction was stirred at ambient temperature overnight. The reaction was poured into water (1 L), and the suspension was stirred for 30 minutes at room temperature. The resulting precipitate was isolated by filtration and washed with water to provide 31.92 g of N-benzyl-2-chloro-3-nitroquinolin-4-amine as a bright yellow powder.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[S:5][C:6]2[CH:12]=[C:11]([O:13][C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][C:7]=2[N:8]=1)[CH3:2].[Cl:18][CH2:19][CH2:20][S:21][CH3:22]>C(C(C)=O)C>[ClH:18].[CH2:1]([N:3]=[C:4]1[N:8]([CH2:19][CH2:20][S:21][CH3:22])[C:7]2[CH:9]=[CH:10][C:11]([O:13][C:14]([F:16])([F:17])[F:15])=[CH:12][C:6]=2[S:5]1)[CH3:2]
Reactant: CCNc1nc2ccc(OC(F)(F)F)cc2s1
Reactant: CSCCCl
Solvent: CCC(C)=O
Product: CCN=c1sc2cc(OC(F)(F)F)ccc2n1CCSC
Product: Cl
Temperature: 20 °C
Reaction time: 94 h
Yield: 7.1 %

Procedure:
A mixture of 2-ethylamino-6-trifluoromethoxybenzothiazole (7.45 g) and 1-chloro-2-methylthioethane (3.76 g) in methyl ethyl ketone (20 cc) is heated to boiling for 94 hours. After cooling to a temperature in the region of 20° C., the precipitate formed is filtered off and washed with methyl ethyl ketone (2×20 cc). After recrystallization in 2-propanol, 2-ethylimino-3-(2-methylthioethyl)-6-trifluoromethoxybenzothiazoline hydrochloride (0.75 g), m.p. 208° C., is obtained.