Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([CH2:10]Br)[C:6]([CH3:12])=[C:5]([CH2:13]Br)[C:4]=1[CH3:15].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[N:18]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[NH2:23][C:19]1[N:18]=[C:17]([NH:16][CH2:2][C:3]2[C:8]([CH3:9])=[C:7]([CH2:10][NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[N:18]=3)[C:6]([CH3:12])=[C:5]([CH2:13][NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[N:18]=3)[C:4]=2[CH3:15])[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1cccc(N)n1
Reactant: Cc1c(CBr)c(C)c(CBr)c(C)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(CNc2cccc(N)n2)c(C)c(CNc2cccc(N)n2)c(C)c1CNc1cccc(N)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
A mixture of 1,3,5-tris(bromomethyl)-2,4,6-trimethyl-benzene (0.72 g, 1.8 mmol), 2,6-diamino-pyridine (1.20 g, 11 mmol), and K2CO3 (0.79 g) in CH3CN (100 mL) was stirred at room temperature for 24 h and then heated under reflux for 2 h. After filtration of the reaction mixture and evaporation of CH3CN, the obtained powder was suspended in CHCl3. The suspension was filtrated, the chloroform solution was washed several times with water, dried, and the solvent was removed under reduced pressure. The crude product was crystallized from THF/hexane. Yield 60%. M.p. 130-132° C.; 1H NMR (500 MHz, CDCl3): δ=2.38 (s, 9H), 4.01 (t, 3H, J=4.4 Hz), 4.15 (s, 6H), 4.35 (d, 6H, J=4.4 Hz), 5.81-5.84 (m, 6H), 7.24 (d, 3H). 13C NMR (125 MHz, CDCl3): δ=15.83, 41.65, 95.70, 96.81, 133.78, 136.84, 139.25, 157.68, 157.99. HR-MS calcd for C27H33N9: 483.2859; found: 483.2867.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].C(N(CC)CC)C.F[C:15]1[C:22]([F:23])=[CH:21][CH:20]=[C:19]([O:24][CH3:25])[C:16]=1[CH:17]=O>CN(C)C=O>[F:23][C:22]1[C:15]2[S:3][C:2]([C:1]([O:5][CH3:6])=[O:4])=[CH:17][C:16]=2[C:19]([O:24][CH3:25])=[CH:20][CH:21]=1
Reactant: COc1ccc(F)c(F)c1C=O
Reactant: COC(=O)CS
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(OC)ccc(F)c2s1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 87.4 %

Procedure:
Methyl thioglycolate (28.8 mL, 320 mmol) was added under nitrogen to a solution of triethylamine (86.6 mL) in dry N,N-dimethylformamide (220 mL) at 80° C. Stirred at 100° C. for 15 mins. A solution of 2,3-difluoro-6-methoxybenzaldehyde (55.1 g, 320 mmol) in N,N-dimethylformamide (80 mL) was added and the mixture heated at 130° C. for 3 h. Allowed to cool then poured onto ice-water (2 L). The resulting yellow solid was filtered, washing with water (2×200 mL). Dried under vacuum over phosphorus pentoxide at room temperature overnight to give the title compound (67.2 g, 87%); δH (300 MHz, CDCl3) 8.20 (1H, d, ArH), 7.06 (1H, t, ArH), 6.68 (1H, m, ArH) and 3.99 (6H, s, OCH3 and CO2CH3).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4](=[O:16])[C:3]=1[N:17]=O.[H][H]>C(O)C.O=[Pt]=O>[CH2:9]([N:5]1[C:4](=[O:16])[C:3]([NH2:17])=[C:2]([NH2:1])[NH:7][C:6]1=[O:8])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1[nH]c(=O)n(Cc2ccccc2)c(=O)c1N=O
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: Nc1[nH]c(=O)n(Cc2ccccc2)c(=O)c1N

Procedure:
This compound can also be prepared by a method similar to that of Wells et al. as described in J. Med. Chem. 1981, 24(8), 954. Catalytic reduction of 6-amino-3-benzyl-5-nitroso-1H-pyrimidine-2,4-dione using PtO2 in ethanol at 50 psi of hydrogen at room temperature. Once the reduction is complete the catalyst is filtered off through a pad of Celite and the filtrate concentrated to give 3-benzyl-5,6-diamino-1H-pyrimidine-2,4-dione as a tan solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)/[C:6]([CH3:18])=[C:5]2[CH2:19][CH2:20][O:21][NH2:22].[CH:23]([C:25]1[NH:29][N:28]=[N:27][N:26]=1)=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)/[C:6]([CH3:18])=[C:5]2[CH2:19][CH2:20][O:21][N:22]=[CH:23][C:25]1[NH:29][N:28]=[N:27][N:26]=1
Reactant: O=Cc1nnn[nH]1
Reactant: CC1=C(CCON)c2cc(F)ccc2/C1=C\c1ccncc1
Product: CC1=C(CCON=Cc2nnn[nH]2)c2cc(F)ccc2/C1=C\c1ccncc1

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-pyridyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with 5-formyltetrazole by the method of Example 1.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:12]=[C:11]([CH:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27]C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1>>[NH2:2][C:3]1[N:12]=[C:11]([CH:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])[CH2:15][CH2:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CC(C)(C)OC(=O)NCCCCCCCC(=O)N1CCC(c2nc(N)nc3ccccc23)CC1
Agent: Cl
Product: NCCCCCCCC(=O)N1CCC(c2nc(N)nc3ccccc23)CC1
Yield: 115.7 %

Procedure:
By a procedure similar to that described in Example 284, the titled compound (91 mg) as hydrochloride was prepared from 2-amino-4-[1-(8-t-butoxycarbonylaminooctanoyl)-4-piperidinyl]quinazoline (100 mg) obtained in Example 28.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:30][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH2:26][CH3:27])[C:20]([CH2:28][CH3:29])=[N:19]4)(=O)=O)=CC=1.[NH:31]1[CH2:36][CH:35]=[C:34]([C:37]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[NH:39][CH:38]=2)[CH2:33][CH2:32]1>CS(C)=O.C(OCC)(=O)C>[CH2:26]([C:21]1[C:20]([CH2:28][CH3:29])=[N:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14][CH:13]([CH2:12][N:31]4[CH2:32][CH:33]=[C:34]([C:37]5[C:45]6[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=6)[NH:39][CH:38]=5)[CH2:35][CH2:36]4)[O:30][C:17]3=2)[N:22]=1)[CH3:27]
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: CCc1nc2ccc3c(c2nc1CC)O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO3
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCc1nc2ccc3c(c2nc1CC)OC(CN1CC=C(c2c[nH]c4ccccc24)CC1)CO3
Temperature: 80 °C

Procedure:
To a solution of (2R)-8,9-diethyl-2,3-dihydro[1,4]dioxino[2,3-f]-quinoxalin-2-ylmethyl 4-methylbenzenesulfonate (0.300 g, 0.700 mmole) in methyl sulfoxide (20 mL) was added 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.555 g, 2.800 mmole) and the reaction mixture was heated to 80° C. for 12 hours. The reaction mixture was allowed to cool to room temperature and was diluted with ethyl acetate (250 mL), washed with water (2×100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, methanol:ethyl acetate 1:9) followed by recrystallization from ethanol provided 0.184 g (58%) of the (S)-enantiomer of the title compound as a yellow crystalline solid. Rf=0.41 (silica, methanol:ethyl acetate 1:9); mp>120° C. dec.
Reaction SMILES: C(N(CC)CC)C.CS(C)=O.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([F:40])=[C:17]([C@:19]23[CH2:28][O:27][C@@H:26]([CH2:29][OH:30])[CH2:25][C@H:24]2[CH2:23][S:22][C:21]([NH:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:20]3)[CH:18]=1>ClCCl.O.[Cl-].[Na+].O>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([F:40])=[C:17]([C@:19]23[CH2:28][O:27][C@@H:26]([CH:29]=[O:30])[CH2:25][C@H:24]2[CH2:23][S:22][C:21]([NH:31][C:32](=[O:39])[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[N:20]3)[CH:18]=1
Reactant: O=C(NC1=N[C@@]2(c3cc(Br)ccc3F)CO[C@@H](CO)C[C@H]2CS1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O
Product: O=C[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2cc(Br)ccc2F)CO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Triethylamine (6.94 mL, 50.0 mmol), dimethyl sulfoxide (4.14 mL, 58.3 mmol) and pyridine-sulfur trioxide complex (5.41 g, 33.3 mmol) were added to a solution of N-[(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-(hydroxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C33) (2.00 g, 4.17 mmol) in dichloromethane (420 mL). The resulting solution was allowed to stir at room temperature for 16 hours. The reaction mixture was diluted with water (200 mL) and brine (200 mL). The resulting biphasic solution was left stirring at room temperature for 10 minutes. The organic layer was then isolated and the resulting aqueous layer was back extracted with dichloromethane (3×100 mL). The combined organics were washed with water (2×200 mL), aqueous 0.2 N hydrochloric acid (200 mL) and brine (200 mL), dried over sodium sulfate, filtered and concentrated. Purification via silica gel chromatography (Gradient: 20% to 100% ethyl acetate in heptane) afforded the product as a white solid. Yield 1.10 g, 55%.
Reaction SMILES: CC1C=CC(C[S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=CC=1.Cl[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=1.CC[O-].[Na+].SCC(OCC)=O>C(O)C>[F:25][C:24]([F:27])([F:26])[C:21]1[CH:22]=[CH:23][C:18]([CH2:17][S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:19][CH:20]=1
Reactant: CCOC(=O)CSCc1ccc(C)cc1
Reactant: FC(F)(F)c1ccc(CCl)cc1
Agent: CCOC(=O)CS
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSCc1ccc(C(F)(F)F)cc1

Procedure:
The procedure is as in Example 29 for the preparation of ethyl (4-methylbenzylthio)acetate, starting with 1-chloromethyl-4-trifluoromethylbenzene (9.8 g), a 2M ethanolic solution of sodium ethylate (25 cc) and ethyl 2-mercaptoacetate (6.1 g) in ethanol (120 cc). Ethyl (4-trifluoromethylbenzylthio)acetate (12.2 g) is thereby obtained, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH2:14])=[CH:5][N:4]=1)#[N:2].[N+:15]([CH:18]=[C:19](SC)SC)([O-:17])=[O:16]>C(O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[CH2:11][CH2:12][CH2:13][NH:14][C:19]2=[CH:18][N+:15]([O-:17])=[O:16])=[CH:5][N:4]=1)#[N:2]
Reactant: N#Cc1ccc(CNCCCN)cn1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CCO
Product: N#Cc1ccc(CN2CCCNC2=C[N+](=O)[O-])cn1
Temperature: 25 °C
Yield: 63.7 %

Procedure:
A mixture of N-(2-cyano-5-pyridylmethyl)trimethylenediamine (1.9 g), 1-nitro-2,2-bis(methylthio)ethylene (1.6 g) and ethanol (30 ml) was refluxed for 5 hours with stirring. The reaction mixture was cooled to room temperature. The precipitated crystals were collected by filtration, and washed with ethanol to give pale yellow 1-(2-cyano-5-pyridylmethyl)-2-(nitromethylene)tetrahydropyrimidine (1.6 g). mp. 214°-216° C.
Reaction SMILES: CC[O:3][C:4]([CH:6]1[C:8]([CH3:10])([CH3:9])[CH:7]1[CH:11]=[C:12]([CH3:14])[CH3:13])=[O:5].B(Br)(Br)Br>C1(C)C=CC=CC=1>[CH3:13][C:12]([CH3:14])=[CH:11][CH:7]1[C:8]([CH3:9])([CH3:10])[CH:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)C1C(C=C(C)C)C1(C)C
Agent: BrB(Br)Br
Solvent: Cc1ccccc1
Product: CC(C)=CC1C(C(=O)O)C1(C)C
Reaction time: 0.5 h
Yield: 112 %

Procedure:
To a solution of the same levo-rotatory ethyl chrysanthemate (10 g) as used in Example 12 in toluene (90 g) was added boron tribromide (0.18 g) at room temperature under a nitrogen atmosphere. Irradiation with a high pressure mercury lamp (110 W) was made for 30 minutes. After the reaction was over, similar after-treatment as in Example 12 was applied to obtain chrysanthemic acid (9.6 g). The optical isomer ratio of the product was (+)-cis, 4.0%; (-)-cis, 2.6%; (+)-trans, 42.5%; and (-)-trans, 50.9%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[CH3:18][C:19]1[O:23][C:22]([C:24](O)=[O:25])=[CH:21][CH:20]=1>>[CH3:18][C:19]1[O:23][C:22]([C:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:25])=[CH:21][CH:20]=1
Reactant: Cc1ccc(C(=O)O)o1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: Cc1ccc(C(=O)Nc2ccc3[nH]c4c(c3c2)CC(N(C)C)CC4)o1
Yield: 53 %

Procedure:
Beginning with 8.7 mg (0.038 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 11.0 mg (0.084 mMol) 5-methylfuran-2-carboxylic acid, 6.8 mg (53%) of the title compound were recovered as a beige solid.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([NH:6][C:7]2[CH:15]=[C:14](/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=3)[CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(OCC)(=O)C>[C].[Pd].CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6][C:7]2[CH:15]=[C:14]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=3)[CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])=[CH:25][CH:26]=1
Reactant: Cc1cccc(/C=C/c2ccc(C(=O)O)c(Nc3ccc(F)cc3)c2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cccc(CCc2ccc(C(=O)O)c(Nc3ccc(F)cc3)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the obtained 2-(4-fluoroanilino)-4-((E)-2-(3-methylphenyl)vinyl)benzoic acid, ethyl acetate 1.0 mL, methanol 1.0 mL and 10% palladium-carbon 2.0 mg were added sequentially, and it was stirred under hydrogen atmosphere at room temperature for 3 hours and 30 minutes. The solvent was removed under reduced pressure after insoluble matter was filtrated to give 2-(4-fluoroanilino)-4-(2-(3-methylphenyl)ethyl)benzoic acid 3.0 mg of a white solid.
Reaction SMILES: [BH4-].[Na+].[C:3]([NH:6][CH2:7][CH2:8][CH2:9][C:10]([C:12]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:13]=1[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[O:11])(=[O:5])[CH3:4]>CO>[C:3]([NH:6][CH2:7][CH2:8][CH2:9][CH:10]([C:12]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:13]=1[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[OH:11])(=[O:5])[CH3:4]
Reactant: COC(=O)CCc1cc(Cl)ccc1C(=O)CCCNC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCc1cc(Cl)ccc1C(O)CCCNC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.38 g (0.01 mol) of sodium borohydride is added to a solution of 3.25 g (0.01 mol) of methyl 2-(4-acetamidobutyryl)-5-chloro-hydrocinnamate in 35 ml of methanol and the mixture is stirred at room temperature for 1 hour. The solution is concentrated, extracted with methylene chloride/water, dried with magnesium sulfate and the solvent is distilled in a vacuum. Chromatography on silica gel with chloroform-methanol (20:1) gives methyl 2-(4-acetamido-1-hydroxybutyl)-5-chlorohydrocinnamate as a yellow oil.
Reaction SMILES: [O:1]=[S:2]1(=[O:22])[CH2:6][CH2:5][CH2:4][N:3]1[C@@H:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[OH:9].[OH-].[Na+].[CH2:25](I)[CH2:26][CH3:27]>CS(C)=O.O>[C:16]1([C@H:7]([N:3]2[CH2:4][CH2:5][CH2:6][S:2]2(=[O:22])=[O:1])[C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:9][CH2:25][CH2:26][CH3:27])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCI
Reactant: O=S1(=O)CCCN1[C@@H](c1ccccc1)[C@H](O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCO[C@H](c1ccccc1)[C@H](c1ccccc1)N1CCCS1(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The product obtained from stage b) (70 mg, 0.221 mmol) was dissolved in 1 ml of DMSO, and 110 mg of powdered NaOH and then 169 mg (0.995 mmol) of n-propyl iodide were added. The reaction mixture was stirred at room temperature for 1.5 hours and then diluted with water. The crystalline precipitate obtained thereby was filtered off with suction. After drying, the material was stirred several times with n-heptane. 14.5 mg of (1S,2R)-2-(1,2-diphenyl-2-propoxyethyl)isothiazolidine 1,1-dioxide were obtained.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[CH2:15][O:14][NH:13][C:12]2=[O:16])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:20]1([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH:24]=[CH:23][C:22](=[O:25])[O:21]1>CN(C)C=O.C(OCC)(=O)C.O>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[CH2:15][O:14][N:13]([C:20]3([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])[CH:24]=[CH:23][C:22](=[O:25])[O:21]3)[C:12]2=[O:16])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C=CC(Cl)(C(=O)OCc2ccccc2)O1
Reactant: O=C(Cc1ccccc1)N[C@@H]1CONC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)N[C@@H]1CON(C2(C(=O)OCc3ccccc3)C=CC(=O)O2)C1=O
Temperature: -10 °C
Yield: 20.1 %

Procedure:
In 3 ml of anhydrous N,N-dimethylformamide was dissolved 220 mg of (4R)-4-phenylacetamido-3-isoxazolidinone. To the solution was added, under ice-cooling and stirring, 60 mg of sodium hydride (50% mineral oil), which was stirred for 10 minutes. Then the reaction solution was cooled to -10° C., to which was added under stirring 0.7 ml of anhydrous N,N-dimethylformamide solution dissolving 250 mg of the Compound (28) obtained in Example 28. The reaction solution was stirred at the same temperature for 45 minutes, followed by pouring into a mixture of ethyl acetate and water. The ethyl acetate layer was taken, washed with water and dried (Na2SO4). The solvent was evaporated off, and the residue was subjected to a silica gel column chromatography, followed by elution with hexane-ethyl acetate (2:1) to give 87 mg of the subject Compound (32) as colorless foamy substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]1[C:7](=[CH:8][C:9](=[O:24])[C:10]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:11]1)[S:6]2.[Br:25]Br.CCCCCC>C(O)(=O)C>[Br:25][C:8]1[C:9](=[O:24])[C:10]([N:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]2)=[CH:11][C:12]2[C:7]=1[S:6][C:5]1[C:14](=[CH:15][CH:16]=[C:3]([O:2][CH3:1])[CH:4]=1)[N:13]=2
Reactant: BrBr
Reactant: COc1ccc2nc3cc(N4CCN(C)CC4)c(=O)cc-3sc2c1
Solvent: CC(=O)O
Solvent: CCCCCC
Product: COc1ccc2nc3cc(N4CCN(C)CC4)c(=O)c(Br)c-3sc2c1
Reaction time: 0.08 h

Procedure:
To a suspension of 7-methoxy-2-(4-methylpiperazin-1-yl)-3H-phenothiazin-3-one (500 mg) in acetic acid (10 ml) was added a solution of bromine in acetic acid (0.5M) (6 ml) and stirred for 5 minutes. Hexane (100 ml) was added and the resulting precipitate was filtered. The solid was suspended in a mixture of aqueous K2CO3 (50 ml), EtOAc (100 ml) and methanol (20 ml) and stirred for 15 minutes. After filtration and decantation, the organic layer was washed with brine, dried and evaporated to dryness to afford the title compound (190 mg) m.p. 209°-210° (dec.).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12].S(=O)(=O)(O)[OH:22].[OH-].[Na+]>C(O)(=O)C.O>[F:18][C:17]([F:20])([F:19])[C:15]1[CH:14]=[CH:13][C:10]2[C:11](=[O:22])[NH:12][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8][C:9]=2[CH:16]=1
Reactant: N#Cc1ccc(C(F)(F)F)cc1Sc1ccccc1N
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C1Nc2ccccc2Sc2cc(C(F)(F)F)ccc21
Temperature: 0 °C

Procedure:
2-(2-Aminophenylthio)-4-trifluoromethylbenzonitrile (12.5 g, 42.5 mmol) in glacial acetic acid (135 ml), water (135 ml), and concentrated sulphuric acid (135 ml) was heated to 125°-130° C. for 2.5 hr before being cooled and added to 1.5 l of ice-water and adjusted to pH 4 with sodium hydroxide solution (10N, 480 ml). The product was extracted into chloroform (1 l), dried (Na2SO4) and evaporated in vacuo. The light brown oil was placed in xylene (800 ml) and refluxed for 18 hr in a Dean-Stark apparatus. The title compound was obtained as off-white crystals (7.8 g. m.p. 216°-217° C., Rf 0.28, hexane/EtOAc 2:1) after reducing the volume to approximately 450 ml and allowing the solution to cool.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:12]=2[C:13]([O:15]CC)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=[CH:18][C:12]=2[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)c1ccc(C(F)(F)F)cc1-c1ccc(OC)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2cc(C(F)(F)F)ccc2C(=O)O)cc1OC
Yield: 89.9 %

Procedure:
1000 ml of absolute ethanol, 290 g (0.82 mol) of ethyl 2-(3,4-dimethoxyphenyl)-4-(trifluoromethyl)benzoate and 170 ml (0.164 mol) of 10N sodium hydroxide solution are introduced successively into a 2-liter round-bottomed flask. The reaction mixture is brought to reflux for two hours and then evaporated to dryness under reduced pressure. The residue is taken up in 2.5 liters of water and extracted successively with 500 ml of ethyl acetate and 500 ml of pentane. 500 g of crushed ice are added to the aqueous phase which is then treated with an excess of concentrated hydrochloric acid. The precipitate which forms is filtered on sintered glass and then dried under a stream of air; there is thus obtained 240.5 g (yield: 90%) of 2-(3,4-dimethoxyphenyl)-4-(trifluoromethyl)benzoic acid in the form of a light-beige solid melting at 194° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH2:8][N:7]([NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5][CH:4]=1.[O:17]1[C:22]2[CH:23]=[CH:24][C:25]([CH:27]=O)=[CH:26][C:21]=2[O:20][CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.ClCCCl>[O:17]1[C:22]2[CH:23]=[CH:24][C:25]([CH2:27][NH:1][CH2:2][C:3]3[CH2:8][N:7]([NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5][CH:4]=3)=[CH:26][C:21]=2[O:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)NN1CCC=C(CN)C1
Reactant: O=Cc1ccc2c(c1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NN1CCC=C(CNCc2ccc3c(c2)OCCO3)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of tert-butyl 5-aminomethyl-3,6-dihydro-2H-pyridine-1-carbamate (0.7 g, 3.3 mmol) and 1,4-benzodioxane-6-carbaldehyde (0.54 g, 3.3 mmol) in THF (2 ml) and DCE (4 ml) was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.770 g, 3.81 mmol) was then added thereto. The reaction mixture was stirred at room temperature for 5 hours and filtered through Hydromatrix (wetted with saturated NaHCO3 solution) and the filtrate was concentrated. The residue was purified by chromatography on silica gel (EtOAc/hex 2/1 and then EtOAc/MeOH 9/1).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH3:22])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:29]([O-])([N+]([O-])=O)=[O:30]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:29]=[O:30])[C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH3:22])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: CCCCN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 78.6 %

Procedure:
3.4 g of 1-(2-chloroethyl)-3-n-butyl-3-D-glucopyranosylurea are dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 2.9 g of 1-(2-chloroethyl)-1-nitroso-3-n-butyl-3-D-glucopyranosylurea are thereby obtained as yellow caramel.