Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:12][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[NH2:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]2[CH2:10][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:34][CH2:35][CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[O:22])(=[O:15])=[O:16])[CH2:12]2)=[CH:28][CH:29]=1
Reactant: O=C(O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Reactant: NCCN1CCOCC1
Product: O=C(NCCN1CCOCC1)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1

Procedure:
The operation is carried out under the conditions described in Example 124 starting with 150 mg of activated 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (165 μM) and 0.0345 cm3 of N-(2-aminoethyl)morpholine. 62 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(2-morpholin-4-ylethyl)benzamide are thus obtained in the form of an ochre-colored foam [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): from 2.30 to 2.45 (mt, 4H), 2.46 (t, J=7.5 Hz, 2H), 2.98 (s, 3H), 3.38 (mt, 2H), from 3.50 to 3.65 (mt, 4H), 3.82 (mt, 2H), 4.24 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8.5 Hz, 4H), 7.46 (d, J=8.5 Hz, 4H), from 7.50 to 7.60 (mt, 2H), 7.83 (broad s, 1H), 7.85 (dd, J=8 and 2 Hz, 1H), 8.45 (t, J=6.5 Hz, 1H)].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[C:4](Br)([F:6])[F:5].[Br:9][C:10]1[CH:11]=[C:12]([N:16]2[CH:20]=[C:19](/[C:21](=[N:23]/[S@@:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])/[CH3:22])[CH:18]=[N:17]2)[CH:13]=[CH:14][CH:15]=1.[CH2:30](O)C>O1CCCC1.[Zn].Cl[Cu]>[CH2:1]([O:2][C:3](=[O:8])[C:4]([F:6])([F:5])[C@@:21]([C:19]1[CH:18]=[N:17][N:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([Br:9])[CH:11]=2)[CH:20]=1)([NH:23][S@@:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])[CH3:22])[CH3:30]
Reactant: COC(=O)C(F)(F)Br
Reactant: C/C(=N\[S@](=O)C(C)(C)C)c1cnn(-c2cccc(Br)c2)c1
Reactant: CCO
Agent: Cl[Cu]
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)[C@](C)(N[S@](=O)C(C)(C)C)c1cnn(-c2cccc(Br)c2)c1
Reaction time: 0.5 h
Yield: 44.8 %

Procedure:
A suspension of activated zinc (1.7 g, 26.6 mmol) and CuCl (269 mg, 2.72 mmol) in dry tetrahydrofuran (15 ml) was refluxed for 30 minutes under vigorous stirring. A solution of bromo-difluoroacetic acid methylester (0.87 ml, 6.79 mmol) in tetrahydrofuran (5 ml) was added dropwise at 25° C. and the mixture was stirred for 30 minutes. Thereafter, a solution of (R)-2-methyl-propane-2-sulfinic acid [1-[1-(3-bromo-phenyl)-1H pyrazol-4-yl]-eth-(E)-ylidene]-amide (1.0 g, 2.72 mmol) in tetrahydrofuran (5 ml) was added dropwise at 25° C., and stirring continued for 30 minutes. For the workup, ethanol (0.3 ml, 4.89 mmol) was added to the reaction mixture at 25° C., and the resultant mixture was filtered over a layer of Celite®. The filtrate was diluted with water (20 ml), and extracted with ethyl acetate (5×30 ml). The combined organic layers were washed with brine (50 ml), dried over sodium sulphate, and evaporated at reduced pressure. The crude material thus obtained was purified by column chromatography on silica gel using a gradient of hexane/ethyl acetate=60:40 to 50:50 as the eluent to give the (R)-3-[1-(3-bromo-phenyl)-1H-pyrazol-4-yl]-2,2-difluoro-3-((R)-2-methyl-propane-2-sulfinylamino)-butyric acid ethyl ester (600 mg, 45% yield) as a yellow solid. MS (ISP): m/z=490.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[S:11][CH3:12].[Br:13][CH2:14][CH2:15][CH2:16]Br>C(#N)C>[Br:13][CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[S:11][CH3:12]
Reactant: CSc1cc(C(C)=O)ccc1O
Reactant: BrCCCBr
Solvent: CC#N
Product: CSc1cc(C(C)=O)ccc1OCCCBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-[4-hydroxy-3-(methylmercapto)phenyl]ethanone (5.4 g; 0.03 mole), K2COO3 (4.2 g), 1,3-dibromopropane (8 g, 0.039 mole) in acetonitrile (150 ml) was heated at reflux for 3 hours and stirred at room temperature overnight. Acetonitrile was removed at reduced pressure and the residue was extracted into dichloromethane (250 ml). Insolubles were filtered off. The dichloromethane solution was concentrated. The crude product was purified on a silica gel columns (SiO2, 100 g; eluted with 3:2 hexane:dichloromethane, 1.6 l). The compound crystallized upon concentration, and the product (3.5 g, 39%) was recrystallized from ethanol (40 ml) to yield 1-[4-(3-bromopropoxy)-3-(methylmercapto)phenyl]ethanone as white needles, 2.0 g; m.p.=120°-122° C.
Reaction SMILES: [C:1]1([S:7]([NH:10][CH2:11][CH2:12][S:13][CH:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][O:17][C:16]3[CH:25]=[CH:26][C:27]([C:29]([OH:31])=[O:30])=[CH:28][C:15]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+:34]>CO>[OH2:8].[C:1]1([S:7]([NH:10][CH2:11][CH2:12][S:13][CH:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][O:17][C:16]3[CH:25]=[CH:26][C:27]([C:29]([O-:31])=[O:30])=[CH:28][C:15]2=3)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+:34]
Reactant: O=C(O)c1ccc2c(c1)C(SCCNS(=O)(=O)c1ccccc1)c1ccccc1CO2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O
Product: O=C([O-])c1ccc2c(c1)C(SCCNS(=O)(=O)c1ccccc1)c1ccccc1CO2

Procedure:
Compound 1b, 3.3 g, obtained in Example 21 was suspended in 100 ml of methanol and sodium methoxide was added to the solution followed by stirring for about an hour. The solvent was distilled off under reduced pressure and the resulting crude product was solidified by isopropyl ether to give 2.3 g of the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:10]2[CH2:11][CH:12]=[C:13]([CH2:14][OH:15])[C@H:9]2[C@H:8]([O:16][C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[O:7][CH:6]=1)=[O:4].C(Cl)(Cl)Cl.CO.S(=O)(=O)(O)O>O>[CH3:1][O:2][C:3]([C:5]1[C@H:10]2[CH2:11][CH:12]=[C:13]([CH2:14][OH:15])[C@H:9]2[C@H:8]([OH:16])[O:7][CH:6]=1)=[O:4]
Reactant: COC(=O)C1=CO[C@@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H]2C(CO)=CC[C@H]12
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: COC(=O)C1=CO[C@@H](O)[C@@H]2C(CO)=CC[C@H]12
Reaction time: 4.5 h
Yield: 67.3 %

Procedure:
To a solution of geniposide (6.5 g) dissolved in distilled water (65 ml), was added β-glucosidase (No.G-0395, β-D-glucoside glucohydrase EC 3.2.1.21) (316.55 mg, 1677.72 units) the mixture was incubated at 37° C. for 4.5 hours. The progress of the reaction was monitored by TLC (chloroform:methanol=8:2, visualized with 50%-sulfuric acid). After the reaction was complete, the reaction solution was extracted several times with ethyl acetate, and subsequently the ethyl acetate layer was concentrated to give genipin as white needles (2.55 g, yield 67.3%).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([OH:23])[C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[CH:10][CH:11]=2)[C:6](=[O:24])[C:5]([C:25]([O:27]CC)=[O:26])=[CH:4]1)[CH3:2].[OH-].[K+]>CO.O>[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([OH:23])[C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[CH:10][CH:11]=2)[C:6](=[O:24])[C:5]([C:25]([OH:27])=[O:26])=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2ccc(OCc3ccc(OC)cc3)c(O)c2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2c(O)c(OCc3ccc(OC)cc3)ccc21
Temperature: 25 °C
Yield: 96.8 %

Procedure:
To a suspension of ethyl 1-ethyl-5-hydroxy-6-((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylate (1.5 g, 3.77 mmol) in a mixture of Methanol (60.0 mL) and Water (20 mL) was added KOH (0.424 g, 7.55 mmol) portionwise. The resulting mixture was stirred under reflux for 1 h. The mixture was cooled down to r.t. and concentrated. Water was added and the mixture was adjusted to pH˜2 using 6 N HCl (aq.). The precipitates were collected by filtration and dried in air to afford 1-ethyl-5-hydroxy-6-((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (1.35 g, 3.65 mmol, 97% yield) as a light yellow solid. LCMS: (M+H)+: 370.2.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9](=[O:24])[C:10]([OH:23])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4][CH2:3]1.[Br:25][CH2:26][C:27]([NH:29][C:30]1[N:35]=[CH:34][N:33]=[CH:32][N:31]=1)=[O:28]>C(#N)C.C(Cl)(Cl)Cl>[Br-:25].[OH:23][C:10]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:9]([O:8][CH:5]1[CH2:6][CH2:7][N+:2]([CH3:1])([CH2:26][C:27](=[O:28])[NH:29][C:30]2[N:35]=[CH:34][N:33]=[CH:32][N:31]=2)[CH2:3][CH2:4]1)=[O:24]
Reactant: O=C(CBr)Nc1ncncn1
Reactant: CN1CCC(OC(=O)C(O)(c2ccccc2)c2ccccc2)CC1
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: C[N+]1(CC(=O)Nc2ncncn2)CCC(OC(=O)C(O)(c2ccccc2)c2ccccc2)CC1
Product: [Br-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution comprising hydroxy-diphenyl-acetic acid 1-methyl-piperidin-4-yl ester (Intermediate F) (0.3 g, 0.9 mmol) and 2-bromo-N-[1,3,5]triazin-2-yl-acetamide (Intermediate J) (0.2 g, 0.9 mmol) in acetonitrile/chloroform (2 ml of a 1:1 mixture) is stirred under an inert atmosphere of argon at room temperature for 2 days. The titled product is observed by LC-MS. (M+462.2)
Reaction SMILES: C(OC([N:8]1[CH2:31][C@H:30]([O:32][C:33]2[C:42]3[C:37](=[CH:38][C:39]([O:43][CH3:44])=[CH:40][CH:41]=3)[N:36]=[C:35]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH:34]=2)[CH2:29][C@H:9]1[C:10]([NH:12][C@H:13]([C:17]([NH:19][S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])=[O:18])[CH2:14][CH2:15][CH3:16])=[O:11])=O)(C)(C)C.C1(C)C=CC=CC=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:44][O:43][C:39]1[CH:38]=[C:37]2[C:42]([C:33]([O:32][C@H:30]3[CH2:31][NH:8][C@H:9]([C:10]([NH:12][C@H:13]([C:17]([NH:19][S:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)(=[O:22])=[O:21])=[O:18])[CH2:14][CH2:15][CH3:16])=[O:11])[CH2:29]3)=[CH:34][C:35]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[N:36]2)=[CH:41][CH:40]=1
Reactant: CCC[C@H](NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)OC(C)(C)C)C(=O)NS(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1)C(=O)NS(=O)(=O)c1ccccc1
Yield: 100 %

Procedure:
Compound 72 was kept in DCM-TFA 2:1 (2 mL) for 2.5 hr at RT. The solution was co-evaporated with toluene to dryness. Yield 100%. M+H 603.12
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:8]([C:9](N)=[O:10])[C:7](=[O:13])[NH:6][C:5]=1[CH3:14])(=[O:3])[CH3:2].S(=O)(=O)(O)[OH:16]>O>[C:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:16])=[O:10])[C:7](=[O:13])[NH:6][C:5]=1[CH3:14])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C(N)=O)c(=O)[nH]c1C
Reactant: O=S(=O)(O)O
Solvent: O
Product: CC(=O)c1cc(C(=O)O)c(=O)[nH]c1C
Reaction time: 6 h

Procedure:
A mixture containing 34 g of 5-acetyl-1,2-dihydro-6-methyl-2-oxonicotinamide, 50 ml of concentrated sulfuric acid and 100 ml of water was heated on a steam bath with stirring for 6 hours. The hot reaction solution was filtered and to the filtrate was added 50 ml of water. The resulting mixture was allowed to stand at room temperature overnight whereupon the product crystallized out. The separated product was collected, washed with water, dried in a vacuum oven at 90°-95° C. to yield 16.8 g of 5-acetyl-1,2-dihydro-6-methyl-2-oxonicotinic acid, m.p. 238°-241° C. This acid was recrystallized from methanol and dried to yield 14.7 g of 5-acetyl-1,2-dihydro-6-methyl-2-oxonicotinic acid, m.p. 241°-243° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:17][O:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[C:20]([CH3:29])=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][N:23]=2.FC(F)(F)C(O)=[O:33].[OH-].[Na+].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]([OH:16])[CH2:17][OH:33])[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[C:20]([CH3:29])=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][N:23]=2
Reactant: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1OCC1CO1
Reactant: O=C(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1OCC(O)CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
3-(6-Methoxy-7-oxiranylmethoxy-quinolin-4-yloxy)-2-methyl-[1,8]naphthyridine (compound 401) (76 mg) was dissolved in methylene chloride (2 ml) to prepare a solution which was then brought to 0° C. Trifluoroacetic acid (0.5 ml) was added to the solution, and the mixture was stirred at 0° C. for 30 min and then at room temperature for 3 hr. The reaction solution was brought to 0° C., was stirred, and was made alkaline by the addition of a 10% aqueous sodium hydroxide solution. Water was added thereto, and the mixture was extracted with chloroform. The chloroform layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (46 mg, yield 56%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[C:15]1([C:21]2[CH:25]=[C:24]([C:26](=O)[CH3:27])[O:23][N:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:26]([C:24]2[O:23][N:22]=[C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:25]=2)[CH3:27])=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Reactant: CC(=O)c1cc(-c2ccccc2)no1
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(C)c1cc(-c2ccccc2)no1

Procedure:
Prepared according to the procedure described in Example 2, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 1-(3-phenyl-isoxazol-5-yl)-ethanone.
Reaction SMILES: O1CCCC1.[C:6]([C:8]1[CH:18]=[CH:17][C:11]2[S:12][C:13]([CH:15]=O)=[CH:14][C:10]=2[CH:9]=1)#[N:7].[Cl-].[CH2:20]([O:22][C:23]1[C:24]([O:56][CH3:57])=[CH:25][C:26]([CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])=[C:27]([C:29]2C=CC=CC=2[P+](C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:28]=1)[CH3:21].C1CCN2C(=NCCC2)CC1>C(O)C>[C:6]([C:8]1[CH:18]=[CH:17][C:11]2[S:12][C:13]([CH2:15][CH2:29][C:27]3[CH:28]=[C:23]([O:22][CH2:20][CH3:21])[C:24]([O:56][CH3:57])=[CH:25][C:26]=3[CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])=[CH:14][C:10]=2[CH:9]=1)#[N:7]
Reactant: N#Cc1ccc2sc(C=O)cc2c1
Reactant: CCOC(=O)CCc1cc(OC)c(OCC)cc1-c1ccccc1[P+](C)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cc(OC)c(OCC)cc1CCc1cc2cc(C#N)ccc2s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.2 %

Procedure:
9.3 g of ethyl 3-(4-ethoxy-3-methoxyphenyl)-propionate obtained in the above step c) was dissolved in 10 ml of acetic acid, followed by adding 7.4 g of chloromethyl methyl ether and subsequently stirring at room temperature for 22 hours. The resulting reaction solution was poured into ice water, extracted with ethyl acetate, washed with water and then dried to distill off the solvent. The residue thus obtained was dissolved in 10 ml of xylene, and the solution was mixed with 8.54 g of triphenylphosphine. The resulting mixture was stirred at room temperature for 18 hours and then at 70 to 80° C. for 5 hours. After cooling, xylene was removed by decantation, and the remaining portion was solidified by adding n-hexane to obtain 6.0 g of crude [5-ethoxy-2-(2-ethoxycarbonylethyl)-4-methoxyphenyl]methyltriphenylphosphonium chloride. e) To a mixture solution of 50 ml of tetrahydrofuran and 50 ml of ethanol were dissolved 1.5 g of 5-cyanobenzo[b]thiophene-2-carbaldehyde and 6.34 g of crude [5-ethoxy-2-(2-ethoxycarbonylethyl)-4-methoxyphenyl]-methyltriphenylphosphonium chloride obtained in the above step d). 1.83 g of 1,8-diazabicyclo[5.4.0]-7-undecene was added thereto, followed by stirring at room temperature for 18 hours. The resulting reaction solution was concentrated under a reduced pressure, and the residue was dissolved in a mixture solution of 20 ml of tetrahydrofuran and 20 ml of ethanol. The thus prepared solution was mixed with 1.70 g of 10% palladium carbon catalyst (50% wet type) and subjected to catalytic hydrogenation under normal pressure until hydrogen absorption was completed. After removing the catalyst by filtration, the solvent was distilled off. By subjecting the resulting residue to silica gel column chromatography, 1.2 g of oily ethyl 3-[2-[2-(5-cyanobenzo-[b]thien-2-yl)ethyl]-4-ethoxy-5-methoxyphenyl]propionate was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21](Cl)=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1)[NH2:28].C1(C)C=CC=CC=1>CCOCC>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]([NH:28][C:27]3[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=[C:25]([O:24][CH3:23])[CH:26]=3)=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Nc1nc2ccccc2nc1Cl)c1ccc(Cl)nc1
Reactant: COc1cc(N)cc(OC)c1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(Cl)nc2)cc(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
6-Chloro-N-(3-chloroquinoxalin-2-yl)pyridine-3-sulfonamide (775 mg, 2.2 mmol), 3,5-dimethoxyaniline (355 mg, 2.3 mmol) and toluene (12 mL) were combined and heated to 125 C with stirring overnight. The reaction was allowed to cool to room temperature and diluted with Et2O with vigorous stirring. The resulting solids were filtered, washed with Et2O and dried to give 6-chloro-N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)pyridine-3-sulfonamide (920 mg, 89%). 1H NMR (400 MHz, DMSO-d6) δ 12.20 (br s, 1H), 9.12 (d, 1H), 9.01 (br s, 1H), 8.53 (dd, 1H), 7.91 (br d, 1H), 7.77 (d, 1H), 7.60 (dd, 1H), 7.40 (m, 4H), 6.26 (m, 1H), 3.78 (s, 6H). MS (EI) for C21H18ClN5O4S: 472.0 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:23]([NH2:27])[CH:24]([CH3:26])[CH3:25].O>CN(C=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:27][CH2:23][CH:24]([CH3:26])[CH3:25])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Reactant: CC(C)CN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a suspension of 7-bromo-4-chloro-3-nitroquinoline (25.0 g, 87.0 mmol) in DMF (70 mL) was added triethylamine (18.2 mL, 130 mmol). A solution of iso-butylamine (9.50 mL, 95.7 mmol) in DMF (20 mL) was added dropwise. The viscous reaction mixture was stirred overnight at ambient temperature. Water (200 mL) was added and the mixture was stirred for 1 hour. A solid was isolated by filtration, washed with water, and dried in a vacuum oven overnight to yield 26.1 g of 7-bromo-N-(2-methylpropyl)-3-nitroquinolin-4-amine as a yellow powder.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:9][C:10]1[S:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1.[OH-].[Na+]>C(O)C.O>[CH2:1]([S:9][C:10]1[S:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: Sc1nc2ccccc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: c1ccc(CSc2nc3ccccc3s2)cc1
Yield: 68.2 %

Procedure:
A solution of 28.1 g (0.2 mol) of benzyl chloride in 50 ml of ethanol is added slowly, with stirring, to a solution of 33.4 g (0.2 mol) of 2-mercaptobenzothiazole and 8 g (0.2 mol) of NaOH in 150 ml of ethanol and 25 ml of water. The resulting solution is refluxed for 2.5 h. After cooling, it is filtered and evaporated to leave 35.1 g of a yellowish solid melting at 39°-40° C. 1H NMR (CDCl3): δ4.41 (2H), δ6.98-7.8 (9H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([N+:19]([O-])=O)[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1>CO.C(O)(=O)C.C(OCC)(=O)C.[Fe]>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([NH2:19])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1O

Procedure:
6.2 g (110 mmol) of iron powder were heated to reflux temperature in a mixture of 66 ml of methanol and 33 ml of glacial acetic acid and treated in portions with a total of 11.7 g (36.7 mmol) of 3-chloro-2-(4-hydroxy-3-nitrophenyl)-5-trifluoromethylpyridine. After addition was complete. The mixture was heated for a further 2 hours at reflux temperature, allowed to cool and diluted with 130 ml of ethyl acetate. The solid components were separted off, washed with ethyl acetate and discarded. The filtrate was treated with water so that two phases were formed. The aqueous phase was separated off and extracted twice with ethyl acetate. The combined organic phases were washed with water, dried over sodium sulfate and filtered through silica gel. Yield: 7.8 g (74%) of a dark oil.
Reaction SMILES: ClC[C:3]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:7][CH:6]=[C:5]([CH3:8])[O:4]1.[OH:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[O:20].[C:24](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:8][C:5]1[O:4][C:3]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:7][C:6]=1[CH2:24][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[O:20]
Reactant: CC1=CNC(CCl)(c2ccccc2)O1
Reactant: O=Cc1cccc(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(C=O)c1
Temperature: 90 °C
Yield: 91.1 %

Procedure:
A mixture of 2-chloromethyl-5-methyl-2-phenyloxazole (20.8 g), 3-hydroxybenzaldehyde (12.2 g), potassium carbonate (27.6 g) and N,N-dimethylformamide (DMF) (200 ml) was heated at 90° C. for 2 hours. The reaction mixture was poured into water, and subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate (MgSO4). The solvent was distilled off, whereby 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzaldehyde (26.5 g, 90%) was obtained. Recrystallization from ethanol gave colorless prisms. Melting point: 67-68° C.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)=[O:5].[Br:18][CH2:19][C:20](Br)=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>CCOCC.O>[Br:18][CH2:19][C:20]([NH:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4](=[O:5])[C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)=[O:21]
Reactant: O=C(Br)CBr
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: O=C(CBr)Nc1ccc(Cl)cc1C(=O)c1ccc(O)cc1

Procedure:
A solution of 41 g (0.165 mole) 2-amino-5-chloro-4'-hydroxybenzophenone in 800 ml of ether and 200 ml of water was cooled to 5°. The mixture was stirred while 20 ml (0.277 mole) of bromoacetyl bromide and a 20% solution of sodium carbonate were added alternately keeping the solution slightly basic. After 20 min. the reaction mixture was filtered to collect 60 g (about 100%) of product mp 201°-202°. Recrystallization from ethanol gave colorless prisms, mp 201°-203°.