Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.[CH2:16]([NH2:19])[CH:17]=[CH2:18]>O1CCCC1.O>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]([NH:19][CH2:16][CH:17]=[CH2:18])=[O:12])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: C=CCN
Reactant: O=C(Cl)N1CC(Oc2ccc(Br)cc2)C1
Solvent: O
Solvent: C1CCOC1
Product: C=CCNC(=O)N1CC(Oc2ccc(Br)cc2)C1
Reaction time: 18 h
Yield: 59.5 %

Procedure:
A stirred solution of 5.8 g (0.02 mole) of 3-(4-bromophenoxy)-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was treated with 4.5 g (0.06 mole) of 2-propenylamine and stirring continued for 18 hr. The reaction mixture was diluted with 200 ml of water and the oil which separated slowly solidified. After collecting the solid by filtration, it was triturated 4 times with boiling isopropyl ether. The combined triturates upon cooling yielded 3.7 g (59.5%) of white crystals, m.p. 100°-101° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:20][CH:21](O)[CH2:22][CH2:23][CH3:24].C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH:21]([CH3:20])[CH2:22][CH2:23][CH3:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Reactant: CCCC(C)O
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCCC(C)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (200 mg, 0.661 mmol) obtained in Example 5 and 2-pentanol (0.144 ml, 1.33 mmol) were dissolved in toluene (3 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (0.320 ml). Under an argon atmosphere, the resulting mixture was heated under reflux for 14 hours. The reaction mixture was then allowed to cool down. The residue obtained by concentrating the reaction mixture under reduced pressure was separated and purified by flash silica gel chromatography (hexane:ethyl acetate=50:1), whereby obtained were the title Isomer 292-A (low polarity) (67 mg, 0.18 mmol, 27%) as a white powder and the title Isomer 292-B (high polarity) (45 mg, 0.12 mmol, 19%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[S:12][CH:13]=2)=[C:4]([CH3:23])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:31]1[CH:32]=[CH:33][C:34]([NH:37][CH2:38][CH2:39][O:40][CH3:41])=[N:35][CH:36]=1>CN(C=O)C>[CH3:41][O:40][CH2:39][CH2:38][NH:37][C:34]1[N:35]=[CH:36][C:31]([O:1][C:2]2[CH:3]=[C:4]([CH3:23])[C:5]([C:9]3[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[S:12][CH:13]=3)=[C:6]([CH3:8])[CH:7]=2)=[CH:32][CH:33]=1
Reactant: COCCNc1ccc(Br)cn1
Reactant: Cc1cc(O)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCNc1ccc(Oc2cc(C)c(-c3csc(NC(=O)c4ccncc4)n3)c(C)c2)cn1
Temperature: 105 °C
Reaction time: 1 h
Yield: 20.2 %

Procedure:
To a solution of 5-3 (325 mg, 1.0 mmol) in DMF (15 mL) were added cesium carbonate (650 mg, 2.0 mmol, 2.0 equiv) and Cu (19.5 mg, 0.30 mmol, 0.3 equiv). The solution was stirred at 100-110° C. for 60 min and added with 5-bromo-N-(2-methoxyethyl)pyridin-2-amine (29-2, 347 mg). The reaction mixture was stirred at 140° C. for 48 h. The reaction was quenched with water (40 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, hexane/ethyl acetate=3/1-1/3) to give 29 (96 mg) in 16% yield: 1H NMR (500 MHz, CDCl3) δ 8.81 (d, 1 H), 7.72 (d, 1 H), 7.71 (d, 1H), 7.24 (m, 1 H), 6.81 (s, 1 H), 6.72 (d, 1 H), 6.49 (s, 1 H), 3.59 (t, 1 H), 3.51 (t, 1 H), 3.35 (s, 3 H), 2.01 (s, 6 H), ESI-MS=m/z 447.5 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[CH:6]=[CH:7][C:8](=O)[NH:9][N:10]=1.P(Cl)(Cl)([Cl:18])=O.[OH-].[NH4+]>CC(C)=O.O>[Cl:18][C:8]1[N:9]=[N:10][C:5]([CH2:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[CH3:1])=[CH:6][CH:7]=1
Reactant: Cc1ccccc1Cc1ccc(=O)[nH]n1
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccccc1Cc1ccc(Cl)nn1

Procedure:
2,3-Dihydro-6-(2-methylbenzyl)pyridaz-3-one (prepared as described above; 36 g.) and phosphorus oxychloride (120 ml.) were heated together on a steam bath to 90° C. The dark red solution thus obtained was immediately cooled to 10°-15° C., diluted with acetone (125 ml.) and added to a stirred solution of acetone and aqueous ammonium hydroxide solution (s.g. 0.880) (1:1; 1000 ml.) maintained at a temperature of from 0° to 20° C. by strong cooling. The mixture was then diluted with water (1000 ml.). A light brown coloured solid was precipitated, filtered off, dried and dissolved in toluene (200 ml.). The toluene solution was filtered and the filtrate evaporated to dryness to give 3-chloro-6-(2-methylbenzyl)pyridazine (34 g.) in the form of an off-white coloured solid, m.p. 73.5° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3].[S-:9][C:10]#[N:11].N1C2C(=CC=CC=2)C=CC=1.C([O-])([O-])=O.[Na+].[Na+]>O>[CH2:5]([O:4][C:2]([N:11]=[C:10]=[S:9])=[O:3])[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)COC(=O)Cl
Reactant: N#C[S-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccc2ncccc2c1
Product: CC(C)COC(=O)N=C=S

Procedure:
136.58 grams (1 mole) of 99% isobutyl chloroformate are added to a 50% thiocyanate solution containing 81 grams (1 mole) of NaSCN, 81 grams of water, 4.36 grams of quinoline (catalyst) and 1.8 grams of Na2CO3 (base) while maintaining a reaction temperature of 25–30° C. with agitation. The reaction is monitored for the consumption of the chloroformate during the formation of an upper layer of isobutoxycarbonyl isothiocyanate (approximately 4 hours). The contents of the reaction vessel are filtered to remove solid sodium chloride and the isobutoxycarbonyl isothiocyanate is isolated in the form of a layer that separates from the aqueous layer.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][CH3:10])[C:6]([CH3:11])=[CH:5][N:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:17].C(Cl)Cl.CO>C(Cl)Cl>[CH3:1][S:2]([C:3]1[N:8]=[C:7]([NH:9][CH3:10])[C:6]([CH3:11])=[CH:5][N:4]=1)=[O:17]
Reactant: CNc1nc(SC)ncc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: CNc1nc(S(C)=O)ncc1C

Procedure:
Prepared from 2-methylsulphenyl-4-methylamino-5-methyl-pyrimidine by reacting with 3-chloro-peroxybenzoic acid in methylene chloride, Rf value: 0.23 (silica gel; methylene chloride/methanol/ conc. aqueous ammonia=20:1:0.1)
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[OH:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25].[OH-].[K+]>CS(C)=O>[N+:14]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:21]1[CH:22]=[CH:23][C:18](=[O:17])[C:19]([N+:24]([O-:26])=[O:25])=[CH:20]1)[NH:9][C:8](=[O:12])[C:7](=[O:13])[NH:6]2)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1cnccc1O
Reactant: O=c1[nH]c2cc(F)c([N+](=O)[O-])cc2[nH]c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=c1ccn(-c2cc3[nH]c(=O)c(=O)[nH]c3cc2[N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 64.7 %

Procedure:
First, 677 mg of 7-fluoro-6-nitro-1,4-dihydroquinoxaline-2,3-dione, 840 mg of 4-hydroxy-3-nitropyridine, 403 mg of powdered potassium hydroxide were added to 6 ml of dry dimethylsulfoxide. The mixture was allowed to react at 130° C. for 2 hours in a nitrogen atmosphere. The subsequent processes were conducted in the same way as in Example 2. The resultant precipitate was recrystallized with dimethylformaldehyde and water, giving 672 mg of red crystals of 6-nitro-7-(3-nitro-4-oxo-4H-pyridin-1-yl)-1,4-dihydroquinoxaline-2,3-dione
Reaction SMILES: Cl[CH:2]([CH2:5][C:6]1[CH:16]=[CH:15][C:9]2[N:10]=[C:11]([S:13][CH3:14])[S:12][C:8]=2[CH:7]=1)[CH:3]=O.[NH2:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][N:25]=1)[C:21]#[N:22]>C(O)CCC>[CH3:14][S:13][C:11]1[S:12][C:8]2[CH:7]=[C:6]([CH2:5][C:2]3[N:25]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]4=[N:17][CH:3]=3)[CH:16]=[CH:15][C:9]=2[N:10]=1
Reactant: CSc1nc2ccc(CC(Cl)C=O)cc2s1
Reactant: N#Cc1ccnc(N)c1
Solvent: CCCCO
Product: CSc1nc2ccc(Cc3cnc4cc(C#N)ccn34)cc2s1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
A mixture of 2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal (0.35 g, 1.3 mmol) and 2-aminoisonicotinonitrile (0.30 g, 2.6 mmol) in 1-butanol (15 mL) was heated at reflux overnight. After cooling to rt, the formed solid was collected and washed with water, then dried to afford 3-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridine-7-carbonitrile as a white solid (0.27 g, 62%). 1H NMR (300 MHz, CDCl3) δ 8.45 (d, J=7.2 Hz, 1H), 8.34 (s, 1H), 7.90 (s, 1H), 7.78 (d, J=8.7 Hz, 1H), 7.75 (s, 1H), 7.37 (dd, J=1.2, 7.8 Hz, 1H), 7.20 (dd, J=1.8, 7.2 Hz, 1H), 4.49 (s, 2H), 2.77 (s, 3H). LCMS (ESI) m/z 337 (M+H)+.
Reaction SMILES: C([CH:3]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)#N.[C:23]([NH2:25])#[N:24]>C1COCC1.O=[Mn]=O>[NH:25]([CH:3]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[N:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:11])[CH2:8][CH2:9]1)[C:23]#[N:24]
Reactant: CC(C)(C)OC(=O)N1CCN(C(C#N)c2ccccc2)CC1
Reactant: N#CN
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(NC#N)c2ccccc2)CC1
Reaction time: 120 h

Procedure:
An excess amount of NiO2—H2O (25 g) was added into a solution of tert-butyl 4-(cyano(phenyl)methyl)piperazine-1-carboxylate (10 g) and cyanamine (7 g) in THF (100 ml). An additional cyanamine (25 g) and MnO2 (100 g) was added after 24 hours, and then the reaction was kept stirring for 5 days. The solids were removed by filtration. The filtrate was concentrated under vaccum to give a residue which was purified by silica gel column chromatography to provide tert-butyl 4-(cyanamido(phenyl)methyl)piperazine-1-carboxylate.
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.C(N(CC)CC)C.[Cl:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>C1(C)C=CC=CC=1>[Cl:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH:1][C:2]2[S:3][C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[C:5]([C:7]([F:10])([F:9])[F:8])([C:11]([F:12])([F:13])[F:14])[N:6]=2)=[O:34])=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In toluene (15 ml) were dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (4.0 g) and triethylamine (1.5 ml), and 4-chlorobenzoyl chloride (2.5 g) was gradually added thereto and the mixture was stirred at room temperature for 3 hours.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:33])[NH:23][S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:17]=1.[OH-].[Na+].C(OCC)(=O)C>CO>[CH3:1][C:2]1([CH3:34])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:33])[NH:23][S:24]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)(=[O:26])=[O:25])[CH:17]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)NS(=O)(=O)c3ccccc3)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(C(=O)NS(=O)(=O)c2ccccc2)c1
Yield: 48.9 %

Procedure:
A mixture of methyl 3,3-dimethyl-2-(3-(phenylsulfonylcarbamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (250 mg, 0.44 mmol, 1.0 eq.) in methanol (8 mL) and 1N sodium hydroxide aqueous solution (6.6 mL, 6.6 mmol, 15.0 eq.) was heated to reflux for 1 h, Thin layer chromatography (petroleum ether:ethyl acetate=1:1) and LC-MS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure and the residual was acidified with 1 M hydrochloric acid solution to pH=3. The white solid precipitated was collected by filtration and washed with acetone to give 100 mg of 3,3-dimethyl-2-(3-(phenylsulfonylcarbamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a off-white solid, yield: 50.4%. LC-MS(M+1)=465.1.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([S:7][CH3:8])[C:5]#N.[NH:10]([CH2:12][CH2:13][OH:14])[NH2:11].Cl>C(O)C>[OH:14][CH2:13][CH2:12][N:10]1[C:3]([NH2:2])=[C:4]([S:7][CH3:8])[CH:5]=[N:11]1
Reactant: NNCCO
Reactant: CSC(C#N)=CN(C)C
Agent: Cl
Solvent: CCO
Product: CSc1cnn(CCO)c1N
Yield: 39.4 %

Procedure:
To a mixture of 3-dimethylamino-2-methylthioacrylonitrile (5 g) and 2-hydrazinoethanol (2.68 g) in ethanol (50 ml) was added conc. hydrochloric acid (2.93 ml) under ice-cooling. The mixture was refluxed for 3 hours. The reaction mixture was evaporated to remove the solvent. The residue was adjusted to pH 7 with a saturated aqueous solution of sodium bicarbonate and extracted with a mixture of tetrahydrofuran and ethyl acetate. The organic layer was dried over magnesium sulfate. The solvent was removed in vacuo and the residue was subjected to column chromatography on silica gel using ethyl acetate as an eluent. Fractions containing the object compound were combined and evaporated to give 1-(2-hydroxyethyl)-4-methylthio-5-aminopyrazole (2.4 g).
Reaction SMILES: [CH3:1][C:2]([S:7][CH3:8])([CH3:6])[CH:3]=[N:4][OH:5].C(N(CC)CC)C.[CH3:16][N:17]=[C:18]=[O:19].P(=O)(O)(O)O>O>[CH3:16][NH:17][C:18]([O:5][N:4]=[CH:3][C:2]([CH3:6])([S:7][CH3:8])[CH3:1])=[O:19]
Reactant: CSC(C)(C)C=NO
Reactant: CN=C=O
Agent: O=P(O)(O)O
Solvent: CCN(CC)CC
Solvent: O
Product: CNC(=O)ON=CC(C)(C)SC
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Into a one liter glass resin kettle equipped with an air-driven stirrer, a pressure-equalizing dropping funnel with Teflon® tube for subsurface addition, a thermometer and a dry ice/acetone cold condenser was added 66.5 grams (0.50 mole) of 2-methyl-2-(methylthio) propionaldehyde oxime (aldicarb oxime) and 266 milliliters of water. After cooling the mixture to a temperature of 5° C. with a water/salt/ice bath, 0.52 grams (0.005 mole) of triethylamine was added to the kettle under a nitrogen atmosphere. A stoichiometric amount of methyl isocyanate (29.5 milliliters, 0.50 mole) was then added over a period of 30 minutes at a temperature of 5° C.-10° C. with vigorous stirring. The water/salt/ice bath was removed and the mixture was stirred for an additional 60 minutes at a temperature of 15° C.-20° C. after which an additional 2.0 milliliters (0.03 mole) of methyl isocyanate was added and the mixture stirred for an additional period of 30 minutes. The water/salt/ice bath was then put back in place and 2.9 grams of phosphoric acid in 10 milliliters of water was added in a slow stream subsurface. The resulting solid product was filtered off on a sintered glass funnel to give 107.1 grams (wet weight) of a fluffy white powder. High pressure liquid chromatographic analysis (internal standard) indicated the following: 76.00 percent 2-methyl-2-(methylthio) propionaldehyde O-(methylcarbamoyl) oxime (aldicarb) (89percent yield based on aldicarb oxime) and 0.36 percent 2-methyl-2-(methylthio) propionaldehyde oxime (aldicarb oxime); 23.64 percent water content was determined by Karl Fischer titration.
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:14]=[C:15]([Si:18]([CH3:21])([CH3:20])[CH3:19])[O:16][CH:17]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[C:22]([O:1][CH:2]([C:13]1[CH:14]=[C:15]([Si:18]([CH3:21])([CH3:20])[CH3:19])[O:16][CH:17]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Solvent: c1ccncc1
Product: CCCCCCCCCCC(OC(C)=O)c1coc([Si](C)(C)C)c1
Reaction time: 14 h

Procedure:
A mixture of 4-(1-hydroxyundecyl)-2-trimethylsilylfuran (1.21 g, 3.89 mmol), acetic anhydride (4 ml) and pyridine (6 ml) was stirred under argon at ca. 20° for 14h. After most of the solvent was removed under high vacuum (<40°), the residue was dissolved in ether (40 ml) and washed thoroughly with aqueous copper sulfate and water. Drying (magnesium sulfate) and evaporation gave a brown oil, which was flash chromatographed on silica using 5% ethyl ether/petroleum ether. Fractions with Rf of about 0.3 on evaporation afforded the captioned compound as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH:14](=O)[CH2:15][CH2:16][CH3:17]>>[CH2:14]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1)[CH2:15][CH2:16][CH3:17]
Reactant: COC(=O)CCc1ccc(N)cc1
Reactant: CCCC=O
Product: CCCCNc1ccc(CCC(=O)OC)cc1
Yield: 35.7 %

Procedure:
Following a procedure analogous to that for the synthesis Example 106, methyl 3-(4-aminophenyl)propanoate (Jakobsen, C. M. et al., J. Med. Chem., 44:4696-4703 (2001)) (896 mg, 5.00 mmol) and butyraldehyde (397 mg, 5.50 mmol) were converted to the title compound (420 mg, 44%). 1H NMR (CDCl3) δ 7.01 (d, J=8.4 Hz, 2H), 6.60-6.47 (m, 2H), 3.68 (s, 3H), 3.10 (t, J=7.2 Hz, 2H), 2.89-2.77 (m, 2H), 2.62-2.46 (m, 2H), 1.66-1.53 (m, 2H), 1.43 (qd, J=15.0, 7.3 Hz, 2H), 0.96 (t, J=7.3 Hz, 3H); MS (ESI+) m/z 236.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.F[C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].C(N(CC)C(C)C)(C)C>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[N+:19]([O-:21])=[O:20])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CC(N)c1cccc(Br)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(Nc1cc(F)ccc1[N+](=O)[O-])c1cccc(Br)c1
Reaction time: 18 h
Yield: 73.7 %

Procedure:
A mixture of 1-(3-bromophenyl)ethanamine (1.0 g, 5.0 mmol), 2,4-difluoro-1-nitrobenzene (0.8 g, 5.0 mmol), N,N-diisopropylethylamine (1.7 mL, 10.0 mmol) and acetonitrile (20 mL) was stirred for 18 h and concentrated in vacuo. The residue was dissolved in ethyl acetate; this solution was washed with water, dried over Na2SO4 and concentrated in vacuo to yield the title compounds as a yellow oil (1.25 g, 74%). 1H NMR (400 MHz, CDCl3): δ 8.51 (d, 1H), 8.25 (m, 1H), 7.48 (s, 1H), 7.41 (m, 1H), 7.25 (m, 2H), 6.36 (m, 1H), 6.24 (m, 1H), 4.55 (m, 1H), 1.63 (d, 3H). MS (ESI) m/z: Calculated: 338; Observed: 339 (M+H+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[O:49]1[CH:53]=[CH:52][C:51]([C:54]2[N:55]=[CH:56][C:57]([NH2:60])=[N:58][CH:59]=2)=[CH:50]1.N1C=CC=CC=1>C(Cl)Cl>[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([NH:60][C:57]2[CH:56]=[N:55][C:54]([C:51]3[CH:52]=[CH:53][O:49][CH:50]=3)=[CH:59][N:58]=2)=[O:42])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: Nc1cnc(-c2ccoc2)cn1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(-c3ccoc3)cn2)cc1Cl
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 48.5 %

Procedure:
A solution of triphenylphosphine (230.0 mg, 0.877 mmol) in methylene chloride (14 mL) cooled to 0° C. was treated with N-bromosuccinimide (160.0 mg, 0.899 mmol). The reaction mixture was stirred at 0° C. for 5 min and then treated with 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 232.0 mg, 0.701 mmol). The reaction mixture was allowed to warm to 25° C. over 15 min. The reaction mixture was then treated with 5-furan-3-yl-pyrazin-2-ylamine (250.0 mg, 1.551 mmol) followed by pyridine (0.12 mL, 1.484 mmol). The resulting reaction mixture was stirred at 25° C. for 2.5 h. The reaction mixture was then diluted with methylene chloride and washed with a dilute aqueous hydrochloric acid solution. The aqueous layer was extracted with methylene chloride. The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 3/2 to 45/55 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-furan-3-yl-pyrazin-2-yl)-propionamide (161.1 mg, 48.5%) as a pale yellow foam: mp 97–101° C. (foam to gel); (ES)+-HRMS m/e calcd for C23H24ClN3O3S2 (M+H)+ 474.1249, found 474.1252.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[N:4]=[C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C@H:15]([CH3:19])[C:16]([OH:18])=O)=[CH:11][CH:10]=2)[S:6][CH:7]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:35][O:36][C:37](=[O:41])[C@@H:38]([CH3:40])[NH2:39]>C(Cl)Cl>[F:20][C:2]([F:1])([F:21])[C:3]1[N:4]=[C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([C@H:15]([CH3:19])[C:16]([NH:39][C@H:38]([CH3:40])[C:37]([O:36][CH3:35])=[O:41])=[O:18])=[CH:13][CH:14]=2)[S:6][CH:7]=1
Reactant: C[C@H](C(=O)O)c1ccc(Nc2nc(C(F)(F)F)cs2)cc1
Reactant: COC(=O)[C@@H](C)N
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COC(=O)[C@@H](C)NC(=O)[C@@H](C)c1ccc(Nc2nc(C(F)(F)F)cs2)cc1
Yield: 78.1 %

Procedure:
A cooled solution of (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoic acid (3) (0.1 g, 0.32 mmol) and CDI (0.054 g, 0.33 mmol) in dry CH2Cl2 (5 mL) was stirred for 1 h at T=0-5° C. After ice-water bath removal, a mixture of D-alanine methyl ester hydrochloride (0.045 g, 0.32 mmol) and TEA (90 μl, 0.65 mmol) was added with vigorous stirring and the resulting mixture was stirred overnight at room temperature. At the complete disappearance of the starting material, a buffer H3PO4/H2PO4− solution (pH=2.0, 5 ml) was added and the reaction mixture was transferred into a separatory funnel. The two phases were separated and the organic one washed with the same buffer (3×5 mL), dried over Na2SO4 and evaporated under vacuum to give a crude which was purified by flash chromatography. Pure methyl (2R)-2-{[(2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoyl]amino}propanoate (0.1 g, 0.25 mmol) was isolated as a yellow oil (78%).
Reaction SMILES: [CH:1]([C:4]1[CH:25]=[CH:24][C:7]([CH2:8][C:9]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:10]=2[O:11][CH2:12][C:13]([O:15]CC)=[O:14])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:10]=2[O:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:24][CH:25]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)COc1cc(C)cc(C)c1Cc1ccc(C(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(C)c(Cc2ccc(C(C)C)cc2)c(OCC(=O)O)c1
Yield: 75 %

Procedure:
Using ethyl (2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)acetate obtained in Reference Example 154, the title compound was synthesized in the same manner as in Reference Example 156. Yield 75%. Melting point: 104-105° C. (ethyl acetate-hexane).
Reaction SMILES: S1C=CC=C1S([NH2:9])(=O)=O.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:9])(=[O:21])=[O:20])=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: NS(=O)(=O)c1cccs1
Product: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
5.2.2 4-nitrobenzenesulfonamide was prepared according to the procedure for thiophene-2-sulfonamide YG1-030 except using 4-nitrobenzenesulfonyl chloride, which afforded the title compound 1.953 g (96.6%) as a pale yellow solid, m.p.: 178-180° C. 1H-NMR, 400 MHz, d6-DMSO, δ (ppm): 8.40 (d, J=8.6 Hz, 2H), 8.04 (d, J=8.6 Hz, 2H), 7.72 (br, 2H).