Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Cl)(Cl)Cl.C([O:9][C:10](=[O:49])[CH:11]=[CH:12][C:13]1[CH:18]=[C:17]([C:19]2[O:23][N:22]=[C:21]([CH3:24])[C:20]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:16]([O:33]CC2C=CC=CC=2)=[CH:15][C:14]=1[O:41]CC1C=CC=CC=1)(C)(C)C.C(=O)=O.CC(C)=O.O>ClCCl.C(OCC)(=O)C>[OH:41][C:14]1[CH:15]=[C:16]([OH:33])[C:17]([C:19]2[O:23][N:22]=[C:21]([CH3:24])[C:20]=2[C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[CH:18][C:13]=1[CH:12]=[CH:11][C:10]([OH:49])=[O:9]
Reactant: COc1ccc(-c2c(C)noc2-c2cc(C=CC(=O)OC(C)(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)cc1
Agent: ClB(Cl)Cl
Agent: O=C=O
Solvent: CC(C)=O
Solvent: O
Solvent: ClCCl
Product: COc1ccc(-c2c(C)noc2-c2cc(C=CC(=O)O)c(O)cc2O)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 30.2 %

Procedure:
Boron trichloride solution (2 ml, 1.0M in dichloromethane) was added slowly to a solution of 3-{2,4-Bis-benzyloxy-5-[4-(4-methoxy-phenyl)-3-methyl-isoxazol-5-yl]-phenyl}-acrylic acid tert-butyl ester (50 mg, 0.09 mmol) in dichloromethane (1 ml), at −78° C. (dry ice/acetone) under a nitrogen atmosphere. The resulting solution was stirred for ˜1 hr at −78° C., and for ˜90 mins. at room temperature. The solution was cooled to −78° C. and water (2 ml) added and the mixture was stirred for ˜30 mins at room temperature. Ethyl acetate (30 ml) was added and the solution washed with water (2×5 ml) and saturated aqueous sodium chloride solution (10 ml). The solution was dried over anhydrous magnesium sulphate and concentrated to a pale yellow gum. Trituration with hexane gave a yellow solid, solids were removed by filtration and washed with hexane, dried in vacuo, to give 3-{2,4-dihydroxy-5-[4-(4-methoxy-phenyl)-3-methyl-isoxazol-5-yl]-phenyl}-acrylic acid (10 mg) as yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[CH2:36]([N:40]([CH2:45][CH2:46][CH2:47][CH3:48])[CH2:41][CH2:42][CH2:43][NH2:44])[CH2:37][CH2:38][CH3:39]>C(Cl)Cl>[CH2:36]([N:40]([CH2:45][CH2:46][CH2:47][CH3:48])[CH2:41][CH2:42][CH2:43][NH:44][C:16]1[N:17]=[C:18]([C:19]2[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=2[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]2[CH2:12][NH:11][C:10](=[O:35])[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[C:14]=2[N:15]=1)[CH2:37][CH2:38][CH3:39]
Reactant: CCCCN(CCCC)CCCN
Reactant: CCCNC(=O)c1ccc(C)c(-c2nc(S(C)=O)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Solvent: ClCCl
Product: CCCCN(CCCC)CCCNc1nc(-c2cc(C(=O)NCCC)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Yield: 80.4 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide (30 mg, 0.06 mmol) in DCM (5 mL) was added N,N-dibutyl-1,3-propanediamine (0.06 mL, 0.26 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (30 mg, 83%). LC-MS m/z 622 (M+H)+; 1H-NMR (MeOD) δ 1.00 (m, 10H), 1.30 (m, 4H), 1.50 (m, 9H), 2.31 (s, 3H), 2.38 (m, 4H), 2.48 (m, 2H), 3.08 (m, 2H), 4.11 (s, 2H), 7.17 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H), 7.69 (s, 1H), 7.86 (d, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][CH2:10][CH2:11][CH2:12][N:13]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:7][CH:6]=1.O.NN>C(O)C>[NH2:13][CH2:12][CH2:11][CH2:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][N:2]([CH3:26])[CH3:1])=[CH:25][CH:24]=1
Reactant: CN(C)CCc1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: CN(C)CCc1ccc(OCCCN)cc1

Procedure:
2-[3-[4-[2-(Dimethylamino)ethyl]phenoxy]propyl]-1H-isoindole-1,3-(2H)-dione (2.1 g) and hydrazine hydrate (1.2 ml) were heated at reflux in ethanol for 4 h. The solvent was evaporated and the residue was distilled to give the title compound as a clear yellow oil b.p. 170° (0.1 mm). TLC silica; ethyl acetate:water:isopropanol:0.88 ammonia 25:8:15:2; Rf 0.35.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[C:6]([C:8]2(O)[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:21])[CH:7]=1.C(N(S(F)(F)[F:41])CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[C:6]([C:8]2([F:41])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:21])[CH:7]=1
Reactant: O=C1Nc2cc(C(F)(F)F)ccc2C1(O)c1cc(Cl)ccc1OCc1ccc(C(F)(F)F)cc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: O=C1Nc2cc(C(F)(F)F)ccc2C1(F)c1cc(Cl)ccc1OCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 77.2 %

Procedure:
To a suspension of (±)-3-[5-chloro-2-[4-(trifluoromethyl)phenyl-methoxy]phenyl]-1,3-dihydro-3-hydroxy-6-(trifluoromethyl)-2H-indole-2-one (Preparation 6, 45 mg, 0.09 mmol) in CH2Cl2 (3 mL), was added dropwise neat diethylaminosulfur trifluoride (0.018 mL, 0.135 mmol) at −78° C. The reaction mixture was warmed to room temperature for 15 minutes and then quenched with water. The organic layer was separated, washed with water, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to provide the title compound (35 mg, 77% yield). MS m/e 502 (MH−). 1H NMR (CDCl3): δ7.84 (d, J=1.95 Hz, 1H), 7.68 (s, 1H), 7.53 (d, J=8.1 Hz, 2H), 7.36 (dd, J=8.7 Hz, 2.5 Hz, 1H), 7.29 (m, 1H), 7.21 (m, 1H), 7.05 (d, J=8.1 Hz, 2H), 6.81(dd, J=8.8 Hz, 1.1 Hz, 1H), 6.73 (s, 1H), 4,88 (d, 11.0 Hz, 1H), 4.73 (d, J=11.0 Hz,1H).
Reaction SMILES: [Li].[Br:2][C:3]1[CH:4]=[C:5]([C:14]([O-])=[CH:15][C:16](=O)[C:17]([O:19]CC)=[O:18])[CH:6]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:8]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[CH3:47][O:48][C:49]1[CH:54]=[C:53]([NH:55][NH2:56])[CH:52]=[CH:51][N:50]=1>>[Br:2][C:3]1[CH:4]=[C:5]([C:14]2[N:55]([C:53]3[CH:52]=[CH:51][N:50]=[C:49]([O:48][CH3:47])[CH:54]=3)[N:56]=[C:16]([C:17]([OH:19])=[O:18])[CH:15]=2)[CH:6]=[C:7]([O:9][C:10]([F:11])([F:12])[F:13])[CH:8]=1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(Br)cc(OC(F)(F)F)c1
Reactant: COc1cc(NN)ccn1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: COc1cc(-n2nc(C(=O)O)cc2-c2cc(Br)cc(OC(F)(F)F)c2)ccn1

Procedure:
500 mg (1.16 mmol) of the compound of Example 5A is reacted analogously to the synthesis of the compound of Example 20A with 305 mg (1.74 mmol) of 2-methoxypyridin-4-yl-hydrazine hydrochloride. After hydrolysis, 18 mg (3% of theory) of the title compound is obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]#[N:9])[N:3]=1.[CH3:10][NH:11][CH3:12].C(#N)C.C1COCC1>O.C(OCC)(=O)C>[C:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:11]([CH3:12])[CH3:10])[N:3]=1)#[N:9]
Reactant: CNC
Reactant: N#Cc1cncc(Cl)n1
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CN(C)c1cncc(C#N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
2-Chloro-6-cyanopyrazine (0.85 g, 6.09 mmol) and 1.67 N dimethylamine in acetonitrile (4.00 ml, 6.70 mmol) were added to THF (100 ml), and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the titled compound (0.50 g, 55%) as pale yellow crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7]P(=O)(OCC)OCC)[CH:2]=1.C(O[K])(C)(C)C.[CH:22]([C:24]1[C:32]2[C:27](=[CH:28][C:29]([C:33]#[N:34])=[CH:30][CH:31]=2)[NH:26][N:25]=1)=O.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[CH:7]=[CH:22]/[C:24]2[C:32]3[C:27](=[CH:28][C:29]([C:33]#[N:34])=[CH:30][CH:31]=3)[NH:26][N:25]=2)[CH:2]=1
Reactant: N#Cc1ccc2c(C=O)n[nH]c2c1
Reactant: CCOP(=O)(Cc1cccnc1)OCC
Agent: CC(C)(C)O[K]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2c(/C=C/c3cccnc3)n[nH]c2c1
Temperature: 0 °C
Reaction time: 0.05 h
Yield: 67 %

Procedure:
Diethyl pyridin-3-ylmethylphosphonate was redissolved in DMF (50 mL), cooled to 0° C. and treated with tBuOK (6.72 g, 60 mmol) portion wise over 3 min; the reaction turned a dark reddish brown. After stiffing for 3 min at 0° C., a solution of 3-formyl-1H-indazole-6-carbonitrile (3.42 g, 20 mmol) in DMF (25 mL) was added dropwise by pipette over 5 min. After addition, the resulting mixture was stirred for 1 h at 0° C. before quenching with ice (100 mL). The reaction mixture was cooled to 0° C. and slowly acidified with 2M HCl until pH 5. During this addition, a copious amount of precipitate was formed. After stirring for 2 min at this temperature, sat NaHCO3 was added slowly until pH 8 and the mixture was stirred for an additional 2 min Water was added until the total volume reached 600 mL. After stirring for 10 min, the resulting precipitate was collected by suction filtration and rinsed thoroughly with water, then dried under high vacuum to give the title compound (3.30 g, 67%) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 13.80 (s, 1H, NH), 8.89 (s, 1H), 8.48 (d, J=4.4 Hz, 1H), 4.42 (d, J=8.4 Hz, 1H), 8.22-8.17 (m, 2H), 7.74 (d, J=16.8 Hz, 1H), 7.59 (d, J=18.0 Hz, 1H, partially overlapping with the doublet at 7.55 ppm), 7.55 (d, J=10.0 Hz, 1H, partially overlapping with the doublet at 7.59 ppm), 7.43 (dd, J=8.0 Hz, 5.6 Hz, 1H); MS ESI 247.0 [M+H]+, calcd for [C15H10N4+H]+ 247.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]([CH2:11][C:12](O)=[O:13])[O:7][C:6]=2[CH:15]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[OH:13][CH2:12][CH2:11][CH:8]1[O:7][C:6]2[CH:15]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[O:10][CH2:9]1
Reactant: Cc1ccc2c(c1)OC(CC(=O)O)CO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2c(c1)OC(CCO)CO2

Procedure:
The preparation of various new starting materials is illustrated as follows: The solution of 48.6 g of 2-(7-methyl-1,4-benzodioxan-2-yl)-acetic acid in the minimum amount of tetrahydrofuran is added dropwise at reflux rate to the stirred suspension of 13.4 g of lithium aluminum hydride in 200 ml dry tetrahydrofuran. The mixture is refluxed overnight, cooled, and decomposed by the addition of 13.4 ml of water, 13.4 ml 15% aqueous sodium hydroxide and 40 ml of water. It is filtered, evaporated, the residue distilled in a molecular still, and the fraction boiling at 155°-165°/0.1 mm Hg collected as colorless oil, to yield the 2-(2-hydroxyethyl)-7-methyl-1,4-benzodioxan.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1([N:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16]2[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(O)(C)C>[C:1]1([NH:7][N:8]=[CH:20][C:19]2[CH:18]=[CH:17][C:16]([N:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: NNc1ccccc1
Solvent: CC(C)O
Product: C(=NNc1ccccc1)c1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
Phenylhydrazine (0.1 mole, commercially available from Aldrich, Milwaukee, Wis.) and 4-(Diphenylamino) benzaldehyde (0.1 mole, available from Fluka, Buchs SG, Switzerland) were dissolved in 100 ml of isopropanol in a 250 ml 3-neck round bottom flask equipped with reflux condenser and mechanical stirrer. The solution was refluxed for 2 hours. Thin layer chromatography indicated the disappearance of the starting materials. At the end of the reaction, the mixture was cooled to room temperature. The 4-(diphenylamino) benzaldehyde phenylhydrazone crystals that formed upon standing were filtered off and washed with isopropanol and dried in vacuum oven at 50° C. for 6 hours.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6][CH2:5]2.C([Li])CCC.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:27]([C:30]2([OH:69])[C@H:35]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C@@H:34]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C@H:33]([O:52][CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C@@H:32]([CH2:60][O:61][CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[O:31]2)=[CH:26][C:23]=1[CH:24]=[O:25].[Li]>C1COCC1.C1(C)C=CC=CC=1>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:27]([C:30]2([OH:69])[C@H:35]([O:36][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C@@H:34]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C@H:33]([O:52][CH2:53][C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[C@@H:32]([CH2:60][O:61][CH2:62][C:63]3[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=3)[O:31]2)=[CH:26][C:23]=1[C:24]([C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6][CH2:5]2)=[O:25]
Reactant: COc1ccc(C2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1C=O
Reactant: Brc1ccc2c(c1)CCC1(CCC1)O2
Agent: [Li]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc(C2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1C(=O)c1ccc2c(c1)CCC1(CCC1)O2
Reaction time: 1 h
Yield: 65.6 %

Procedure:
To a stirred solution of 6-bromospiro[chromane-2,1′-cyclobutane] (0.563 g, 2.23 mmol) in THF (3 mL) at −78° C. was added n-butyl lithium (1.45 mL, 2.23 mmol) and stirred for 1 h. Compound obtained in step III (0.3 g, 0.45 mmol) in toluene (3 mL) was cooled to −78° C. and lithium salt prepared above was added to this at −78° C. This reaction mixture was stirred for 1 h, quenched with sat. NH4Cl (10 mL) and extracted with ethyl acetate (2×20 mL). The ethyl acetate layer was washed with water, brine, dried over sodium sulphate, concentrated and purified by silica gel column chromatography to furnish [2-methoxy-5-[(3R,4S,5R,6R)-3,4,5-tribenzyloxy-6-(benzyloxymethyl)-2-hydroxytetrahydropyran-2-yl]phenyl]-spiro[chromane-2,1′-cyclobutane]-6-yl-methanone (0.250 g).
Reaction SMILES: [NH:1]([CH2:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:23]([O:25][CH3:26])=[O:24]>C(OCC)(=O)C>[CH3:26][O:25][C:23]([N:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][CH:13]=1)=[O:10])=[O:24]
Reactant: COC(=O)Cl
Reactant: NS(=O)(=O)c1ccc(NC(=O)CNc2ccccc2)cc1
Solvent: CCOC(C)=O
Product: COC(=O)N(CC(=O)Nc1ccc(S(N)(=O)=O)cc1)c1ccccc1

Procedure:
2-Anilino-N-(4-sulphamoylphenyl)-acetamide (9.0 g) was heated with methyl chloroformate (30 ml) for 45 min. at 140°C. Work up from ethyl acetate/wate gave 7.0 g, m.p. 196° - 199°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=O.[NH:13]1[CH2:19][C:17](=[O:18])[NH:16][C:14]1=[O:15].C(CN)O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=[C:19]1[NH:13][C:14](=[O:15])[NH:16][C:17]1=[O:18]
Reactant: O=C1CNC(=O)N1
Reactant: COc1cc(C=O)cc(OC)c1
Solvent: NCCO
Solvent: O
Product: COc1cc(C=C2NC(=O)NC2=O)cc(OC)c1
Reaction time: 4 h
Yield: 76.9 %

Procedure:
A mixture of 3,5-dimethoxybenzaldehyde (2.550 g.) and hydantoin (1.505 g., 1 molar ratio) in water (15 ml) was heated to 70°. Monoethanolamine (1.38 g., 1.5 molar ratio) was added and the 2 layer liquid mixture was magnetically stirred at 90°-92° (bath temperature) for 4 hours. Isolation in the usual manner gave the title compound as a beige solid (2.870 g.), m.p. 285°-287°.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:4]([NH2:15])[CH:3]=1.[O:16]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23](Cl)=O)=[CH:17]1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[C:49]([OH:54])(=[O:53])[C:50]([OH:52])=[O:51]>C(OCC)(=O)C>[C:49]([OH:54])(=[O:53])[C:50]([OH:52])=[O:51].[O:16]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[C:5]3[CH:13]=[CH:14][C:2]([CH3:1])=[CH:3][C:4]=3[N:15]=2)=[CH:17]1
Reactant: Cc1ccc(Nc2ccccn2)c(N)c1
Reactant: O=C(Cl)/C=C/c1ccoc1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)nc(/C=C/c1ccoc1)n2-c1ccccn1

Procedure:
Free base of the titled compound was prepared from 4-methyl-2-amino-N-(2-pyridyl)aniline and (E)-3-(3-furyl)acryloyl chloride according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate/n-hexane yielded the titled compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:27][C:28]1[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:29]=1[CH2:30][O:31][C:32]1[CH:47]=[CH:46][C:35]2[C:36]([O:42][CH2:43][O:44][CH3:45])=[C:37]([C:39](O)=[O:40])[S:38][C:34]=2[CH:33]=1>O.CN(C=O)C>[Cl:27][C:28]1[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:29]=1[CH2:30][O:31][C:32]1[CH:47]=[CH:46][C:35]2[C:36]([O:42][CH2:43][O:44][CH3:45])=[C:37]([C:39]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[O:40])[S:38][C:34]=2[CH:33]=1
Reactant: COCCN
Reactant: COCOc1c(C(=O)O)sc2cc(OCc3ccc(Cl)cc3Cl)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COCCNC(=O)c1sc2cc(OCc3ccc(Cl)cc3Cl)ccc2c1OCOC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-methoxyethylamine (0.082 mL), EDCI (181 mg), HOBt (128 mg), 6-((2,4-dichlorobenzyl)oxy)-3-(methoxymethoxy)-1-benzothiophene-2-carboxylic acid (260 mg) and DMF (5 mL) was stirred at room temperature for 18 h. Water was added to the mixture, and the mixture was extracted with EtOAc. The EtOAc extract was washed successively with 1N HCl, saturated aqueous NaHCO3 and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (205 mg). The obtained crystals were recrystallized from EtOAc-hexane.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:38][O:39][CH2:40][C:41]([O:43][CH2:44][C:45]([Cl:48])([Cl:47])[Cl:46])=[O:42])[C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([O:22]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(OC(C)C)(C)C>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:38][O:39][CH2:40][C:41]([O:43][CH2:44][C:45]([Cl:46])([Cl:48])[Cl:47])=[O:42])[C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OCC(Cl)(Cl)Cl)c3csc(N)n3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Solvent: COc1ccccc1
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)OCC(Cl)(Cl)Cl)c3csc(N)n3)[C@H]2SC1
Yield: 79.6 %

Procedure:
A solution of benzhydryl 7-[2-(2-aminothiazol-4-yl)-2-(2,2,2-trichloroethoxycarbonylmethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (2.5 g) in trifluoroacetic acid (7.5 ml) and anisole (2.5 ml) was stirred at ambient temperature for 30 minutes. The reaction mixture was poured into diisopropyl ether, and the precipitates were collected by filtration, followed by dissolving them in a saturated aqueous sodium bicarbonate (50 ml). The aqueous solution was washed with ethyl acetate, adjusted to pH 2.0 with 10% hydrochloric acid and then extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride and then dried over magnesium sulfate. Removal of the solvent gave 7-[2-(2-aminothiazol-4-yl)-2-(2,2,2-trichloroethoxycarbonylmethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (1.55 g).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[OH:5].[C:14](=[S:16])=[S:15]>>[C:14](=[S:16])([SH:15])[NH2:2].[CH3:1][NH:2][CH2:3][C@@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[OH:5]
Reactant: S=C=S
Agent: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: NC(=S)S

Procedure:
N-Methyl-D-glucamine and carbon disulfide were obtained from Aldrich (Milwaukee, Wis.). N-Methyl-D-glucamine dithiocarbamate (MGD) was synthesized by following the method of Shinobu et al. (Acta Pharmacol. Toxicol. 54:189-194 (1984)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[C:11]([CH2:16][OH:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)O)=[CH:4][CH:3]=1.P(=O)(O)(O)O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:10]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:16][O:17]2)=[CH:6][CH:7]=1
Reactant: OCc1ccccc1C(O)c1ccc(F)cc1
Agent: O=P(O)(O)O
Product: Fc1ccc(C2OCc3ccccc32)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 200 parts of α-(4-fluorophenyl)-1,2-benzenedimethanol and 2295 parts of phosphoric acid 60% was stirred for 3 hours at 100° C. Stirring was continued overnight at room temperature. The reaction mixture was poured onto water and the product was extracted twice with 1,1'-oxybisethane. The combined extracts were washed with water, with a 10% sodium carbonate solution and again with water, dried, filtered and evaporated. The residue was distilled, yielding 57 parts of 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran; bp. 108° C. at 0.2 mm. pressure (intermediate 9).
Reaction SMILES: [F:1][C:2]1[C:3]([N:8]2[CH:12]=[C:11]([C:13](OC(C)C)=[O:14])[C:10]([CH2:19][O:20][CH:21]([CH3:23])[CH3:22])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C(OCC)C.O1CCCC1>[F:1][C:2]1[C:3]([N:8]2[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([CH2:19][O:20][CH:21]([CH3:23])[CH3:22])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)OCc1nn(-c2ncccc2F)cc1C(=O)OC(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)OCc1nn(-c2ncccc2F)cc1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a solution of isopropyl 1-(3-fluoro-2-pyridyl)-3-(isopropoxymethyl)pyrazole-4-carboxylate (316 mg, 0.98 mmol) in diethyl ether (4.9 mL) under nitrogen and cooled to 0° C., 1M lithium aluminium hydride in tetrahydrofuran (1.2 mL) is added. The mixture is stirred at 0° C. for 1 hour. Water (46 μL) is added and stirred for 5 min, then 15% aqueous solution of NaOH (46 μL) and water (138 μL) are successively added. Solids are filtered and solvent evaporated to obtain 241 mg of [1-(3-fluoro-2-pyridyl)-3-(isopropoxymethyl)pyrazol-4-yl]methanol that is used without further purification. MS (m/z): 266 (M+1).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][P:7](=[O:14])([O:11]CC)[O:8]CC>Cl.CCO>[F:18][C:2]([F:1])([F:19])[C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][P:7](=[O:8])([OH:11])[OH:14]
Reactant: CCOP(=O)(Cc1cccc(C(F)(F)F)c1)OCC
Agent: Cl
Solvent: CCO
Product: O=P(O)(O)Cc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Yield: 85.4 %

Procedure:
Diethyl 3-trifluoromethylbenzylphosphonate (3.0 g, 10.0 mmol) was dissolved in a mixture of 50 mL of conc hydrochloric acid and 1.5 mL of EtOH and was heated at reflux for 17 hours. After cooling the clear reaction mixture in an ice-water mixture, the white crystalline solid which formed was collected to give 2.05 g (84.3%) of the analytical product, mp=163°-164° C.; D.C.I.M.S.[MH+,241].