Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N+:3]([CH:6]=[C:7]1[NH:11][CH2:10][CH2:9][NH:8]1)([O-:5])=[O:4].[CH2:12](Br)[CH:13]=[CH2:14].S([O-])([O-])(=O)=O.[Na+].[Na+]>CN(C)C=O>[N+:3]([CH:6]=[C:7]1[NH:11][CH2:10][CH2:9][N:8]1[CH2:14][CH:13]=[CH2:12])([O-:5])=[O:4]
Reactant: O=[N+]([O-])C=C1NCCN1
Reactant: C=CCBr
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN1CCNC1=C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 31.1 %

Procedure:
To 1.77 grams of a 57% by weight dispersion of sodium hydride in oil in 50 milliliters of dry dimethylformamide was added 5.16 grams of 2-(nitromethylene)imidazolidine. The mixture was cooled with an icebath, stirred and maintained under a nitrogen atmosphere. After 1.5 hours, 5.08 grams of allyl bromide was added. The mixture was stirred at about 10° for an additional hour, then allowed to warm to room temperature and poured into 400 milliliters of saturated aqueous sodium sulfate. The resulting mixture was extracted thrice with 300 milliliter portions of methylene chloride. The combined extract was dried (magnesium sulfate) and the solvent was evaporated. Addition of ether to the residue gave an oily red solid, which on recrystallization from chloroform (charcoal), gave 2.1 grams of 4 as tan crystals, melting point: 97°-98°.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:43])[C@@H:24]([NH:25][C:26](=[O:42])[CH:27]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[NH:28]C(OC(C)(C)C)=O)[C@H:21]3[S:20][CH2:19][C:18]=2[S:44][CH:45](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:46][C:47]2[N:48]=[N:49][NH:50][CH:51]=2)=[O:16])C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)C(O)=O.C(OCC)(=O)C>C1(OC)C=CC=CC=1.ClCCl>[C:36]1([CH:27]([C:26]([NH:25][C@@H:24]2[C:23](=[O:43])[N:22]3[C:17]([C:15]([OH:16])=[O:14])=[C:18]([S:44][CH2:45][S:46][C:47]4[N:48]=[N:49][NH:50][CH:51]=4)[CH2:19][S:20][C@H:21]23)=[O:42])[NH2:28])[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)NC(C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SC(Sc3c[nH]nn3)C(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: NC(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(SCSc3c[nH]nn3)CS[C@H]12)c1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 67.4 %

Procedure:
To a solution of 7β-(N-t-butoxycarbonyl-2-phenylglycylamino)-3-(trityl-1,2,3-triazol-4-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (480 mg: 0.487 mMol.) in a mixture of anisole (1.2 ml) and dichloromethane (3 ml) under ice cooling is added trifluoro- acetic acid (3 ml), and the mixture is stirred under ice cooling for 30 minutes and at room temperature for 50 minutes. The reaction mixture is shaken with ice water and ethyl acetate under ice cooling. The aqueous layer is taken, concentrated to remove the remaining organic solvents under reduced pressure, and subjected to column chromatography over styrene-divinylbenzene copolymer resin (methanol: water=4:1). The residue is pulverized from ethyl acetate to give 7β-(2-phenylglycylamino)-3-(1,2,3-triazol-4-ylthiomethylthio)-3-cephem-4-carboxylic acid (157 mg) as white powder. Yield: 67%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([C:14]2[NH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=3)=[CH:17][N:18]=2)[CH:12]2[CH2:26][CH:9]1CC2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[C:32]([N:34]1CC(C#N)CC1C(=O)NCC(C1C=CC(Br)=CC=1)=O)=O)(C)(C)C.C(OC(N1C(C(=O)NCC(C2C=CC(Br)=CC=2)=O)C2CC1CC2)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:26]([C:32]#[N:34])[CH2:12][CH:13]1[C:14]1[NH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)=[CH:17][N:18]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(Br)cc2)[nH]1
Reactant: CC(C)(C)OC(=O)N1CC(C#N)CC1C(=O)NCC(=O)c1ccc(Br)cc1
Agent: CC(C)(C)OC(=O)N1C2CCC(C2)C1C(=O)NCC(=O)c1ccc(Br)cc1
Product: CC(C)(C)OC(=O)N1CC(C#N)CC1c1ncc(-c2ccc(Br)cc2)[nH]1

Procedure:
Title compound was prepared according to the method employed to prepare 3-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (Example AS), 2-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-4-cyano-pyrrolidine-1-carboxylic acid tert-butyl ester for 3-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[N:16][C:17]=4[NH2:19])[N:12]([CH3:20])[N:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30](O)=[O:31])[CH:25]=[C:26]([Cl:28])[CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O>[Cl:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]4[C:18]5[C:13](=[N:14][CH:15]=[N:16][C:17]=5[NH2:19])[N:12]([CH3:20])[N:11]=4)=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)=[O:31])[CH:25]=[C:26]([Cl:28])[CH:27]=1
Reactant: O=C(O)Cc1cc(Cl)cc(Cl)c1
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1nc(-c2ccc3c(c2)CCN3C(=O)Cc2cc(Cl)cc(Cl)c2)c2c(N)ncnc21
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
A solution of 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (89 mg, 0.293 mmol), (3,5-dichlorophenyl)acetic acid (60 mg, 0.293 mmol), HATU (111 mg, 0.293 mmol), DIEA (0.204 mL, 1.171 mmol) was stirred at room temperature overnight. The crude was poured into water and stirred for 30 minutes. The precipitate that formed was collected by filtration, washed with water and dried at the pump for 30 minutes. The crude was adsorbed onto silica and purified by flash chromatography (0-10% methanol in DCM), concentrated and dried overnight in a vacuum oven to afford 3-{1-[(3,5-dichlorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (80 mg) as a white solid. LCMS (ES) m/z=453, 455 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.29 (t, J=9.60 Hz, 2H), 3.94 (s, 3H), 3.97 (s, 2H), 4.26 (t, J=8.59 Hz, 2H), 7.40 (d, J=2.02 Hz, 2H), 7.45 (d, J=8.08 Hz, 1H), 7.53 (d, J=1.77 Hz, 2H), 8.17 (d, J=8.34 Hz, 1H), 8.25 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:11][N:10](C(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:9]2)=[CH:4][CH:3]=1.[C:25](Cl)(Cl)=[O:26]>ClCCl.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][N:10]([C:25]([NH:10][CH2:9][C:8]#[CH:5])=[O:26])[CH2:11]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(C2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C#CCNC(=O)N1CC(c2ccc(F)cc2)C1
Reaction time: 1.5 h

Procedure:
To a stirred solution of 3-(4fluorophenyl)-1-(diphenylmethyl)azetidine (17) (0.38 g) in dichloromethane (5 mL) at 0° C. was added dropwise a solution of 20% phosgene in toluene (1.4 mL). The mixture was stirred for 90 minutes then concentrated in vacuo. To the concentrate was added dichloromethane (5 mL) and to this solution at 0° C. was added, dropwise, with stirring propargylaminc (0.3 mL). The mixture was stirred for 18 hrs at room temperature, diluted with dichworomethane (20 mL), washed (water, brine), dried (Na2SO4) and concentrated in vacuo. The crude material was purified by flash column chromatography (50% ethyl acetate hexane) and then crystallised from diisopropyl ether to give 3-(4-fluoropenyl)-N-(2-propynyl)azetidine-1-carboxamide (19) (0.14 g), m.p. 141° C. (diisopropyl ether). Found: C, 67.32; H, 5.65; N, 11.93. C13Hi3FN2O requires C, 67.23; H, 5.64; N, 12.06%.
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5]CC)[O:2][CH2:3][CH3:4].Br[CH2:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[C:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:19]2[CH3:22])=[C:15]([C:28]([F:31])([F:30])[F:29])[CH:14]=1>>[CH2:9]([O:8][P:1]([CH2:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[C:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:19]2[CH3:22])=[C:15]([C:28]([F:31])([F:30])[F:29])[CH:14]=1)([O:2][CH2:3][CH3:4])=[O:5])[CH3:10]
Reactant: CCOC(=O)c1cc2c(C(F)(F)F)cc(CBr)cc2n1C
Reactant: CCOP(OCC)OCC
Product: CCOC(=O)c1cc2c(C(F)(F)F)cc(CP(=O)(OCC)OCC)cc2n1C
Temperature: 140 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
Under nitrogen, triethyl phosphite (589 μl, 3.43 mmol) was added to ethyl 6-(bromomethyl)-1-methyl-4-(trifluoromethyl)-1H-indole-2-carboxylate (250 mg, 0.687 mmol), and the resulting mixture was stirred for 2 hours while being maintained at 140° C. The excess triethyl phosphite was distilled off as much as possible, and the resulting concentrated residue was purified by a silica gel column chromatography (eluent: n-hexane/ethyl acetate=15/1, 10/1, 3/1, 1/1, 1/4 and 0/10) to obtain 276 mg of ethyl 6-[(diethoxyphosphoryl)methyl]-1-methyl-4-(trifluoromethyl)-1H-indole-2-carboxylate as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=[O:21])=[CH:16][CH:15]=3)=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30]C#N)=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:21][N:20]=[C:17]3[CH:18]=[CH:19][C:14]([C:13]4[N:9]([C:6]5[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)[N:10]=[CH:11][CH:12]=4)=[CH:15][C:16]=23)=[CH:26][CH:25]=1
Reactant: N#CCc1ccc(F)cc1
Reactant: COc1ccc(-n2nccc2-c2ccc([N+](=O)[O-])cc2)cc1
Product: COc1ccc(-n2nccc2-c2ccc3noc(-c4ccc(F)cc4)c3c2)cc1

Procedure:
The title compound, light green solid (51 mg, 39%), MS (ISP) m/z=386.2 [(M+H)+], mp 179° C., was prepared in accordance with the general method of example 1 from 1-(4-methoxy-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate G) (100 mg, 353 μmol) and commercially available 2-(4-fluoro-phenyl)-acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:28])[C:9]=1[N:10]1[CH:27]=[C:13]2[C:14]([NH:19][C:20]3[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22][N:21]=3)=[N:15][CH:16]=[C:17](Cl)[C:12]2=[N:11]1)[C:5]#[N:6].ClC1C=C(C=C(Cl)C=1N1C=C2C(Cl)=NC=C([F:46])C2=N1)C#N.CC1N=CN=C(N)C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:28])[C:9]=1[N:10]1[CH:27]=[C:13]2[C:14]([NH:19][C:20]3[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22][N:21]=3)=[N:15][CH:16]=[C:17]([F:46])[C:12]2=[N:11]1)[C:5]#[N:6]
Reactant: N#Cc1cc(Cl)c(-n2cc3c(Cl)ncc(F)c3n2)c(Cl)c1
Reactant: Cc1cc(Nc2ncc(Cl)c3nn(-c4c(Cl)cc(C#N)cc4Cl)cc23)ncn1
Agent: Cc1cc(N)ncn1
Product: Cc1cc(Nc2ncc(F)c3nn(-c4c(Cl)cc(C#N)cc4Cl)cc23)ncn1
Yield: 41 %

Procedure:
Following the procedure described for 3,5-dichloro-4-[7-chloro-4-(6-methylpyrimidin-4-ylamino)pyrazolo[4,3-c]pyridin-2-yl]benzonitrile, 3,5-dichloro-4-(4-chloro-7-fluoro-pyrazolo[4,3-c]pyridin-2-yl)-benzonitrile and 6-methylpyrimidin-4-ylamine were reacted to afford the title compound as a white solid (35 mg, 41% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.79 (s, 1H), 9.33 (d, J=2.6 Hz, 1H), 8.69 (d, J=1.2 Hz, 1H), 8.51 (s, 2H), 8.34 (s, 1H), 8.00 (d, J=3.5 Hz, 1H), 2.44 (s, 3H). LCMS (Method B): RT=3.39 min, m/z: 416 [M+H+].
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]2[CH2:17][O:16]2)=[CH:9][CH:8]=1)(C)(C)C.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]1[C:33]2[C:32]([N:34]3[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]3)=[N:31][CH:30]=[N:29][C:28]=2[S:27][CH:26]=1>>[OH:16][CH:15]([CH2:17][NH:40][CH:37]1[CH2:36][CH2:35][N:34]([C:32]2[C:33]3[C:25]([C:21]4[S:20][CH:24]=[CH:23][CH:22]=4)=[CH:26][S:27][C:28]=3[N:29]=[CH:30][N:31]=2)[CH2:39][CH2:38]1)[CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([OH:6])=[CH:12][CH:11]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(OCC2CO2)cc1
Reactant: NC1CCN(c2ncnc3scc(-c4cccs4)c23)CC1
Product: Oc1ccc(OCC(O)CNC2CCN(c3ncnc4scc(-c5cccs5)c34)CC2)cc1
Yield: 27 %

Procedure:
Synthesis followed SP6 (5 h), using 150 μmol tert-butyldimethyl(4-(oxiran-2-ylmethoxy)phenoxy)silane and 1-(5-(2-thienyl)thieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine to give O-silylated intermediate upon purification by prep. HPLC (reversed phase) and prep. TLC (1 mm silica gel, CH2Cl2MeOH 95:5) with 27% yield. Product was obtained by deprotection according to SP7 and purification by prep. HPLC (reversed phase) with 27% yield.
Reaction SMILES: [C:1]([C:3]1[C:8](Cl)=[CH:7][C:6]([Cl:10])=[CH:5][N:4]=1)#[N:2].[C:11]([O:15][CH3:16])(=[O:14])[CH2:12][SH:13].C[O-].[Na+]>C1COCC1>[NH2:2][C:1]1[C:3]2=[N:4][CH:5]=[C:6]([Cl:10])[CH:7]=[C:8]2[S:13][C:12]=1[C:11]([O:15][CH3:16])=[O:14]
Reactant: N#Cc1ncc(Cl)cc1Cl
Reactant: COC(=O)CS
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1sc2cc(Cl)cnc2c1N
Reaction time: 2 h
Yield: 25.3 %

Procedure:
The product from Example 27A (3,46 g, 20 mmol) and methyl thioglycolate (1.8 mL, 20 mmol) were combined in 40 mL THF. To the solution was added 1.08 g NaOMe (20 mmol) After 1.5 h, and additional 1.08 g NaOMe was added, and then after an additional 2 h, the reaction was quenched in 5% aq. NaHCO3 and extracted with diethyl ether. The organic extracts were dried (MgSO4), evaporated, and the product was purified by silica gel colmun chromatography to yield 1.23 g (25%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 3.92 (s, 3H), 6.20 (br s, 2H), 8.04 (d, 1H), 8.54 (d, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][CH2:23][O:24][Si](C(C)(C)C)(C)C)[C:20]([CH2:32][Cl:33])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][CH2:23][OH:24])[C:20]([CH2:32][Cl:33])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCCn1c(CCl)nc2cnc3cc(OCc4ccccc4)ccc3c21
Solvent: CC(=O)O
Solvent: O
Product: OCCn1c(CCl)nc2cnc3cc(OCc4ccccc4)ccc3c21
Temperature: 50 °C
Reaction time: 1 h
Yield: 104.2 %

Procedure:
A 500 mL round bottom flask was charged with 7-(benzyloxy)-1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-(chloromethyl)-1H-imidazo[4,5-c]quinoline (30 g, 0.06 mol), acetic acid (300 mL), and water (60 mL). The suspension was heated at 50° C. for 24 hours. The heat was removed and the greenish homogeneous solution was concentrated to dryness. The solid was stirred in diethyl ether (300 mL) for 1 hour, isolated by vacuum filtration, washed with diethyl ether (100 mL), and dried on vacuum funnel to provide 23 g of 2-[7-(benzyloxy)-2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethanol as a green solid.
Reaction SMILES: [CH:1](=[C:8]([CH2:12][C:13]([N:15]1[CH2:23][C@H:22]2[C@H:17]([CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:16]1)=[O:14])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Rh].C1CCC=CCCC=1.F[B-](F)(F)F.[H+]>[CH:5]1[CH:4]=[CH:3][C:2]([CH2:1][C@H:8]([C:9]([OH:11])=[O:10])[CH2:12][C:13]([N:15]2[CH2:16][C@H:17]3[C@H:22]([CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:23]2)=[O:14])=[CH:7][CH:6]=1
Reactant: O=C(O)C(=Cc1ccccc1)CC(=O)N1C[C@H]2CCCC[C@H]2C1
Agent: [Rh]
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: C1=CCCC=CCC1
Product: O=C(O)[C@H](CC(=O)N1C[C@H]2CCCC[C@H]2C1)Cc1ccccc1

Procedure:
The preparation was carried out in the same manner as in Example 1, except that 1.94 mg of rhodium-1,5-cyclooctadiene-tetrafluoroboric acid complex hydrate (S/C=10000) was used instead of 1.18 mg of rhodium-1,5-cyclooctadiene-chloride complex of Example 1. After the reaction, the residual ratio of 2-benzylidene-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionic acid was 2.21%, and the optical purity of mitiglinide thus obtained was 95.9% e.e.
Reaction SMILES: O.NN.[C:4]([O:8][C:9]([N:11]1[C:24]2[C:16](=[CH:17][C:18]3[CH2:19][O:20][CH2:21][C:22]=3[CH:23]=2)[C@@H:15]([N:25]([CH2:44][C:45]2[CH:50]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:48]=[C:47]([C:55]([F:58])([F:57])[F:56])[CH:46]=2)[C:26]2[N:27]=[N:28][N:29]([CH2:31][CH2:32][N:33]3C(=O)C4C(=CC=CC=4)C3=O)[N:30]=2)[CH2:14][CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].CO.ClCCl>CO>[C:4]([O:8][C:9]([N:11]1[C:24]2[C:16](=[CH:17][C:18]3[CH2:19][O:20][CH2:21][C:22]=3[CH:23]=2)[C@@H:15]([N:25]([C:26]2[N:27]=[N:28][N:29]([CH2:31][CH2:32][NH2:33])[N:30]=2)[CH2:44][C:45]2[CH:46]=[C:47]([C:55]([F:57])([F:58])[F:56])[CH:48]=[C:49]([C:51]([F:52])([F:53])[F:54])[CH:50]=2)[CH2:14][CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(CCN3C(=O)c4ccccc4C3=O)n2)c2cc3c(cc21)COC3
Agent: NN
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(CCN)n2)c2cc3c(cc21)COC3
Temperature: 60 °C
Reaction time: 14 h

Procedure:
Add hydrazine monohydrate (1.94 mmol) to a solution of (S)-9-((3,5-Bis-trifluoromethyl-benzyl)-{2-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-2H-tetrazol-5-yl}-amino)-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]indene-5-carboxylic acid tert-butyl ester (0.13 mmol) in methanol (5 mL). After heating the mixture at 60° C. for 4 h cool to room temperature and stir for 14 h. Remove solvent under vacuum. Chromatograph over silica gel eluting with methanol/dichloromethane (0-5%) to provide the title compound as a colorless foam. MS (ES+): 642 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([I:13])[CH:7]=1)[CH3:2].[C:15]([O:21][CH2:22][CH3:23])(=[O:20])[CH2:16][C:17]([CH3:19])=O>C1C=CC=CC=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1>[CH2:22]([O:21][C:15](=[O:20])[CH:16]=[C:17]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:14])=[CH:7][C:8]=1[I:13])[CH3:19])[CH3:23]
Reactant: CCOC(=O)Cc1ccc(N)c(I)c1
Reactant: CCOC(=O)CC(C)=O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C=C(C)Nc1ccc(CC(=O)OCC)cc1I
Temperature: 25 °C
Yield: 92.8 %

Procedure:
A solution of (4-amino-3-iodo-phenyl)acetic acid ethyl ester (9.85 g, 32.3 mmol), ethyl acetoacetate (4.2 g, 32.3 mmol), and toluenesulfonic acid monohydrate (0.3 g, 1.6 mmol) in benzene (150 mL) is refluxed under Dean-Stark conditions overnight. The solution is then cooled to room temperature and washed with sodium bicarbonate (NaHCO3) (2×50 mL) and concentrated in vacuo to give the desired product (12.5 g, 93%). The product is used without further purification in Step 3. MS: 418 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][C:18]4[C:22]([Cl:23])=[CH:21][N:20]([CH3:24])[N:19]=4)[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[C:31]([OH:33])=[O:32])=[CH:4][CH:3]=1.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[Cl:23][C:22]1[C:18]([CH2:17][O:16][C:13]2[CH:14]=[CH:15][C:10]3[N:9]=[C:8]([C@H:25]4[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]4[C:31]([OH:33])=[O:32])[N:7]([CH2:6][C:5]4[CH:34]=[CH:35][C:2]([N:36]5[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]5)=[CH:3][CH:4]=4)[C:11]=3[CH:12]=2)=[N:19][N:20]([CH3:24])[CH:21]=1
Reactant: Cn1cc(Cl)c(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4ccc(Br)cc4)c3c2)n1
Reactant: C1CCNCC1
Product: Cn1cc(Cl)c(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4ccc(N5CCCCC5)cc4)c3c2)n1

Procedure:
The title compound was prepared from racemic cis-2-(1-(4-bromobenzyl)-6-((4-chloro-1-methyl-1H-pyrazol-3-yl)methoxy)-1H-benzo[d]imidazol-2-yl)cyclohexanecarboxylic acid using analogous conditions described in Example 152 using piperidine. MS (ESI): mass calcd. for C31H36ClN5O3, 562.12; m/z found, 562.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 7.65 (s, 1H), 7.53 (d, J=8.8, 1H), 7.03 (d, J=8.9, 3H), 6.92 (d, J=8.8, 3H), 5.44 (d, J=16.6, 1H), 5.37 (d, J=16.4, 1H), 4.98 (s, 2H), 3.81 (s, 3H), 3.60-3.49 (m, 1H), 3.14-3.09 (m, 4H), 2.91-2.79 (m, 1H), 2.40-2.28 (m, 1H), 2.03-1.93 (m, 1H), 1.91-1.63 (m, 8H), 1.62-1.53 (m, 2H), 1.53-1.37 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][CH2:15][OH:16])[O:11][CH:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].O>CN(C=O)C.C(Br)C1C=CC=CC=1>[CH2:8]([O:16][CH2:15][CH2:14][CH2:13][C:10]1[O:11][CH:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]=1)[C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: OCCCc1nc(-c2ccc(Cl)cc2)co1
Agent: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(-c2coc(CCCOCc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 123.7 %

Procedure:
To a solution of 3-[4-(4-chlorophenyl)-2-oxazolyl] propanol (0.6 g) in DMF (10 ml) were added 60% (W/W) sodium hydride in oil (0.12 g) and benzyl bromide (0.3 ml), followed by stirring for 3 hours at room temperature. After additional stirring for an hour at 30° C., the reaction mixture was poured into water and then extracted with ether. The ether layer was washed with water, dried over MgSO4, and distilled to remove the solvent. The oily residue was subjected to a silica gel column chromatography. Oily 3-[4-(4-chlorophenyl)-2-oxazolyl]propyl benzyl ether (0.512 g, 62%) was obtained from the fraction eluted with ether-hexane (1:4, V/V).
Reaction SMILES: [C:1]([C:3]1[C:12]([C:13]#[N:14])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)#[N:2].C[O-].[Na+].[NH3:18]>CO>[NH:14]=[C:13]1[C:12]2[CH:11]=[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]3=[CH:4][C:3]=2[C:1](=[NH:18])[NH:2]1
Reactant: N#Cc1cc2ccccc2cc1C#N
Reactant: N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N=C1NC(=N)c2cc3ccccc3cc21
Yield: 66 %

Procedure:
In 2.5 moles of 2,3-dicyanonaphthalene, 0.075 mole of sodium methoxide and 1 liter of methanol, an ammonia gas was flowed with a suitable flow rate for 40 minutes. Then, the reaction solution was refluxed with heating while flowing the ammonia gas for 4 hours. After cooling, the product was filtered, and recrystallized from a mixed solvent of methanol/ether to yield yellow 1,3-diiminobenz(f)isoindoline in 66% yield.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:26])[C:7]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:8][C:9](=[N:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=2[OH:21])[C:15]([OH:17])=[O:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(O)C.[H][H]>O1CCCC1>[C:1]([C:5]1[CH:10]=[C:9]([CH:8]=[C:7]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:6]=1[OH:26])[NH:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[OH:21])[C:15]([OH:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)C1=CC(=Nc2cc(C(=O)O)ccc2O)C=C(C(C)(C)C)C1=O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)c1cc(Nc2cc(C(=O)O)ccc2O)cc(C(C)(C)C)c1O
Yield: 63.6 %

Procedure:
A mixture of 5.0 g of 3-(2,6-di-tertiary-butylcyclohexadienon-4-ylideneamino)-4-hydroxybenzoic acid, 0.05 g of 5% palaldium on charcoal catalyst, 250 ml of ethanol and 50 ml of tetrahydrofuran was placed on a Paar apparatus. Hydrogen uptake was complete in about 10 minutes. The reaction mixture was filtered to remove catalyst. The filtrate was evaporated to give a tan solid which was recrystallized from a mixture of 40 ml of ethanol and 15 ml of water to give 3.2 g of reddish tan granular 3-(3,5-di-tertiary-butyl-4-hydroxyanilino)-4-hydroxybenzoic acid, m.p. 254.5°-255° C. (dec). Analysis: Calculated for C21H27NO4 : % C, 70.6; % H, 7.6; % N, 3.9; Found: % C, 71.0; % H, 7.6; % N, 4.1.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19]([OH:20])=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[C:12]([NH:21][CH3:22])[N:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:25][Si](C=[N+]=[N-])(C)C>CO.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19]([O:20][CH3:25])=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[C:12]([NH:21][CH3:22])[N:11]=2)=[O:9])=[CH:23][CH:24]=1
Reactant: CNc1nc(C(=O)NCc2ccc(F)cc2)c(O)c2ncccc12
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: CNc1nc(C(=O)NCc2ccc(F)cc2)c(OC)c2ncccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of N-(4-fluorobenzyl)-8-hydroxy-5-(methylamino)-1,6-naphthyridine-7-carboxamide (2.65 g, 8.12 mmol) in methanol (50 mL) and CH2Cl2 (20 mL) was added trimethylsilyldiazomethane (12.1 ml of a 2M solution in hexanes, 24.4 mmol) and the mixture was stirred for 16 hr at rt. Additional trimethylsilyldiazomethane (24.0 ml of a 2M solution in hexanes, 48 mmol) was added and the reaction was stirred for 16 hr. The reaction was quenched by the addition of acetic acid (2 mL) and the solvent was evaporated in vacuo. The residue was purified by flash chromatography eluting with MeOH/CH2Cl2 (5-15% gradient elution), to afford the title compound.