Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].C([CH:14]1[N:26]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]3[NH:44][N:43]=[N:42][N:41]=3)=[CH:30][CH:29]=2)[C:17]2=[N:18][C:19](=S(=O)=O)[CH:20]=[C:21]([CH3:22])[C:16]2=[N:15]1)C.Cl>O.CN(C=O)C>[CH2:1]([O:5][C:14]1[N:26]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]3[NH:44][N:43]=[N:42][N:41]=3)=[CH:32][CH:33]=2)[C:17]2=[N:18][CH:19]=[CH:20][C:21]([CH3:22])=[C:16]2[N:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO
Reactant: CCC1N=C2C(C)=CC(=S(=O)=O)N=C2N1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1nc2c(C)ccnc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 0.08 h
Yield: 49 %

Procedure:
A mixture of 100 mg (1.3 mmol) of n-butanol, 400 mg (3.6 mmol) of potassium tert. butoxide and DMF was heated at 80 degree C. for 5 minutes. 300 mg (0.65 mmol) of 2-ethyl-sulfonyl-7-methyl-3[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazo[4.5-b]pyridine was added to the mixture. The resultant was heated for 2 hours. The reaction product mixture was mixed with water, neutralized with 2n HCl and extracted with dichloromethane. The dichloromethane phase was washed with a saturated saline and dried with anhydrous magnesium sulfate. The solvent was distilled out at a reduced pressure and the residue was treated with ether hexane-dichloromethane or re-crystallization to obtained 140 mg of the intended compound.
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[F:27][CH:28]([F:37])[C:29]1[N:30]2[CH:36]=[N:35][CH:34]=[C:31]2[S:32][CH:33]=1>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:35]3[CH:34]=[C:31]4[S:32][CH:33]=[C:29]([CH:28]([F:37])[F:27])[N+:30]4=[CH:36]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Reactant: FC(F)c1csc2cncn12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(Cn3cc4scc(C(F)F)[n+]4c3)[C@H](C)[C@H]12
Yield: 7.5 %

Procedure:
The same procedure as in Example 1 was repeated except that 97 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 70 mg of 3-difluoromethylimidazo[5,1-b]thiazole were used, thereby obtaining 7.9 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[CH:12]=[N:11][CH:10]=[C:9]3[S:13][C:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=4)=[CH:15][C:8]=23)=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[CH:12]=[N:11][CH:10]=[C:9]3[S:13][C:14]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=4)=[CH:15][C:8]=23)=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2cc3c(Oc4ccc(Cl)cc4)cncc3s2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-c2cc3c(Oc4ccc(Cl)cc4)cncc3s2)cc1
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of Example 270B (0.09 g, 0.24 mmmol) in anhydrous CH2Cl2 (4 mL) was added a 1 M solution of boron tribromide in CH2Cl2 (0.96 mL, 0.96 mmol). After 2 hours, the reaction was quenched by slow addition of MeOH (2 mL) and then concentrated. The residue was diluted with CH2Cl2 (50 mL) and organic washed with 1:1 sat. NaHCO3/brine (50 mL), partially dried (Na2SO4), then concentrated. The residue was purified by flash chromatography on silica gel using EtOAc/hexane as eluent to yield the title compound as a solid (0.08, 96%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]#[N:6].[N:7]1[CH:12]=[CH:11][CH:10]=[N:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[Na+].[Na+].C(O)CCC>O>[C:5]([CH2:4][CH2:3][CH2:2][N:16]1[CH2:17][CH2:18][N:13]([C:8]2[N:9]=[CH:10][CH:11]=[CH:12][N:7]=2)[CH2:14][CH2:15]1)#[N:6]
Reactant: N#CCCCCl
Reactant: c1cnc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Solvent: O
Product: N#CCCCN1CCN(c2ncccn2)CC1

Procedure:
A mixture of 4-chlorobutyronitrile (3.3 g; 0.032 mol), 1-(2-pyrimidinyl)piperazine (3.3 g; 0.032 mol), sodium carbonate (6.4 g; 0.0608 mol) and n-butanol (50 ml) was heated under reflux for 19 hours. After completion of the reaction, the resultant mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography to give 1-(3-cyanopropyl)-4-(2-pyrimidinyl)-piperazine. M.P., 56°-57° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[N:6][N:5]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=2[Cl:19])[N:4]=1.[CH2:20]([SH:22])[CH3:21].[H-].[Na+].O>O1CCCC1>[Cl:19][C:9]1[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:13]([Cl:14])[C:8]=1[N:5]1[N:4]=[C:3]([CH2:2][S:22][CH2:20][CH3:21])[CH:7]=[N:6]1
Reactant: CCS
Reactant: FC(F)(F)c1cc(Cl)c(-n2ncc(CBr)n2)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCSCc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Bromomethyl-2-(2,6-dichloro-4-trifluoromethylphenyl) 2H-1,2,3-triazole (2.9 g) was added portionwise to a stirred mixture of ethanethiol (0.5 g) and sodium hydride (0.25 g) in tetrahydrofuran (30 ml) and the mixture stirred at room temperature for 3 hours. The mixture was added to water and extracted with ether. The extract was worked up to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-(ethylthiomethyl)-2H-1,2,3-triazole, m.p. 53°-54°. (Compound 19)
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([CH:13]2[CH2:18][CH2:17][CH2:16][CH:15]=[CH:14]2)[CH2:4][CH:3]1[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>C(O)C.[C].[Pd]>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:4][CH:3]1[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: CC(C)(C)OC(=O)NC1CN(C2C=CCCC2)c2ccccc2NC1=O
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CN(C2CCCCC2)c2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To a solution of (±)-2-oxo-3-tert-butoxycarbonylamino-5-(2-cyclohexen-1-yl)-1,3,4,5-tetrahydro-2H-1,5-benzo diazepine (4.5 g) in ethanol (200 mL), 10% palladium carbon (1 g) was added, followed by stirring at room temperature for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under the reduced pressure. The residue was then recrystallized from ethanol, whereby the title compound (3.35 g) was obtained. Yield: 74%.
Reaction SMILES: C(OC([N:8]([C:10]1([C@@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[CH2:12][CH2:11]1)[CH3:9])=O)(C)(C)C.C(N(CC)CC)C.[NH2:25][C:26]1[CH:35]=[C:34](F)[C:33]([CH3:37])=[C:32]2[C:27]=1[C:28](=[O:45])[C:29]([C:42]([OH:44])=[O:43])=[CH:30][N:31]2[C@@H:38]1[CH2:40][C@@H:39]1[F:41]>CS(C)=O>[NH2:25][C:26]1[CH:35]=[C:34]([N:15]2[CH2:16][CH2:17][C@@H:13]([C:10]3([NH:8][CH3:9])[CH2:11][CH2:12]3)[CH2:14]2)[C:33]([CH3:37])=[C:32]2[C:27]=1[C:28](=[O:45])[C:29]([C:42]([OH:44])=[O:43])=[CH:30][N:31]2[C@@H:38]1[CH2:40][C@@H:39]1[F:41]
Reactant: Cc1c(F)cc(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reactant: CN(C(=O)OC(C)(C)C)C1([C@@H]2CCNC2)CC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CNC1([C@@H]2CCN(c3cc(N)c4c(=O)c(C(=O)O)cn([C@@H]5C[C@@H]5F)c4c3C)C2)CC1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 19.9 %

Procedure:
After adding 3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)amino]cyclopropyl]pyrrolidine (690 mg, 2.25 mmol) and triethylamine (0.50 ml) to dried dimethyl sulfoxide (4 ml), 5-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (250 mg, 850 μmol) was added thereto and heated under reflux in an oil bath of 70° C. for 24 hours under a nitrogen atmosphere. After concentrating the reaction solution under a reduced pressure, the residue was dissolved in chloroform (100 ml). After washing the organic layer with a 10% aqueous citric acid solution (100 ml) and saturated saline solution (100 ml), the organic layer was dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, and after adding dropwise concentrated hydrochloric acid (5 ml) to the residue while cooling with ice, it was stirred at room temperature for 30 minutes. After adding 1 mol/l hydrochloric acid (2 ml) to the reaction solution and washing the yellow acidic aqueous solution with chloroform (50 ml×3), the pH was adjusted to 12.0 with an aqueous sodium hydroxide solution. After adjusting the pH of the basic aqueous solution to 7.4 with 1 mol/l hydrochloric acid, extraction with chloroform (100 ml×3) was performed. After drying over anhydrous sodium sulfate, the solvent was evapolated under a reduced pressure. The residue thus obtained was then purified by preparative chromatography (developed into the lower layer of a 7:3:1 mixture of chloroform:methanol:water), purified further by recrystallization from ethanol, and then dried under a reduced pressure. 70.0 mg (20%) of the title compound was thereby obtained in the form of yellow crystals.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]([CH2:16][CH2:17][CH:18]=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:20]([CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)#[N:21]>C(Cl)Cl>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]([CH2:16][CH2:17][CH2:18][N:28]3[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][CH2:22][C:20]#[N:21])[CH2:26][CH2:27]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=CCCN1c2ccccc2CCc2ccccc21
Reactant: N#CCCCN1CCNCC1
Solvent: ClCCl
Product: N#CCCCN1CCN(CCCN2c3ccccc3CCc3ccccc32)CC1
Reaction time: 16 h
Yield: 68.2 %

Procedure:
Na(Oac)3BH3 (171 mg, 0.80 mmol) were added to a solution of 3-(10,11-dihydro-dibenzo[b,f]azepine-5-yl)-propionaldehyde (100 mg, 0.40 mmol) and N-(3-cyanopropyl)-piperazine (122 mg, 0.80 mmol) in CH2Cl2 (10 ml). After 16 hours of stirring, the mixture was diluted with CH2Cl2 (50 ml) and washed with a saturated solution of NaHCO3. The organic phase was dried (Na2SO4) and evaporated. Purification using flash chromatography of the residue obtained yielded N-[3-(10,11-dihydro-dibenzo[b,f]azepine-5-yl)-propyl]-N′-(3-cyanopropyl)-piperazine (yield: 106 mg, 68%).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:12][CH:11]=3)[C:7]3[CH:29]=[C:30]([C:34]4[N:38]([CH3:39])[C:37]5[CH:40]=[CH:41][CH:42]=[CH:43][C:36]=5[N:35]=4)[CH:31]=[C:32]([CH3:33])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]4[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:14][CH:15]=3)[C:7]3[CH:29]=[C:30]([C:34]4[N:38]([CH3:39])[C:37]5[CH:40]=[CH:41][CH:42]=[CH:43][C:36]=5[N:35]=4)[CH:31]=[C:32]([CH3:33])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(-c2nc3ccccc3n2C)cc2c1nc(C1CC1)n2Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2nc3ccccc3n2C)cc2c1nc(C1CC1)n2Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.butyl 4'-[(2-cyclopropyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6](O)=[O:7].S(Cl)([Cl:12])=O>>[CH3:1][CH:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6]([Cl:12])=[O:7]
Reactant: CC(C)CCCC(=O)O
Reactant: O=S(Cl)Cl
Product: CC(C)CCCC(=O)Cl
Yield: 85.9 %

Procedure:
A mixture of 5-methylhexanoic acid (25 mL, 175 mmol) and thionyl chloride (50 mL, 0.69 mol) was stirred at reflux for 90 minutes. The mixture was concentrated, then distilled at reduced pressure to give the desired product (22.35 g).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].[Na].[CH3:13][CH:14]1[CH2:19][C:18](=O)[CH2:17][C:16](=[O:21])[CH:15]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(O)C.O>[OH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]1[C:17]2[C:16](=[O:21])[CH:15]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:14]([CH3:13])[CH2:19][C:18]=2[O:1][N:2]=1
Reactant: CCOC(=O)C1C(=O)CC(=O)CC1C
Reactant: ON=C(Cl)c1ccccc1O
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1C(=O)c2c(-c3ccccc3O)noc2CC1C
Temperature: 25 °C

Procedure:
N,2-Dihydroxybenzenecarboximidoyl chloride in 100 mL of ethanol was added to sodium salt of ethyl 2-methyl4,6-dioxocyclohexanecarboxylate in a solvent mixture of 125 mL of water and 75 mL of ethanol at a temperature of 55° C. over an hour. The reaction mixture was maintained at this temperature for 4 hours and then cooled down to room temperature. After diluting with water (100 mL), the mixture was extracted with ethyl acetate (2×100 mL). The resulting extract was washed with saturated sodium chloride aqueous solution (150 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was treated with diethyl ether to give the product (2.48 g) as white powders. The residue was further purified by silica gel preparative thin layer chromatography to give additional 2.15 g of the product as white powders (total amount yielded at the 2 steps: 4.63 g, yield: 60%). The physicochemical properties of the compound obtained are shown below.
Reaction SMILES: [Na].C1(C)C=CC=CC=1.[CH3:9][O:10][CH:11]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:12]([O:14]C)=O>C(O)(=O)C>[CH3:9][O:10][CH:11]1[CH2:16][CH2:17][CH:18]([C:19]([O:21][CH3:22])=[O:20])[C:12]1=[O:14]
Reactant: COC(=O)CCCC(OC)C(=O)OC
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)C1CCC(OC)C1=O
Temperature: 60 °C
Yield: 54.2 %

Procedure:
1.38 g of sodium metal was added to 100 ml of toluene, and the mixture was heated to 60° C. 10.2 g of dimethyl α-methoxyadipate [prepared as described in step (a) above] were then added dropwise to the hot mixture. The mixture was then heated under reflux for 8 hours, after which it was cooled to room temperature and added to a 10% w/v aqueous solution of acetic acid. The organic layer was separated, washed first with a saturated aqueous solution of sodium carbonate and then with water, and then dried over anhydrous sodium sulfate. The solvent was then evaporated off under reduced pressure, and the residue was distilled, to give 4.66 g of the title compound as a pale oil, boiling at 83°-87° C./3 mm Hg (about 400 Pa).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:7][CH:6]=[C:5]([O:15]C)[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1.B(Cl)(Cl)Cl>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].C(Cl)Cl>[F:25][C:24]([F:26])([F:27])[C:23]([C:20]1[CH:19]=[CH:18][C:17]([C:4]2[C:5]([OH:15])=[CH:6][CH:7]=[C:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:3]=2[O:2][CH3:1])=[CH:22][CH:21]=1)=[O:28]
Reactant: CCCCCCc1ccc(OC)c(-c2ccc(C(=O)C(F)(F)F)cc2)c1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Solvent: ClCCl
Product: CCCCCCc1ccc(O)c(-c2ccc(C(=O)C(F)(F)F)cc2)c1OC
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 68 %

Procedure:
Compound 39.3 (1 equiv.) and n-Bu4NI (3 equiv.) were stirred in dry CH2Cl2 at −78° C. under nitrogen. A solution of BCl3 (3.2 mL, using 1M solution in CH2Cl2) was added over 2 min period. After 5 min, the solution was warmed to 0° C. and stirring was continued for 2 h. The reaction was quenched with ice-water, the resulting mixture was stirred for 30 min, and partially concentrated to remove CH2Cl2. Water was added and the mixture was extracted with diethyl ether. The combined organic layer was washed with saturated aqueous NaCl solution, dried over MgSO4, and evaporated. Purification by flash column chromatography on silica gel (18% acetone in hexane) gave the product 40.3 in 68% yield (270 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[C:15]3[CH:16]=[C:17]([CH2:20][CH2:21][CH2:22][CH2:23]OS(C)(=O)=O)[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)=[N:8][C:7]=1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[C:15]3[CH:16]=[C:17]([CH2:20][CH2:21][CH2:22][CH2:23][N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)=[N:8][C:7]=1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(-n2cnc3ccc(CCCCOS(C)(=O)=O)cc32)nc1-c1cccc(Cl)c1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1sc(-n2cnc3ccc(CCCCN4CCOCC4)cc32)nc1-c1cccc(Cl)c1
Yield: 74.3 %

Procedure:
A mixture of 0.107 g (0.2 mmole) of 4-(3-chloro-phenyl)-2-[6-(4-methanesulfonyloxy-butyl)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid ethyl ester (I.41e), 0.138 g (1 mmole) of potassium carbonate, 2 mL of acetonitrile and 0.035 mL (0.4 mmole) of morpholine was refluxed for 6 hours. The solid was removed by filtration and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with methanol-dichloromethane (gradient 0:100-5:95) to give 0.078 g of 4-(3-chloro-phenyl)-2-[6-(4-morpholin-4-yl-butyl)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid ethyl ester (I.41f) as a yellow solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH:27]1([C:30]2[N:34]([CH3:35])[N:33]=[C:32]([NH:36][C:37](=O)[O:38]C3C=CC=CC=3)[CH:31]=2)[CH2:29][CH2:28]1.[H-].[Na+]>CN(C=O)C>[CH:27]1([C:30]2[N:34]([CH3:35])[N:33]=[C:32]([NH:36][C:37]([N:1]3[C:9]4[C:4](=[CH:5][C:6]([O:10][C:11]5[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH:12]=5)=[CH:7][CH:8]=4)[CH:3]=[CH:2]3)=[O:38])[CH:31]=2)[CH2:28][CH2:29]1
Reactant: Cn1nc(NC(=O)Oc2ccccc2)cc1C1CC1
Reactant: CN(Cc1cc(Oc2ccc3[nH]ccc3c2)ccn1)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1cc(Oc2ccc3c(ccn3C(=O)Nc3cc(C4CC4)n(C)n3)c2)ccn1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (4-(1H-indol-5-yloxy)pyridin-2-yl)methyl(methyl)carbamate (115 mg, 0.325 mmol), in DMF (5 ml) is added phenyl 5-cyclopropyl-1-methyl-1H-pyrazol-3-ylcarbamate (126 mg, 0.488 mmol), prepared as described in Example 5-N. The resulting mixture is placed at 0° C. and sodium hydride (60% dispersion in oil; 39.0 mg, 0.98 mmol) is added. The reaction is permitted to stir at 0° C. for 30 min at which time the reaction is quenched with saturated aqueous NH4Cl. The resulting mixture is diluted with brine and DCM. The resulting layers are separated and the aqueous layer is extracted twice with DCM. The organic layers are combined, dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue is purified via FCC (0-100% EtOAc/heptane) to give the title compound. MS (ESI) m/z 517.6 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[C:30]1([CH2:36][C:37](Cl)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][C:37](=[O:38])[CH2:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(Cc1ccccc1)Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and phenyl-acetyl chloride according to the procedure of Example 61. MS (ES) m/z 508.9.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([CH2:10][CH2:11][N:12]([CH:32]([CH3:34])[CH3:33])[C:13](=[O:31])[C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][NH:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH:17]=[C:16]([CH3:30])[CH:15]=1)#[N:9]>ClCCl.FC(F)(F)C(O)=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([CH2:10][CH2:11][N:12]([CH:32]([CH3:34])[CH3:33])[C:13](=[O:31])[C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][NH:23][C:24]2[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=2)[CH:17]=[C:16]([CH3:30])[CH:15]=1)(=[O:4])[NH2:9]
Reactant: Cc1cc(OCCNc2ccncc2)cc(C(=O)N(CCC#N)C(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(OCCNc2ccncc2)cc(C(=O)N(CCC(N)=O)C(C)C)c1

Procedure:
A solution of N-(2-cyano-ethyl)-N-isopropyl-3-methyl-5-[2-(pyridin-4-ylamino)-ethoxy]-benzamide trifluoroacetate (0.011 g) in dichloromethane (1.5 ml) and trifluoroacetic acid (0.5 ml) was stored at room temperature overnight and then concentrated under reduced pressure. The title compound was obtained as a pale yellow foam (0.012 g).
Reaction SMILES: [Si:1]([N:8]1[CH:11]([C:12](C)([CH3:15])[CH:13]=C)[CH:10]([CH:17]([OH:19])[CH3:18])[C:9]1=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:21](=[O:23])=[O:22].CC(C)=O.ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl>[Si:1]([N:8]1[CH:11]([C:12]([C:21]([OH:23])=[O:22])([CH3:13])[CH3:15])[CH:10]([CH:17]([OH:19])[CH3:18])[C:9]1=[O:20])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C=CC(C)(C)C1C(C(C)O)C(=O)N1[Si](C)(C)C(C)(C)C
Reactant: O=C=O
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(O)C1C(=O)N([Si](C)(C)C(C)(C)C)C1C(C)(C)C(=O)O

Procedure:
A solution of 1-(t-butyldimethylsilyl)-3-(1-hydroxyethyl)-4-(1,1-dimethyl-prop-2-enyl)-azetidin-2-one (3.0 mmol) in dry methylene chloride (30 ml) is cooled to -78° C. (dry ice-acetone) and a stream of ozone is bubbled through until the reaction mixture becomes blue. The ozone flow is then stopped and the reaction is purged by bubbling through nitrogen until the blue color disappears. Solid m-chloroperbenzoic acid (3.0 mmol) is added and the cold bath is removed. When the reaction mixture reaches room temperature, the flask is fitted with a reflux condenser and the mixture is heated at reflux for three days. Removal of solvents in vacuo gives a crude product which is chromatographed on silica gel (2% glacial acetic acid in methylene chloride) to yield 6.