Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[SH:4][C:5]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13](=[O:21])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.Cl.Cl[CH2:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][N:26]=1.O>CO>[C:15]1([N:14]2[C:13](=[O:21])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]=[C:5]2[S:4][CH2:24][C:25]2[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][N:26]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=c1c2ccccc2nc(S)n1-c1ccccc1
Reactant: Cc1ccnc(CCl)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccnc(CSc2nc3ccccc3c(=O)n2-c2ccccc2)c1
Reaction time: 5 h
Yield: 30.7 %

Procedure:
8.7 ml of 28% methanolic solution of sodium methoxide were added to a solution of 5.0 g of 2-mercapto-3-phenyl-4(3H)-quinazolinone and 4.0 g of 2-chloromethyl-4-methylpyridine hydrochloride in methanol, and the stirring was continued at room temperature for 5 hours. The reaction solution was poured into water and extracted with chloroform. The chloroform layer was washed with an aqueous solution of sodium carbonate and dried over sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography. The fraction eluted with 8% ethyl acetate in chloroform was collected and crystallized from ethyl acetate to give 2.17 g (30.7%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[C:9][CH3:10])[CH:7]=1.CC1CCCO1.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.[Li]CCCC.Cl>C1(C)C=CC=CC=1>[C:8]([C:6]1[CH:7]=[C:2]([B:17]([OH:22])[OH:18])[CH:3]=[N:4][CH:5]=1)#[C:9][CH3:10]
Reactant: CC#Cc1cncc(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CC1CCCO1
Solvent: Cc1ccccc1
Product: CC#Cc1cncc(B(O)O)c1
Temperature: -50 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
3-Bromo-5-(prop-1-ynyl)pyridine (Intermediate 14, 25 g, 117 mmol), 2-methyl-tetrahydrofuran (60 mL), toluene (200 mL) and triisopropyl borate (33.2 mL, 140.78 mmol) were mixed. The mixture was cooled to −50° C. To the cold mixture was added n-BuLi (59.8 mL, 149.5 mmol) dropwise during 30 min. The mixture was stirred for 60 min. at −50° C. 2 M HCl aq. (100 mL) was added. The mixture was then allowed to reach r.t. and stirred for 20 min. The organic and water phase were separated. The organic phase was extracted with NaOH (2 M aq.) (2×100 mL). The water phases were combined and the pH was adjusted to pH 5. The product was extracted with 2-methyl-THF (2×100 mL). The organic phase was dried with Na2SO4, filtered and concentrated to give the title compound (16.47 g, 87% yield): 1H NMR (500 MHz, CD3OD) δ ppm 2.11 (s, 3H) 8.21 (br. s., 1H) 8.53 (m, 2H); MS (APCI+) m/z 162.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1[N:8]=[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[N:10]([C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)[CH:11]=1)=[O:6].[CH3:28][S:29]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30].C([O-])([O-])=O.[K+].[K+].COCCOC>CCOC(C)=O.O>[F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1[N:8]=[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[N:10]([C:12]2[CH:17]=[CH:16][C:15]([C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([S:29]([CH3:28])(=[O:31])=[O:30])[CH:37]=3)=[CH:14][CH:13]=2)[CH:11]=1)=[O:6]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: O=C(NCC(F)(F)F)c1cn(-c2ccc(Br)cc2)c(-c2ccccc2Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: CS(=O)(=O)c1cccc(-c2ccc(-n3cc(C(=O)NCC(F)(F)F)nc3-c3ccccc3Cl)cc2)c1
Temperature: 75 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
To a 50 mL round bottom flask attached with Vigreux column and magnetic stir bar was added 1-(4-Bromo-phenyl)-2-(2-chloro-phenyl)-1H-imidazole-4-carboxylic acid (2,2,2-trifluoro-ethyl)-amide (249 mg, 540 μmol), 3-methylsulfonylphenyl boronic acid (130 mg, 650 μmol), PdCl2dppf (40 mg, 10 mol %), K2CO3 (260 mg, 1.90 mmol), 1,2-dimethoxyethane (14 mL) and H2O (2 mL). The reaction solution was allowed to stir at 75° C. for 2 hrs. The reaction solution was diluted with EtOAc (150 mL) and filtered through a Celite padded Buchner funnel to remove spent Pd. The filtrate was transferred to a separatory funnel and washed with aq NH4Cl (100 mL) and aq NaCl (100 mL). The organic phase was dried over Na2SO4, filtered, concentrated on the Rotavapor and chromatographed through a 25 g SiO2 column using a mobile phase gradient of 2% EtOAc to 90% EtOAc to afford 212 mg (74% yield) of the title compound. MS (ES): 534 [M+H]+, 557 [M+Na]+. 1H NMR. (400 MHz, CDCl3): δ 8.13 (s, 1H), 7.99 (s, 1H), 7.92 (d, 1H), 7.65 (t, 1H), 7.57 (d, 2H), 7.52 (d, 2H), 7.41-7.34 (m, 3H), 7.24 (d, 2H), 4.11 (q, 2H), 3.08 (s, 3H); 19F NMR (400 MHz, CDCl3) 5-72.4 ppm.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][CH:5]1[NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH3:39])=[O:32]>O1CCCC1>[C:34]1([CH3:39])[C:33]([C:31]([CH2:30][N:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][CH:5]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:4]2=[O:3])=[O:32])=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)C(C)(C)C)c2ccccc2NC1=O
Reactant: Cc1ccccc1C(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)CN1C(=O)C(NC(=O)OC(C)(C)C)CN(C(=O)C(C)(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
60% Sodium hydride (1.6 g) was suspended in tetrahydrofuran (100 ml), 2-Oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (7.23 g) was added thereto under ice-cooling, and the resultant mixture was stirred for one hour. Subsequently, 2-bromo-2′-methylacetophenone (4.88 g) was added thereto, and the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure. Ice-water was added to the residue. The resultant mixture was extracted with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), to thereby obtain 7.8 g of the title compound (yield: 79%)
Reaction SMILES: C[O:2][C:3]1[CH:9]=[CH:8]C(O)=[CH:5][CH:4]=1.[CH3:10][CH:11]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17].C(C(CC)=O)=C.[Cl-].[Na+]>C1C=CC=CC=1.O.C(O)(=O)C>[CH3:10][C:11]1([CH2:5][CH2:4][C:3](=[O:2])[CH2:9][CH3:8])[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17]
Reactant: CC1C(=O)CCC1=O
Reactant: COc1ccc(O)cc1
Agent: C=CC(=O)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CCC(=O)CCC1(C)C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 360 h

Procedure:
A total of 88 mg. of hydroquinone monomethyl ether was added to 10 ml. of ether vinyl ketone to stabilize the latter compound. There was then added to the above mixture 0.08 ml. of glacial acetic acid, 26 ml. of dimeneralized water and 11.2 g. of 2-methyl-1,3-cyclopentanedione. The resulting mixture was stirred under argon at room temperature for 15 days. An additional 9 ml. of ethyl vinyl ketone was added at the fourth day and 9.5 ml. of ethyl vinyl ketone was added at the ninth day. After 15 days, 50 ml. of benzene was added and sufficient sodium chloride was added to the aqueous phase to allow separation after shaking. The phases were separated and the aqueous phase re-extracted with 50 ml. of benzene. The combined benzene extracts were treated with a mixture of sodium sulfate, magnesium sulfate and activated charcoal. The solids were filtered off and were washed with a mixture of chloroform and ether. The combined filtrates were evaporated in vacuo and the residue was treated with an additional portion of benzene followed by concentration to dryness in vacuo. There was obtained 21.1 g. of an oil residue which was fractionally distilled at 0.05 mmHg and the fraction boiling in the range of 105°-118°C. was collected; yield 17.47 g. (89 percent). This fraction was redistilled at 0.025 mmHg to give a fraction boiling at 97°-115°C.; yield 16 g. (83.5 percent) of the above-captioned product.
Reaction SMILES: [C:1]([C:4]1[C:32]([OH:33])=[CH:31][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:27]=[CH:26][C:16]3[CH2:17][CH2:18][CH:19]([C:21]([O:23]CC)=[O:22])[O:20][C:15]=3[C:14]=2[CH2:28][CH2:29][CH3:30])=[C:6]([CH2:34][CH3:35])[CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+:37]>O1CCOCC1.CO>[Na+:37].[C:1]([C:4]1[C:32]([OH:33])=[CH:31][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:27]=[CH:26][C:16]3[CH2:17][CH2:18][CH:19]([C:21]([O-:23])=[O:22])[O:20][C:15]=3[C:14]=2[CH2:28][CH2:29][CH3:30])=[C:6]([CH2:34][CH3:35])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCOc2cc(O)c(C(C)=O)cc2CC)ccc2c1OC(C(=O)OCC)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CCCc1c(OCCCOc2cc(O)c(C(C)=O)cc2CC)ccc2c1OC(C(=O)[O-])CC2
Temperature: 25 °C

Procedure:
A solution of ethyl 7-[3-(4-acetyl-2-ethyl-5-hydroxyphenoxy)propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylate in dioxane (3.5M solution) was treated with 2N NaOH (3.0 eqv) and stirred at room temperature. After stirring for 4 hours, the dioxane was removed from the reaction, and the remaining solution was diluted with water and acidified with 5N HCl. The resulting milky solution was extracted with EtOAc. The ethyl acetate extract was dried over MgSO4 and filtered. Solvent removal gave a white solid. The free acid was stirred in methanol and treated with 3 eqv. of NaOH(aq). The solvent was removed from the reaction and the product was purified by CHP-20 reverse phase chromatography eluting with a water/methanol gradient. The pure product was obtained in 68% yield by lyophilization of the product containing fractions.
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:23])[CH2:15][CH:16]([C:20](=O)[CH3:21])[C:17](=O)[CH3:18])[CH3:12].C([O-])(=O)C.[Na+]>C(O)C>[CH2:11]([O:13][C:14](=[O:23])[CH2:15][C:16]1[C:17]([CH3:18])=[N:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:10])=[CH:3][CH:4]=2)[C:20]=1[CH3:21])[CH3:12]
Reactant: Cc1ccc(NN)cc1
Reactant: CCOC(=O)CC(C(C)=O)C(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)Cc1c(C)nn(-c2ccc(C)cc2)c1C
Yield: 89 %

Procedure:
8.0 grams p-tolylhydrazine-hydrochloride, 9.3 grams 3,3-diacetyl-propionic acid-ethyl ester, 4.1 grams anhydrous sodium acetate and 70 milliliters ethanol were mixed and the mixture was heated to the boiling temperature under reflux for 1.5 hour. The reaction mixture was worked up as described in Example (3a). After distillation, 12.1 grams 3,5-dimethyl-1-(p-tolyl)-pyrazol-4-acetic acid-ethyl ester were obtained as a viscous oil having a Kp0.001 of 145°-146° C., representing a yield of 89%. For analysis, the product was redistilled resulting in an n20D 1.5455.
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[O:6][CH:7]=[CH:8][C:9]=1[SH:10].[CH3:11][S:12][CH2:13]Cl>CO>[CH3:11][S:12][CH2:13][S:10][C:9]1[CH:8]=[CH:7][O:6][C:5]=1[CH3:4]
Reactant: CSCCl
Reactant: Cc1occc1S
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CSCSc1ccoc1C

Procedure:
Into a 25 ml round bottom flask equipped with magnetic stirrer, thermometer, water bath, and reflux condenser is added a solution containing 0.27 g of sodium methoxide (0.005 moles) in 3 ml. absolute methanol. While maintaining the solution at 25° - 30° C, 0.57 g (0.005 moles) of 2-methyl-3-furan thiol in 2 ml of absolute methanol is added thereto. At 25° C, 0.483 g (0.005 moles) of chloromethyl methyl sulfide having the formula:
Reaction SMILES: [C:1]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:5])[C:2]([CH3:4])=[CH2:3].O[N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22].CC(C)=[O:25]>>[OH:25][N:6]([C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])[CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22])[C:12]([OH:14])=[O:13]
Reactant: CC(C)=O
Reactant: O=C1CCC(=O)N1O
Reactant: C=C(C)C(=O)NCCCCCC(=O)O
Product: C=C(C)C(=O)N(O)CCCCC(C(=O)O)N1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 81 %

Procedure:
N-methacryloyl-6-aminocaproic acid (3.98 g, 20 mmol) was dissolved in 50 ml of acetone, and then to this solution 1,3-dicyclohexlylcarbodiimide (4.5 g, 22 mmol) and N-hydroxysuccinimide (2.55 g, 22 mmol) were added. Resulting mixture was stirred at room temperature for 6 hours. The reaction was quenched by addition of 1 ml of water, the precipitate of 1,3-dicyclohexylurea was removed by filtration and washed with acetone. The solution was concentrated in vacuum and purified by column chromatography on silica gel using step gradient of acetone (0-5%) in chlorophorm to give activated ester (3, Met=b, n=2) with yield 81% (4.8 g). MALDI MS: found 296.1, C14H20N2O5, calc. 296.09.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:26])[CH:3]=1.[CH3:27][N:28]1[C:32](=[O:33])[C:31]([CH3:35])([CH3:34])[NH:30][C:29]1=[O:36]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:30]5[C:31]([CH3:35])([CH3:34])[C:32](=[O:33])[N:28]([CH3:27])[C:29]5=[O:36])=[CH:3][C:4]=4[F:26])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: CN1C(=O)NC(C)(C)C1=O
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2F)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)N(C)C(=O)C3(C)C)cc2F)CC1
Yield: 10.4 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (167 mg) described in Preparation Example 121 and 3,5,5-trimethylimidazolidine-2,4-dione (63 mg) described in Preparation Example 218 and by the reaction and treatment in the same manner as in Example 536, the title compound (20 mg) was obtained.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([CH3:27])=[CH:21][C:22](=[O:26])[O:23]2)=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Br-].[OH-:29].[K+].Cl>O.C(O)C.C(Cl)Cl>[CH3:27][C:20]1[C:19]2[CH:18]=[CH:17][C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:25][C:24]=2[O:23][C:21]=1[C:22]([OH:26])=[O:29]
Reactant: CCCCCCCCCCCCCCOc1ccc2c(C)cc(=O)oc2c1
Reactant: [OH-]
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CCCCCCCCCCCCCCOc1ccc2c(C)c(C(=O)O)oc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
10.9 g (0.0292 mole) of 7-tetradecyloxy-4-methyl-coumarin and 250 ml of dry methylene chloride is stirred at room temperature. 4.68 g (0.0292 mole) of bromide and 100.0 ml of dry methylene chloride are added over a period of 20 minutes. The mixture is stirred at room temperature for 1 hour and refluxed for 15 minutes. The mixture is then cooled and extracted with 10% Na2SO3. It is washed with a saline solution, dried (Na2SO4) and evaporated to dryness. The product obtained is stirred into a cold solution of 60 g KOH and 150 ml of ethanol. The mixture is heated to reflux for 2 hours and then is diluted with water. After refluxing is continued for about 10 minutes, it is poured into 1 liter of water, acidified with concentrated HCl and extracted with diethyl ether. The ether layer is washed with water and saline solution, dried (Na2SO4) and evaporated with replacement of the solvent with a total volume of 150 ml of hexane. The mixture is allowed to stand at room temperature. The product is collected and dried, yielding 10.4 g (92%) of 3-methyl-6-tetradecyloxybenzofuran-2-carboxylic acid, m.p. 108°-110° C. The mother liquor is concentrated to about 50 ml and cooled, yielding an additional 0.4 g of the 3-methyl-6-tetradecyloxy-benzofuran-2-carboxylic acid, m.p. 105°-108° C. (Overall yield -- 96%.)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)=[CH:6][C:5]=1I.[F-:29].[K+].COC(=O)[C:34](Cl)([F:36])[F:35].O>CN(C)C=O.[Cu]I>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)=[CH:6][C:5]=1[C:34]([F:36])([F:29])[F:35]
Reactant: COC(=O)C(F)(F)Cl
Reactant: [F-]
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1I
Agent: [Cu]I
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Temperature: 120 °C
Reaction time: 5 h
Yield: 98.7 %

Procedure:
In a solution of 0.51 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-iodo benzoic acid methyl ester in 5 ml of N,N-dimethylformamide, 0.18 g of copper (I) iodide, 0.06 g of potassium fluoride and 0.27 g of chlorodifluoro acetic acid methyl ester were added, and stirred at 120° C. for 5 hours. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, 50 ml of water was added and extracted with ethyl acetate (50 ml×2). The organic phase was washed with water, dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:4), and 0.45 g of the aimed product was obtained as pale yellow oily substance.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])[N:6]=[CH:5][C:4]=1[C:16]([NH2:18])=O.S(Cl)(Cl)=O.CN(C=O)C>C1(C)C=CC=CC=1>[F:20][C:2]([F:1])([F:19])[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])[N:6]=[CH:5][C:4]=1[C:16]#[N:18]
Reactant: NC(=O)c1cnn(-c2ccc(Cl)cc2Cl)c1C(F)(F)F
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1cnn(-c2ccc(Cl)cc2Cl)c1C(F)(F)F

Procedure:
5-(Trifluoromethyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-4-carboxamide (2.36 grams, 0.073 mole) was suspended in 30 ml of toluene, 10 ml of thionyl chloride, and about 1 ml of DMF. The suspension was stirred and heated to reflux, then refluxed for 11/2 hours. Solvent and excess thionyl chloride was removed in vacuo. The crude solid was crystallized from toluene yielding 5-(trifluoromethyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-4-carbonitrile, yield 0.7 gram, mp=83°-85° C.
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.[CH3:27][C:28]1[N:29]=[CH:30][N:31]2[CH:35]=[CH:34][S:33][C:32]=12>>[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:29]3[C:28]([CH3:27])=[C:32]4[S:33][CH:34]=[CH:35][N+:31]4=[CH:30]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: Cc1ncn2ccsc12
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
Product: Cc1c2scc[n+]2cn1CC1=C(C(=O)[O-])N2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@H]1C
Yield: 7.7 %

Procedure:
The same procedure as in Example 1 was repeated except that 103 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 117 mg of 7-methylimidazo[5,1-b]thiazole were used, thereby obtaining 7.8 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:33]([C:36]1[CH:37]=[CH:38][C:39]([CH3:42])=[N:40][CH:41]=1)=[C:34]=[O:35]>ClCCl.C1(C)C=CC=CC=1>[CH3:42][C:39]1[N:40]=[CH:41][C:36]([NH:33][C:34]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:35])=[CH:37][CH:38]=1
Reactant: Cc1ccc(N=C=O)cn1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (80 mg, 0.21 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (74.3 ul, 0.53 mmol) (Aldrich), followed by the addition of solution of 5-Isocyanato-2-methyl-pyridine (1.26 mL, 0.25 mmol) in toluene (from Example 71a supra). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (6-methyl-pyridine-3-yl)-amide as a white solid. (Yield 52 mg, 48.1%).
Reaction SMILES: [CH:1]([Si:4](Cl)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[Na].[Br:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[CH:17]2.[H-].[Na+]>CN(C)C=O.ClCCl>[Br:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([Si:4]([CH:8]([CH3:10])[CH3:9])([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])[CH:18]=[CH:17]2
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triisopropylsilyl chloride (6.87 g) was added to the sodium salt prepared from 5bromoindole (6.35 g) and sodium hydride (1.71 g, 50% suspension in oil) in dimethylformamide (32 ml) and the mixture was stirred at room temperature for 2 hours then poured into ice water (150 ml). The crude intermediate obtained by evaporation of the dichloromethane extract was column chromatographed (silica gel, 40°-60° C. petroleum ether) to give 5-bromo-1-triisopropylsilylindole isolated as an oil.