Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:48])[CH2:25][C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([CH2:39][O:40]C3CCCCO3)[CH:34]=2)[CH:28]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:40][CH2:39][C:35]1[CH:34]=[C:33]([C:29]2[CH:28]=[C:27]([C:26]3[CH2:25][C:24](=[O:48])[NH:23][C:9]4[CH:10]=[C:11]([C:19]([F:21])([F:20])[F:22])[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:13][C:8]=4[N:7]=3)[CH:32]=[CH:31][CH:30]=2)[CH:38]=[CH:37][N:36]=1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(COC4CCCCO4)c3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(CO)c3)c1)=N2

Procedure:
The title compound was prepared from (RS)-[5-(methyl-propyl-amino)-2-(3-oxo-3-{3-[2-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M282) (0.25 g, 0.36 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (109 mg, 62%).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[N:7]([CH:8]([CH3:11])[CH2:9]O)[C:6]2[CH:12]=[C:13]([N:17]3[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]3=[O:29])[C:14]([F:16])=[CH:15][C:5]=2[N:4]=1.N1C=CC=CC=1.S(Cl)([Cl:40])=O>C(OCC)C>[CH3:28][N:19]1[C:20]([C:24]([F:26])([F:27])[F:25])=[CH:21][C:22](=[O:23])[N:17]([C:13]2[C:14]([F:16])=[CH:15][C:5]3[N:4]=[C:3]([C:2]([F:31])([F:30])[F:1])[N:7]([CH:8]([CH3:11])[CH2:9][Cl:40])[C:6]=3[CH:12]=2)[C:18]1=[O:29]
Reactant: CC(CO)n1c(C(F)(F)F)nc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc21
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(CCl)n1c(C(F)(F)F)nc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 0.4 gram (0.0009 mole) of 2-[2-trifluoromethyl-5-fluoro-6-(1-methyl-6-trifluoromethyluracil-3-yl)benzimidazol-1-yl]propan-1-ol (Compound 7--prepared as in Step A of Example 8) in 10 mL of diethyl ether was cooled in an ice-water bath, and 0.07 mL (0.0009 mole) of pyridine was added at a rate to maintain the reaction mixture temperature below 5° C. Upon completion of the addition, 0.1 mL (0.0013 mole) of thionyl chloride was added dropwise from a syringe. Upon completion of the addition, the reaction mixture stirred at about 0° C. for 30 minutes. After this time, the reaction mixture was allowed to warm to ambient temperature, where it stirred for about 18 hours. Analysis of the reaction mixture by thin layer chromatography (TLC) indicated the reaction was not complete. The reaction mixture was concentrated under reduced pressure to a residue. The residue was dissolved in methylene chloride, and 0.1 mL of thionyl chloride and 0.07 mL of pyridine were added. The mixture was warmed to reflux, where it stirred for about 24 hours. Analysis of the reaction mixture using TLC indicated the reaction was still not complete. Additional equivalents of thionyl chloride and pyridine were were added to the reaction mixture each day for a period of five days, as the reaction mixture stirred at reflux. At the end of five days the reaction mixture was allowed to cool to ambient temperature, where it stirred for two days. The reaction mixture was then poured into water and extracted with ethyl acetate. The extract was washed with an aqueous solution saturated with sodium chloride and dried with sodium sulfate. The mixture was filtered, and the filtrate concentrated under reduced pressure, yielding about 0.3 gram of 1-methyl-3-[1-(1-methyl-2-chloroethyl)-2-trifluoromethyl-5-fluorobenzimidazol-6-yl]-6-trifluoromethyluracil, mp 93°-95° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][CH:2](Cl)[B:3]1[O:7][C:6]([CH3:9])([CH3:8])[C:5]([CH3:11])([CH3:10])[O:4]1.[CH2:13]([Mg]Br)[CH3:14]>O1CCCC1>[Cl:1][CH:2]([B:3]1[O:7][C:6]([CH3:9])([CH3:8])[C:5]([CH3:11])([CH3:10])[O:4]1)[CH2:13][CH3:14]
Reactant: CC1(C)OB(C(Cl)Cl)OC1(C)C
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(Cl)B1OC(C)(C)C(C)(C)O1
Temperature: -78 °C
Reaction time: 18 h
Yield: 79.8 %

Procedure:
2.64 g (12.5 mmol) of 2-(dichloromethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were dissolved in 30 ml of tetrahydrofuran and the solution was cooled under a nitrogen atmosphere to -78° C. 11.8 ml (12.5 mmol) of 1.06M ethylmagnesium bromide were added dropwise and the solution was stirred at room temperature for 18 hours. The solution was partitioned between ethyl acetate, saturated sodium chloride solution and 2M hydrochloric acid solution. The aqueous layer was extracted with ethyl acetate and the organic layers were combined and dried over anhydrous sodium sulphate. After filtration and evaporation the oil obtained was distilled to give 2.04 g of 2-[1(RS)-chloropropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane; b.p. 53° C./0.8 mm Hg.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:10](Cl)[CH:11]=[CH2:12]>O1CCCC1>[CH2:12]([C:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:11]=[CH2:10]
Reactant: O=C(O)C1CCCCC1
Reactant: C=CCCl
Solvent: C1CCOC1
Product: C=CCC1(C(=O)O)CCCCC1
Temperature: -20 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
300 cm3 of dry tetrahydrofuran (THF) and 40 g of diisopropylamine redistilled over calcium hydride were introduced into a 1 liter three-necked flask fitted with a condenser closed with a calcium chloride guard tube, a low-temperature thermometer, a mechanical stirrer and a nitrogen inlet tube. The solution was cooled to -20° C. and 220 cm3 of a 1.47 M solution of butyl-lithium in hexane were added. The addition was made in the course of 1 hour; the temperature of the mixture was kept at -10° C. 25.5 g (0.2 mole) of 1-cyclohexyl-carboxylic acid, dissolved in 50 cm3 of dry THF, were then introduced in the course of 20 minutes and the temperature of the whole was then raised gradually to 50° C. and this temperature was maintained for 2 hours. The yellow solution was cooled to -70° C. 15.3 g of dry allyl chloride were added and the mixture was stirred for a further 2 hours whilst allowing the temperature to return to ambient temperature, after which the whole was left to stand for 12 hours. The solution was concentrated in vacuo and then poured into 100 cm3 of ice-cold distilled water and 100 cm3 of hexane. The aqueous phase, which had been separated off, was acidified with dilute hydrochloric acid. The 1-allyl-1-cyclohexylcarboxylic acid obtained was extracted with ether. It was purified by distillation under reduced pressure and was in the form of a colourless liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:17])[C:9]=1[O:10]COCCOC)[CH:5]=O.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:23][C:24]#[N:25]>>[CH3:18][O:19][C:20]1[CH:21]=[C:22](/[C:23](=[CH:5]/[C:4]2[CH:7]=[C:8]([CH3:17])[C:9]([OH:10])=[C:2]([CH3:1])[CH:3]=2)/[C:24]#[N:25])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COCCOCOc1c(C)cc(C=O)cc1C
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2cc(C)c(O)c(C)c2)cc1OC
Yield: 57.8 %

Procedure:
The hydroxyl group of 3,5-dimethyl-4-hydroxybenzaldehyde (2.3 g) was protected by use of 2-methoxyethoxymethyl chloride (3.4 g) in accordance with (production process 1), to thereby produce 3,5-dimethyl-4-methoxyethoxymethoxybenzaldehyde (2.7 g, yield: 62%). The thus-produced 3,5-dimethyl-4-methoxyethoxymethoxybenzaldehyde (2.0 g) and 3,4-dimethoxybenzyl cyanide (1.5 g) were subjected to condensation in accordance with process A of (production process 2), to thereby yield an MEM form of the target product. Subsequently, the protective group was removed from the MEM form in accordance with (production process 3), to thereby produce the target product (1.5 g, yield: 57%).
Reaction SMILES: [CH2:1]1[C@@H:5]2[CH2:6][NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10](=[O:11])[N:4]2[CH2:3][CH2:2]1.[C:16]1([C:22]2[CH:39]=[CH:38][CH:37]=[CH:36][C:23]=2[C:24]([NH:26][C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)=[O:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([C:22]2[CH:39]=[CH:38][CH:37]=[CH:36][C:23]=2[C:24]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([N:7]3[C:8]4[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=4[C:10](=[O:11])[N:4]4[CH2:3][CH2:2][CH2:1][C@@H:5]4[CH2:6]3)=[O:32])=[CH:34][CH:35]=2)=[O:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1c2ccccc2NC[C@H]2CCCN12
Reactant: O=C(O)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1
Product: O=C(Nc1ccc(C(=O)N2C[C@H]3CCCN3C(=O)c3ccccc32)cc1)c1ccccc1-c1ccccc1
Yield: 43 %

Procedure:
The same procedures used in Example 25 were repeated using (11aR)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one prepared in Reference Example 25 and 4-[(2-phenylbenzoyl)amino]benzoic acid to thus give the title compound. Yield 43.0%.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[C@@H:11]([CH3:16])[CH2:10]2)[N:5]=[C:4]([CH3:17])[N:3]=1.O.[NH2:19][NH2:20]>CS(C)=O>[CH3:16][C@@H:11]1[N:12]([CH3:15])[CH2:13][CH2:14][N:9]([C:6]2[C:7]([F:8])=[C:2]([NH:19][NH2:20])[N:3]=[C:4]([CH3:17])[N:5]=2)[CH2:10]1
Reactant: Cc1nc(Cl)c(F)c(N2CCN(C)[C@@H](C)C2)n1
Reactant: NN
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc(NN)c(F)c(N2CCN(C)[C@@H](C)C2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 64 %

Procedure:
To 4-chloro-6-[(3S)-3,4-dimethyl-1-piperazinyl]-5-fluoro-2-methylpyrimidine (0.254 g, 0.98 mmol) in DMSO (3 mL) was added hydrazine monohydrate (2 mL). The reaction was stirred at room temperature for 3 days. The volatiles were removed in vacuo, and the residue was purified by RP-HPLC to provide 4-[(3S)-3,4-dimethyl-1-piperazinyl]-5-fluoro-6-hydrazino-2-methylpyrimidine as a yellow solid (0.161 g, 64%). LCMS: (M+H)+=255.6.
Reaction SMILES: F[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[CH3:15].[C:16]1([OH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:15][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:2]=1[O:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1F
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(C(=O)OC(C)(C)C)ccc1Oc1ccccc1
Temperature: 120 °C
Reaction time: 12 h
Yield: 65.7 %

Procedure:
A mixture of tert-butyl 4-fluoro-3-methylbenzoate (740 mg, 3.5 mmol), phenol (700 mg, 7.4 mmol), potassium carbonate (993 mg, 7.2 mmol) and methylsulfinylmethane (10 mL) was stirred at 120° C. for 12 hours. The mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=80:1) to give tert-butyl 3-methyl-4-phenoxybenzoate as a colorless oil (654 mg, 66%). 1H NMR (300 MHz, CDCl3): δ 8.08 (s, 1H), 7.68 (s, 1H), 7.38 (s, 1H), 7.32-7.28 (m, 2H), 6.84-6.77 (m, 3H), 2.26 (s, 3H), 1.56 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:16]O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([O:7][CH3:16])=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1Cl
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C)c(Cl)c1
Yield: 96 %

Procedure:
To a solution of 3-chloro-4-methylbenzoic acid (20 g, 117 mmol) in MeOH (200 mL) was added dropwise thionyl chloride (25.6 mL, 352 mmol) at 0° C. with stirring. The mixture was stirred at room temperature for 5 days. The reaction was concentrated. The residue was dissolved in EA (500 mL), washed with 10% Na2CO3 (250 mL×2), water (250 mL) and brine (250 mL), dried over Na2SO4, filtered and concentrated to afford product as a yellow solid (20.8 g, 96%).
Reaction SMILES: C[Al](C)C.Cl.[CH2:6]([O:8][NH2:9])[CH3:7].[CH3:10][C:11]1[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([NH:18][C:19]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31](OC)=[O:32])(=[O:24])=[O:23])=[O:20])[N:12]=1.Cl>C(Cl)Cl>[CH3:10][C:11]1[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([NH:18][C:19]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([NH:9][O:8][CH2:6][CH3:7])=[O:32])(=[O:24])=[O:23])=[O:20])[N:12]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(C)n1
Reactant: CCON
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: CCONC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(C)n1
Temperature: 25 °C

Procedure:
To 2.9 g of trimethylaluminum in 100 ml of methylene chloride is added 2.0 g of ethoxyamine hydrochloride with stirring at ambient temperature. To this mixture is added 3.0 g of N-[(4,6-dimethylpyrimidin-2-yl)aminocarbonyl]-2-methoxycarbonylbenzenesulfonamide and the solution is refluxed for 18 hours. The reaction mixture is treated with aqueous hydrochloric acid and the resulting precipitated product is purified by chromatography.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1.[N:20]1([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[CH:27][CH:26]=2)[CH:24]=[N:23][N:22]=[N:21]1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[O:1]=[C:2]1[CH2:7][N:6]([C:32](=[O:33])[CH2:31][C:28]2[CH:27]=[CH:26][C:25]([N:20]3[CH:24]=[N:23][N:22]=[N:21]3)=[CH:30][CH:29]=2)[CH2:5][CH2:4][N:3]1[CH:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1
Reactant: O=C(O)Cc1ccc(-n2cnnn2)cc1
Reactant: N#Cc1ccc2c(c1)CCC(N1CCNCC1=O)C2
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)CCC(N1CCN(C(=O)Cc3ccc(-n4cnnn4)cc3)CC1=O)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 6-(2-Oxopiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (40 mg, 0.16 mmol) and [4-(1H-tetrazol-1-yl)phenyl]acetic acid (38 mg, 0.19 mmol) in DCM (3 ml) was added DMAP (25 mg, 0.20 mmol) and EDC (39 mg, 0.20 mmol). The mixture was allowed to stir at RT for 4 hours. LC showed formation of the desired product. The solvent was removed under vacuum, and the residue was redissolved in methanol, and purified by reverse phase HPLC to give the title product. LC-MS (IE, m/z): 442 [M+1]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][NH2:11])=[O:4].C(N(CC)CC)C.C[O:20][C:21](=O)[N:22]=[C:23](SC)[C:24]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([O:46][CH3:47])[CH:39]=1)=[N:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]=[C:35]([CH3:37])[O:34][N:33]=2)=[CH:28][CH:27]=1>CN(C=O)C>[CH3:47][O:46][C:40]1[CH:39]=[C:38]([CH:24]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[N:36]=[C:35]([CH3:37])[O:34][N:33]=3)=[CH:28][CH:27]=2)[C:23]2[NH:22][C:21](=[O:20])[N:10]([C:9]3[CH:8]=[CH:7][S:6][C:5]=3[C:3]([OH:2])=[O:4])[N:11]=2)[CH:43]=[CH:42][C:41]=1[O:44][CH3:45]
Reactant: COC(=O)c1sccc1NN
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1ccc(OC)c(OC)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ccsc3C(=O)O)c(=O)[nH]2)cc1OC
Temperature: 85 °C
Reaction time: 18 h
Yield: 75.2 %

Procedure:
After adding 30 mg of 3-hydrazinothiophene-2-carboxylic acid methyl ester and 25 μl of triethylamine to a solution of 80 mg of {2-(3,4-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (Example (36d)) in 3 ml of DMF, the mixture was stirred at 85° C. for 18 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 2 ml of methanol and 2 ml of THF. After adding 35 μl of acetic acid and 56 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 15 hours. Next, 2 ml of an aqueous 1N sodium hydroxide solution was added to the reaction mixture, and stirring was continued at room temperature for 2 hours. After adding 2 ml of 1N hydrochloric acid to the reaction mixture, extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 70 mg of 3-(3-{(3,4-dimethoxyphenyl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)thiophene-2-carboxylic acid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O=[C:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22]([O:24][CH3:25])=[O:23].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:25][O:24][C:22]([C:18]1[CH2:19][CH2:20][CH2:21][C:17]=1[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[O:23]
Reactant: COC(=O)C1CCCC1=O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCC1
Reaction time: 72 h
Yield: 72.9 %

Procedure:
Trifluoromethanesulfonic anhydride (1.5 mL, 8.9 mmol) was slowly added to a solution of methyl 2-oxocyclopentanecarboxylate (1.0 mL, 8.1 mmol) and N,N-diisopropylethylamine (2.2 mL, 13.0 mmol) in methylene chloride (30 mL) under a nitrogen atmosphere at room temperature. The reaction was stirred for 72 h, and then partitioned between methylene chloride and water. The organic layer was washed with 1 N HCl, aqueous NaHCO3, and brine; dried over magnesium sulfate; and concentrated to give an oil. The product was purified by FCC on silica gel eluting ethyl ether:hexane (5:95) to give 2-trifluoromethanesulfonyloxy-cyclopent-1-enecarboxylic acid methyl ester (1.62 g, 73%) as a yellow oil.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1.[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C>O1CCCC1>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([B:19]([OH:24])[OH:20])[CH:13]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1ccc(Br)cc1
Agent: CC1(C)CCCC(C)(C)N1
Solvent: C1CCOC1
Product: OB(O)c1cc(Br)ccc1F
Temperature: -78 °C
Reaction time: 3 h
Yield: 76.2 %

Procedure:
A cooled (−20° C.) solution of 2,2,6,6-tetramethylpiperidine (28 ml, 165 mmol) in tetrahydrofuran (400 ml) was treated with m-butyllithium (63 ml of a 2.5M solution in hexanes, 157.5 mmol). This mixture was then cooled to −78° C. 1-Bromo-4-fluorobenzene (16.5 ml, 150 mmol) was then added neat and dropwise over 10 min and stirring at −78° C. was continued for 3 h. Triisopropyl borate (40 ml, 172.5 mmol) was then added and stirring at −78° C. continued for 30 min before removing the cooling bath. When the internal temperature of the reaction reached −4° C., 5N hydrochloric acid (75 ml) was added and the mixture was stirred to ambient temperature. After stirring at ambient temp for 1 h the majority of the tetrahydrofuran was removed and the mixture partitioned between ether (500 ml) and 1N hydrochloric acid (500 ml). The organics were then extracted with 2N sodium hydroxide (400 ml) and the organics were discarded. The aqueous was cooled in an ice-water bath and 5N hydrochloric acid (150 ml) was added dropwise over 15 min. The resulting white solid was collected and dried under vacuum to afford 5-bromo-2-fluorobenzeneboronic acid (25 g, 76%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][C:9]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:10]=1[C:11](O)=[O:12]>>[NH2:8][C:9]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:10]=1[C:11]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:12]
Reactant: Brc1ccccn1
Reactant: Nc1ccc(Br)cc1C(=O)O
Product: Nc1ccc(Br)cc1C(=O)c1ccccn1

Procedure:
The anion of 2-bromo-pyridine 121 and 2-amino-5-bromobenzoic acid 122 were condensed to provide the 2′-pyridylketone 123.
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:15]([OH:17])=[O:16])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.S(=O)(=O)(O)O>>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2([C:15]([O:17][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:16])[CH2:14][CH2:13]2)=[CH:10][CH:11]=1
Reactant: C=C(C)C
Reactant: O=C(O)C1(c2ccc(Br)cc2)CC1
Agent: O=S(=O)(O)O
Product: CC(C)(C)OC(=O)C1(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Isobutylene (80.0 mL, 0.847 mol) was passed through a mixture of 1-(4-bromophenyl)cyclopropanecarboxylic acid (10.0 g, 0.0415 mol, example 238, step 1) and sulfuric acid (1.0 mL, 0.019 mol) at −78° C. The mixture was sealed and was stirred at room temperature overnight. The isobutylene was evaporated at room temperature and the residue was dissolved in ethyl acetate (100 mL), and washed with water and brine successively. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=1[S:34]([N:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]([CH:46]=O)=[CH:38]1)(=[O:36])=[O:35].N1CCCCC1>CO>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=1[S:34]([N:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39](/[CH:46]=[C:7]2\[O:8][C:4]3[C:3]([CH2:12][N:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]4)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[CH:38]1)(=[O:36])=[O:35]
Reactant: O=Cc1cn(S(=O)(=O)c2c(Cl)cccc2Cl)c2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2cn(S(=O)(=O)c4c(Cl)cccc4Cl)c4ccccc24)C3=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.100 g, 0.287 mmol) obtained in Example A16, Step 1 in methanol (1.2 mL) was added with 1-(2,6-dichlorophenylsulfonyl)-1H-indole-3-carboxaldehyde (0.0918 g, 0.287 mmol) and piperidine (0.00244 g, 0.0287 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was added with methanol (2 mL), and the solid was suspended in methanol and thereby washed to obtain tert-butyl (Z)-4-[(2-{[1-(2,6-dichlorophenylsulfonyl)-1H-indol-3-yl]methylene}-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.137 g, 69%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.C1COCC1.[CH:16]12[O:21][CH:20]1[CH2:19][CH2:18][CH2:17]2.[NH4+].[Cl-]>[Cu]I>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:19]1[CH2:18][CH2:17][CH2:16][CH:20]1[OH:21]
Reactant: COc1ccccc1[Mg]Br
Reactant: C1CC2OC2C1
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccccc1C1CCCC1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
To a solution of (2-methoxyphenyl)magnesium bromide in THF (47.4 ml, 47.4 mmol) was added Copper(I) iodide (0.632 g, 3.32 mmol). The resulting solution was stirred at RT for 10 min. 6-oxabicyclo[3.1.0]hexane (4.11 ml, 47.4 mmol) was slowly added and the reaction mixture was stirred at RT overnight. Sat. NH4Cl was slowly added and the mixture was stirred at RT for 30 min. The product was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (SG, 0% to 60% EtOAc/Hex) to get 2-(2-methoxyphenyl)cyclopentanol (9.03 g, 47.0 mmol, 99% yield). LC-MS (M+Na)+=215.1. 1H NMR (500 MHz, CDCl3) δ 7.21 (t, J=5.8 Hz, 2H), 6.97 (t, J=7.3 Hz, 1H), 6.88 (d, J=8.2 Hz, 1H), 4.24 (q, J=5.9 Hz, 1H), 3.79 (s, 3H), 3.38-3.27 (m, 2H), 2.23-2.10 (m, 1H), 2.09-1.97 (m, 1H), 1.95-1.85 (m, 1H), 1.85-1.71 (m, 3H).