Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([Cl:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:25]=[CH:24][CH:23]=[CH:22][C:15]=1[O:16][CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1>CCOCC>[ClH:11].[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:19][CH2:18][CH2:17][CH2:21][N:19]2[CH2:20][CH2:21][CH:17]([O:16][C:15]3[CH:22]=[CH:23][CH:24]=[CH:25][C:14]=3[O:13][CH3:12])[CH2:18]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1ccccc1OC1CCNC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: CCOCC
Product: COc1ccccc1OC1CCN(CCCNS(=O)(=O)c2ccc(F)cc2)C1
Product: Cl
Reaction time: 2 h
Yield: 62 %

Procedure:
0.78 g (4.0 mmol) of 4-fluorophenylsulphonyl chloride in 15 ml of ether were added dropwise to a solution of 1.0 g (4.0 mmol) of 1-3-aminopropyl)-3-(2-methoxyphenoxy)-pyrrolidine in 20 ml of anhydrous ether at 0° C. After 2 hours at room temperature, the mixture was freed from solvent in vacuo and the remaining oily residue was brought to crystallization by trituration with diethyl ether/hexane. In this manner, 1.1 g (62%) of title compound were obtained as a slightly reddish, hygroscopic solid. It melted from 50° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:21]([N:23]1[CH2:42][CH2:41][CH2:40][C@H:24]1[C:25]([NH:27][C@H:28]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH3:29])=[O:26])=[O:22])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:20])[NH:9][S:10]([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[NH:43]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[C@H:44]([C:46](O)=[O:47])[CH3:45].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(Cl)(Cl)Cl.CO>[NH:43]([C:49]([O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:50])[C@H:44]([C:46]([NH:2][C@H:3]([C:21]([N:23]1[CH2:42][CH2:41][CH2:40][C@H:24]1[C:25]([NH:27][C@H:28]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH3:29])=[O:26])=[O:22])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:20])[NH:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:17])=[CH:18][CH:19]=1)(=[O:11])=[O:12])=[O:47])[CH3:45]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](N)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)OCc2ccccc2)cc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 54 %

Procedure:
At 0° C. the solution of 45 mg (0.072 mmol) of HCl.Arg(Tos)-Pro-Ala-OBzl in 15 ml of anhydrous tetrahydrofuran was adjusted to pH 9, to which the pre-cold solution of 15 mg (0.079 mmol) Boc-Ala-OH, 10 mg (0.074 mmol) of 1-hydroxybenzotriazole and 16 mg (0.077 mmol) of dicyclohexylcarbodiimide in 20 ml of anhydrous tetrahydrofuran was added. The reaction mixture was stirred at 0° C. for 2 h and at room temperature for 6 h and TLC (chloroform/methanol, 30:1) indicated complete disappearance of HCl.Arg(Tos)-Pro-Ala-OBzl. The resulted precipitates of N,N-dicyclohexylurea were filtrated and the filtrate was diluted with 80 ml of ethyl acetate. The solution obtained was washed successively with saturated NaCO3 in water (50 ml×3), saturated NaCl in water (50 ml×3) and KHSO4 in water (5%, 30 ml×3). The separated ethyl acetate layer was dried with anhydrous MgSO4, and then evaporated to provide 30 mg (54%) of the title compound as a colorless powder. Mp 80–82° C., FAB-MS (m/e) 758[M+H]+.
Reaction SMILES: [CH:1]1([C:4](=[O:17])[C:5]2[CH:10]=[CH:9][C:8]([C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.C[Si]([I:22])(C)C.S(=O)(O)[O-].[Na+]>C(Cl)Cl>[I:22][CH2:3][CH2:2][CH2:1][C:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)=[O:17]
Reactant: C[Si](C)(C)I
Reactant: CC(C)(C(=O)O)c1ccc(C(=O)C2CC2)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C(=O)O)c1ccc(C(=O)CCCI)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
A solution of 10.5 g of 4-(cyclopropyl-oxo-methyl)-α,α-dimethylphenylacetic acid, prepared in accordance with Example 2, in 250 mL of CH2Cl2 was cooled in an ice-MeOH bath and 25 g of trimethylsilyliodide was then added rapidly via pipette. The mixture was stirred in the ice bath for one hour, warmed to ambient temperature, and stirred for one hour. A solution of aqueous sodium bisulfite was then added and the mixture was stirred well. The phases were partitioned and the aqueous layer was extracted with CH2Cl2. The combined organics were washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated in vacuo to afford 12.6 g (77%) of 4-(4-iodo-1-oxobutyl)-α,α-dimethylphenylacetic acid.
Reaction SMILES: [H][H].[CH3:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH:6]([CH3:10])[CH:5]1[OH:11]>[Pt]>[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[OH:11]
Reactant: [H][H]
Reactant: CC1CCCC(C)C1O
Agent: [Pt]
Product: Cc1cccc(C)c1O
Yield: 95 %

Procedure:
500 ml of catalyst were introduced into a fluidized-bed reactor having a capacity of 0.7 liter. The catalyst contained 0.25% by weight of platinum on a magnesium aluminum spinel carrier and had a particle size of from 0.2 to 0.6 mm and a BET specific surface area of 125 m2 /g. The temperature of the reactor was brought to 275° C., and the mixture which was preheated to this temperature and consisted of 200 liters/hour of nitrogen and 20 liters/hour of hydrogen was passed in. 60 g/hour of gaseous 2,6-dimethylcyclohexanol were passed continuously through the fluidized catalyst bed produced in this manner. The reaction product was obtained by cooling the exit gases, and was distilled. 100 g of 2,6-dimethylcyclohexanol were converted to 90.5 g (yield: 95% of theory) of 2,6-dimethylphenol.
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].C([Li])CCC.[C:13]([O:17][C:18](=[O:46])[CH:19]([NH:27][S:28]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)=[CH:33][CH:32]=1)(=[O:30])=[O:29])CCCC(=O)CC)([CH3:16])([CH3:15])[CH3:14].Cl.[CH2:48]1[CH2:52][O:51][CH2:50][CH2:49]1>>[C:13]([O:17][C:18]([CH:19]1[C:52]([OH:51])([CH2:1][CH3:2])[CH2:48][CH2:49][CH2:50][N:27]1[S:28]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=2)=[CH:33][CH:32]=1)(=[O:30])=[O:29])=[O:46])([CH3:14])([CH3:16])[CH3:15]
Reactant: CC(C)NC(C)C
Reactant: C1CCOC1
Reactant: CCC(=O)CCCC(NS(=O)(=O)c1ccc(OCc2ccc(F)cc2)cc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li]CCCC
Product: CCC1(O)CCCN(S(=O)(=O)c2ccc(OCc3ccc(F)cc3)cc2)C1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of diisopropylamine (0.35 mL, 2.5 mmol) in 10 mL of THF at −78° C. was added n-butyllithium. The mixture was warmed to room temperature and stirred for 20 min. After cooling to −78° C., a solution of 2-[4-(4-fluoro-benzyloxy)-benzenesulfonylamino]-6-oxo-octanoic acid tert-butyl ester (1.0 g, 2.1 mmol) in 2.5 mL of THF was added dropwise. The mixture was warmed to room temperature and stirred for 3 h. After acidifying with 1M HCl, the mixture was extracted 2× into ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification of the residue by radial chromatography (1% acetone-CH2Cl2, 2 mm plate) afforded ca. 0.37 g of the (2R,3S) diastereomer and 0.09 g of the (2R,3R) diastereomer of 1-[4-(4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-ethyl-piperidine-2-carboxylic acid tert-butyl ester as colorless syrups:
Reaction SMILES: BrC[CH2:3][CH2:4][CH2:5][C:6]([CH3:21])([C:15]1C=CC=CC=1)[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1.[Br:22]CCCC(C)(C)CO.O1C=CCCC1>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:22][CH2:3][CH2:4][CH2:5][C:6]([CH3:21])([CH3:15])[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1
Reactant: CC(C)(CO)CCCBr
Reactant: CC(CCCCBr)(COC1CCCCO1)c1ccccc1
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(CCCBr)COC1CCCCO1
Yield: 90 %

Procedure:
According to the procedure for the preparation of 207d, 206a (78.0 g, 0.40 mol) was reacted with 3,4-dihydro-2H-pyran (41.5 g, 0.49 mol) and p-toluenesulfonic acid hydrate (0.42 g, 2.2 mmol) in CH2Cl2 (0.5 L) to yield 207a (101.0 g, 90%) as a pale-yellow oil, which was used without further purification. 1H NMR (CDCl3): δ 4.55 (t, 1H, J=2.9), 3.83 (m, 1H), 3.51 (m, 1H), 3.47 (d, 1H, J=9.0), 3.38 (t, 2H, J=6.8), 2.98 (d, 1H, J=9.0), 1.94-1.75 (m, 2H), 1.75-1.44 (m, 6H), 1.40 (t, 2H, J=8.5), 0.91 (s, 3H), 0.90 (s, 3H). 13C NMR (CDCl3): δ 99.01, 76.17, 61.85, 37.89, 34.66, 34.04, 30.62, 27.92, 25.60, 24.64, 24.56, 19.41. HRMS (LSIMS, nba): Calcd for C12H24BrO2 (MH+): 279.0960, found: 279.0955.
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH2:12](Br)[CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O.CCCCCC>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:14][CH:13]=[CH2:12])=[CH:7][CH:6]=1
Reactant: C=CCBr
Reactant: Oc1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: O
Product: C=CCOc1ccc(OCCBr)cc1

Procedure:
To a solution of 45.0 g of 4-(2-bromoethoxy)-phenol (0.207 mol) in 310 ml of acetone was added 54 ml of allyl bromide (0.619 mol) and 45.0 g of anhydrous potassium carbonate (0.326 mol). The reaction mixture was stirred under reflux for eleven hours and was cooled and poured into 2500 ml of water. The mixture was extracted twice with 3:1 ether:methylene-chloride, and the organic layers were washed twice with 1 N NaOH, once with H2O, dried (Na2SO4) and concentrated to dryness under reduced pressure to yield a colorless oil. The analytical sample was prepared by crystallization from hexane to give colorless crystals, mp 27°-28°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].Cl.[NH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([OH:23])[CH2:19][CH2:18]1.CCN(CC)CC.Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([OH:23])[CH2:19][CH2:18]2)=[O:10])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)N[C@H]1CC[C@H](O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (5 g, 22.6 mmol) in DMF (35 mL) were added trans-4-aminocyclohexanol hydrochloride (3.8 g, 24.8 mmol) and Et3N (3.5 mL, 24.8 mmol) at 0° C. The reaction mixture was warmed up to room temperature and stirred overnight. After adding 1N HCl (40 mL) and water, the resulting white precipitates were collected by suction filtration. The collected solid was thoroughly washed with water. White powers collected were dissolved in EtOH (200 mL) then aqueous 30% NaOH (25 mL) was added. The reaction mixture was refluxed overnight. EtOH was removed in vacuo. The precipitates were filtered and washed with water. Recrystallization from methanol afforded 9.5 g (42%) of the title compound as a white solid. Mp: 239.5-241.1° C. NMR (DMSO-d6): δ 8.79 (s, 1H), 8.06 (d, J=2 Hz, 1H), 7.55-7.47 (m, 2H), 6.20 (d, J 8 Hz, 1H), 4.54 (d, J=4 Hz, 1H), 3.45-3.34 (m, 2H), 1.86-1.75 (m, 4H), 1.28-1.11 (m, 4H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][CH:16]([P:20]([CH3:25])(=[O:24])[O:21][CH2:22][CH3:23])[O:17][CH2:18][CH3:19])[CH3:14].[CH3:26][O:27][C:28]1[CH:38]=[CH:37][C:31]([CH:32]=[CH:33][N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([CH:32]([CH2:33][N+:34]([O-:36])=[O:35])[CH2:25][P:20]([CH:16]([O:17][CH2:18][CH3:19])[O:15][CH2:13][CH3:14])(=[O:24])[O:21][CH2:22][CH3:23])=[CH:37][CH:38]=1
Reactant: COc1ccc(C=C[N+](=O)[O-])cc1
Reactant: CCOC(OCC)P(C)(=O)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CCOC(OCC)P(=O)(CC(C[N+](=O)[O-])c1ccc(OC)cc1)OCC
Reaction time: 0.17 h

Procedure:
To a solution of 8.7 g of diisopropylamine in 40 ml of tetrahydrofuran at -78° C. under an atmosphere of nitrogen are added 53.6 ml of a 1.6M solution of n-butyllithium in hexane. This solution is then stirred for a period of 10 minutes at this temperature, after which time a solution of 15.0 g of ethyl (diethoxymethyl)methylphosphinate in 20 ml of tetrahydrofuran is added. This mixture is then stirred for a period of 1 hour at -78° C. after which time a solution of 12.8 g of 4-methoxy-β-nitrostyrene in 20 ml of tetrahydrofuran is introduced. This mixture is then allowed to warm to room temperature when 40 ml of a saturated ammonium chloride solution is added. The aqueous layer is then extracted with 2×25 ml of diethyl ether and the organic extracts are combined and dried over magnesium sulphate. The solvent is then evaporated under reduced pressure and the crude product chromatographed on silica gel using ethyl acetate as an eluent to give ethyl 2-(4-methoxyphenyl)-3-nitropropyl(diethoxymethyl)phosphinate as a viscous oil, 31 p=+42.4 and +42.1 ppm (CDCl3).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[Li]CCCC.[C:20](=[O:22])=[O:21].O>C1COCC1.CCCCCC>[F:12][C:11]([F:14])([F:13])[C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([C:20]([OH:22])=[O:21])[CH:3]=1)[NH:9][CH:8]=[CH:7]2
Reactant: O=C=O
Reactant: FC(F)(F)c1cc(Br)c2[nH]ccc2c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(C(F)(F)F)cc2cc[nH]c12
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
584 mg of 7-bromo-5-trifluoromethyl-indole (2.2 mmol) were dissolved in 15 ml THF and 4.1 ml of a 1.6 molar solution of n-BuLi in hexane were added at −78° C. The reaction mixture was then allowed to warm to 0-5° C. and was stirred at this temperature for 30 min. Then it was cooled again to −78° C., dry ice was added and the mixture was allowed to warm to rt. After 15 min at rt it was poured into water and extracted twice with ether. The aqueous phase was then acidified with 1 N HCl solution and extracted several times with DCM. The combined DCM extracts were then washed with brine, dried with magnesium sulfate, filtered and the solvent was evaporated. The remaining residue was triturated with n-hexane. Final filtration yielded 157 mg (31%) of 5-trifluoromethyl-1H-indole-7-carboxylic acid as an off-white solid. 1H NMR (DMSO-d6, 300 MHz): δ 6.66 (m, 1H), 7.48 (m, 1H), 7.89 (s, 1H), 8.18 (s, 1H), 11.46 (br s, 1H), 13.48 (br s, 1H).
Reaction SMILES: C([Li:5])CCC.[CH3:6][Si:7]([CH3:21])([CH3:20])[O:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH:12]=1>CCCCCC.CCOCC>[CH3:20][Si:7]([CH3:6])([CH3:21])[O:8][CH2:9][CH2:10][C-:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1.[Li+:5]
Reactant: C[Si](C)(C)OCCC1=CCc2ccccc21
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: C[Si](C)(C)OCC[c-]1ccc2ccccc21
Product: [Li+]
Reaction time: 2 h
Yield: 91.5 %

Procedure:
10.3 ml (16.4 mmol) of a 1.6 M butyllithium solution in hexane was added to 3.8 g (16.4 mmol) of [3-(2-trimethylsiloxyethyl)indene] in ether at −78° C. The immediate formation of a white solid was observed. The mixture was maintained under stirring for 2 h. Then the solvent was removed under vacuum and the residue was washed twice with 25 ml of hexane to give a white solid. (3.6 g, 15 mmol, yield: 91.5%).
Reaction SMILES: [S:1]1C=C[N:3]2[CH:6]=[N:7][CH:8]=[C:2]12.[Cl:9]N1C(=O)CCC1=O.[Cl:17][CH:18](Cl)[CH3:19]>C(OCC)(=O)C>[Cl:9][C:6]1[N:7]2[C:19]([S:1][CH:2]=[CH:8]2)=[C:18]([Cl:17])[N:3]=1
Reactant: CC(Cl)Cl
Reactant: c1cn2cncc2s1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Product: Clc1nc(Cl)n2ccsc12
Temperature: 62.5 °C

Procedure:
To a solution of imidazo[5,1-b]thiazole (18.624 g) in dichloroethane (450 ml) was added 20.030 g of N-chlorosuccinimide, the mixture was heated in a bath at a temperature of 60-65° C. for 1 hour. After air cooling, insolubles were removed by filtration, and the solvent was removed under reduced pressure. The residue thus obtained was dissolved in 3.0 l of ethyl acetate, and washed three times with 3.0 l of distilled water. After the organic layer was dried over anhydrous magnesium sulfate and the magnesium sulfate was removed by filtration, the solvent was removed under reduced pressure. The solid product thus obtained was purified by column chromatography on silica gel (ethyl acetate) to give 2.020 g of 5,7-dichloroimidazo[5,1-b]thiazole as a pale brown powder from the fraction of Rf=0.85.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[NH:21][C:20](=[O:27])[CH2:19]2.N1CCCCC1>C(O)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[NH:21][C:20](=[O:27])[C:19]2=[CH:11][C:8]1[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=1[CH3:13]
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Reactant: COc1cc2c(cc1OC)NC(=O)C2
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cc2c(cc1OC)C(=Cc1[nH]cc(CCC(=O)O)c1C)C(=O)N2
Yield: 58.8 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (90 mg), 97 mg 5,6-dimethoxy-2-oxindole, and 75 μL piperidine in 2 mL of ethanol were heated at 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven to give 104 mg (58%) of the title compound as a brown solid.
Reaction SMILES: [OH-].[Na+].[N+:3]([CH3:6])([O-:5])=[O:4].[CH3:7][CH:8]([CH2:11][CH2:12][CH3:13])[CH:9]=[O:10]>O.C(O)C>[CH3:7][CH:8]([CH2:11][CH2:12][CH3:13])[CH:9]([OH:10])[CH2:6][N+:3]([O-:5])=[O:4]
Reactant: C[N+](=O)[O-]
Reactant: CCCC(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCC(C)C(O)C[N+](=O)[O-]
Reaction time: 2 h
Yield: 82.6 %

Procedure:
After dissolving 7.0 g of sodium hydroxide in 50 ml of water and 50 ml of ethanol at 4° C., 10.7 g of nitromethane and 10.0 g of 2-methylpentanal were added thereto. The temperature of the solution was allowed to rise to room temperature, and the solution was stirred for two hours. After concentrating the ethanol under reduced pressure, the solution was neutralized with 1 mol/l of hydrochloric acid so that the pH of the solution was approximately 7. Ethyl acetate was added to the solution, and the organic layer was washed with saturated saline. The organic layer was dried with magnesium sulfate and concentrated, and then purified by silica gel chromatography (hexane/ethyl acetate=8/1), thereby obtaining 13.3 g of 3-methyl-1-nitro-2-hexanol (yield: 94.2%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([Br:12])[CH:3]=1.[C:13]([N:21]=[C:22]=[S:23])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCCCCC>O1CCCC1>[C:13]([NH:21][C:22](=[S:23])[NH:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([Br:12])[CH:3]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1cc(Br)cc(N)n1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)c1cc(Br)cc(NC(=S)NC(=O)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
2.74 g of methyl 6-amino-4-bromopyridine-2-carboxylate was dissolved in 15 ml of tetrahydrofuran and 1.63 ml of benzoyl isothiocyanate was added thereto, followed by stirring at room temperature for 13 hours. To the reaction mixture was added 40 ml of hexane. The resulting solid was filtered and washed with hexane. The obtained solid was dried in vacuo to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:5]=[C:4]([CH3:16])[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23]O)[CH:18]=1.P(Cl)(Cl)([Cl:27])=O.O.CO>CN(C)C=O>[Cl:27][CH2:23][C:19]1[CH:18]=[C:17]([C:3]2[C:2]([CH3:1])=[CH:7][C:6]([O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:5][C:4]=2[CH3:16])[CH:22]=[CH:21][CH:20]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(CO)c1
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(CCl)c1
Reaction time: 0.33 h
Yield: 92.2 %

Procedure:
To {2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methanol (2.40 g) was added N,N-dimethylformamide (7.2 mL), and the mixture was stirred for 20 min. The N,N-dimethylformamide solution was added dropwise at 25° C. to a separately prepared solution of phosphorus oxychloride (1.37 g) in N,N-dimethylformamide (4.8 mL). After stirring at 25° C. for 1 hr, water (2.4 mL), then methanol (12 mL), and water (2.4 mL) were added dropwise. Seed crystal was added, and the mixture was stirred at room temperature for 1 hr and at 10° C. or below for 1 hr. The precipitated crystals were collected by filtration, washed with water (24 mL), and dried at 50° C. under reduced pressure to give 3′-chloromethyl-2,6-dimethyl-4-[3-(methylsulfonyl)propoxy]biphenyl (2.33 g).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([CH2:27][NH:28]C(=O)OC(C)(C)C)[CH2:23]2)=[N:4][CH:5]=[C:6]([C:8](=[O:21])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:7]=1.[CH3:36][C:37]1[N:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1>>[NH2:28][CH2:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:40]3[CH:41]=[N:42][C:37]([CH3:36])=[CH:38][CH:39]=3)=[CH:7][C:6]([C:8]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:19])([F:20])[F:18])=[CH:12][CH:11]=3)=[O:21])=[CH:5][N:4]=2)[CH2:23]1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Reactant: Cc1ccc(B(O)O)cn1
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](CN)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 93 using (S)-tert-butyl ((1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)carbamate (Stage 108.1) and (6-methylpyridin-3-yl)boronic acid. LC-MS (Condition 6) tR=0.79 min, m/z=472.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11]Br)=[CH:4][CH:3]=1.[N:13]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)(=O)C>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][N:16]2[CH2:15][CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17]2)=[CH:4][CH:3]=1
Reactant: BrCCCOc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(Br)cc2)CC1
Temperature: 75 °C
Reaction time: 5 h
Yield: 73.7 %

Procedure:
To a mixture of 1-bromo-4-(3-bromopropoxy)benzene (300 mg, 1.02 mmol) and tert-butyl piperazine-1-carboxylate (144 mg, 1.02 mmol) in acetonitrile (6.0 mL) was added Cs2CO3 (365 mg, 1.10 mmol). The mixture was stirred at 75° C. for 5 hours. The mixture was poured into ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, filtered, and concentrated to give the title compound (300 mg, 75% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.40 (d, 2H), 6.75 (d, 2H), 3.95 (m, 2H), 3.42 (m, 4H), 2.54 (t, 2H), 2.40 (m, 4H), 2.01-1.89 (m, 2H), 1.50-1.40 (s, 9H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[CH2:6]1[O:16][C:15]2[CH:14]=[CH:13][C:10]([CH2:11]Cl)=[CH:9][C:8]=2[O:7]1>C(Cl)Cl>[O:16]1[C:15]2[CH:14]=[CH:13][C:10]([CH2:11][N:2]([CH3:1])[CH2:3][CH2:4][OH:5])=[CH:9][C:8]=2[O:7][CH2:6]1
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: CNCCO
Solvent: ClCCl
Product: CN(CCO)Cc1ccc2c(c1)OCO2
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 82.3 %

Procedure:
2-(Methylamino)ethanol (22.0 g, 290 mmol) is added all at once to a stirred solution of 3,4-methylenedioxybenzyl chloride (25.0 g, 147 mmol) in DCM (45 mL) at −78° C. under nitrogen. The solution is stirred for 15 minutes at −78° C. then allowed to warm to room temperature overnight (16 h). The reaction is quenched with 1.2 M NaOH (100 mL), washed twice with water, dried of MgSO4, and filtered. Concentration under reduced pressure afforded 25.3 g (83%) of 2-(benzo[1,3]dioxol-5-ylmethyl-methyl-amino)-ethanol as a clear oil which was suitable for use in the next step.