Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C2C(OCC3(C(F)(F)F)CCCCC3)=CC(F)=C(C=2)C(O)=O)CC1.[CH:26]1([C:29]2[C:30]([O:39][CH2:40][C:41]3([CH3:49])[CH2:46][CH2:45][C:44]([F:48])([F:47])[CH2:43][CH2:42]3)=[CH:31][C:32]([F:38])=[C:33]([CH:37]=2)[C:34](O)=[O:35])[CH2:28][CH2:27]1.CS(N)(=O)=O.[CH:55]1([S:58]([NH2:61])(=[O:60])=[O:59])[CH2:57][CH2:56]1>>[CH:26]1([C:29]2[C:30]([O:39][CH2:40][C:41]3([CH3:49])[CH2:46][CH2:45][C:44]([F:48])([F:47])[CH2:43][CH2:42]3)=[CH:31][C:32]([F:38])=[C:33]([CH:37]=2)[C:34]([NH:61][S:58]([CH:55]2[CH2:57][CH2:56]2)(=[O:60])=[O:59])=[O:35])[CH2:27][CH2:28]1
Reactant: NS(=O)(=O)C1CC1
Reactant: CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)CCC(F)(F)CC1
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Product: CC1(COc2cc(F)c(C(=O)NS(=O)(=O)C3CC3)cc2C2CC2)CCC(F)(F)CC1

Procedure:
Following the procedure as described in Example 158 step 5, and making variations as required to replace 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)methoxy)-benzoic acid with 5-cyclopropyl-4-((4,4-difluoro-1-methylcyclohexyl)methoxy)-2-fluorobenzoic acid and to replace methanesulfonamide with cyclopropanesulfonamide, the title compound was obtained (0.17 g, 61%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.75-8.62 (m, 1H), 7.68-7.58 (m, 1H), 6.63-6.50 (m, 1H), 3.76 (s, 2H), 3.15-3.05 (m, 1H), 2.09-1.74 (m, 7H), 1.69-1.57 (m, 2H), 1.50-1.41 (m, 2H), 1.22-1.09 (m, 5H), 1.00-0.89 (m, 2H), 0.70-0.60 (m, 2H); MS (ES+) m/z 446.1 (M+1).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[C:6]1([N:12]2[CH2:17][CH2:16][N:15]([C:18]([C@@H:20]3[C@@H:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][C:23]4([CH2:25][CH2:24]4)[CH2:22][NH:21]3)=[O:19])[CH2:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C>C(#N)C.C(OCC)C>[C:6]1([N:12]2[CH2:13][CH2:14][N:15]([C:18]([C@@H:20]3[C@@H:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][C:23]4([CH2:24][CH2:25]4)[CH2:22][N:21]3[C:2]([O:4][CH3:5])=[O:3])=[O:19])[CH2:16][CH2:17]2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)[C@H]1CC2(CC2)CN[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Reactant: COC(=O)Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)N1CC2(CC2)C[C@H](C(=O)OC(C)(C)C)[C@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl chloroformate (55 μL, 700 μL) was added to a solution of tert-butyl(6S,7S)-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxylate (248.4 mg, 0.62 mmol) and di-isopropylethylamine (0.70 mmol, 0.125 mL) in 5 mL acetonitrile. The mixture was stirred at RT for 3 h. Solvent was removed to afford a residue which was dissolved in ethyl ether (15 mL), washed with water (3×2 mL) and dried over Na2SO4. The solution was filtered and concentrated to afford 281 mg of the 7-tert-butyl 5-methyl(6S,7S)-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-5,7-dicarboxylate.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH2:24]([C:28]1[CH2:32][C:31](=[O:33])[NH:30][N:29]=1)[CH:25]([CH3:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.C(OCC)(=O)C.O>[CH2:24]([C:28]1[NH:29][N:30]=[C:31]([O:33][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:32]=1)[CH:25]([CH3:27])[CH3:26]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: CC(C)CC1=NNC(=O)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(CC(C)C)[nH]n3)ncnc2cc1OCCCN1CCOCC1
Temperature: 100 °C
Yield: 0 %

Procedure:
A suspension of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (150 mg, 0.44 mol), (prepared as described for the starting material in Example 2), and 3-isobutyl-4,5-dihydro-1H-pyrazol-5-one (75 mg, 0.53 mol), (Org. Synth. 1976, 55, 73), in DMF (2 ml) containing potassium carbonate (92 mg, 0.67 mol) was heated at 100° C. for 2.5 hours. After cooling, water was added and the aqueous layer was adjusted to pH6.5 with 2M hydrochloric acid. Ethyl acetate was added. The organic layer was separated, washed with water, brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was purified by column chromatography eluting the ethyl acetate/methylene chloride (1/1) followed by methanol/ethyl acetate/methylene chloride (1/4/5) and by methanol/methylene chloride (1/9) to give 4-(5-isobutylpyrazol-3-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (85 mg, 43%).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:9]([N:12]1[C:17](=[O:18])[CH2:16][O:15][CH:14]([C:19]([O:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[CH2:27][CH2:26][CH2:25]3)=[O:20])[CH2:13]1)([CH3:11])[CH3:10].O.C(OCC)(=O)C>O1CCCC1>[OH:20][C:19]([O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][CH2:26][CH2:25]2)([CH:14]1[O:15][CH2:16][C:17](=[O:18])[N:12]([CH:9]([CH3:10])[CH3:11])[CH2:13]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CC(C)N1CC(C(=O)Oc2ccc3c(c2)CCC3)OCC1=O
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)N1CC(C(O)(Oc2ccc3c(c2)CCC3)c2ccccc2)OCC1=O
Reaction time: 0.5 h
Yield: 77 %

Procedure:
A solution of 2.7 g. of phenylmagnesium bromide in 20 ml. of tetrahydrofuran was added dropwise to a mixture of 3.03g. of 4-isopropyl-5-oxo-2-(1-oxo-5-indanyloxymethyl)morpholine in 100 ml of tetrahydrofuran with stirring at room temperature and the mixture thus obtained was stirred for 30 minutes. Then, after adding to the mixture a small amount of water, tetrahydrofuran was distilled off under reduced pressure. To the residue formed were added 100 ml. of ethyl acetate and 100 ml. of water to dissolve the residue and the ethyl acetate layer formed was recovered, washed twice each with 50 ml. of water and then 50 ml. of saturated aqueous sodium chloride aqueous solution, and then ethyl acetate was distilled off. The residue formed was adsorbed on a silica gel column prepared from 150 ml. of silica gel in chloroform and then eluted with ethyl acetate. After removing the first 10 ml. of the ethyl acetate eluate emerging from the column, 300 ml. of the subsequent ethyl acetate eluate was collected and dried to provide 2.93 g. (yield 77%) of oily 2-(1-hydroxy-1-phenyl-5-indanyloxymethyl)-4-isopropyl-5-oxomorpholine.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11]Cl)(=[O:10])=[O:9])=[CH:6][CH:7]=1.[CH2:13]=[C:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[Br-].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>CC#N>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[C:14]3([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:13]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)NCl)cc1
Reactant: C=C1CCCCC1
Agent: C[N+](C)(C)c1ccccc1
Agent: [Br-]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)N2CC23CCCCC3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.3 %

Procedure:
To a stirred suspension of dried Chloramine-T (5.10 g, 20.76 mmol) in CH3CN (100 mL) under a nitrogen atmosphere methylenecyclohexane (9.98 g, 104 mmol) was added. Phenyltrimethylammonium tribromide (7.80 g, 20.76 mmol) was added in three portions over 10 min. The mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the residue was partitioned between dichloromethane and water. The organic layer was dried over Na2SO4 and the solvent was evaporated. The residue was chromatographed on silica gel with an ISCO Combiflash using EtOAc/hexanes (5-30% gradient) to afford the title compound as a white solid (2.66 g).
Reaction SMILES: [C:1]([N:4]([CH3:17])[C:5]1[CH:6]=[C:7]([N:12]([CH3:16])[C:13](=[O:15])[CH3:14])[CH:8]=[C:9]([NH2:11])[CH:10]=1)(=[O:3])[CH3:2].[NH:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19]([CH3:21])=[O:20].[S:28](Cl)(O)(=[O:30])=[O:29]>N1C=CC=CC=1.O>[C:19]([NH:18][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:11][C:9]2[CH:8]=[C:7]([N:12]([CH3:16])[C:13](=[O:15])[CH3:14])[CH:6]=[C:5]([N:4]([C:1](=[O:3])[CH3:2])[CH3:17])[CH:10]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1)(=[O:20])[CH3:21]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)N(C)c1cc(N)cc(N(C)C(C)=O)c1
Reactant: CC(=O)Nc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2cc(N(C)C(C)=O)cc(N(C)C(C)=O)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.1 %

Procedure:
0.15 g (0.00063 mol) of N-[3-(acetyl-methyl-amino)-5-amino-phenyl]-N-methyl-acetamide was dissolved in 3 ml of pyridine, treated with 0.154 g (0.00064 mol) of 4-acetamino-benzene-sulfochloride and stirred at room temperature for 16 hours. Subsequently, the mixture was freed from solvent, the residue was taken up in 25 ml of water, extracted four times with 200 ml of ethyl acetate each time and the combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulfate. After removal of the solvent the residue was chromatographed on silica gel, firstly with 2% and then 5% methanol in dichloromethane. There was obtained 0.15 g (55%) of N-[3-(4-acetylamino-phenylsulfonylamino)-5-(acetyl-methyl-amino)-phenyl]-N-methyl-acetamide as an orange colored, amorphous solid. MS (ISN): me/e=431 (C20H23N4O5S-).
Reaction SMILES: [N+](C1C=C(C=O)C(O)=CC=1)([O-])=[O:2].C(C[C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19])#N.C(COC1C=CC=CC=1C([O-])=O)#N.B#B>O1CCCC1>[C:21]1(=[O:2])[O:20][C:18](=[O:19])[C:17]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:16]12
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Reactant: COC(=O)c1ccccc1CC#N
Agent: B#B
Agent: N#CCOc1ccccc1C(=O)[O-]
Solvent: C1CCOC1
Product: O=C1OC(=O)c2ccccc21

Procedure:
The intermediates for reacting with 5-nitrosalicylaldehyde to prepare compounds wherein --Y-- contains an ethylbenzyl or ethoxybenzyl group were prepared by the reduction of the appropriate methyl cyanomethylbenzoate or cyanomethoxybenzoate with diborane in tetrahydrofuran solution, followed by the reaction of the amino compound thus obtained with phthalic anhydride at 100° C. and then with phosphorus tribromide also at 100° C. The various intermediates which were characterised have melting points as follows: 4-(2-aminoethyl)benzyl alcohol hydrochloride m.p. 160°-162° C. 3-(2-aminoethyl)benzyl alcohol hydrochloride m.p. 115°-118° C. 2-(2-aminoethyl)benzyl alcohol hydrochloride m.p. 103°-104° C. 4-(2-aminoethoxy)benzyl alcohol m.p. 92°-94° C. 3-(2-aminoethoxy)benzyl alcohol hydrochloride m.p. 143°-145° C. 4-(2-phthalimidoethyl)benzyl bromide 158°-161° C. 3-(2-phthalimidoethyl)benzyl bromide 93°-94° C. 2-(2-phthalimidoethyl)benzyl bromide 140°-141° C. 3-(2-phthalimidoethoxy)benzyl bromide 116°-117° C. 4-(2-phthalimidoethoxy)benzyl chloride 109°-112° C. (prepared by reacting with mesyl chloride and triethylamine in place of phosphorus tribromide).
Reaction SMILES: Br[C:2]1[C:3]([CH3:14])=[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[C:66]1([CH2:72][SH:73])[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:72]([S:73][C:2]1[C:3]([CH3:14])=[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1)[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1
Reactant: Cc1c(Br)cccc1-c1cccnc1
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(SCc2ccccc2)cccc1-c1cccnc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
Intermediate 73 (3 g, 12.09 mmol) in dioxane (50 ml) was stirred under argon, then DIPEA (3.82 ml, 24.18 mmol), xantphos (0.42 g, 0.73 mmol) and Pd2(dba)3 (0.33 g, 0.36 mmol) were added and the reaction was heated to 100° C. Phenyl-methanethiol (1.56 ml, 13.3 mmol) was slowly added and the reaction stirred for 16 h. The reaction was quenched by addition of 150 ml of H2O. After extraction (three times) with ethyl acetate the combined organic layers were washed with water, dried with Na2SO4, evaporated to dryness and the compound was obtained and used without further purification in step 22.3.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[C:9]([N:13]([CH3:23])[C:14](=[O:22])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=2)[CH:10]=[CH:11][CH:12]=1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([C:37](=[O:52])[C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH:39]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].[NH4+].[Cl-]>C1COCC1.O>[C:24]([O:28][C:29]([N:31]1[CH2:32][CH2:33][CH:34]([C:37]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:46])[CH3:47])[CH:39]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:14](=[O:22])[N:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([F:6])[CH:8]=3)[CH3:23])[CH:16]=2)[OH:52])[CH2:35][CH2:36]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: CN(C(=O)c1cccc(I)c1)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2cccc(O[Si](C)(C)C(C)(C)C)c2)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)c1cccc(C(O)(c2cccc(O[Si](C)(C)C(C)(C)C)c2)C2CCN(C(=O)OC(C)(C)C)CC2)c1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
n-Butyllithium (1.61 mL of 1.92 M solution; 3.10 mmol) was added to a mixture of N-(3-fluorophenyl)-3-iodo-N-methylbenzamide (1.0 g; 2.82 mmol) and 4-[3-(tert-butyl-dimethyl-silanyloxy)benzoyl]-piperidine-1-carboxylic acid tert-butyl ester (1.182 g; 2.82 mmol) in THF (150 mL) at −78° C. under nitrogen in one portion. The reaction was stirred under nitrogen overnight while the temperature warmed to room temperature. Saturated NH4Cl solution (25 mL) was added to the reaction mixture, followed by the addition of 25 mL of water. The mixture was extracted by ether (300 mL×2). The ether layer was washed by water (200 mL×2) and brine (200 mL×1), dried by Na2SO4 and concentrated to give 2.03 g of crude product, which was purified by silica gel column chromatography eluted with 30% EtOAc in pentane to give 4-([3-(tert-butyldimethylsilanyloxy)phenyl]{3-[N-(3-fluorophenyl)-N-methylcarbamoyl]phenyl}hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (763 mg; 42%). 1H NMR (600 MHz, DMSO-d6) δ 7.34 (bs, 1H), 7.29 (s, 1H), 7.23-7.16 (m, 3H), 7.09 (m, 2H), 6.94 (m, 2H), 6.85 (m, 2H), 6.60 (d, 1H, J=7.0 Hz), 5.25 (s, 1H), 3.88 (m, 2H), 3.35 (s, 3H), 2.60 (bs, 2H), 2.34 (m, 1H), 1.37 (s, 9H), 1.36 (m, 2H), 1.16 (m, 2H), 0.91 (s, 9H), 0.12 (s, 6H).
Reaction SMILES: O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:14]1[N:15]=[C:16]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]3[C:35](=[O:36])[NH:34][CH2:33][CH2:32][N:31]3[CH2:37][CH3:38])=[CH:26][CH:25]=2)[C:17](=[O:22])[N:18]([CH2:20]C)[CH:19]=1.[F:39][C:40]1[C:45]([NH:46][C:47]([C:49]2[S:53][C:52]3[CH2:54][CH2:55][CH2:56][CH2:57][C:51]=3[CH:50]=2)=[O:48])=[C:44]([CH3:58])[C:43](B2OC(C)(C)C(C)(C)O2)=[CH:42][CH:41]=1>O>[CH2:37]([N:31]1[CH2:32][CH2:33][NH:34][C:35](=[O:36])[CH:30]1[C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:16]2[C:17](=[O:22])[N:18]([CH3:20])[CH:19]=[C:14]([C:43]3[C:44]([CH3:58])=[C:45]([NH:46][C:47]([C:49]4[S:53][C:52]5[CH2:54][CH2:55][CH2:56][CH2:57][C:51]=5[CH:50]=4)=[O:48])[C:40]([F:39])=[CH:41][CH:42]=3)[N:15]=2)=[CH:29][CH:28]=1)[CH3:38]
Reactant: CCN1CCNC(=O)C1c1ccc(Nc2nc(Br)cn(CC)c2=O)cc1
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)ccc(F)c1NC(=O)c1cc2c(s1)CCCC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCN1CCNC(=O)C1c1ccc(Nc2nc(-c3ccc(F)c(NC(=O)c4cc5c(s4)CCCC5)c3C)cn(C)c2=O)cc1
Temperature: 25 °C
Yield: 41 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was charged with 1,4-dioxane (13 mL), water (3 mL) and sodium carbonate (417 mg, 3.93 mmol). After bubbling nitrogen through the resulting mixture for 15 min, 34 (150 mg, 0.370 mmol), N-(6-Fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4,5,6,7-tetrahydro benzo[b]thiophene-2-carboxamide. (192 mg, 0.460 mmol and tetrakis(triphenyl phosphine)palladium(0) (75 mg, 0.065 mmol) were added, and the reaction mixture then heated at reflux for 5 h. After this time, the reaction mixture was cooled to room temperature, filtered and the filter cake washed with diethyl ether (10 mL). The resulting solid was dissolved in methylene chloride/methanol (10:1), absorbed onto silica gel and purified by flash chromatography to afford 35 in 41% yield (93 mg) as a yellow solid: mp 179-180° C.; 1H NMR (500 MHz, CDCl3) δ 8.31 (bs, 1H), 7.79 (d, 2H, J=8.5 Hz), 7.39 (m, 3H), 7.33 (m, 1H), 7.22 (s, 1H), 7.04 (t, 1H, J=8.0 Hz), 6.68 (s, 1H), 5.80 (d, 1H, J=3.5 Hz), 3.99 (s, 1H), 3.65 (s, 3H), 3.64 (m, 1H), 3.36 (m, 1H), 3.11 (m, 1H), 2.82 (t, 2H, J=6.0 Hz), 2.66 (t, 2H, J=6.0 Hz), 2.59 (m, 2H), 2.36 (s, 3H), 2.27 (m, 1H), 1.85 (m, 4H), 0.99 (t, 3H, J=7.0 Hz); MS (ESI+) m/z 615.3 (M+H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]([O:17][CH2:18]C)=[O:16])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N+:22]([CH3:25])([O-:24])=[O:23].[OH-].[CH2:27]([N+](CCCC)(CCCC)CCCC)CCC>[Cl-].[NH4+]>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([CH:13]([CH:25]([N+:22]([O-:24])=[O:23])[CH3:27])[CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:4]=[C:3]([C:2]([F:1])([F:21])[F:20])[CH:8]=1
Reactant: C[N+](=O)[O-]
Reactant: CCOC(=O)C=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [NH4+]
Agent: [OH-]
Product: COC(=O)CC(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(C)[N+](=O)[O-]

Procedure:
Ethyl 3-[3,5-bis(trifluoromethyl)phenyl]acrylate (170 mg, 0.54 mmol) and nitromethane (736 uL, 10.29 mmol) were treated with a solution of tetrabutylammonium hydroxide (1.0 M solution in MeOH, 1.5 mL) and the mixture heated to reflux for 3 h, diluted with 10% aqueous ammonium chloride (10 mL) and extracted with EtOAC (4×30 mL). The combined organic extracts were washed with 10% ammonium chloride (20 mL), dried over MgSO4, concentrated in vacuo to give the crude product. This was purified by flash chromatography using 10% EtOAC/hexanes to afford methyl 3-[3,5-bis(trifluoro methyl)phenyl]-4-nitropentanoate as a colorless oil. 1H NMR (CDCl3, 500 MHz) δ 7.82 (br s 1H), 7.64 (br s, 2H), 4.91 (m, 1H), 3.91 (m, 1H), 3.61 (s, 3H), 2.82 (m, 2H), 1.42 (d, J=6.7 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:12])([S:9]([O-:11])=[O:10])[C:3]([F:8])([F:7])[CH2:4][CH2:5][OH:6].[CH2:13]([NH+:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:14].O.OO.S([O-])([O-])=[O:24].[Na+].[Na+]>CC(C)=O>[F:12][C:2]([F:1])([S:9]([O-:24])(=[O:11])=[O:10])[C:3]([F:7])([F:8])[CH2:4][CH2:5][OH:6].[CH2:13]([NH+:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:14]
Reactant: O=S([O-])C(F)(F)C(F)(F)CCO
Reactant: O=S([O-])[O-]
Agent: CC[NH+](CC)CC
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=S(=O)([O-])C(F)(F)C(F)(F)CCO
Temperature: 40 °C
Reaction time: 6 h
Yield: 95 %

Procedure:
A 500 mL reactor was charged with 65 g (93% purity, 0.194 mole/1.0 equivalent) of triethylammonium 1,1,2,2-tetrafluoro-4-hydroxy-butane-1-sulfinate obtained in Example 2-1 by purification, 200 g of water and 46 g (0.40 mole/2.1 equivalents) of 30% hydrogen peroxide at room temperature, followed by 6 hours of stirring at 40° C. Upon confirming the termination of the reaction, the reaction liquid underwent cooling, and 7.5 g of sodium sulfite was added to the reaction liquid, followed by stirring. Thereafter, 350 g of acetone was added to a liquid obtained by distilling the solvent out of the reaction liquid, followed by 1 hour of stirring at room temperature. Thereafter, filteration was performed in the use of a filter paper. An obtained filtrate was concentrated and dried, thereby obtaining 65.6 g of a target triethylammonium 1,1,2,2-tetrafluoro-4-hydroxy-butane-1-sulfonate. It exhibited a purity of 92% and a yield of 95% at this time.
Reaction SMILES: [CH3:1][C:2]1[N:3]([S:9]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[CH:4]=[CH:5][C:6]=1[CH:7]=[O:8].[Br:18]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:18][C:4]1[N:3]([S:9]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)(=[O:10])=[O:11])[C:2]([CH3:1])=[C:6]([CH:7]=[O:8])[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(C=O)ccn1S(=O)(=O)c1cccnc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C=O)cc(Br)n1S(=O)(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.7 %

Procedure:
To a solution of 2-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (974 mg) in N,N-dimethylformamide (10 mL) was added N-bromosuccinimide (1.17 g) at 0° C., and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:1) to give the title compound as white crystals (yield 675 mg, 53%).
Reaction SMILES: [CH2:1]([N:8]([CH2:12][Si](C)(C)C)[CH2:9]OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1(=[O:22])[CH2:21][CH2:20][CH:19]=[CH:18]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:9][C@@H:19]2[CH2:20][CH2:21][C:17](=[O:22])[C@@H:18]2[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=C1C=CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Temperature: 0 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
A round bottom flask purged with argon was charged with N-benzyl-1-methoxy-N-(trimethylsilylmethyl)methanamine (31.2 g, 131.4 mmol) and cyclopent-2-ene-1-one (9.0 g, 9.2 mL, 109.5 mmol). The reaction mixture was cooled to 0° C. and a solution of trifluoroacetic acid (1.25 g, 847 μL, 11.0 mmol) in DCM (11 mL) was added to it. The reaction mixture was stirred at 0° C. for 4 h, warmed to room temperature and stirred for 18 h. The reaction was quenched by the addition of saturated sodium bicarbonate and the layers were separated. The aqueous layer was extracted with DCM and the combined organic layers was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified via silica gel column chromatography using 40 to 80% EtOAc in hexanes to obtain (3aR,6aS)-2-benzyl-1,3,3a,4,5,6a-hexahydrocyclopenta[c]pyrrol-6-one (19.8 g, 84%) as a light yellow oil.