Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[OH:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BrH:13].CS(C)=O>C(O)(=O)C.O>[Br:13][C:10]1[CH:9]=[CH:8][C:7]([OH:12])=[C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:11]=1
Reactant: Oc1ccccc1C1CCCC1
Reactant: Br
Solvent: O
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: Oc1ccc(Br)cc1C1CCCC1
Yield: 89.4 %

Procedure:
To a stirring solution of 2-cyclopentyl phenol (7.9 g, 48.7 mmol) in acetic acid (32 mL) and water (16 mL) was added HBr (33% in AcOH, 50.45 mL, 292.2 mmol) followed by the dropwise addition of DMSO (34.8 g, 31.6 mL, 445.0 mmol) over 10 min. The reaction was quenched with saturated aqueous NaHCO3 and concentrated in vacuo to remove gasses. The residue was brought up in ether (200 mL), washed with water (2×100 mL) and brine (100 mL) then dried over Na2SO4. The solution was filtered and concentrated in vacuo to produce an oil which was purified by silica gel chromatography (0-10% ethyl acetate/hexane) to provide 4-bromo-2-cyclopentylphenol (10.5 g, 89% yield) as a colorless oil. 1H NMR (400.0 MHz, DMSO-d6) δ 9.59 (s, 1H), 7.20 (d, J=2.5 Hz, 1H), 7.13 (dd, J=2.5, 8.5 Hz, 1H), 6.73 (d, J=8.5 Hz, 1H), 3.21-3.13 (m, 1H), 1.95-1.88 (m, 2H), 1.77-1.69 (m, 2H), 1.65-1.44 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]=1[C:11]([OH:13])=O.[NH2:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[N:19]=1>>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]=1[C:11]([NH:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)=[CH:25][CH:26]=2)[N:19]=1)=[O:13]
Reactant: Nc1nc(Cc2ccc(-c3ccncc3)cc2)cs1
Reactant: CC1=C(C(=O)O)Cc2ccccc21
Product: CC1=C(C(=O)Nc2nc(Cc3ccc(-c4ccncc4)cc3)cs2)Cc2ccccc21

Procedure:
Using a procedure similar to the synthesis of Example 2, 3-methyl-1H-indene-2-carboxylic acid was reacted with 2-amino-4-(4-(pyridin-4-yl)benzyl)thiazole to give Example 170. MS Found: (M+H)+=424.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1.[CH3:30][CH:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:32]=O>C1COCC1>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[CH:30][CH:31]([CH3:32])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:8][CH:9]=1
Reactant: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCCCCCCC(C)C=O
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCCCCCCCC(C)C=Cc1ccc(OC)cc1
Yield: 52.8 %

Procedure:
Starting from (4-methoxyphenyl)methyltriphenylphosphonium bromide (6.00 g, 13.0 mmol, 1.0 equiv.), KtBuO (14 mL, 14.2 mmol, 1.1 equiv., 1M in THF) and 2-methylundecanal (2.86 g, 15.5 mmol, 1.2 equiv.), 1.98 g (53%) of the title compound was obtained after purification by flash chromatography on SiO2 (hexane/EtOAc 99:1) as a colorless oil.
Reaction SMILES: [NH2:1][CH:2]1[CH:5]([O:6][CH2:7][CH:8]([CH3:10])[CH3:9])[N:4]([Si](C(C)(C)C)(C)C)[C:3]1=[O:18].C(N(C(C)C)CC)(C)C.[C:28](Cl)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C)C=O.O>[CH2:7]([O:6][CH:5]1[NH:4][C:3](=[O:18])[CH:2]1[NH:1][C:28]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH:8]([CH3:9])[CH3:10]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)COC1C(N)C(=O)N1[Si](C)(C)C(C)(C)C
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)COC1NC(=O)C1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 18 h

Procedure:
A solution of (3RS,4RS)-3-amino-1-(tert-butyldimethylsilyl)-4-(isobutoxy)azetidin-2-one (0.2 g) was dissolved in dimethylformamide (8 mL), cooled in an ice bath, and treated with diisopropylethylamine (0.1 mL) followed by trityl chloride (167 mg, 0.6 mmol). The mixture was stirred for 18 h, diluted with water (40 mL) and extracted with ethyl acetate. The combined organic phase was dried (magnesium sulfate), concentrated, and the residue was chromatographed on silica gel eluted with 20% ethyl acetate:hexane to give the title compound. MS(ES) m/e 515 [M+H]+.
Reaction SMILES: [C:1]([O:4][N:5]=[C:6]([C:10](=[O:12])[CH3:11])[C:7](=[O:9])[CH3:8])(=O)C.C(=O)/C=C/CCC>C1(C)C=CC=CC=1.C(NC(C)C)(C)C>[CH3:1][O:4][N:5]=[C:6]([C:10](=[O:12])[CH3:11])[C:7](=[O:9])[CH3:8]
Reactant: CC(=O)ON=C(C(C)=O)C(C)=O
Agent: CCC/C=C/C=O
Solvent: CC(C)NC(C)C
Solvent: Cc1ccccc1
Product: CON=C(C(C)=O)C(C)=O

Procedure:
To a solution of 3-(acetoxyimino)pentane-2,4-dione 12 (0.2 mmol, 1.0 eq) and (E)-hex-2-enal (0.5 mmol, 2.5 eq) in toluene (0.8 mL) was added catalyst VII (0.04 mmol, 0.2 eq) in toluene (0.2 mL) at room temperature. The resulting mixture was stirred vigorously. After 12 hours the reaction still didn't proceed.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6](/[CH:10]=[C:11]2\[CH:12]=[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)[CH:14]([CH2:17][N:18]([CH3:20])[CH3:19])[CH2:15][CH2:16]\2)[CH:5]=1.[OH-].[K+].Cl>CO>[CH3:19][N:18]([CH2:17][CH:14]1[CH2:15][CH2:16]/[C:11](=[CH:10]/[C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:28])=[O:2])/[CH:12]=[C:13]1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=1)[CH3:20]
Reactant: COC(=O)c1cccc(/C=C2\C=C(c3cccc(O)c3)C(CN(C)C)CC2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN(C)CC1CC/C(=C/c2cccc(C(=O)O)c2)C=C1c1cccc(O)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
3 g of the Z-3-[4-Dimethylaminomethyl-3-(3-hydroxy-phenyl)-cyclohex-2-enylidenmethyl]-benzoic acid methyl ester, as the base, prepared according to example 32 were dissolved in 30 ml methanol, and 30 ml 1 N potassium hydroxide solution were added. The mixture was stirred at 60° C. for 2 hours. After the reaction mixture had cooled to room temperature, 1 N hydrochloric acid was added to the mixture until a pH of 4 was established. The phases were separated and the aqueous phase was washed 3 times with 20 ml ethyl acetate each time. The combined organic phases were dried over magnesium sulfate and freed from the solvent in vacuo. Z-3-[4-Dimethylaminomethyl-3-(3-hydroxy-phenyl)-cyclohex-2-enylidenmethyl]-benzoic acid, 2.7 g in the form of an orange-yellow oil, was obtained in this way. To prepare the hydrochloride, the base was dissolved in 10 ml acetone, and an equimolar amount of trimethylchlorosilane and water was added. 2.4 g (77.7% of theory) Z-3-[4-dimethylaminomethyl-3-(3-hydroxy-phenyl)-cyclohex-2-enylidenmethyl]-benzoic acid hydrochloride were obtained in this way.
Reaction SMILES: C([O:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH:14]([CH3:17])[CH:15]=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH:14]([CH3:17])[CH:15]=[O:16])=[CH:18][CH:19]=1
Reactant: CC(C=O)Oc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C=O)Oc1ccc(O)cc1
Reaction time: 5 h
Yield: 36.6 %

Procedure:
A mixture of 2-[p-(benzyloxy)phenoxy]propionaldehyde (34.6 g, 0.135 mol) and 5% Pd on carbon (2.0 g) in ethanol (250 mL) is placed on a Parr hydrogenerator. Over 5 hours, the pressure drops from 37 psi to 28 psi. The reaction mixture is then filtered through celite and concentrated in vacuo to obtain a dark yellow syrup. Flash chromatography of the syrup using silica gel and eluting with methylene chloride followed by 1% to 10% ethyl acetate in methylene chloride gives the title product as a dark yellow syrup (8.2 g) which is identified by 1H NMR spectral analysis.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:28])[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:29]=[N+:30]=[N-:31].[Na+]>>[N:29]([CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C:15]=2[O:14]1)=[N+:30]=[N-:31]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccccc4Cl)c3O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: [N-]=[N+]=NCC1Cc2cccc(-c3ccccc3Cl)c2O1

Procedure:
Treatment of (±)-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (2.6 g, 6.26 mmol) with sodium azide (1.63 g, 25.05 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (0.17 g, 5 wt. %) generally according to the procedure described for Example 1 provided 1.05 g (57%) of (±)-1-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp >250° C.; Anal. calcd. for C15H14ClNOHCl: C, 60.83; H, 5.1; N, 4.73. Found: C, 60.71; H, 5.48; N, 4.55.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH3:18].[I-:19].[Na+]>CC(C)=O>[I:19][CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH3:18]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CI
Yield: 47.4 %

Procedure:
A suspension of 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole [4 g, 13.7 mmol; PCT Int. Appl. (2002), WO 0262774 A1] and sodium iodide (10.3 g, 68.6 mmol) in acetone (70 ml) was stirred at reflux temperature for 2 h under an argon atmosphere. The yellow precipitate was filtered off, the filtrate evaporated to dryness under reduced pressure and dissolved in tert-butyl methyl ether and brine/ice water 1/1. The aqueous layer was extracted one more time with tert-butyl methyl ether, the combined extracts washed with ice water/aqueous sodium thiosulfate, ice water/brine 1/1 and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue recrystallized from tert-butyl methyl ether/heptane to give 2.5 g (6.5 mmol, 48%) of the title compound as yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[OH:15].[Na+].ClC1C=C(C=CC=1)C(OO)=O>ClCCl.CCCCCC>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]2[O:15][CH:12]2[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N1CC=CCC1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2OC2C1
Reaction time: 2 h
Yield: 66.7 %

Procedure:
To a solution of 1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridine (18.9 g) in dichloromethane (400 ml). was added in turn sodium hydrogen carbonate (11.3 g) and m-chloroperoxybenzoic acid (23.4 g) with care at 0° C., and which was stirred for 2 hours. Insoluble material was removed by filtration, mother liquor was washed saturated sodium chloride in water (100 ml) and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was dissolved in n-hexane (300 ml) and insoluble material was removed by filtration. Mother liquor was concentrated in vacuo, the remainings were dissolved in ethyl acetate (300 ml) and washed in turn with saturated sodium hydrogen carbonate in water (100 ml×5) and saturated sodium chloride in water (100 ml×2), which was dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (350 ml) eluting in turn with 10%, 20% and 30% ethyl acetate in n-hexane. Tractions, containing desired product, were collected and concentrated in vacuo to give 1-tert-butoxycarbonyl-3,4-epoxypiperidine (13.7 g).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2=[CH:16][S:17][C:18]([CH3:19])=[C:5]12)=[O:3].[CH3:20][N:21]1[CH2:28][CH:27]2[CH:23]([CH2:24][NH:25][CH2:26]2)[CH2:22]1>C(O)C>[CH3:19][C:18]1[S:17][CH:16]=[C:6]2[C:7](=[O:15])[NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:4]([C:2]([N:25]3[CH2:26][CH:27]4[CH:23]([CH2:22][N:21]([CH3:20])[CH2:28]4)[CH2:24]3)=[O:3])[C:5]=12
Reactant: Cc1scc2c1N(C(=O)Cl)c1ccccc1NC2=O
Reactant: CN1CC2CNCC2C1
Solvent: CCO
Product: Cc1scc2c1N(C(=O)N1CC3CN(C)CC3C1)c1ccccc1NC2=O
Yield: 13 %

Procedure:
Prepared analogously to Example 1 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 3-methyl-3,7-diazabicyclo-[3.3.0]octane in a yield of 13% of theory. Colourless crystals of m.p. 220°-222° C. (ethanol).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=3)[CH2:15][CH2:14][CH:13]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:8][CH:7]=1>CC#N>[CH3:23][O:22][C:18]1[CH:17]=[C:16]2[C:21](=[CH:20][CH:19]=1)[CH:12]([C:9]1[CH:10]=[CH:11][C:6]([CH:5]=[CH:4][C:3]([OH:30])=[O:2])=[CH:7][CH:8]=1)[CH:13]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:14][CH2:15]2
Reactant: COC(=O)C=Cc1ccc(C2c3ccc(OC)cc3CCC2c2ccccc2)cc1
Solvent: CC#N
Product: COc1ccc2c(c1)CCC(c1ccccc1)C2c1ccc(C=CC(=O)O)cc1

Procedure:
Prepared by saponifying (hydrolyzing) ester 6d in accordance with the general method described in Example VII. Yield (93%); APcI m/z: 426 (M+H+CH3CN+, 100%).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([OH:14])[CH:8]=[CH:7]2)[CH2:2][CH3:3].[F:15]C(F)(F)S([O-])(=O)=O.[Na+].Cl>ClCCl.O>[F:15][C:10]1[C:11]2[C:6](=[CH:5][C:4]([CH2:1][CH2:2][CH3:3])=[CH:13][CH:12]=2)[CH:7]=[CH:8][C:9]=1[OH:14]
Reactant: CCCc1ccc2cc(O)ccc2c1
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCCc1ccc2c(F)c(O)ccc2c1
Reaction time: 8 h
Yield: 800.3 %

Procedure:
To a solution of 20 g of 6-propyl-2-naphthol and 1.8 g of sodium trifluoromethanesulfonate in 80 ml of dichloromethane was added 23.7 g of N,N′-difluoro-2,21′-dipyridinium bistetrafluoroborate. The reaction mixture was then stirred for 8 hours. The reaction solution was then poured in water. To the reaction mixture was then added diluted hydrochloric acid. The resulting organic phase was then separated. The resulting aqueous phase was extracted with toluene. The organic phase and the material thus extracted were together washed sequentially with water and saturated brine, and then dehydrated and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain an oily matter which was then purified through silica gel column chromatography (hexane/ethyl acetate=9/1) to obtain 17.1 g of 1-fluoro-6-propyl-2-naphthol.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:9])[CH3:8].[C:10]([NH:20][CH2:21][C:22](O)=[O:23])([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[C:14]1([CH2:13][O:12][C:10](=[O:11])[NH:20][CH2:21][C:22]([NH:1][N:2]2[CH:6]=[CH:5][CH:4]=[C:3]2[C:7](=[O:9])[CH3:8])=[O:23])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CC(=O)c1cccn1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(=O)c1cccn1NC(=O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.8 %

Procedure:
To a stirred solution consisting of 1-(1-amino-1H-pyrrol-2-yl)ethanone (3.88 g) and carbobenzyloxyglycine (6.54 g) in dry DCM (115 ml) was added DCC (6.77 g) at 0° C. under nitrogen. The reaction mixture was allowed to stir at room temperature for 18 hours. The precipitated DCU was removed by filtration and washed with ethyl acetate. The combined filtrates were concentrated to give the crude product. Purification via flash column chromatography (silica gel, 10% EtOAc/hexane) afforded 6.98 g of the product as a solid, m.p. 109°-111° C.
Reaction SMILES: CO[C:3]1[CH:11]=[CH:10][C:9](S(=O)(=O)N)=[CH:8][C:4]=1[C:5](O)=[O:6].CC(C)=O.ClC(OCC(C)C)=O.C1(C[N:32]2CCCC2CN)CC1>O.C(N(CC)CC)C>[C:5]([NH2:32])(=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:3]=1
Reactant: COc1ccc(S(N)(=O)=O)cc1C(=O)O
Reactant: NCC1CCCN1CC1CC1
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: NC(=O)c1ccccc1

Procedure:
5.8 g of 2-methoxy-5-sulphamoyl benzoic acid, 50 ml of acetone, 10 ml of water and 3.6 ml of triethylamine (density 0.726) are placed in a 250 ml flask fitted with an agitator, a thermometer and a dropping funnel. The solution is cooled to about +10° C., then 3.6 g of isobutyl chloroformate is added drop by drop. The medium is reacted for 30 minutes at 0° C., after which 4.5 g of 1-cyclopropylmethyl-2-aminomethyl-pyrrolidine is poured in drop by drop. The medium is reacted for 1 hour at room temperature, 50 ml of water is added and the acetone is evaporated under vacuum. The reaction medium is further diluted with 50 ml of water and made alkaline with 10 ml of ammonia (density 0.91). The viscous product which is precipitated crystallises slowly. The solid is filtered off, washed with water and re-crystallised in 50 ml of ethanol. 3.8 g 841%) of benzamide is obtained, melting at 177° C.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH:6]([NH:9][C:10]([N:12]1[C:16]([CH3:17])=[CH:15][C:14]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=2[N+:29]([O-:31])=[O:30])=[N:13]1)=[O:11])([CH3:8])[CH3:7]>C(O)(=O)C>[CH:6]([NH:9][C:10]([N:12]1[C:16]([CH3:17])=[C:15]([Cl:4])[C:14]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:21][C:20]=2[N+:29]([O-:31])=[O:30])=[N:13]1)=[O:11])([CH3:8])[CH3:7]
Reactant: Cc1cc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])nn1C(=O)NC(C)C
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: Cc1c(Cl)c(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])nn1C(=O)NC(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.3 %

Procedure:
Sulfuryl chloride (0.24 g, 1.8 mmol) was added to a solution of N-isopropyl-5-methyl-3-(2-nitro-4-trifluoromethylphenyloxy)pyrazole-1-carboxamide (0.56 g, 1.5 mmol) in acetic acid (5 ml), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was poured into ice water and extracted with ethyl acetate (20 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant. The solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a yellowish solid of N-isopropyl-4-chloro-5-methyl-3-(2-nitro-4-trifluoromethylphenyloxy)pyrazole-1-carboxamide (0.60 g, yield: 98.4%). mp: 89-91° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.24 (d, J=6.6 Hz, 6H), 2.63 (s, 3H), 3.90-4.10 (m, 1H), 6.40-6.65 (m, 1H), 7.38 (d, J=8.7 Hz, 1H), 7.85 (dd, J=2.0 and 8.7 Hz, 1H), 8.29 (d, J=2.0 Hz, 1H).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([NH:17][S:18]([C:21]1[S:25][C:24]2[S:26](=[O:33])(=[O:32])[CH:27]([C:29]([OH:31])=[O:30])[CH2:28][C:23]=2[CH:22]=1)(=[O:20])=[O:19])([CH3:16])([CH3:15])[CH3:14]>C(Cl)CCC>[C:13]([NH:17][S:18]([C:21]1[S:25][C:24]2[S:26](=[O:32])(=[O:33])[CH:27]([C:29]([O:31][CH3:1])=[O:30])[CH2:28][C:23]=2[CH:22]=1)(=[O:20])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)NS(=O)(=O)c1cc2c(s1)S(=O)(=O)C(C(=O)O)C2
Solvent: CCCCCl
Product: COC(=O)C1Cc2cc(S(=O)(=O)NC(C)(C)C)sc2S1(=O)=O
Reaction time: 1 h
Yield: 74 %

Procedure:
Carbonyldiimidazole (5.3 g, 32.7 mmol) was added at room temperature to a stirred solution of product from Step A (7.7 g, 21.8 mmol) in dry, degassed DMF under an N2 atmosphere. After 1 h, methanol (150 mL) was added and the reaction stirred for 30 min. The solvents were removed under high vacuum, and the residue taken up in ethyl acetate. This solution was extracted with water and saturated brine, dried over MgSO4, filtered, and the filtrate evaporated to dryness to give a foam. This foam was treated with n-butyl-chloride and the resulting solid filtered and dried in the air to give the title compound (5.7, 74%). 1H NMR (300 MHz,DMSO-d6) 1.20(s,9H), 3.53(d,2H), 3.80(s,3H), 5.30(t,1H), 7.60(s,1H, 8.20(s,1H,exch.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:13]([NH:14][CH2:15][CH3:16])[CH2:12][N:11]([C:17]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([C:27]4([CH3:30])[CH2:29][CH2:28]4)=[O:26])[CH2:21][CH2:20]3)=[O:18])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)C(C)C)(C)C.Cl[C:41]([O:43][C:44]1[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=1)=[O:42]>ClCCl>[F:50][C:47]1[CH:48]=[CH:49][C:44]([O:43][C:41](=[O:42])[N:14]([C@H:13]2[C@H:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:10][N:11]([C:17]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([C:27]4([CH3:30])[CH2:29][CH2:28]4)=[O:26])[CH2:21][CH2:20]3)=[O:18])[CH2:12]2)[CH2:15][CH3:16])=[CH:45][CH:46]=1
Reactant: CCN[C@@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)Oc1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a solution of rac-[(3R,4S)-3-(3,4-dichloro-phenyl)-4-ethylamino-pyrrolidin-1-yl]-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone (25 mg, 0.06 mmol) in dichloromethane (1 mL) was added N,N-diisopropylethylamine (10 uL, 0.06 mmol). It was cooled to 0° C. and 4-fluorophenyl chloroformate (8 uL, 0.06 mmol) was added and the reaction mixture was stirred for 30 min at this temperature and then 2 h at ambient temperature. Concentration and purification by chromatography (SiO2, ethyl acetate) afforded the title compound (17 mg, 52%) as a colorless foam. MS m/e: 590.4 [M]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19]2[NH:21][C:22](=[O:44])[C:23]3([CH:27]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:26][N:25]([C:33](Cl)=[O:34])[CH:24]3[C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:37]=3[F:43])[C:18]2=[CH:17][CH:16]=1.O>CN(C)C=O>[CH3:9][O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:33]([N:25]2[CH2:26][CH:27]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:23]3([C:18]4[C:19](=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=4)[NH:21][C:22]3=[O:44])[CH:24]2[C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:37]=2[F:43])=[O:34])=[CH:11][CH:10]=1)=[O:7]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)CC1CN(C(=O)Cl)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC(=O)N2CC(CC(C)(C)C)C3(C(=O)Nc4cc(Cl)ccc43)C2c2cccc(Cl)c2F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 18 %

Procedure:
To a solution of methyl 4-hydroxybenzoate (Aldrich) (20 mg, 0.13 mmol) in N,N-dimethylforamide (3 mL) was added NaH (60%, 7.8 mg, 0.2 mmol). The reaction mixture was stirred at room temperature for 10 min, then rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carbonyl chloride prepared in Example 8 (56 mg, 0.13 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. Water was added. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated. The residue was triturated with dichloromethane and hexanes to give rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid 4-methoxycarbonyl-phenyl ester as a white solid (Yield 14 mg, 18%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[N:10]12[CH2:17][CH2:16][CH2:15][C:14]1([CH2:18][CH2:19][NH2:20])[CH2:13][CH2:12][CH2:11]2>>[N:10]12[CH2:17][CH2:16][CH2:15][C:14]1([CH2:18][CH2:19][NH:20][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH2:13][CH2:12][CH2:11]2
Reactant: N#Cc1ccc(F)cc1
Reactant: NCCC12CCCN1CCC2
Product: N#Cc1ccc(NCCC23CCCN2CCC3)cc1

Procedure:
The procedures described in Example 1 were repeated except that 4-fluorobenzonitrile (1.00 g, 8.26 mmol ) and 2-(1-azabicyclo[3.3.0]octan-5-yl)ethylamine (3.15 g, 20.4 mmol) were employed. In this case, the desired compound was obtained as a colorless liquid (2.02 g, 99.1%).