Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[CH3:11]>[Ni].CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc([N+](=O)[O-])ccc1Br
Agent: [Ni]
Solvent: CO
Product: Cc1cc(N)ccc1Br
Reaction time: 3 h
Yield: 98.7 %

Procedure:
Activated Raney Nickel® (0.4 g) was added to a suspension of 1-bromo-2-methyl-4-nitrobenzene (4 g, 18.51 mmol) in 200 mL of methanol and the mixture was stirred under hydrogen atmosphere (30 psi) for 3 hours. After this time, the reaction mixture was filtered through Celite®, the solvent eliminated under reduced pressure and the residue dried under vacuum to afford the title compound (3.4 g, 99%) as a white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:17]I>O1CCCC1>[CH2:3]([N:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH:12]([CH3:17])[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1CN(Cc2ccccc2)CCC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
To a suspension (160 ml) of 3.2 g of sodium hydride in tetrahydrofuran (THF) was added a solution (15 ml) of 15.0 g of 1-benzyl-4-piperidone in THF in an ice bath, and the solution was stirred at room temperature for 30 minutes. 5.92 ml of methyl iodide was added to this solution, and the solution was stirred at 60° C. for 4 hours. The salt precipitated was separated by filtration, and after concentrating the filtrate under reduced pressure, water was added to the concentrate. The solution was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and from the fractions eluted with ethyl acetate-hexane (1:1 v/v) was obtained 3.98 g of 1-benzyl-3-methyl-4-piperidone (yield: 25%).
Reaction SMILES: CC1C=CC2NN=NC=2C=1.[O:11]1[CH2:16][CH2:15][N:14](NC(Cl)=O)[CH2:13][CH2:12]1.C(N(C1C=CC=CC=1)[C:24]([N:26]1[C:30]2[CH:31]=[CH:32][C:33]([CH3:35])=[CH:34][C:29]=2[N:28]=[N:27]1)=[O:25])C>>[O:11]1[CH2:12][CH2:13][N:14]([C:24]([N:26]2[C:30]3[CH:31]=[CH:32][C:33]([CH3:35])=[CH:34][C:29]=3[N:28]=[N:27]2)=[O:25])[CH2:15][CH2:16]1
Reactant: O=C(Cl)NN1CCOCC1
Reactant: CCN(C(=O)n1nnc2cc(C)ccc21)c1ccccc1
Agent: Cc1ccc2[nH]nnc2c1
Product: Cc1ccc2c(c1)nnn2C(=O)N1CCOCC1

Procedure:
Compound 2 was prepared by treating 5-methylbenzotriazole (C) (8.89 g, 67 m.mole) with morpholinocarbamoyl chloride (E) (10 g, 67 m.mole) in a manner similar to that described in the preparation of (1). The product which included the 6-methyl isomer, was crystallized from methanol (100 ml). Yield, 13.2 g, 81 percent, m.p. 81° to 82° C. (uncorr.).
Reaction SMILES: [NH3:1].[Br:2][C:3]1[C:8]([CH:9]([CH3:11])[CH3:10])=[CH:7][C:6]([S:12](Cl)(=[O:14])=[O:13])=[C:5]([CH:16]([CH3:18])[CH3:17])[CH:4]=1>CCOCC>[Br:2][C:3]1[C:8]([CH:9]([CH3:11])[CH3:10])=[CH:7][C:6]([S:12]([NH2:1])(=[O:14])=[O:13])=[C:5]([CH:16]([CH3:18])[CH3:17])[CH:4]=1
Reactant: CC(C)c1cc(S(=O)(=O)Cl)c(C(C)C)cc1Br
Reactant: N
Solvent: CCOCC
Product: CC(C)c1cc(S(N)(=O)=O)c(C(C)C)cc1Br
Reaction time: 2 h

Procedure:
To a one-liter flask containing 90 parts of concentrated aqueous ammonia and 150 parts of ether, there is added over three hours, 105 parts of 4-bromo-2,5-diisopropylbenzenesulfonyl chloride in 180 parts of ether. After stirring 2 hours longer, the excess ammonia is neutralized by adding 10% HC1. The organic layer is washed two times with 200 parts of saturated sodium chloride and is dried over sodium sulfate. Removal of the solvent gives 92 parts of 4-bromo-2,5-diisopropylbenzenesulfonamide which may be recrystallized from 1-chlorobutane, m.p. 145°-152°.
Reaction SMILES: [Cl:1][C:2]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:12]=[C:13]([C:14]([O:16]C)=[O:15])[C:8]=2[N:7]=[C:6]1[CH:24]([F:26])[F:25].[Li+].[OH-]>C1COCC1>[Cl:1][C:2]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:12]=[C:13]([C:14]([OH:16])=[O:15])[C:8]=2[N:7]=[C:6]1[CH:24]([F:25])[F:26]
Reactant: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C(F)F)n2Cc1cccc(Cl)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc(N2CCOCC2)cc2c1nc(C(F)F)n2Cc1cccc(Cl)c1Cl
Temperature: 45 °C
Reaction time: 4 h
Yield: 45.7 %

Procedure:
A mixture of methyl 1-(2,3-dichlorobenzyl)-2-(difluoromethyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate (1350 mg, 2.88 mmol) and 2 N LiOH (10 mL) in THF (2.0 mL) was stirred at 45° C. for 4 h. It was filtered, the filter cake was dissolved in water (10 mL) and formic acid was added to adjust pH=3-4. Then a filtration was performed and the filter cake was dried under vacuum to give the desired product (600 mg, 46%) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 3.15 (s, 4H), 3.73 (s, 4H), 5.76 (s, 2H), 6.22 (d, 1H, J=7.5 Hz), 7.20-7.60 (m, 5H), 12.98 (br s, 1H); LC-MS: m/e=456 [M+1]+
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.C(=O)([O-])O.[Na+].[S:27]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28]1.CCOCC>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:29]1[CH:30]=[CH:31][S:27][CH:28]=1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1ccsc1
Reaction time: 8 h

Procedure:
To a rapidly stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (0.447 g) in toluene (2 ml) containing tetrakis(triphenylphosphine)palladium(0) (0.02 g) was added saturated aqueous sodium hydrogen carbonate solution (1 ml) and a solution of thiophene-3-boronic acid (0.256 g) in ethanol (1 ml). The mixture was heated under reflux for 3 hours, then left at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution (0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (0.01 g) were added and the mixture heated under reflux for 3 hours. Thiophene-3-boronic acid (0.178 g) and tetrakis(triphenylphosphine)palladium(0) (0.02 g) were added and heating under reflux continued for 16 hours. The cooled reaction mixture was then poured into ether (25 ml) and water (25 ml). The layers were separated and the aqueous phase extracted with a second portion of ether (25 ml). The combined organic layers were washed with water (2×25 ml), brine (25 ml) and then dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel (50 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a white crystalline solid, m.p. 210-2° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7](=[O:13])[NH:8][C:9](=[O:12])[NH:10][CH:11]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][Cl:19].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.C(OCC)(=O)C.O>[Cl:19][CH2:18][CH2:17][CH2:16][CH2:15][N:10]1[CH:11]=[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[C:7](=[O:13])[NH:8][C:9]1=[O:12]
Reactant: O=c1[nH]cc(-c2cccs2)c(=O)[nH]1
Reactant: ClCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c(=O)n(CCCCCl)cc1-c1cccs1
Yield: 21.8 %

Procedure:
The solution of 5-(thiophen-2-yl)pyrimidine-2,4(1H,3H)-dione (Prep22, 2.5 g, 12.9 mmol), 1-bromo-4-chlorobutane (2.2 g, 12.9 mmol) and potassium carbonate (1.8 g, 12.9 mmol) in DMF (150 ml) was stirred at room temperature for 5 hours. Water was added and the solution was adjusted to pH=6 with 3N hydrochloride acid. Ethyl acetate was added and the aqueous layer was extracted three times, the combined organic layer was dried and concentrated, the residue was purified by FC(P:E=3:1) to give the title compound (800 mg, y=22%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][C:4]=1[CH:5]=[O:6].CC(=CC)C.O.P([O-])(O)(O)=[O:23].[Na+].Cl([O-])=O.[Na+].[OH-].[Na+]>C(O)(C)(C)C.O.C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:13])([F:14])[F:15])=[CH:7][C:4]=1[C:5]([OH:23])=[O:6]
Reactant: O=P([O-])(O)O
Reactant: COc1ccc(OC(F)(F)F)cc1C=O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(C)(C)O
Product: COc1ccc(OC(F)(F)F)cc1C(=O)O
Reaction time: 4 h

Procedure:
According to the method of Heterocycles, 16, 2091 (1981), combine 2-methoxy-5-trifluoromethoxybenzaldehyde (0.58 g, 2.65 mmol) and 2-methylbut-2-ene (37 mL) in t-butanol (16 mL). Add dropwise a solution of sodium dihydrogen phosphate hydrate (0.92 g) and sodium chlorite (0.42 g, 4.7 mmol) in water (10 mL). After 4 hours, adjust the pH of the reaction mixture to about 8 to 9 using a.1 M aqueous sodium hydroxide solution. Evaporate the reaction mixture in vacuo at about ambient temperature to remove most of the t-butanol. Add water (40 mL) and extract three times with hexane (10 mL). Adjust the pH of the aqueous layer to about 1 using a 1 M aqueous hydrochloric acid solution and extract five times with diethyl ether. Combine the organic layers, dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 1/1 ethyl acetate/hexane containing 0.5% acetic acid to give 2-methoxy-5-trifluoromethoxybenzoic acid: Rf=0.34 (silica gel, 1/1 ethyl acetate/hexane containing 0.5% acetic acid).
Reaction SMILES: C(C1NC=CN=1)(C1[NH:4]C=CN=1)=O.[C:13]([O:17][C:18]([N:20]([CH2:24][C:25]1[CH:34]=[C:33]2[C:28]([CH:29]=[CH:30][C:31]([Cl:39])=[C:32]2[CH2:35][C:36](O)=[O:37])=[CH:27][CH:26]=1)[CH2:21][CH2:22][F:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].N>CN(C=O)C>[C:13]([O:17][C:18](=[O:19])[N:20]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]2[C:33](=[C:32]([CH2:35][C:36](=[O:37])[NH2:4])[C:31]([Cl:39])=[CH:30][CH:29]=2)[CH:34]=1)[CH2:21][CH2:22][F:23])([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CC(C)(C)OC(=O)N(CCF)Cc1ccc2ccc(Cl)c(CC(=O)O)c2c1
Agent: N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCF)Cc1ccc2ccc(Cl)c(CC(N)=O)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Carbonyl diimidazole (95 mg, 0.58 mmol) was added at RT under an atmosphere of argon to a solution of (7-{[tert-butoxycarbonyl-(2-fluoro-ethyl)-amino]-methyl}-2-chloro-naphthalen-1-yl)-acetic acid (210 mg, 0.53 mmol) in DMF (2.0 ml). After 2 h at RT, concentrated aqueous ammonia (4.3 ml) is added, and the mixture is stirred for 15 minutes at RT. The emulsion is extracted with EtOAc. The organic layer is washed with brine and dried over Na2SO4. After concentration, the residue is purified by FCC (EtOAc) to yield the title compound. 1H NMR (d6-DMSO, 400 MHz): δ 1.38+1.46 (2×br s, 9H), 3.3-3.6 (br m, 2H), 4.08 (s, 2H), 4.40-4.65 (br m, 2H), 4.61 (s, 2H), 7.02 (br s, NH), 7.42 (br d, J=9 Hz, 1H), 7.48-7.58 (br m, 3H), 7.80-7.90 (br m, 2H), 7.95 (br d, J=9 Hz, 1H). ES+-MS: 412.3, 414.2 [M+H+H2O]+. ES−-MS: 393.3, 395.3 [M−H]−.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.O[CH2:13][CH:14]1[CH2:22][CH:21]2[CH:17]([CH2:18][N:19]([C:23](=[O:33])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])[CH2:20]2)[C:16]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[O:41][CH3:42])([OH:34])[CH2:15]1.C(N(CC)CC)C>ClCCl>[CH3:42][O:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[C:16]1([OH:34])[CH2:15][CH:14]([CH2:13][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:22][CH:21]2[CH:17]1[CH2:18][N:19]([C:23](=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32])[CH2:20]2
Reactant: COc1ccccc1CC(=O)N1CC2CC(CO)CC(O)(c3ccccc3OC)C2C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1CC(=O)N1CC2CC(CS(=O)(=O)c3ccc(C)cc3)CC(O)(c3ccccc3OC)C2C1
Temperature: 20 °C
Reaction time: 20 h
Yield: 91 %

Procedure:
3.05 g of p-toluenesulphonyl chloride are added to a solution of 3.4 g of (3aRS,4RS,6SR,7aSR)-6-hydroxymethyl-4-(2-methoxyphenyl)-2-[(2-methoxyphenyl)acetyl]perhydroisoindol-4-ol and 2.24 cm3 of triethylamine in 150 cm3 of dichloromethane. The mixture is stirred at 20° C. for 20 hours, washed with 100 cm3 of water, dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa). 4.1 g of (3aRS,4RS,6SR,7aSR)-4-(2-methoxyphenyl)-2-[(2-methoxyphenyl)acetyl]-6-tosylmethylperhydroisoindol-4-ol are obtained in the form of a thick white foam.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[C:15]=2[Cl:22])[C:7]=1[N:8]1[CH:11]([CH3:12])[CH2:10][C:9]1=[O:13])#[N:2].[CH2:23]([NH:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26]>>[C:1]([C:3]1[CH:4]=[N:5][N:6]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[C:15]=2[Cl:22])[C:7]=1[NH:8][CH:11]([CH3:12])[CH2:10][C:9]([N:27]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:23][CH2:24][CH2:25][CH3:26])=[O:13])#[N:2]
Reactant: CC1CC(=O)N1c1c(C#N)cnn1-c1ccc(Cl)c(Cl)c1Cl
Reactant: CCCCNCCCC
Product: CCCCN(CCCC)C(=O)CC(C)Nc1c(C#N)cnn1-c1ccc(Cl)c(Cl)c1Cl

Procedure:
A solution of 4-cyano-5-(4-methyl-2-oxo-azetidin-1-yl)-1-(2,3,4-trichlorophenyl)pyrazole (1.0 g; prepared as described in Example 32) in di-n-butylamine (20 ml) was heated under reflux for 31/2 hours. The reaction mixture was evaporated to dryness and the residue chromatographed using dichloromethane-ethyl acetate (40:1) as eluent. Evaporation of the eluate containing the major component gave 4-cyano-5-[2-di-(n-butyl)aminocarbonyl-1-methylethyl]amino-1-(2,3,4-trichlorophenyl)pyrazole (0.95 g), m.p. 101°-103° C., in the form of a colourless solid.
Reaction SMILES: [O:1]=[C:2]1[CH:10]([C:11]2[C:16]3=[C:17]([CH3:23])[C:18]([C:20](O)=[O:21])=[CH:19][N:15]3[N:14]=[CH:13][N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:57][CH2:58][CH2:59][CH2:60][N:61]1[CH2:65][CH2:64][CH2:63][CH2:62]1.Cl>CN(C=O)C.ClCCl>[O:1]=[C:2]1[CH:10]([C:11]2[C:16]3=[C:17]([CH3:23])[C:18]([C:20]([NH:57][CH2:58][CH2:59][CH2:60][N:61]4[CH2:65][CH2:64][CH2:63][CH2:62]4)=[O:21])=[CH:19][N:15]3[N:14]=[CH:13][N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: Cc1c(C(=O)O)cn2ncnc(C3C(=O)Nc4ccccc43)c12
Reactant: NCCCN1CCCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C(=O)NCCCN2CCCC2)cn2ncnc(C3C(=O)Nc4ccccc43)c12
Reaction time: 0.17 h
Yield: 37.3 %

Procedure:
To a solution of Example 95 (50 mg, 0.16 mmol) in DMF (1 mL), dichloromethane (0.5 mL) were added PyBrop (113 mg, 0.24 mmol) and diisopropylethyl amine (0.08 mL, 0.5 mL). After 10 min, 1-(3-aminopropyl)pyrrolidine (61 mg, 0.48 mmol) was added. After 15 h, the reaction mixture was purified by preparative RP HPLC. The yellow oil obtained was converted to the HCl salt and lyophilized to afford a red orange solid (25 mg, 34%). MS: (M+H)+=419.
Reaction SMILES: [CH3:1][N:2]([CH2:16][CH2:17][OH:18])[C:3](=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](Cl)=[O:25]>>[CH3:1][N:2]([CH2:16][CH2:17][O:18][C:24]([C:20]1[O:19][CH:23]=[CH:22][CH:21]=1)=[O:25])[C:3](=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=C(Cl)c1ccco1
Reactant: CCCCCCCCCCCC(=O)N(C)CCO
Product: CCCCCCCCCCCC(=O)N(C)CCOC(=O)c1ccco1

Procedure:
N-methyl-N-(2-furoyloxyethyl)lauramide was prepared by the procedure of example 1 from 26 gms. (0.1 mole) of N-methyl-N-(2-hydroxyethyl)lauramide and 13 gms. (0.1 mole) of furoyl chloride. The structure of the final product was characterized on the basis of IR and NMR spectral analyses as described in example 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:24])[CH:5]=[CH:6][CH:7]=1.Br[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:24])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(F)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(F)c1
Reaction time: 0.05 h
Yield: 63.2 %

Procedure:
40% Methanolic Triton B (0.086 mL, 0.19 mM) was added to a solution of the 9-[(3-fluorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (51.9 mg, 0.155 mM) in 3 mL DMF at room temperature. After 3 minutes, t-butyl bromoacetate (87.8 mg, 0.44 mM) was added and the resultant mixture stirred at room temperature for 5 hours. The mixture was diluted with ethyl acetate, washed four times with H2O, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 44.0 mg (63%) of the {9-[(3-fluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, tert-butyl ester as a white solid. 1H NMR (DMSO-d6) δ 7.6 (d, 1H, J=8 Hz), 7.5-6.8 (m, 10H), 6.55 (d, 1H, J=8 Hz), 5.7 (s, 2H), 4.8 (s, 2H), and 1.45 (s, 9H). IR (CHCl3, cm−1) 3450, 3400, 1746, 1674, 1592, 1457, 1369, and 1151. MS (FD) m/e 448.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[N:55]1([CH2:60][C@H:61]2[CH2:65][CH2:64][CH2:63][NH:62]2)[CH2:59][CH2:58][CH2:57][CH2:56]1>CN(C=O)C.O.C(=O)(O)[O-].[Na+]>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:62]2[CH2:63][CH2:64][CH2:65][C@@H:61]2[CH2:60][N:55]2[CH2:59][CH2:58][CH2:57][CH2:56]2)=[O:32])[C:25]=1[CH3:33])(=[O:11])=[O:12]
Reactant: C1CN[C@@H](CN2CCCC2)C1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)N1CCC[C@@H]1CN1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.2 mmol), EDAC (80 mg, 0.41 mmol), HOBt (35 mg, 0.41 mmol), TEA (0.1 mL) and (R)-2-pyrrolidin-1-ylmethyl-pyrrolidine (0.5 mL) in DMF (4 mL) was stirred at rt for overnight. The reaction was diluted with water and sodium bicarbonate, extracted with ethyl acetate. The organic layer was concentrated and purified on a silica gel column to give the titled compound.
Reaction SMILES: [CH3:1][N:2]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][CH2:15]Br)=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:3]1=[O:4].[C:17]([C:20]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)(=[O:19])[CH3:18].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:1][N:2]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][CH2:15][N:23]3[CH2:24][CH2:25][C:20]([C:17](=[O:19])[CH3:18])([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:21][CH2:22]3)=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:3]1=[O:4]
Reactant: CC(=O)C1(c2ccccc2)CCNCC1
Reactant: CN1C(=O)CCc2cc(OCCBr)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)C1(c2ccccc2)CCN(CCOc2ccc3c(c2)CCC(=O)N3C)CC1

Procedure:
1.43 Grams of 1-methyl-6-(2-bromoethoxy)-3,4-dihydrocarbostyril, 1.3 g of 4-acetyl-4-phenylpiperidine and 1 g of triethylamine were mixed with 30 ml of dimethylformamide and the mixture was heated at 60°-70° C. for 5 hours. The reaction mixture thus obtained was concentrated under a reduced pressure to dryness, and to the residue thus obtained was added 5% sodium hydrogencarbonate aqueous solution and stirred. The insoluble matters were collected by filtration, washed with water then dried and recrystallized from ethanol-water to obtain 1.3 g of 1-methyl-6-[2-(4-acetyl-4-phenyl-1-piperidyl)ethoxy]-3,4-dihydrocarbostyril as in the form of colorless prism-like crystals. Melting point: 101°-103° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.C[Si](C)(C)[C:17]([F:20])([F:19])[F:18].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>C1COCC1>[F:18][C:17]([F:20])([F:19])[C:2]1([OH:1])[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(O)(C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.5 %

Procedure:
After tert-butyl 3-oxopiperidine-1-carboxylate (1 g, 5.02 mmol) was dissolved in THF (20 ml), and then trimethyl(trifluoromethyl)silane (0.5M solution in THF, 20 ml, 10.0 mmol) and tetrabutylammonium fluoride (1.0M solution in THF, 10.5 ml, 10.5 mmol) were sequentially added thereto at 0° C., followed by stirring at room temperature for 2 hours. A saturated aqueous ammonium chloride solution (5 ml) was added to the resulting reaction liquid, followed by stirring for 20 minutes. The resulting reaction liquid was concentrated under reduced pressure, and then MC (100 ml) was added to the residue thus obtained, followed by washing with distilled water (20 ml). The organic layer was dried over anhydrous magnesium sulfate, followed by filtration and concentration, and then the residue thus obtained was subjected to MPLC (20% EtOAc/Hexanes), to obtain 709 mg of white solid (53%).
Reaction SMILES: CC1C[N@@]1S(C1C=CC=C(C(F)(F)F)C=1)(=O)=O.CC1C=CC(S(O[CH2:29][C@@H:30]([NH:32][S:33]([C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH3:31])(=O)=O)=CC=1>>[CH3:29][CH:30]1[CH2:31][N@@:32]1[S:33]([C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=1)(=[O:35])=[O:34]
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](C)COS(=O)(=O)c2ccc(C)cc2)cc1
Agent: CC1C[N@@]1S(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: CC1C[N@]1S(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)[N@@]2CC2C)cc1
Product: Cc1ccc(S(=O)(=O)[N@]2CC2C)cc1

Procedure:
Proceeding as described for (49), but using (S)-2-(4-methylbenzenesulfonamido)propyl 4-methylbenzenesulfonate afforded (S)-2-methyl-1-(4-methylbenzene-sulfonyl)aziridine (48).