Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]=1[NH:15][C:16](=[O:24])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:27]I.Cl>CN(C)C=O>[N+:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]=1[N:15]([C:16](=[O:24])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH3:27])([O-:3])=[O:2]
Reactant: CI
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])c(NC(=O)Cc2ccccc2)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc([N+](=O)[O-])c(N(C)C(=O)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.924 g of ethyl 4-nitro-3-phenylacetylaminobenzoate in 10 ml of N,N-dimethylformamide were added 0.166 g of 60% sodium hydride while being cooled with ice, and the mixture was stirred at room temperature for 1 hour. Methyl iodide (0.50 ml) was added thereto, and the resulting mixture was stirred at room temperature for 1 hour. The reaction solution was poured into cold 1-N hydrochloric acid, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with 1-N hydrochloric acid and then with water, and was dried. The solvent was distilled off under reduced pressure. The residue was purified through silica-gel column chromatography (developing eluent: a mixture of ethyl acetate and hexane at a ratio of from 1:10 to 1:4) to obtain 0.510 g of ethyl 4-nitro-3-[N-(methyl)phenylacetylamino]benzoate. To 0.148 g of this compound were added 2 ml of ethanol, 1 ml of acetic acid and 0.240 g of reduced iron, and the mixture was refluxed for 2 hours. The solid material was separated through filtration. The filtrate was concentrated, and was then purified through preparative thin-layer silica-gel chromatography (eluent: a mixture of chloroform and ethyl acetate at a ratio of 2:1) to give 0.090 g of 2-benzyl-6-ethoxycarbonyl-1-methylbenzimidazole (115).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][O:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][NH2:26]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:26][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[O:22][CH3:21])=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: COc1ccccc1CN
Product: COc1ccccc1CNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (0.1 mg, 0.28 mmol) and 2-methoxy-benzylamine (46 mg, 0.33 mmol). The title compound was obtained as a yellow solid (25.0 mg, 19.0% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.20 (1H, m), 8.98 (2H, s), 8.58 (1H, s), 7.25 (1H, m), 7.18 (1H, m), 7.00 (1H, m), 6.90 (1H, m), 4.36 (2H, m), 3.79 (3H, s). MS m/z: 468.05, 470.05 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([CH3:8])[CH:4]=1.[CH2:9]([NH2:11])[CH3:10]>C1COCC1>[CH2:9]([NH:11][CH2:2][C:3]1[O:7][N:6]=[C:5]([CH3:8])[CH:4]=1)[CH3:10]
Reactant: Cc1cc(CCl)on1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNCc1cc(C)no1

Procedure:
prepared by reaction of 5-chloromethyl-3-methyl-isoxazole (Li W.-T. et al J. Med. Chem. 2003, 46, 9, 1706-1715) with 2M ethylamine in THF.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[CH:9][CH:8]=1)=[CH2:6])[CH3:2].[C:25]([OH:28])(=[S:27])[CH3:26]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:24])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[CH:9][CH:8]=1)[CH2:6][S:27][C:25](=[O:28])[CH3:26])[CH3:2]
Reactant: CC(O)=S
Reactant: C=C(C(=O)OCC)c1ccc(NC(=O)OCc2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(CSC(C)=O)c1ccc(NC(=O)OCc2ccccc2)cc1

Procedure:
A solution of 2-(4-(benzyloxycarbonylamino)phenyl)prop-2-enoic acid ethyl ester (2.2 g, 7.55 mmol) and thioacetic acid (5 mL) in 10 mL of chloroform was heated for 18 hours. The reaction mixture was evaporated in vacuo and purified by flash chromatography through silica gel (5/1 hexanes/ethyl acetate) to afford 2-(4-(benzyloxycarbonylamino)phenyl)-3-(acetylthio)propanoic acid ethyl ester, 0.22 g (8%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].[CH:38]1([CH2:41]Br)[CH2:40][CH2:39]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][CH2:41][CH:38]3[CH2:40][CH2:39]3)[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: BrCC1CC1
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Product: COc1ccc(CC2c3cc(OCC4CC4)c(OC)cc3CCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with cyclopropyl-methyl bromide
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]1([F:31])[CH2:17][CH2:16][CH:15]([CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=2)[CH2:19][NH2:20])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([CH:15]1[CH2:14][CH2:13][C:12]([F:31])([F:11])[CH2:17][CH2:16]1)[C:21]1[CH:26]=[N:25][C:24]([C:27]([F:28])([F:29])[F:30])=[N:23][CH:22]=1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: NCC(c1cnc(C(F)(F)F)nc1)C1CCC(F)(F)CC1
Product: O=C(NCC(c1cnc(C(F)(F)F)nc1)C1CCC(F)(F)CC1)c1ccccc1Cl

Procedure:
From 2-chlorobenzoic acid and 2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine. LCMS (MH+): m/z=448.1, tR (minutes, Method F)=2.95
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]2Cl.[N:18]1([CH2:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:22][CH2:21][CH2:20][CH2:19]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]2[N:27]1[CH2:26][CH2:25][CH:24]([CH2:23][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:29][CH2:28]1
Reactant: C1CCN(CC2CCNCC2)C1
Reactant: CC(C)C(=O)c1cnc2ccc(Br)cc2c1Cl
Product: CC(C)C(=O)c1cnc2ccc(Br)cc2c1N1CCC(CN2CCCC2)CC1
Yield: 68.3 %

Procedure:
Following general procedure B, 1-(6-bromo-4-chloroquinolin-3-yl)-2-methylpropan-1-one (250 mg, 0.800 mmol) was reacted with 4-(pyrrolidin-1-ylmethyl)piperidine (168 mg, 1.00 mmol) to afford the desired product (243 mg, 68%) as a yellow solid: ESI MS m/z 444 [C23H30BrN3O+H]+.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].Br[C:8]1[CH:9]=[N:10][CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1.C(N(CC)CC)C>C(OCC)(=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:15][O:14][C:12]1[CH:11]=[N:10][CH:9]=[C:8]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:13]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1cncc(Br)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cncc(C#C[Si](C)(C)C)c1
Temperature: 25 °C

Procedure:
Add (trimethylsilyl)acetylene (1.3 mL, 9.45 mmol) and bis(triphenylphosphine)palladium (II) dichloride (0.102 g, 0.15 mmol) to a mixture of 3-bromo-5-methoxypyridine from PREPARATION 9 (1.366 g, 7.26 mmol), copper (I) iodide (0.055 g, 0.29 mmol) and triethylamine (4.1 mL, 29.04 mmol) in ethyl acetate (7.5 mL) in a sealed tube. Stir the resultant reaction mixture at 75° C. for 20 h and cool to room temperature. Dilute the reaction mixture with ethyl acetate and filter through a pad of diatomaceous earth. Wash with ethyl acetate and concentrate the filtrate to give the title compound as a solid which is used without further purification (1.48 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].Cl.[S:38]1[CH:42]=[C:41]([C:43]2[CH:50]=[CH:49][C:46]([CH2:47][NH2:48])=[CH:45][CH:44]=2)[N:40]=[N:39]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([NH:48][CH2:47][C:46]1[CH:45]=[CH:44][C:43]([C:41]2[N:40]=[N:39][S:38][CH:42]=2)=[CH:50][CH:49]=1)=[O:24]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Reactant: NCc1ccc(-c2csnn2)cc1
Agent: Cl
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCc2ccc(-c3csnn3)cc2)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with 4-(1,2,3-thiadiazol-4-yl)benzylamine hydrochloride.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH:5]=[N:4][CH:3]=[N:2]1.F[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>>[C:11]([C:10]1[CH:13]=[CH:14][C:7]([CH:6]([C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:8][CH:9]=1)#[N:12]
Reactant: N#Cc1ccc(F)cc1
Reactant: N#Cc1ccc(Cn2cncn2)cc1
Product: N#Cc1ccc(C(c2ccc(C#N)cc2)n2cncn2)cc1

Procedure:
U.S. Pat. No. 4,978,672 (referred to herein as '672, Indian Reference not available) provides 4-[alpha-(4-cyanophenyl)-1-(1,2,4-triazolyl)-methyl]benzonitrile and the process of its preparation. The patent discloses reacting 4-bromomethylbenzonitrile with 1,2,4-triazole to yield 4-[1-(1,2,4-triazol-1-yl)methyl]benzonitrile. 4-[1-(1,2,4-triazol-1-yl)methyl]benzonitrile is then reacted with 4-fluorobenzonitrile to give 4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile. This patent does not disclose the purity of 4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile, compound of formula 1. When we followed the patented process we also get the unwanted isomer 4-[1-(1,2,4-triazol-4-yl)methyl]benzonitrile, a compound of formula 4 (20 to 40%) in step 1. When the reaction mixture of step 1 is treated with 4-fluorobenzonitrile it yields 4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-1-yl)-methyl]-benzonitrile, a compound of formula 1, and its isomer, a compound of formula 5. Thus the impurity of formula 4 has to be separated before treating it with 4-fluorobenzonitrile, which involves an additional step of column purification, which is reported in '672 and makes the process tedious and commercially unviable.
Reaction SMILES: Cl.[O:2]=[C:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH:4]1[C:9]([O:11][CH3:12])=[O:10].CCN(CC)CC.[S:20](Cl)([CH3:23])(=[O:22])=[O:21]>C(Cl)Cl.CCOC(C)=O>[CH3:23][S:20]([N:6]1[CH2:7][CH2:8][C:3](=[O:2])[CH:4]([C:9]([O:11][CH3:12])=[O:10])[CH2:5]1)(=[O:22])=[O:21]
Reactant: COC(=O)C1CNCCC1=O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CN(S(C)(=O)=O)CCC1=O
Reaction time: 1 h
Yield: 23 %

Procedure:
To a mixture of 1 g (6.36 mmol) of methyl 4-oxopiperidine-3-carboxylate hydrochloride and 2.2 mL of Et3N in 12 mL of DCM is added dropwise at room temperature 0.5 mL of mesyl chloride. The reaction medium is stirred for 1 hour and then taken up in 50 mL of EtOAc, washed with 20 mL of water and 20 mL of brine and then dried over Na2SO4, filtered and concentrated under reduced pressure. 0.35 g of methyl 1-(methylsulfonyl)-4-oxopiperidine-3-carboxylate is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:15][CH3:16])[C:7]3[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=3[C:13]=2[CH:14]=1.[CH:17]([O-])=[O:18].[Na+]>CN(C)C=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:15]([N:6]1[C:5]2[CH:4]=[CH:3][C:2]([CH:17]=[O:18])=[CH:14][C:13]=2[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=2)[CH3:16]
Reactant: O=C[O-]
Reactant: CCn1c2c(c3cc(Br)ccc31)CCCC2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1c2c(c3cc(C=O)ccc31)CCCC2
Temperature: 110 °C
Yield: 91.4 %

Procedure:
A 250-mL round-bottomed flask was charged with a solution of 3-bromo-9-ethyl-6,7,8,9-tetrahydro-5H-carbazole (2 g, 7.22 mmol, 1.00 equiv) in N,N-dimethylformamide (100 mL), sodium formate (740 mg, 10.88 mmol, 1.50 equiv), Pd(PPh3)2Cl2 (500 mg, 0.72 mmol, 0.10 equiv) and CO (500 mL). The resulting solution was heated to 110° C. in an oil bath for 3 hours. The reaction progress was monitored by TLC (EtOAc:PE=1:5). Upon completion, the resulting solution was diluted with ethyl acetate (200 mL) and then quenched by the addition of brine (200 mL). The resulting mixture was extracted with ethyl acetate (2×100 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered off and concentrated on a rotary evaporator affording 9-ethyl-6,7,8,9-tetrahydro-5H-carbazole-3-carbaldehyde as pale yellow solid (1.5 g, 70%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[CH2:16](N(CC)CC)C.[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1.C(OCC)(=O)C>C(Cl)Cl>[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](=[O:29])[CH2:16][NH:1][C:2]2[C:10]3[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=3)[NH:4][C:3]=2[C:12]([O:14][CH3:15])=[O:13])=[CH:26][CH:25]=1
Reactant: COC(=O)c1[nH]c2cc(Cl)ccc2c1N
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1[nH]c2cc(Cl)ccc2c1NCC(=O)c1ccc(F)cc1

Procedure:
Suspend the 3-amino-2-carbmethoxy-6-chloroindole (1.15 g, 5.12 mmol) in methylene chloride (80 mL) and add triethylamine (0.497 mL, 5.5 mmol). Addthe p-fluorobenzoyl chloride (0.650 mL, 5.5 mmol) and stir for 30 minutes at room temperature to produce a precipitate. Dilute the reaction with ethyl acetate (150 mL), rinse with water, dry over magnesium sulfate, filter and concentrate in vacuo to yield the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH:11]([N:14]=[C:15]=[O:16])([CH3:13])[CH3:12].C(N(CC)CC)C>C1C=CC=CC=1>[O:4]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][O:1][C:15](=[O:16])[NH:14][CH:11]([CH3:13])[CH3:12]
Reactant: O=C(CO)c1ccccc1
Reactant: CC(C)N=C=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)OCC(=O)c1ccccc1
Yield: 36.9 %

Procedure:
A mixture of α-hydroxyacetophenone (7.0 g, 51.4 mmol), isopropyl isocyanate (10.1 ml, 102.8 mmol) and triethylamine (7.2 ml, 51.4 mmol) in 150 ml of benzene was refluxed under nitrogen overnight. The reaction was diluted with benzene, extracted with 1N HCl, dried (MgSO4) and the solvent removed under reduced pressure to 9.741 g of a brown solid. Recrystallization of the solid from isopropyl alcohol gave isopropyl-carbamic acid 2-oxo-2-phenyl-ethyl ester (4.2 g, 38%) as yellow solid, mp 108-110° C.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][C@H:31]2[CH2:36][CH2:35][C@H:34]([OH:37])[CH2:33][CH2:32]2)=[CH:26][C:25]=1[C:38]([F:41])([F:40])[F:39])([O-:23])=[O:22].[H-].[Na+].O1CCCC1>ClCCl.CN(C)C=O>[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][C@H:31]2[CH2:36][CH2:35][C@H:34]([O:37][CH2:2][C:3]([N:5]3[CH2:10][CH2:9][N:8]([C:11]4[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=4)[CH2:7][CH2:6]3)=[O:4])[CH2:33][CH2:32]2)=[CH:26][C:25]=1[C:38]([F:39])([F:40])[F:41])([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc(N[C@H]2CC[C@H](O)CC2)cc1C(F)(F)F
Reactant: O=C(CCl)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(CO[C@H]1CC[C@H](Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(c2ccc(C(F)(F)F)cc2)CC1

Procedure:
2-Chloro-1-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-ethanone (26 mg, 0.09 mmol, prepared in accordance with Example 4), trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanol (26 mg, 0.09 mmol, prepare in accordance with Example 5), and sodium hydride (10 mg, 60% in oil, 0.26 mmol) were placed under an inert atmosphere. Tetrahydrofuran (1 mL) was added under stirring. Next, dimethylformamide (300 μL) was added under stirring. The resulting mixture was stirred for 40 min at room temperature and then diluted with dichloromethane (5 mL). The mixture was washed with water (5 mL) and then washed with saturated aqueous sodium hydrogencarbonate (5 mL). The organic phase was collected, dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude product was purified by preparative HPLC. Following lyophilization of the fractions of interest, the desired product was isolated as a yellow solid (21 mg, 43% yield). The structure was confirmed using Protocol II-A. Calculated mass=575; observed mass=575; HPLC retention time=4.51 min.
Reaction SMILES: [CH2:1]([Li])[CH3:2].[Li].C(Br)C.[F:8][C:9]1[CH:23]=[CH:22][C:12]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[O:14])=[CH:11][CH:10]=1.[Cl-].[NH4+]>O1CCCC1.CCOCC>[F:8][C:9]1[CH:23]=[CH:22][C:12]([C:13]([CH2:1][CH3:2])([OH:14])[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1
Reactant: [Li]CC
Reactant: O=C(c1ccc(O)cc1)c1ccc(F)cc1
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: CCBr
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(O)(c1ccc(O)cc1)c1ccc(F)cc1
Temperature: 0 °C

Procedure:
To a solution of ethyl lithium prepared from 2.8 g. of lithium metal and 21.8 g. of ethyl bromide in 265 ml. of dry ether a solution of 10.8 g. of 4-fluoro-4'-hydroxy-benzophenone in 50 ml. of dry tetrahydrofurane is added dropwise, with stirring in argon atmosphere, at a temperature between -40° C. and -30° C. When the addition is complete, the mixture is allowed to warm up to 0° C., and is then stirred at this temperature for further 30 minutes. The mixture is decomposed with a 20% aqueous ammonium chloride solution under cooling. The aqueous phase is extracted with ether, the ethereal phases are combined, washed to neutral with water, and dried over anhydrous magnesium sulfate. The solution is evaporated under reduced pressure, and the solid residue is crystallized from a mixture of n-hexane and ethyl acetate to yield 8.2 g. of the named product, melting at 125° to 126° C.
Reaction SMILES: [CH3:1][C:2]1(C)[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:38])[CH2:13][NH:14][CH2:15][CH2:16][C:17]3[CH:37]=[CH:36][C:20]([O:21][CH2:22][CH2:23][O:24][CH2:25][C:26]4[CH:27]=[C:28]([NH:32][C:33]([NH2:35])=[O:34])[CH:29]=[CH:30][CH:31]=4)=[CH:19][CH:18]=3)=[CH:11][C:5]=2[CH2:4][O:3]1>C(O)(=O)C.O>[C:2]([OH:7])(=[O:3])[CH3:1].[OH:38][C@H:12]([C:10]1[CH:9]=[CH:8][C:6]([OH:7])=[C:5]([CH2:4][OH:3])[CH:11]=1)[CH2:13][NH:14][CH2:15][CH2:16][C:17]1[CH:37]=[CH:36][C:20]([O:21][CH2:22][CH2:23][O:24][CH2:25][C:26]2[CH:27]=[C:28]([NH:32][C:33]([NH2:35])=[O:34])[CH:29]=[CH:30][CH:31]=2)=[CH:19][CH:18]=1
Reactant: CC1(C)OCc2cc([C@@H](O)CNCCc3ccc(OCCOCc4cccc(NC(N)=O)c4)cc3)ccc2O1
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)Nc1cccc(COCCOc2ccc(CCNC[C@H](O)c3ccc(O)c(CO)c3)cc2)c1
Yield: 208.9 %

Procedure:
N-[3-({2-[4-(2-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}ethyl)phenoxy]ethoxy}methyl)phenyl]urea (12 mg) in acetic acid (1.5 mL) and water (0.5 mL) was heated at 75° C. for 0.5 h. The solution was then concentrated in vacuo and azeotroped with MeOH to give the title compound (13 mg). LCMS RT=2.18 min. ES+ve 496 (MH)+
Reaction SMILES: OO.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:6].P([O-])([O-])(O)=O.[Na+].[Na+].[Cl:23][C:24]([Cl:35])([Cl:34])[CH2:25][O:26][C:27]([N:29]1[CH2:33][CH:32]=[CH:31][CH2:30]1)=[O:28]>C(Cl)Cl.O>[O:6]1[CH:31]2[CH:32]1[CH2:33][N:29]([C:27]([O:26][CH2:25][C:24]([Cl:23])([Cl:34])[Cl:35])=[O:28])[CH2:30]2
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CC=CC1
Agent: O=P([O-])([O-])O
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(OCC(Cl)(Cl)Cl)N1CC2OC2C1
Reaction time: 0.25 h

Procedure:
12 ml of 90% strength hydrogen peroxide (0.48 mol) are dissolved in 40 ml of methylene chloride and the solution is treated at 0° with 63.5 ml (0.45 mol) of trifluoroacetic anhydride. After stirring for 15 minutes at 0°, the solution is added dropwise to a suspension, which is kept at 0°, of 196 g of anhydrous disodium hydrogen phosphate in 800 ml of methylene chloride, in which 41.8 g (0.17 mol) of N-(β,β,β-trichloroethoxycarbonyl)-3-pyrroline has been dissolved. Subsequently, the reaction mixture is stirred for 2 hours at room temperature and then stirred into 900 ml of water and the resulting mixture is stirred for a further one hour. The organic phase is separated off and the aqueous phase is extracted by shaking with 3 times 200 ml of methylene chloride; the combined organic phases are washed successively with aqueous sodium chloride solution, aqueous iron-II sulphate solution and then with water, dried over sodium sulphate and evaporated under a water pump vacuum, whereupon 3,4-epoxy-1-(β,β,β-trichloroethoxycarbonyl)-pyrrolidine is obtained in the form of white crystals with a melting point of 52°-55°.
Reaction SMILES: C([C:3]1([C:21]([O-:23])=[O:22])[CH:7]2[CH2:8][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:10]([CH3:12])[CH2:11][N:6]2[N:5]=[C:4]1[I:20])C.[OH-].[Na+]>CCO.O>[C:16]([O:15][C:13]([N:9]1[CH:10]([CH3:12])[CH2:11][N:6]2[N:5]=[C:4]([I:20])[C:3]([C:21]([OH:23])=[O:22])=[C:7]2[CH2:8]1)=[O:14])([CH3:17])([CH3:18])[CH3:19]
Reactant: CCC1(C(=O)[O-])C(I)=NN2CC(C)N(C(=O)OC(C)(C)C)CC21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1Cn2nc(I)c(C(=O)O)c2CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.7 %

Procedure:
To a stirred solution of Intermediate 340D (0.85 g, 1.953 mmol) in EtOH (2.0 mL) was added a solution of NaOH (0.391 g, 9.76 mmol) in water (1.0 mL) and the resulting solution was stirred at RT for 16 h. The reaction mixture was concentrated and the residue was acidified by the addition of a 1N aq. solution of HCl (5 mL) which was allowed to stir for 10 min. The generated precipitate was filtered and dried to afford Intermediate 340E as a white solid (0.65 g, 82%). MS(ES): m/z=408 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 5.05 (d, J=18.89 Hz, 1H), 4.67 (br. s., 1H), 4.36 (d, J=18.13 Hz, 1H), 4.13-4.25 (m, 1H), 3.93-4.13 (m, 2H), 1.44 (s, 9H), 1.08 (t, J=6.99 Hz, 3H).
Reaction SMILES: CC(C1C=CC=C(C(C)C)C=1C[C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:15])C.C(C1C=CC=C(C(C)C)C=1CC(O)=O)(C)C.[CH3:49][C:50]1[CH:55]=[C:54]([CH3:56])[CH:53]=[C:52]([CH3:57])[C:51]=1[CH2:58]C(O)=O>>[CH3:49][C:50]1[CH:55]=[C:54]([CH3:56])[CH:53]=[C:52]([CH3:57])[C:51]=1[CH2:58][C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:28])(=[O:29])[NH2:27])[C:19]([CH:22]([CH3:23])[CH3:24])=[CH:20][CH:21]=1)=[O:15]
Reactant: Cc1cc(C)c(CC(=O)O)c(C)c1
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Agent: CC(C)c1cccc(C(C)C)c1CC(=O)O
Product: Cc1cc(C)c(CC(=O)c2ccc(C(C)C)c(OS(N)(=O)=O)c2C(C)C)c(C)c1

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with 2,4,6-trimethylphenylacetic acid, mp 159°-161° C.