Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][N:7]([CH2:21][CH3:22])[C:8]2[N:13]=[C:12]3[N:14]([CH3:18])[N:15]=[C:16]([CH3:17])[C:11]3=[CH:10][C:9]=2[CH:19]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:23][C:24]([F:38])([F:37])[C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:28][NH2:29].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[F:23][C:24]([F:37])([F:38])[C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=1)[CH2:28][NH:29][CH2:19][C:9]1[CH:10]=[C:11]2[C:16]([CH3:17])=[N:15][N:14]([CH3:18])[C:12]2=[N:13][C:8]=1[N:7]([CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:21][CH3:22]
Reactant: CCN(CC1CCCC1)c1nc2c(cc1C=O)c(C)nn2C
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCN(CC1CCCC1)c1nc2c(cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c(C)nn2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
A mixture of 6-(cyclopentylmethyl-ethyl-amino)-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (5.3 g, 17.0 mmol) and 3,5-bis-trifluoromethylbenzylamine (4.7 g, 0.019 mol) in MeOH and acetic acid (2 drops) was stirred at RT for 30 min. After cooling to 0° C., sodium cyanoborohydride (2.2 g, 35.0 mmol) was added slowly over a period of about 10 min. After stirring at RT for 30 min, the reaction mixture was concentrated in vacuo. Water (50 mL) was added to the residue and stirred for 30 min. The solid was filtered off, washed with water followed by petroleum ether, and dried in vacuo to yield colorless solid (72%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:20])[CH:15]2[CH2:19][CH2:18][O:17][CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:20][N:14]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH:15]1[CH2:19][CH2:18][O:17][CH2:16]1
Reactant: CN(C1CCN(C(=O)OC(C)(C)C)CC1)C1CCOC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C1CCNCC1)C1CCOC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-[methyl(tetrahydrofuran-3-yl)amino]piperidine-1-carboxylic acid tert-butyl ester (132 mg, 0.46 mmol) and TFA (2 mL) in DCM (5 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording Methyl(piperidin-4-yl)(tetrahydro-furan-3-yl)amine as a white solid (84 mg, quant.). 1H NMR (CDCl3, 300 MHz): δ 3.98-3.91 (m, 1H); 3.88-3.83 (m, 1H); 3.80-3.73 (m, 1H); 3.61-3.53 (m, 1H); 3.42-3.35 (m, 1H); 3.26-3.14 (m, 2H); 2.71-2.53 (m, 2H); 2.57-2.46 (m, 1H); 2.23 (s, 3H); 2.05-1.97 (m, 1H); 1.93-1.77 (m, 1H); 1.78-1.72 (m, 2H); 1.64-1.49 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:7]=[C:6]([N+:29]([O-:31])=[O:30])[CH:5]=1.[OH-].[Na+]>CO.O1CCOCC1>[N+:29]([C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:7]=1)[C:3]([OH:32])=[O:2])([O-:31])=[O:30]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(C(=O)OC)cc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOc1cc(C(=O)O)cc([N+](=O)[O-])c1
Yield: 61.9 %

Procedure:
A solution of 4.5 g of 3-nitro-5-(octadecyloxy)benzoic acid methyl ester and 4 ml of 6N NaOH in 200 ml of methanol and 50 ml of dioxane was stirred at reflux for 2.5 hours. The solvents were removed at reduced pressure and the residue was acidified with 1N HCl. The solid was filtered and recrystallized from methanol-water to give 2.7 g (62% yield, mp 101°-103°) of 3-nitro-5-(octadecyloxy) benzoic acid.
Reaction SMILES: C([N:4]([C@@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[C:5](=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])C=C.[C:22]([Mg]Cl)(C)([CH3:24])[CH3:23].Cl>C1(C)C=CC=CC=1>[CH2:24]([C@@H:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([NH:4][CH:14]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH3:15])=[O:13])[CH:22]=[CH2:23]
Reactant: C=CCN(C(=O)CCCCCCC)[C@H](C)c1ccccc1
Reactant: CC(C)(C)[Mg]Cl
Agent: Cl
Solvent: Cc1ccccc1
Product: C=CC[C@@H](CCCCCC)C(=O)NC(C)c1ccccc1
Reaction time: 6 h
Yield: 54.9 %

Procedure:
To a solution of 24.0 g (83.0 mmol) of (R)-N-allyl-N-octanoyl-1-phenylethylamine in 240 ml of toluene was added dropwise 61.5 ml (98.0 mmol) of tert-butylmagnesium chloride (1.6 M) at room temperature and, after completion of the addition, the reaction was allowed to proceed at 70° C. for 6 hours. After completion of the reaction, the reaction mixture was added dropwise to 240 ml of 1 N aqueous hydrochloric acid on an ice bath. The resulting mixture was extracted with 300 ml of hexane, and the organic layer was washed with 100 ml of a saturated aqueous solution of sodium chloride and then concentrated under reduced pressure to give 25.0 g of a crude product. The crude product was purified by column chromatography on silica gel (hexane:ethyl acetate=10:1) to give 13.1 g (76%, (1R,2S):(1R,2R)=80:20) of N-[(R)-2-allyloctanoyl]-1-phenylethylamine.
Reaction SMILES: [C:1]([Si:5]([CH3:11])([CH3:10])[O:6][CH2:7][C:8]#[CH:9])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.B(F)(F)F.[CH3:21][CH2:22][O:23]CC.C(OC(=O)C)(=O)C>C1COCC1>[Si:5]([O:6][CH2:7][C:8]#[C:9][C:22](=[O:23])[CH3:21])([C:1]([CH3:3])([CH3:4])[CH3:2])([CH3:10])[CH3:11]
Reactant: C#CCO[Si](C)(C)C(C)(C)C
Reactant: CCOCC
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)C#CCO[Si](C)(C)C(C)(C)C
Temperature: 10 °C
Reaction time: 0.08 h
Yield: 48.9 %

Procedure:
To a solution of tert-butyldimethyl(prop-2-yn-1-yloxy)silane (15.1 g, 88.3%) in THF (300 mL), n-BuLi (67 mL, 105.9 mmol, 1.6 N in hexane) was added slowly at −78° C. After the addition was complete, the temperature was increased slowly to 10° C. over a period of 2 h. The reaction mixture was cooled again to −78° C. and BF3.OEt2 (14 mL, 105.9 mmol) added slowly and reaction mixture stirred at this temperature for 5 min. Acetic anhydride (11 mL, 115.6 mmol) was slowly added and the reaction was continued while temperature was allowed to rise to room temperature over a period of 2 h. After this time, reaction mass was quenched with 1N NaOH till pH 7-8 and biphasic solution was extracted with ethyl acetate. The organic layer was concentrated to obtain crude material which was further purified by column chromatography over silica gel to yield 5-((tert-butyldimethylsilyl)oxy)pent-3-yn-2-one (9.2 g, 52.6%).
Reaction SMILES: CC(C)(OC([NH:7][CH:8]1[C:15](=[O:16])[N:14]2[CH:9]1[CH2:10][S:11][C:12]([S:20][CH3:21])=[C:13]2[C:17]([OH:19])=[O:18])=O)C.[N+](C)([O-])=O.[ClH:27]>CCOCC>[ClH:27].[NH2:7][CH:8]1[C:15](=[O:16])[N:14]2[CH:9]1[CH2:10][S:11][C:12]([S:20][CH3:21])=[C:13]2[C:17]([OH:19])=[O:18]
Reactant: CSC1=C(C(=O)O)N2C(=O)C(NC(=O)OC(C)(C)C)C2CS1
Agent: Cl
Solvent: CCOCC
Solvent: C[N+](=O)[O-]
Product: CSC1=C(C(=O)O)N2C(=O)C(N)C2CS1
Temperature: 0 °C

Procedure:
1.3 g of (6RS) (7RS) 7-[(1,1-dimethylethyloxy)-carbonylamino]-3-methylthio-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylic acid and 13 ml of nitromethane were stirred together cooled to 0° C., and a current of hydrochloric acid gas was passed through it for 15 minutes. 130 ml of ether were added, and after separating and rinsing with ether, 0.74 g of 7-amino-3-methylthio-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylic acid hydrochloride were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[C:12]([CH:16]=O)[CH:13]=[N:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[O:19]([NH2:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:20][O:19][N:21]=[CH:16][C:12]1[CH:13]=[N:14][CH:15]=[C:10]([C:9]#[C:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH:11]=1
Reactant: CON
Reactant: O=Cc1cncc(C#Cc2cccc(F)c2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CON=Cc1cncc(C#Cc2cccc(F)c2)c1
Temperature: 25 °C
Yield: 47 %

Procedure:
Heat a mixture of 5-(3-fluorophenylethynyl)-pyridine-3-carbaldehyde, (prepared essentially as described in EXAMPLE 89), (90 mg, 0.38 mmol) and methoxylamine hydrochloride (160 mg, 3.02 mmol) and potassium carbonate (260 mg, 1.89 mmol) in ethanol at 80° C. overnight. Cool to room temperature, filter solids and concentrate. Purify the residue by silica gel chromatography, eluting with 5:45:45 ethyl acetate:chloroform:hexanes, to give the title compound as a white solid (45 mg, 47%).
Reaction SMILES: Cl.[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:19][C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3].[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CN1CCOCC1>C(Cl)Cl>[C:28]1([NH:34][C:35]([N:7]2[CH2:6][CH2:5][C:4]([NH:10][C:11]([CH:13]([NH:19][C:20]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[O:21])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12])([C:2]#[N:3])[CH2:9][CH2:8]2)=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)CC(NC(=O)N1CCOCC1)C(=O)NC1(C#N)CCNCC1
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)CC(NC(=O)N1CCOCC1)C(=O)NC1(C#N)CCN(C(=O)Nc2ccccc2)CC1

Procedure:
The title compound is prepared from morpholine-4-carboxylic acid [1-(4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide hydrochloride and phenyl isocyanate in the presence of a tertiary amine base such as N-methylmorpholine in a solvent such as methylene chloride.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:15][OH:16])[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14].C(N(CC)CC)C.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[S:34])[CH:29]=[CH:30][CH:31]=1>O1CCCC1>[OH:16][CH2:15][C:3]1([CH2:2][O:1][C:33](=[S:34])[NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=2)[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14]
Reactant: O=C1c2ccccc2SCCC1(CO)CO
Reactant: FC(F)(F)c1cccc(N=C=S)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2SCCC1(CO)COC(=S)Nc1cccc(C(F)(F)F)c1

Procedure:
To a solution of 4,4-bis(hydroxymethyl)-3,4-dihydro-2H-benzo[b]thiepin-5-one (555 mg, 2.33 mmol) in 29 ml of tetrahydrofuran were added, at room temperature, triethylamine (0.35 ml, 2.56 mmol) and 3-(trifluoromethyl)phenyl isothiocyanate (885 μl, 5.82 mmol). The mixture was heated to reflux for 72 hours, concentrated and purified by column chromatography on silica gel (eluent: 1:2 ethyl acetate/hexane). The product was obtained in a yield of 320 mg (31%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](Br)[CH:6]=1.[CH:13]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)=[O:14].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CO>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:6]=[C:7]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:13]=[O:14])[CH:20]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1cccc(Br)c1
Reactant: O=Cc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cccc(-c2cccc(C=O)c2)c1

Procedure:
A mixture of (3-bromo-phenyl)-acetic acid methyl ester (5 g), 3-formyl phenyl boronic acid (5 g) and potassium carbonate (9 g) in toluene/methanol [10:1] (33 mL) was degassed with nitrogen for 1 hour. Tetrakis(triphenylphosphine)palladium(0) (1.3 g) was washed with ethanol, under nitrogen, until golden in colour and added to the mixture. The resultant mixture was heated to reflux for 24 hours. On cooling, the reaction was diluted with iso-hexane/diethyl ether [4:1] (100 mL) and filtered through a Celite pad. The filtrate was evaporated and the residue purified on silica, eluting iso-hexane/ethyl acetate [4:1] to give the subtitle product, as an oil (3.7 g).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1.[NH:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH2:20][C:21]#[N:22].Cl>C(Cl)Cl>[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([C:19]2[NH:15][C:16]([CH2:20][C:21]#[N:22])=[CH:17][CH:18]=2)=[O:11])=[CH:8][CH:7]=1
Reactant: N#CCc1ccc[nH]1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: N#CCc1ccc(C(=O)c2ccc(Cl)cc2)[nH]1
Temperature: 0 °C

Procedure:
To a chilled suspension of 26.80 g. (0.2 mole) of aluminum chloride in 110 ml. of methylene chloride is added dropwise 35 g. (0.2 mole) of p-chlorobenzoyl chloride. The mixture is added dropwise to a solution of 21.22 g. (0.2 mole) of pyrrole-2-acetonitrile in 125 ml. methylene chloride which is cooled externally with an ammonium chloride ice bath. After addition is complete, the reaction mixture is stirred for ten minutes at 0°C. and then poured into ice acidified with dilute hydrochloric acid. A solid precipitate, 5-(p-chlorobenzoyl)-pyrrole-2-acetonitrile, which is filtered off, washed with hot methanol and dried, m.p. 203°-205°C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]2[CH2:16][N:15]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:14](=[O:25])[CH2:13][NH:12]2)=[CH:2]1.N1C=CC=CC=1.[F:32][C:33]([F:48])([F:47])[C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[C:37](Cl)=[O:38]>ClCCl>[F:32][C:33]([F:47])([F:48])[C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([C:43]([F:46])([F:44])[F:45])[CH:42]=1)[C:37]([N:12]1[C@H:11]([CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:16][N:15]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:14](=[O:25])[CH2:13]1)=[O:38]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)CCCN1C[C@@H](Cc2c[nH]c3ccccc23)NCC1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CCCN1C[C@@H](Cc2c[nH]c3ccccc23)N(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1=O
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 35.8 %

Procedure:
To an ice-cooled solution of (5R)-5-(1H-indol-3-ylmethyl)-1-[3-(ethoxycarbonyl)propyl]piperazin-2-one (0.56 g) and pyridine (0.26 ml) in dichloromethane (10 ml) was added a solution of 3,5-bis(trifluoromethyl)benzoyl chloride (0.45 g) in dichloromethane (1 ml). The solution was stirred for 40 minutes at the same temperature. After concentration, the residue was extracted with ethyl acetate. The organic layer was washed successively with aqueous sodium bicarbonate solution, water, 0.5N hydrochloric acid and brine, and dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (20 g) eluting with a mixture of dichloromethane-methanol (from 0% to 5% gradient solution) to give (5R)-4-[3,5-bis(trifluoromethyl)benzoyl]-1-[3-(ethoxycarbonyl)propyl]-5-(1H-indol-3-ylmethyl)piperazin-2-one (0.34 g) as an amorphous solid.
Reaction SMILES: [ClH:1].[F:2][C:3]([F:31])([F:30])[CH2:4][N:5]=[C:6]([NH2:29])[NH:7][C:8]1[S:9][C:10]([CH3:28])=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]2C(=O)C3=CC=CC=C3C2=O)[N:12]=1.[OH-].[Na+].Cl>O.C(O)C>[ClH:1].[ClH:1].[F:31][C:3]([F:2])([F:30])[CH2:4][N:5]=[C:6]([NH2:29])[NH:7][C:8]1[S:9][C:10]([CH3:28])=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[N:12]=1
Reactant: Cc1sc(NC(N)=NCC(F)(F)F)nc1CCCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1sc(NC(N)=NCC(F)(F)F)nc1CCCCN
Temperature: 25 °C
Reaction time: 1 h
Yield: 128.6 %

Procedure:
To a mixture of 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-phthalimidobutyl)-5-methylthiazole hydrochloride (0.60 g.) in water (2 ml.) and ethanol (2 ml.) was added sodium hydroxide pellets (0.2 g.). The resulting yellow solution was heated on a steam bath for 10 minutes and then allowed to cool to ambient temperature. The reaction mixture was adjusted to pH3 by addition of 2N hydrochloric acid and then reheated on a steam bath for 1 hour. After cooling to ambient temperature the mixture was extracted three times with equal volumes of ethyl acetate. The aqueous layer was evaporated to dryness, azeotroped twice with toluene, the residue dissolved in methanol (10 ml.) and the solution filtered. The filtrate was evaporated to dryness to give 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)-5-methylthiazole dihydrochloride (0.31 g.) as an oil which was used without further purification.
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH:13]1([CH2:19][O:20][C:21]2[CH:22]=[C:23]([CH:37]=[CH:38][CH:39]=2)[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33](=[O:36])(=[O:35])[NH2:34])=[O:25])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>CN(C)C1C=CN=CC=1.O1CCCC1>[CH:13]1([CH2:19][O:20][C:21]2[CH:22]=[C:23]([CH:37]=[CH:38][CH:39]=2)[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([NH:34][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:36])=[O:35])=[O:25])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCCCCCCCCC(=O)Cl
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCC2CCCCC2)c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 149 %

Procedure:
In a stream of nitrogen and at 0° C., 0.24 ml (1.10 mmol) of decanoyl chloride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 400 mg (0.68 mmol) of 3-cyclohexylmethoxy-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 7 and 237 mg (1.90 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 550 mg (yield: 98.4%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[CH:10]OCC)=[CH:5][CH:4]=1.[Cl:14][C:15]1[C:16]2[CH:28]=[C:27]([OH:29])[CH:26]=[CH:25][C:17]=2[S:18][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[Cl:14][C:15]1[C:16]2[C:28]([CH:10]=[N:9][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[C:27]([OH:29])[CH:26]=[CH:25][C:17]=2[S:18][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)c1sc2ccc(O)cc2c1Cl
Reactant: CCOC=Nc1ccc(OC)cc1
Product: CCOC(=O)c1sc2ccc(O)c(C=Nc3ccc(OC)cc3)c2c1Cl
Temperature: 160 °C
Reaction time: 4 h

Procedure:
A round bottomed flask containing a mixture of the product from the previous reaction (6.04 g) and ethyl N-(4-methoxyphenyl)formimidate (4.50 g) was submerged rapidly in an oil bath pre-heated to 160° C., and the mixture stirred at 160-80° C. for 4 hours, the ethanol produced in the reaction being removed by distillation. More of the formimidate (0.80 g) was then added and the mixture heated at 180-90° C. for a further 1 hour. The cooled mixture was then treated with boiling methanol (100 ml) and the resulting light brown solid collected by filtration, washed with methanol (100 ml) and dried to give ethyl 3-chloro-5-hydroxy-4-[N-(4-methoxyphenyl)iminomethyl]benzo[b]thiophene-2-carboxylate (4.03 g); m.p. 162-163° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[O:8][C:7]([CH2:9][S:10][CH2:11][CH2:12][NH2:13])=[CH:6][CH:5]=1.[CH3:14][S:15][CH:16](SC)[CH2:17][N+:18]([O-:20])=[O:19].[C:23]([OH:28])(=[O:27])[C:24]([OH:26])=[O:25]>CN(C)C=O>[C:23]([OH:28])(=[O:27])[C:24]([OH:26])=[O:25].[CH3:1][NH:2][CH2:3][C:4]1[O:8][C:7]([CH2:9][S:10][CH2:11][CH2:12][NH:13][C:16]([S:15][CH3:14])=[CH:17][N+:18]([O-:20])=[O:19])=[CH:6][CH:5]=1
Reactant: CNCc1ccc(CSCCN)o1
Reactant: CSC(C[N+](=O)[O-])SC
Agent: O=C(O)C(=O)O
Solvent: CN(C)C=O
Product: CNCc1ccc(CSCCNC(=C[N+](=O)[O-])SC)o1
Yield: 26.6 %

Procedure:
A solution of 2-[[5-[(methylamino)methyl]-2-furanylmethyl]thio]ethanamine (6.0 g) and 1,1-bis-(methylthio)-2-nitroethane (19.8 g) in dry dimethylformamide (150 ml) was stirred for 1 hour at 0° and for 5 hours at room temperature. A solution of oxalic acid (4.0 g) in dry dimethylformamide (16 ml) was added and the solid which formed during 18 hours was filtered, washed with dimethylformamide, ethanol and ether and dried. The solid was suspended in water (200 ml) at 55° and on cooling was filtered, washed with water and dried to give the title compound (3.25 g) m.p. 158°-160° dec.
Reaction SMILES: O.NN.[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:12]2[CH2:17][CH2:16][CH:15]([O:18][N:19]3[C:27](=[O:28])C4C(=CC=CC=4)C3=O)[CH2:14][CH2:13]2)=[CH:7][CH:6]=1.[F:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]=C=O)=[CH:40][CH:39]=1>C(Cl)Cl>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH:11]([C:8]2[CH:9]=[CH:10][C:5]([F:4])=[CH:6][CH:7]=2)[N:12]2[CH2:17][CH2:16][CH:15]([O:18][NH:19][C:27]([NH:44][C:41]3[CH:42]=[CH:43][C:38]([F:37])=[CH:39][CH:40]=3)=[O:28])[CH2:14][CH2:13]2)=[CH:31][CH:32]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: O=C1c2ccccc2C(=O)N1OC1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: NN
Solvent: O
Solvent: ClCCl
Product: O=C(NOC1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 131.7 %

Procedure:
Hydrazine monohydrate (0.059 ml, 1.2 mmol) was added to a solution of 2-(1-(bis(4-fluorophenyl)methyl)piperidin-4-yloxy)isoindoline-1,3-dione (193 mg, 0.406 mmol) in CH2Cl2 (5 ml) and stirred at room temperature for 15 hours. The resulting solid was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in tetrahydrofuran (5 ml), 4-fluorophenyl isocyanate (0.023 ml, 0.20 mmol) was added and the whole was stirred at room temperature for 15 hours. The reaction mixture was concentrated in vacuo, the residue was purified by column chromatography (ethyl acetate/hexane: 25/75 to 45/55) and the resulting solid was recrystallized from ethyl acetate/hexane to give 1-(1-(bis(4-fluorophenyl)methyl)piperidin-4-yloxy)-3-(4-fluorophenyl)urea (120 mg, 65%) as a white solid: LCMS: 456 [M+1]+. 1H NMR (DMSO-d6) δ: 1.68 (m, 2H), 1.90-2.02 (m, 4H), 2.62 (m, 2H), 3.70 (m, 1H), 4.40 (s, 1H), 7.10 (m, 6H), 7.43 (m, 4H), 7.55 (m, 2H), 8.61 (s, 1H), 9.38 (s, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:6]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18].[NH:27]1[CH:31]=[CH:30][N:29]=[CH:28]1>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH:7]2[N:6]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:5]([CH2:4][CH2:3][CH2:2][N:27]3[CH:31]=[CH:30][N:29]=[CH:28]3)[CH2:9][CH2:8]2)=[CH:11][CH:12]=1
Reactant: c1c[nH]cn1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCCl)CCC2c2ccc(F)cc2)cc1
Product: Cc1ccc(S(=O)(=O)N2C(CCCn3ccnc3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=428.5 (M+H+), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(3-chloro-propyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 1H-imidazole.