Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][CH2:8][C:7](=O)[N:6]1C(OC(C)(C)C)=O)=[O:4].Br[C:20]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[C:22]([F:28])[CH:21]=1.[Mg]>C1COCC1.FC1C=C([Mg]Br)C=C(F)C=1F>[F:26][C:24]1[CH:25]=[C:20]([C@H:7]2[NH:6][C@@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9][CH2:8]2)[CH:21]=[C:22]([F:28])[C:23]=1[F:27]
Reactant: COC(=O)[C@H]1CCCC(=O)N1C(=O)OC(C)(C)C
Reactant: Fc1cc(Br)cc(F)c1F
Agent: Fc1cc([Mg]Br)cc(F)c1F
Agent: [Mg]
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CCC[C@@H](c2cc(F)c(F)c(F)c2)N1
Reaction time: 2 h
Yield: 39.6 %

Procedure:
To a solution of (R)-6-oxopiperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (13.0 g) in THF (140 mL), 3,4,5-trifluorophenylmagnesium bromide (prepared from 1-bromo-3,4,5-trifluorobenzene (11.7 g) and magnesium (1.48 g) by the method described in Org. Synth., 2001, 79, 176) was added in a nitrogen atmosphere at −78° C. over 30 minutes. The reaction solution was stirred at −78° C. to −10° C. for two hours, and then quenched with a saturated ammonium chloride solution at −10° C. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. A solution of 4 N hydrochloric acid in ethyl acetate (150 mL) was added to a solution of the residue in ethyl acetate (150 mL) at room temperature, and the reaction solution was stirred at room temperature for nine hours. The reaction solution was concentrated under reduced pressure, and the residue was made basic with a saturated sodium bicarbonate solution. Then, chloroform was added to the residue, and the mixture was stirred at room temperature for two hours. The organic layer was separated, dried over magnesium sulfate, and then concentrated under reduced pressure. 10% palladium-carbon (700 mg) was added to a solution of the residue in methanol (200 mL), and the reaction solution was stirred in a hydrogen atmosphere at room temperature for nine hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 5.47 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Br[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([N:5]2[CH2:6][C@@H:1]3[CH2:7][C@H:4]2[CH2:3][N:2]3[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:17]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: Brc1cccnc1
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1cccnc1
Yield: 99 %

Procedure:
tert-Butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, prepared as described in J. Med. Chem., (1988) 31, 1598-1611, and 3-bromopyridine (Aldrich Chemical Company) were processed as described in Example 1A to provide the title compound (99% yield). 1H NMR (CDCl3, 300 MHz) δ 1.42 (s, 4.5H), 1.48 (s, 4.5H), 1.91-2.03 (m, 2H),3.14 (d, J=14.7 Hz, 0.5H), 3.23 (d, J=14.7 Hz, 0.5H), 3.37-3.48 (m, 2H), 3.60 (d, 8.45 Hz, 1H), 4.41 (s, 1H), 4.53 (s, 0.5H), 4.67 (s, 0.5H), 6.85 (dd, J=2.94, 8.83 Hz, 1H), 7.09-7.21 (m, 1H), 7.95-8.06 (m, 2H); MS (DCI/NH3) m/z 276 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:7][N:8]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:9](=[O:28])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([O:25][CH2:26][CH3:27])[C:20]([O:22]CC)=[O:21])=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+]>C1COCC1>[CH:1]1([CH2:7][N:8]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:9](=[O:28])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([O:25][CH2:26][CH3:27])[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCCCCCCN(CC1CCCCC1)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCN(CC1CCCCC1)C(=O)COc1ccc(C[C@H](OCC)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.6 %

Procedure:
To a solution of ethyl(2S)-3-(4-{2-[(cyclohexylmethyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxy-propanoate (0.031 g, 0.057 mmol) in THF (2.0 mL) were added water (2.0 mL) and lithium hydroxide (0.006 g, 0.26 mmol), and the reaction mixture was stirred at room temperature overnight. The mixture was acidified with 2M HCI and extracted with ethyl acetate (4×25 mL). The combined organic phase was washed with brine (25 mL), dried over Na2SO4, and concentrated in vacuo to afford 0.027 g (93%) of a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[NH2:14][C@@H:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C@H:16]1[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:14][C@@H:15]1[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C@H:16]1[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:13])=[CH:5]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2ccccc2C[C@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 0.08 h
Yield: 93.9 %

Procedure:
5-Chloroindole-2-carboxylic acid (391 mg, 2 mmol), tert-Butyl [(1R,2R)-2-amino-2,3-dihydro-1H-inden-1-yl]carbamate (497 mg, 2 mmol), DIPEA (350 μL, 2 mmol) and HOBT (270 mg, 2 mmol) were dissolved in DCM (10 mL), stirred for 5 mins, then EDCI (479 mg, 2.5 mmol) was added and the reaction stirred for 3 hours. The volatiles were removed by evaporation under reduced pressure, EtOAc (25 mL) was added and the organic solution washed with water (2×10 mL), brine (10 mL), dried (MgSO4) and the volatiles removed by evaporation under reduced pressure to give the title compound (800 mg, 94%) as a pale brown foam.
Reaction SMILES: CC([N:5]([C@@:9]([CH3:31])([C:12]([NH:14][C:15]1[CH:16]=[N:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([O:29][CH3:30])[CH:23]=2)=[CH:19][CH:20]=1)=[O:13])[CH2:10][CH3:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][C:18]2[N:17]=[CH:16][C:15]([NH:14][C:12](=[O:13])[C@:9]([CH3:31])([CH2:10][CH3:11])[NH2:5])=[CH:20][CH:19]=2)=[CH:23][C:24]=1[O:29][CH3:30]
Reactant: CC[C@](C)(C(=O)Nc1ccc(Oc2ccc(C)c(OC)c2)nc1)N(C(=O)[O-])C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@](C)(N)C(=O)Nc1ccc(Oc2ccc(C)c(OC)c2)nc1
Reaction time: 2 h
Yield: 88.1 %

Procedure:
To a solution of 1,1-dimethylethyl((1R)-1-methyl-1-{[(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)amino]carbonyl}propyl)carbamate (Intermediate 98, 65 mg) in dry dichloromethane (3 mL) cooled to 0° C., TFA (0.700 mL, 9.08 mmol) was added dropwise. The reaction was stirred at that temperature for 2 hours. The reaction was quenched with a saturated aqueous solution of NaHCO3 (20 mL) added at 0° C., and extracted with dichloromethane (3×7 mL). The combined organic layers were dried over sodium sulphate, filtered and evaporated to afford the title compound as a white solid (44 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][CH2:19][CH3:20])=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>CN(C=O)C>[Cl:24][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[N:9]1[CH2:18][CH2:19][CH3:20]
Reactant: O=S(Cl)Cl
Reactant: CCCN1C(=O)c2ccccc2C1(O)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: CCCN1C(=O)c2ccccc2C1(Cl)c1ccc(Cl)cc1

Procedure:
Distilled THF (5 mL) was added to 3-(4-chlorophenyl)-3-hydroxy-2-propylisoindolin-1-one (104 mg, 0.33 mmol), thionyl chloride (86.83 mg, 0.73 mmol, 0.05 mL) and catalytic DMF (3 drops) as for general procedure B1. 3-Chloro-3-(4-chlorophenyl)-2-propylisoindolin-1-one was produced as an orange oil (105 mg, 0.33 mmol) which was used immediately without further purification. Distilled THF (6 mL) was added to 3-chloro-3-(4-chlorophenyl)-2-propylisoindolin-1-one (211.2, 0.66 mmol), cis-cyclopentene diol (330 mg, 3.3 mmol) and potassium carbonate (456 mg, 3.3 mmol) as for general procedure B. Removal of the solvent yielded the crude product as a colourless oil (160.2 mg). The sample was purified by flash column chromatography (EtOAc:Petrol, 40:60) to yield the title product as an colourless viscous oil. (129 mg, 0.43 mmol, 51% yield). 1H NMR: (300 Hz, DMSO) δ ppm 0.76 (t, 3H, H11), 1.36 (m, 1H, H13/H13′), 1.49, 1.76 (m, 1H, H13/H13′), 3.12 (m, 2H H10) 3.96 (m, 1H, H9/H9′), 4.26 (m, 1H, H9/H9′), 5.29, 5.87, (dd, 1H, H15/H16) 5.74, 5.79 (dd, 1H, H15/H16) 7.23 (d, 1H,), 7.38 (m, 4H, H1-H5), 7.61 (m, 2H, H6-H7), 7.76 (d, 1H, H8). IR: 1365, 1682, 2969, 3363 cm−1.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])=[CH:5][CH:4]=1.CCN(CC)CC.[CH3:37][S:38](Cl)(=[O:40])=[O:39].C([O-])(O)=O.[Na+]>C(Cl)Cl>[N+:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([N:8]([CH2:7][C:6]1[CH:28]=[CH:29][C:3]([CH2:2][O:1][S:38]([CH3:37])(=[O:40])=[O:39])=[CH:4][CH:5]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)(=[O:10])=[O:11])([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N(Cc1ccc(CO)cc1)Cc1ccccn1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc(CN(Cc2ccccn2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a stirring solution of N-(4-hydroxymethyl-benzyl)-2-nitro-N-pyridin-2-ylmethyl-benzenesulfonamide (Bridger, et al., U.S. Ser. No. 09/111,895) (0.2096 g, 0.51 mmol) in CH2Cl2 (5 mL) at 0° C. under Ar, was added Et3N (0.14 mL, 1.02 mmol) and MsCl (0.05 mL, 0.66 mmol). The mixture was stirred at 0° C. for 2 hours, then stirred at room temperature for 3 hours. Additional Et3N (0.30 mL, 2.16 mmol) and MsCl (0.10 mL, 1.32 mmol) were added, and stirred for 18 hours. Saturated NaHCO3 (10 mL) was added and extracted with CH2Cl2 (3×30 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to provide 0.2383 g (95%) of methanesulfonic acid 4-{[(2-nitro-benzenesulfonyl)-pyridin-2-ylmethyl-amino]-methyl}-benzyl ester as a yellow oil. 1H NMR (CDCl3) δ 3.14 (s, 3H), 4.51 (s, 2H), 4.60 (s, 4H), 7.02-7.24 (m, 6H), 7.54-7.57 (m, 2H), 7.66 (d, 2H, J=3.0 Hz), 7.94 (d, 1H, J=9.0 Hz), 8.41-8.43 (m, 1H).
Reaction SMILES: [F:1][CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:21]([O-])=O)[CH:9]=2)[N:4]=1.C(O)(=O)C>[H][H].C(Cl)(Cl)Cl.[C].[Pd]>[F:1][CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:21])[CH:9]=2)[N:4]=1
Reactant: Cc1ccccc1-n1c(CF)nc2ccc([N+](=O)[O-])cc2c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1ccccc1-n1c(CF)nc2ccc(N)cc2c1=O
Yield: 5.2 %

Procedure:
A mixture of 2.0 g(0.064 mol) of 2-fluoromethyl-3-(o-tolyl)-6-nitro-4(3H)-quinazolinone, 0.2 g of 5 % palladium-carbon and 100 ml of acetic acid is shaken for 30 minutes in hydrogen gas. The initial pressure of hydrogen gas is adjusted to 46 lb and the mixture is heated with an infrared lamp during the reaction. After 30 minutes of said reaction, the pressure of hydrogen gas decreases to 6 lb. After the mixture is cooled, said mixture is filtered to remove the catalyst. The filtrate is evaporated to remove acetic acid, and the residue is dissolved in chloroform. The chloroform solution is washed with 5 % aqueous sodium hydroxide and water, successively. Then, the solution is dried and evaporated to remove solvent. The oily residue thus obtained is dissolved in 2 ml of chloroform, and the chloroform solution is passed through a column of 200 g of silica gel. The silical gel column is eluted with ethyl acetate-benzene(1 : 1). Then, the eluate is evaporated to remove solvent. The crude crystal obtained is washed with isopropylether and recrystallized from isopropanol. 0.95 g of 2-fluoromethyl-3-(o-tolyl)-6-amino-4(3H)-quinazolinone is obtained.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[CH3:2].[CH3:11][N:12]=[C:13]=[S:14]>C(OCC)C>[CH3:11][NH:12][C:13]([N:3]([CH2:1][CH3:2])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)=[S:14]
Reactant: CCNCc1cccnc1
Reactant: CN=C=S
Solvent: CCOCC
Product: CCN(Cc1cccnc1)C(=S)NC
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
In 50 ml of ethyl ether was dissolved 2.4 g of N-ethyl-N-(3-pyridylmethyl)amine followed by addition of 1.3 g of methyl isothiocyanate. The mixture was stirred at room temperature (25° C.) for 1 hour. The resulting precipitate was collected by filtration, washed with a small amount of ethyl ether and dried to give 3.7 g of N-methyl-N'-ethyl-N'-(3-pyridylmethyl)thiourea as white prisms.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6]([C:8]1[C:9]([NH:13][NH2:14])=[N:10][NH:11][CH:12]=1)=[O:7])[CH3:4].C[O:16][C:17](=O)[N:18]=[C:19](SC)[C:20]([C:34]1[CH:43]=[C:42]([O:44][CH3:45])[C:37]2[O:38][CH2:39][CH2:40][O:41][C:36]=2[C:35]=1[F:46])=[N:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:32]=[C:31]([CH3:33])[O:30][N:29]=2)=[CH:24][CH:23]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:3]([O:5][C:6]([C:8]1[CH:12]=[N:11][NH:10][C:9]=1[N:13]1[C:17](=[O:16])[NH:18][C:19]([CH:20]([C:34]2[CH:43]=[C:42]([O:44][CH3:45])[C:37]3[O:38][CH2:39][CH2:40][O:41][C:36]=3[C:35]=2[F:46])[NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[N:32]=[C:31]([CH3:33])[O:30][N:29]=3)=[CH:24][CH:23]=2)=[N:14]1)=[O:7])[CH3:4]
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c2c(c1F)OCCO2
Reactant: CCOC(=O)c1c[nH]nc1NN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn[nH]c1-n1nc(C(Nc2ccc(-c3noc(C)n3)cc2)c2cc(OC)c3c(c2F)OCCO3)[nH]c1=O
Temperature: 25 °C
Yield: 54.2 %

Procedure:
A solution of 62 mg of 3-hydrazino-1H-pyrazole-4-carboxylic acid ethyl ester bishydrochloride (Example (157b)), 106 mg of [2-(5-fluoro-8-methoxy-2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester (Example 41d) and 88 μl of triethylamine in 5 ml of DMF was heated at 85° C. for 15 hours under a nitrogen atmosphere with stirring. After cooling the reaction mixture to room temperature, the solvent was removed under reduced pressure. The residue was dissolved in 8 ml of methanol, and then 133 mg of sodium cyanotrihydroborate, 49 μl of acetic acid and 0.5 g of MS3A were added and the mixture was stirred at room temperature for 20 hours. Next, 100 ml of ethyl acetate and 50 ml of water were added, and the organic layer was washed with 50 ml of water and 50 ml of saturated brine in that order and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-methanol) to give the title compound (68 mg) as a light green solid.
Reaction SMILES: [C:1]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[C:1]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:28]=[CH:27][C:26]([NH:29][S:39]([CH3:38])(=[O:41])=[O:40])=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(NC(=O)c2cc(N)ccc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2cc(NS(C)(=O)=O)ccc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73 %

Procedure:
To a solution of 2-(4-tert-butylbenzoylamino)-5-amino-N-(4-methoxyphenyl)benzamide (150 mg, 0.36 mmol) in methylene chloride (5 mL) cooled to 0° C. was added pyridine (32 μl, 0.40 mmol) followed by-,methanesulfonyl chloride. (31 μl, 0.40 mmol). After 5 min, the reaction mixture was allowed to warm to room temperature and stirred for 30 min. The reaction mixture was diluted with methylene chloride and washed twice with water. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was chromatographed (silica gel, 30% ethyl acetate/70% methylene chloride) to give 130 mg (73%) of the title compound.
Reaction SMILES: [N:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)=[C:2]=[O:3].[C:14]1([CH2:22][OH:23])[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=1>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:4]1([NH:1][C:2](=[O:3])[O:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:22][OH:23])=[CH:15][CH:16]=2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccc(CO)cc1
Reactant: O=C=Nc1cccc2ccccc12
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Nc1cccc2ccccc12)OCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56 %

Procedure:
To a solution of 1-isocyanatonaphthalene (1.69 g, 10 mmol) and 1,4-phenylene-dimethanol (4.14 g, 30 mmol) in anhydrous DMF was added DMAP (0.06 g, 0.5 mmol). The resulting mixture was stirred at room temperature for 12 h. The solvent was removed in vacuo to give a solid, which was recrystallized using ethyl acetate to produce 7 (1.72 g, 5.6 mmol) as a white solid in 56% yield: m.p.: 158-159° C.; IR (thin film): 3325, 1691, 1542, 1420, 1245, 1237 cm−1; 1H NMR (500 MHz, CDCl3): 6 1H NMR (500 MHz, CDCl3) δ 7.95-7.83 (m, 3H), 7.68 (d, J=8.2 Hz, 1H), 7.58-7.47 (m, 4H), 7.44-7.35 (m, 3H), 5.27 (s, 2H), 4.73 (d, J=5.8 Hz, 2H), 1.70 (t, J=6.0 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3): δ 154.43, 141.33, 140.53, 136.51, 135.70, 134.28, 132.55, 128.98, 128.90, 127.44, 127.41, 126.49, 126.24, 126.02, 125.35, 120.61, 67.25, 65.24 ppm. HRMS (m/z): [M+Na]+ calcd. for C19H17NNaO3, 330.1100; found, 330.1095.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=1.Cl.Cl[C:21]1[N:22]([C:26]2[CH2:30][CH2:29][CH2:28][N:27]=2)[CH2:23][CH2:24][CH:25]=1>>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([C:21]3[N:22]([C:26]4[CH2:30][CH2:29][CH2:28][N:27]=4)[CH2:23][CH2:24][CH:25]=3)[C:5]=2[CH:4]=1
Reactant: FC(F)(F)c1ccc2c(c1)Nc1ccccc1O2
Reactant: ClC1=CCCN1C1=NCCC1
Agent: Cl
Product: FC(F)(F)c1ccc2c(c1)N(C1=CCCN1C1=NCCC1)c1ccccc1O2

Procedure:
Reaction of 2-trifluoromethylphenoxazine with 2-chloro-1-(1-pyrrolin-2-yl)pyrroline hydrochloride according to the procedure of Example 7 affords the free base, 2-TRIFLUOROMETHYL-10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2YL]PHENOXAZINE, m.p. 140°-142° C., from n-hexane. Conversion of the free base affords 2-TRIFLUOROMETHYL-10-[1-(1-PYRROLIN-2-YL)2-PYRROLIN-2-YL]PHENOXAZINE HYDROCHLORIDE HYDRATE, m.p. 222.5°-229° C. (dec.)(corr.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:33]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:38]([N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)=[O:39])[CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Reactant: O=C(Cl)N1CCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(N1CCCC1)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (80 mg, 0.20 mmol) (from Example 25a supra) in tetrahydrofuran (3 mL) was added triethylamine (32 mg, 0.3 mmol) (Aldrich), followed by the addition of 1-pyrrolidinecarbonyl chloride (34 mg, 0.24 mmol) (Aldrich). The mixture was stirred at 50° C. for 1 hour, then cooled to room temperature. The mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with another two portions of ethyl acetate. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue were triturated with dichloromethane-hexanes to give rac-6-chloro-3-(3-chloro-benzyl)-3-[1-(pyrrolidine-1-carbonyl)-piperidin-3-yl]-1,3-dihydro-indol-2-one as a white solid. (Yield 50 mg, 50%).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[ClH:12].Cl.[F:14][C:15]1[C:20]([F:21])=[C:19]([F:22])[CH:18]=[CH:17][C:16]=1[NH:23][C:24]([NH:26][C:27]([NH2:29])=[NH:28])=[NH:25]>C(O)C>[ClH:12].[NH2:25][C:24]1[N:23]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[C:20]([F:21])[C:15]=2[F:14])[CH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[N:28]=[C:27]([NH2:29])[N:26]=1
Reactant: N=C(N)NC(=N)Nc1ccc(F)c(F)c1F
Reactant: CCCCCCCCCC=O
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCC1N=C(N)N=C(N)N1c1ccc(F)c(F)c1F

Procedure:
100 ml of ethanol, 5.3 ml (28.1 mmol) of 1-decanal and 0.8 ml of concentrated hydrochloric acid were added to 5.0 g (18.7 mmol) of N1-(2,3,4-trifluorophenyl)-biguanide hydrochloride, and the mixture was refluxed for 4 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution with a mixture of chloroform and methanol (9:2)), and recrystallized from 80% aqueous acetonitrile to obtain 4.7 g of colorless crystals having a melting point of 210 to 212° C.
Reaction SMILES: OO.[O:3]=[C:4]([CH3:19])[CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:7].[Br-:20].[K+].Cl>C1(C)C=CC=CC=1.O>[Br:20][CH:5]([C:4](=[O:3])[CH3:19])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][CH:10]=1)=[O:7]
Reactant: [Br-]
Reactant: CC(=O)CC(=O)Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)C(Br)C(=O)Nc1ccc(C(F)(F)F)cc1
Yield: 48.5 %

Procedure:
Hydrogen peroxide (8.096 ml) was added dropwise to the well stirred solution of 3-oxo-N-[4-(trifluoromethyl)phenyl]butanamide (10 g) [obtained from above step-a], potassium bromide (4.85 g) and conc. HCl (7.446 ml) in toluene (100 ml) at room temperature. Reaction was monitored by TLC. D.M water was added to the reaction mixture and organic layer was separated. Aqueous layer was extracted with ethyl acetate (50 ml×2). Combined organic layer was washed with brine, dried over sodium sulfate and concentrated to give crude compound. The crude was purified by column chromatography to give pure 2-bromo-3-oxo-N-[4-(trifluoromethyl)phenyl]butanamide (6.4 g).