Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:17][C:18]([CH3:23])([CH3:22])[C:19](Cl)=[O:20]>N1C=CC=CC=1>[C:19]([O:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:19](=[O:20])[C:18]([CH3:23])([CH3:22])[CH3:17])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1)(=[O:20])[C:18]([CH3:23])([CH3:22])[CH3:17]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1ccc(C(=O)c2ccc(OC(=O)C(C)(C)C)cc2)cc1

Procedure:
A solution of 10 g of 4,4' dihydroxybenzophenone in pyridine (40ml) was treated with trimethylacetyl chloride and refluxed for 5 hours. The resultant solution was concentrated under reduced pressure and ETOAc added. The organic layer was washed with H2O, 5% aq. K2CO3, 1% aq. NaOH and dried over MgSO4 and concentrated to give approximately 13 g of a beige solid which was further chromatographed using 7/93 ethyl acetate-toluene to yield 2.83 g (20%) of the monoester (a) and 3.42 g (19%) (b) of the title compound; M.P.=166°-167° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C([O-])([O-])=O.[K+].[K+].[CH3:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:22]=1[CH2:23]Cl>CN(C=O)C.CCOC(C)=O>[CH3:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:22]=1[CH2:23][O:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1cccc(O)c1C
Reactant: Cc1cccc(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(OCc2c(C)cccc2C)c1C
Reaction time: 16 h

Procedure:
To a stirred solution of Ethyl 3-hydroxy-2-methylbenzoate (Step A, 3.1 g, 17.22 mmol), K2CO3 (3.09 g, 22.38 mmol) in dry DMF (15 ml) was added 2,6-Dimethylbenzyl chloride (3.19 g, 20.66 mmol) at room temperature under argon. The reaction mixture was stirred for 16 hours, diluted with EtOAc (40 ml), washed with water (20 ml) and brine. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex: ethyl acetate 4:1) to give the title compound as a white solid.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.Cl.[C:17]1([NH:23][CH:24]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[C:25]([OH:27])=[O:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1C=CC2N(O)N=NC=2C=1.[N:48]12[CH2:55][CH2:54][CH:51]([CH2:52][CH2:53]1)[C@@H:50](O)[CH2:49]2>C1COCC1>[N:48]12[CH2:55][CH2:54][CH:51]([CH2:52][CH2:53]1)[C@@H:50]([O:26][C:25](=[O:27])[CH:24]([NH:23][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:30][CH:29]=1)[CH2:49]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(Nc1ccccc1)c1ccc(C(F)(F)F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccccc1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
PS-DCC (907 mg, 1.21 mmol, loading: 1.33 mmol/g) is suspended in dry THF (10 mL). Phenylamino-(4-trifluoromethyl-phenyl)-acetic acid hydrochloride (I104) (200 mg, 0.60 mmol), HOBT (185 mg, 1.21 mmol), and (R)-quinuclidin-3-ol (230 mg, 1.81 mmol) are added and the mixture is shaken at RT overnight. PS-DCC is filtered off, the filtrate is evaporated and the residue is dissolved in EtOAc and washed with NaHCO3, water and brine. The organic layer is dried over Na2SO4, filtered and evaporated to dryness. The resulting crude compound is purified by filtration through a pad of silica-gel using DCM/MeOH=9/1 as the eluent. The title compound is obtained as a colorless oil (110 mg, 45% yield, mixture of diastereoisomers).
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]([F:41])([C:19]([F:40])([F:39])[C:20]([F:38])([F:37])[C:21]([F:36])([F:35])[C:22]([F:34])([F:33])[C:23]([F:32])([F:31])[C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])[CH2:5][CH2:6][CH2:7]C1C=C(C)C=CC=1S([O-])(=O)=O>O1CCCC1>[F:3][C:4]([F:41])([C:19]([F:40])([F:39])[C:20]([F:38])([F:37])[C:21]([F:36])([F:35])[C:22]([F:34])([F:33])[C:23]([F:32])([F:31])[C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])[CH2:5][CH2:6][CH2:7][NH:2][CH3:1]
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)[O-])c(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c1
Solvent: C1CCOC1
Product: CNCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
3.95 g of methylamine is condensed in a solution of 4.3 g of 4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-heptadecafluor-undecyltosylate in 10 ml of absolute tetrahydrofuran at −20° C., and it is stirred overnight in a pressure vessel at room temperature. After the pressure vessel was opened at −20° C., it is allowed to come to room temperature to allow excess methylamine to evaporate off. The reaction solution is taken up in dichloromethane, washed with water, dried on magnesium sulfate and concentrated by evaporation in a vacuum. 3.1 g of (4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-heptadecafluor-undecyl)-methyl-amine is obtained as a crude product.
Reaction SMILES: C(O[C:4]([C:6]1[C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]=1[NH2:15])=[O:5])C.C([O-])=O.[NH4+].O.[CH:21]([NH2:23])=O>>[N:15]1[C:7]2[NH:8][C:9]3[C:10](=[CH:11][N:12]=[CH:13][CH:14]=3)[C:6]=2[C:4]([OH:5])=[N:23][CH:21]=1
Reactant: CCOC(=O)c1c(N)[nH]c2ccncc12
Reactant: NC=O
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Product: Oc1ncnc2[nH]c3ccncc3c12
Temperature: 175 °C

Procedure:
2-Amino-1H-pyrrolo[3,2-c]pyridine-3-carboxylic acid ethyl ester (600 mg, 3 mmol) and ammonium formate (185 mg, 3 mmol) were suspended in 10 mL formamide and heated at 175° C. for 5 hours. Water was added to the cooled reaction mixture and the resulting precipitate collected and dried in vacuo. Unprecipitated product was recovered from the filtrate by using a MP-TsOH SPE cartridge and eluting with 7 N ammonia to give a combined mass of 330 mg of the title compound. LCMS (1): Rt 0.67 min; m/z 188 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[N:8][OH:9])[NH2:7])=[CH:4][CH:3]=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[OH-].[Na+].[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](Cl)=O>CC1CCCO1.O>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[N:7]=[C:31]([C:27]3[O:26][CH:30]=[CH:29][CH:28]=3)[O:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: NC(=NO)c1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccco1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC1CCCO1
Solvent: O
Product: Clc1ccc(-c2noc(-c3ccco3)n2)cc1
Temperature: 25 °C
Yield: 68.1 %

Procedure:
The 4-chlorobenzamidoxime (1.24 g, 7.25 mmol) was dissolved in 2-methyltetrahydrofuran (10.0 mL) and water (1.0 mL). A 40% aqueous solution of benzyltrimethylammonium hydroxide (100 uL) and 50% aqueous solution of sodium hydroxide (736 mg, 9.20 mmol) were added. The mixture was stirred and a precipitate formed. Furoyl chloride (1.24 g, 7.25 mmol) was added dropwise and an exotherm was noted. The mixture was stirred at 70° C. for 1 hour and cooled to room temperature. The solution was poured into water (25 mL) and the 2-methyltetrahydrofuran removed at reduced pressure. The resulting solids were isolated by vacuum filtration. The 3-(4-chlorophenyl)-5-(2-furanyl)-1,2,4-oxadiazole (1.22 g, 4.94 mmol) was obtained as a white solid. (68% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:27][CH2:26][CH2:25][C@H:24]3[C:28]([F:31])([F:30])[F:29])=[N:21][CH:22]=2)O1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>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.CO>[F:31][C:28]([F:29])([F:30])[C@@H:24]1[CH2:25][CH2:26][CH2:27][N:23]1[C:20]1[N:19]=[CH:18][C:17]([C:2]2[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][CH:3]=2)=[CH:22][N:21]=1
Reactant: CC1(C)OB(c2cnc(N3CCC[C@H]3C(F)(F)F)nc2)OC1(C)C
Reactant: Nc1cncc(Cl)n1
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: C1COCCO1
Solvent: CO
Product: Nc1cncc(-c2cnc(N3CCC[C@H]3C(F)(F)F)nc2)n1
Reaction time: 8 h
Yield: 68.3 %

Procedure:
A round bottom flask was charged with 6-chloropyrazin-2-amine (0.401 g, 3.09 mmol), (S)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidine (1.062 g, 3.09 mmol), Pd(PPh3)4 (0.358 g, 0.309 mmol) and 1,4-Dioxane (Volume: 7.74 ml). The reaction mixture was purged with nitrogen for several minutes before an aqueous 2M sodium carbonate (3.09 ml, 6.19 mmol) was added. The reaction mixture was purged for another 10 minutes under nitrogen before it was placed in a 90° C. oil bath and allowed to stir overnight. 1,4-Dioxane was removed in vacuo and the crude mixture was diluted with EtOAc. The product was wash with water (3×) and brine. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified on silica gel using normal phase flash chromatography, eluting with CH2Cl2:MeOH to yield 0.655 g (2.11 mmol, 68.2%) of the title product; 1H NMR (300 MHz, DMSO-d6) δ 9.01 (s, 2H), 8.26 (s, 1H), 7.83 (s, 1H), 6.55 (s, 2H), 5.16-5.02 (m, 1H), 3.77-3.60 (m, 2H), 2.29-2.01 (m, 4H); m/z [M+H]+=311.12
Reaction SMILES: [F:1][C:2]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[C:3](O)=[O:4].C(Cl)(=O)C([Cl:17])=O.CN(C=O)C>C(Cl)Cl>[F:1][C:2]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[C:3]([Cl:17])=[O:4]
Reactant: O=C(O)C(F)(F)c1ccc(F)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C(F)(F)c1ccc(F)cc1
Reaction time: 3 h

Procedure:
To a solution of 2,2-difluoro-2-(4-fluorophenyl)acetic acid (1.33 g, 7.0 mmol) in DCM (50 mL) was added oxalyl chloride (0.640 mL, 7.5 mmol) and a catalytic amount of DMF. After stirring for 3 h, the mixture was concentrated under reduced pressure to afford 2,2-difluoro-2-(4-fluorophenyl)acetyl chloride. To a solution of 2-aminobenzamide (0.857 g, 6.3 mmol) and TEA (1.04 mL, 0.0075 mol) in DCE (100 mL) at rt was added 2,2-difluoro-2-(4-fluorophenyl)acetyl chloride from above in DCE (100 mL) and the reaction mixture was stirred overnight. After adding EtOAc (200 mL) the mixture was washed with 1 N HCl, sat. NaHCO3 and brine. The organic solution was concentrated to yield an off-white solid (0.989 mg, 51%). 1H NMR (300 MHz, DMSO-d6) δ 7.15 (t, 1H), 7.27 (m, 2H), 7.54 (m, 1H), 7.74 (m, 2H), 7.92 (m, 2H), 8.44 (d, 2H), 13.37 (s, 1H).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][N:14]=[C:15]3[Cl:20])C=CC=CC=1.Cl.[CH2:23]([CH:30]1[C:39]2[C:34](=[CH:35][C:36]([F:40])=[CH:37][CH:38]=2)[CH2:33][CH2:32][CH:31]1[NH2:41])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)(O)[O-].[Na+]>CS(C)=O>[CH2:23]([CH:30]1[C:39]2[C:34](=[CH:35][C:36]([F:40])=[CH:37][CH:38]=2)[CH2:33][CH2:32][CH:31]1[NH:41][C:8]([NH:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][N:14]=[C:15]2[Cl:20])=[O:21])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: NC1CCc2cc(F)ccc2C1Cc1ccccc1
Reactant: O=C(Nc1cccc2c(Cl)nccc12)Oc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(Nc1cccc2c(Cl)nccc12)NC1CCc2cc(F)ccc2C1Cc1ccccc1
Yield: 27.8 %

Procedure:
(1-Chloro-isoquinolin-5-yl)-carbamic acid phenyl ester (150 mgs, 0.5 mmol), 1-Benzyl-6-fluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamine hydrochloride (146 mgs, 0.5 mmol), and sodium bicarbonate (42 mgs, 0.5 mmol) were combined and stirred for one hour in DMSO (4 ml) at ambient temperature. The product was purified by directly injecting the crude reaction onto a reverse phase prep-HPLC (10-90% water:acetonitrile gradient). The appropriate fractions were lyophilized to yield 1-(1-Benzyl-6-fluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-3-(1-chloro-isoquinolin-5-yl)-urea (64 mgs, 28%) MS (MH+) 459; 1H NMR (CD3OD) δ 1.93-2.06 (m, 1H), 2.09-2.13 (m, 1H), 2.91-3.07 (m, 4H), 3.40-3.42 (m, 1H), 4.07-4.10 (s, 1H), 6.69-6.78 (m, 1H), 6.80-6.89 (m, 2H), 7.12-7.26 (m, 5H), 7.72 (t, 1H, J=8.2 Hz), 7.83 (d, 1H, J=6.1 Hz), 8.19 (d, 1H, J=8.6 Hz), 8.17-8.24 (m, 2H). HPLC Rt=4.04 min (50-90% water:acetonitrile gradient, 100% pure).
Reaction SMILES: C([O:3][C:4](=[O:23])[CH:5]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)(=[O:9])=[O:8])C>Cl.O>[CH2:16]([CH:5]([CH2:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)(=[O:9])=[O:8])[C:4]([OH:23])=[O:3])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)c1ccccn1
Agent: Cl
Solvent: O
Product: O=C(O)C(Cc1ccccc1)CS(=O)(=O)c1ccccn1

Procedure:
233 mg of 2-benzyl-3-(2-pyridyl)sulphonyl-propionic acid ethyl ester are boiled under reflux for 2 hours in 4 ml of 4N HCl. The reaction mixture is diluted with water and extracted with ethyl acetate. The organic phases are washed with water, dried and concentrated by evaporation. The residue is chromatographed by evaporation. The residue is chromatographed on silica gel with eluant H and yields white crystals of the title compound of Rf (I)=0.3.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=[O:11].Br[C:14]1[CH:15]=[C:16]([O:20][CH3:21])[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:21][O:20][C:16]1[CH:15]=[C:14]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[C:2]2[C:10]([OH:12])=[O:11])[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(Br)c1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(-n2c(C(=O)O)cc3ccccc32)c1
Temperature: 170 °C
Yield: 45.7 %

Procedure:
The starting ester is prepared in the following manner: A mixture of indole-2-carboxylic acid (8.06 g), m-bromoanisole (9.35 g), anhydrous potassium carbonate (7 g) and cupric oxide (0.25 g) in dimethylformamide (10 ml) is heated at 170° C. under nitrogen for 18 hrs., diluted with a further 20 ml of solvent and heated 6 hours longer. It is cooled, diluted with water (500 ml) and extracted with methylene chloride (3×100 ml). The filtered aqueous layer is acidified with cold concentrated hydrochloric acid, refrigerated overnight and the precipitated product recrystallized from methanol to afford pure 1-(3-methoxypheny)indole-2-carboxylic acid (6.1 g), mp. 194°-196°. This acid (3.3 g) absolute ethanol (100 ml) and concentrated sulphuric acid (1.1 ml) are refluxed overnight, cooled, treated with water (50 ml) and the ethyl ester crystallizes. The crude ester (34 g) in trifluoroacetic acid (280 ml) is reduced with sodium borohydride (17.3 g) as described in Example 5 to afford ethyl 2,3-dihydro-1-(3-methoxyphenyl)indole-2-carboxylate as an oil.
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[O:20])[CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH:19]([C:15]1[CH:14]=[C:13]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([CH:11]=[O:12])=[C:2]2[CH:22]2[CH2:23][NH:24][CH2:25][CH2:26][NH:21]2)[CH:18]=[CH:17][CH:16]=1)=[O:20]
Reactant: O=Cc1cccc(-n2c(Cl)c(C=O)c3ccccc32)c1
Reactant: C1CNCCN1
Product: O=Cc1cccc(-n2c(C3CNCCN3)c(C=O)c3ccccc32)c1
Yield: 59 %

Procedure:
2-Chloro-1-(3-formylphenyl)-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Step 2 of Example 29 to afford 1-(3-formylphenyl)-2-(piperazin-2-yl)-1H-indole-3-carboxaldehyde (59% yield) as a cream solid. ESI/MS 334 (M+H); RT 2.29 min.
Reaction SMILES: [NH2:1][C:2]1[C:13]([CH3:14])=[CH:12][C:11]([Br:15])=[CH:10][C:3]=1[C:4]([NH:6][CH:7]([CH3:9])[CH3:8])=[O:5].[C:16](Cl)(Cl)=[O:17].C1(C)C=CC=CC=1>O1CCOCC1>[Br:15][C:11]1[CH:10]=[C:3]2[C:2](=[C:13]([CH3:14])[CH:12]=1)[NH:1][C:16](=[O:17])[N:6]([CH:7]([CH3:9])[CH3:8])[C:4]2=[O:5]
Reactant: O=C(Cl)Cl
Reactant: Cc1cc(Br)cc(C(=O)NC(C)C)c1N
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1cc(Br)cc2c(=O)n(C(C)C)c(=O)[nH]c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the anthranilamide of Step F, (1.11 g, 4.1 mmol) in dioxane (20 mL) was added a 2.0 M solution of phosgene in toluene (2.3 mL, 4.6 mmol). The reaction was stirred at room temperature for 1 hour then heated to reflux for 4 hours and cooled to room temperature. The white solids were filtered and dried to afford the title compound (0.89 g).
Reaction SMILES: [H-].[Na+].[C:3](=[N:6][OH:7])([NH2:5])[CH3:4].[CH3:8][N:9]1[CH2:14][CH:13]([C:15](OC)=O)[CH2:12][N:11]=[CH:10]1.C(O)C>C1COCC1>[CH3:8][N:9]1[CH2:14][CH:13]([C:15]2[O:7][N:6]=[C:3]([CH3:4])[N:5]=2)[CH2:12][N:11]=[CH:10]1
Reactant: COC(=O)C1CN=CN(C)C1
Reactant: CC(N)=NO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1noc(C2CN=CN(C)C2)n1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
Sodium hydride (60% dispersion in mineral oil 112 mg, 2.8 mmol) and acetamidoxime (207 mg, 2.8 mmol) are suspended in dry THF (16 ml) in an oven dried round bottom flask under nitrogen with stirring at 0° C. After 10 minutes the grey suspension is refluxed for 30 minutes giving a white suspension. 1-Methyl-1,4,5,6-tetrahydro-5-methoxycarbonylpyrimidine (593 mg, 2.8 mmol) dissolved in dry THF (4 ml) and anhydrous ethanol (1 ml) is added via syringe and reflux continued 15 hours. The suspension is evaporated in vacuo to a yellow gum and chromatographed (silica, chloroform/methanol, 9:1) to yield 24 mg (rf=0.07, 4%) solids identified by 300 MHz nmr and ms m/z=180.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:25]2[CH:29]([CH3:30])[C:28](=[O:31])[NH:27][C:26]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=2)[CH2:12][CH2:11]1)=[O:9].[CH3:33]I>>[F:1][C:2]1[CH:3]=[C:4]([N:25]2[CH:29]([CH3:30])[C:28](=[O:31])[N:27]([CH3:33])[C:26]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=2)[CH2:12][CH2:11]1)=[O:9]
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C(=O)NC(=O)C4C)cc3F)CC2)nc1C
Reactant: CI
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C(=O)N(C)C(=O)C4C)cc3F)CC2)nc1C

Procedure:
Using 1-{3-fluoro-4-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-5-methylimidazolidine-2,4-dione (50 mg) described in Example 552 and methyl iodide (7.8 μL) and by the reaction and treatment in the same manner as in Example 551, the title compound (27 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]2[C:30]3[CH:29]=[C:28]4[C:31]5([CH2:37][O:38][C:27]4=[CH:26][C:25]=3[CH2:24][CH2:23]2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]5)=[O:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:46][CH2:47][OH:48]>C(O)C>[OH:48][CH2:47][CH2:46][N:34]1[CH2:33][CH2:32][C:31]2([C:28]3[C:27](=[CH:26][C:25]4[CH2:24][CH2:23][N:22]([C:20]([C:17]5[CH:16]=[CH:15][C:14]([C:3]6[CH:4]=[CH:5][C:6]([C:8]7[O:9][C:10]([CH3:13])=[N:11][N:12]=7)=[CH:7][C:2]=6[CH3:1])=[CH:19][CH:18]=5)=[O:21])[C:30]=4[CH:29]=3)[O:38][CH2:37]2)[CH2:36][CH2:35]1
Reactant: Cc1nnc(-c2ccc(-c3ccc(C(=O)N4CCc5cc6c(cc54)C4(CCNCC4)CO6)cc3)c(C)c2)o1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nnc(-c2ccc(-c3ccc(C(=O)N4CCc5cc6c(cc54)C4(CCN(CCO)CC4)CO6)cc3)c(C)c2)o1
Yield: 56.4 %

Procedure:
A stirred solution of 5-(2'-methyl-4'-(5-methyl-1,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (E17 in WO 96/19477, 1.5 g, 2.9 mmole) in ethanol (30 ml) was treated with sodium carbonate (1.2 g, 11.6 mmole) and 2-bromoethanol (0.41 ml, 5.8 mmole) and heated under reflux for 20 hours. The reaction mixture was concentrated in vacuo and the residue treated with water (10 ml) and extracted with chloroform. The extract was dried (Na2SO4), concentrated in vacuo and the residue chromatographed on silica gel eluting with 0-6% methanol/chloroforn to afford the title compound as a yellow solid (0.9 g, 56%). This was converted to its hydrochloride salt and crystallised from acetone m.p. >250° C.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[C:7]1([CH2:19]O)[CH:8]=[N:9][N:10]2[CH:15]=[CH:14][C:13]3[O:16][CH2:17][CH2:18][C:12]=3[C:11]=12>ClCCl.C(=O)([O-])O.[Na+]>[C:7]1([CH2:19][C:5]#[N:6])[CH:8]=[N:9][N:10]2[CH:15]=[CH:14][C:13]3[O:16][CH2:17][CH2:18][C:12]=3[C:11]=12
Reactant: OCc1cnn2ccc3c(c12)CCO3
Reactant: C[Si](C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#CCc1cnn2ccc3c(c12)CCO3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.6 %

Procedure:
To a solution of boron trifluoride diethyl ether complex (1.26 mL, 9.94 mmol) and trimethylsilyl cyanide (1.77 mL, 13.3 mmol) in dichloromethane (13 mL) was added a solution of 8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridin-1-ylmethanol (630 mg, 3.31 mmol) in dichloromethane (39 mL) under ice-cooling and an argon atmosphere, and the mixture was stirred at room temperature for 30 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→40/60) to give the title compound (274 mg, yield 42%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].Cl[CH:12]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.[OH-].[Na+].Cl>C(Cl)(Cl)Cl>[O:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][CH:12]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[OH:4])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:17]1
Reactant: NCC(O)c1ccccc1
Reactant: ClC(CCN1CCOCC1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: OC(CNC(CCN1CCOCC1)c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 46.5 %

Procedure:
2-Amino-1-phenylethanol (2.50 g, 18.2 mmol) and 4-(3-chloro-3-phenylpropyl)morpholine (4.37 g, 18.2 mmol) were mixed and heated to cause reaction at 110° C. for 40 minutes. The resulting mixture was cooled to room temperature, and then dissolved into chloroform (200 ml). After the solution was chilled with ice, 1N NaOH was added so that the hydrochloride was libereated. The chloroform portion was collected and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure. The residue was purified by medium pressure silica gel column chromatography (chloroform/methanol=100/1) to obtain 2.88 g of the titled compound as a yellow oil (Yield: 46.5%)