Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[C:24]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:23][C:9]2[C:10](=[O:22])[C:11]([N:14]([CH:20]=[O:21])[CH2:15][C:16]([O:18]C)=[O:17])=[CH:12][O:13][C:8]=2[CH:7]=1)(=[O:4])=[O:3].Cl>[OH-].[Na+]>[CH3:1][S:2]([NH:5][C:6]1[C:24]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:23][C:9]2[C:10](=[O:22])[C:11]([N:14]([CH2:15][C:16]([OH:18])=[O:17])[CH:20]=[O:21])=[CH:12][O:13][C:8]=2[CH:7]=1)(=[O:3])=[O:4]
Reactant: COC(=O)CN(C=O)c1coc2cc(NS(C)(=O)=O)c(Oc3ccccc3)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)Nc1cc2occ(N(C=O)CC(=O)O)c(=O)c2cc1Oc1ccccc1
Reaction time: 1.5 h
Yield: 82.6 %

Procedure:
In 45 ml of a 1N aqueous sodium hydroxide solution was dissolved 4.46 g of 7-methylsulfonylamino- 3-(N-formyl-N-methoxycarbonylmethylamino)-6-phenoxy-4H-1-benzopyran-4-one. The solution was stirred for 1.5 hours at 25°-30° C. The solution was then adjusted to pH 3 with 4N hydrochloric acid and extracted with two 50-ml portions of ethyl acetate. The extracts (the organic layers) were combined, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was mixed with diethyl ether. The resulting crystal was collected by filtration to obtain 3.57 g (yield: 82.6%) of 7-methylsulfonylamino-3-(N-carboxymethyl-N-formylamino)-6-phenoxy-4H-1-benzopyran-4-one having a melting point of 98°-100° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH:7]=[N:8][N:9]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:10]=2[CH:11]=[C:12]([Br:14])[CH:13]=1)=[O:4].[OH-].[Na+].Cl>O.CO>[Br:14][C:12]1[CH:13]=[C:5]([C:3]([OH:4])=[O:2])[C:6]2[CH:7]=[N:8][N:9]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[C:10]=2[CH:11]=1
Reactant: COC(=O)c1cc(Br)cc2c1cnn2-c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(Br)cc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 6-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid methyl ester (1.7 g, 4.8 mmol) in water (15 mL) and methanol (15 mL) was added a solution of 2 N aqueous sodium hydroxide (10 mL, 20 mmol). The solution was warmed at reflux for 1 hour. The reaction mixture was cooled to room temperature and acidified with 1 N aqueous HCl (pH=3-4) to afford a precipitate which was collected by filtration, washed with MeOH and air dried to afford 6-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl.[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][N:30]([C:8]([NH:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[O:15])[CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Nc1ccccn1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccccn1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 55.5 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl pyridin-2-ylcarbamate (270 mg, 0.610 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.129 ml, 0.738 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:7) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 124 mg (55.4%) of the desired product as a solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH:15]=O)[NH:11][C:10]=1[CH3:17])=[O:8])[CH3:2].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2.C1CCCCCC1.N1CCCC1>C1CCCCC1.C1CCCC1>[CH3:2][CH2:1][N:3]([CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12](/[CH:15]=[C:24]2/[C:23]3[CH:22]=[C:21]([F:20])[CH:29]=[CH:28][C:27]=3[NH:26][C:25]/2=[O:30])[NH:11][C:10]=1[CH3:17])=[O:8])[CH2:18][CH3:19]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: C1CCCCCC1
Solvent: C1CCCCC1
Solvent: C1CCCC1
Solvent: C1CCNC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C

Procedure:
According to the process of the present invention, 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide (IX) and 5-Fluoro-1,3-dihydro-indol-2-one (X) in non-polar alicyclic hydrocarbon solvents like cyclopentane, cyclohexane or cycloheptane are reacted in presence of catalytic amount of pyrrolidine as base at reflux temperature for 1-6 hours. The resultant Sunitinib base is again triturated with the same solvent at reflux temperature for 1-2 hours and isolated at a temperature ranging from 20-45° C., preferably at 25-35° and most preferably at 25-30° C. and dried at 60° C. for 5-20 hours to get Sunitinib base (I) as orange crystalline solid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[NH:5][C:6]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])=[C:7]([CH3:9])[N:8]=1.Cl[CH2:17][O:18][CH2:19][CH2:20][CH2:21][CH3:22]>O1CCCC1>[CH2:19]([O:18][CH2:17][N:5]1[C:6]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])=[C:7]([CH3:9])[N:8]=[C:4]1[Br:3])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCOCCl
Reactant: Cc1nc(Br)[nH]c1C(=O)OC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOCn1c(Br)nc(C)c1C(=O)OC(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a suspension of 293 milligrams (1.22 mM) of sodium hydride in 30 ml of anhydrous tetrahydrofuran was added, in portions, 3 g (1.22 mM) of isopropyl 2-bromo-4-methyl-5-imidazolecarboxylate. The resulting suspension was cooled to 0° C. and 1.5 g (1.22 mM) of chloromethyl-n-butyl ether was added dropwise. The reaction mixture was stirred overnight at room temperature. The precipitated sodium chloride was removed by filtration and concentration of the filtrate in vacuo gave 3.6 g of isopropyl N-n-butoxymethyl-2-bromo-4-methyl-5-imidazolecarboxylate as a golden oil (87%). Subsequent analysis indicated that the 3-isomer/1-isomer ratio was 91/9.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:11]C(=O)OC(C)(C)C)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[ClH:19].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:19].[Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Br)cc2c1OCC2
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1cc(Br)cc2c1OCC2
Yield: 92.8 %

Procedure:
The compound (6.27 g, 20.0 mmol) obtained in step A was dissolved in ethyl acetate, 4N hydrochloric acid-ethyl acetate solution (25 ml, 100 mmol) was added at room temperature with stirring, and the mixture was stirred at the same temperature overnight. The precipitated solid was filtered, washed with ethyl acetate, and dried under reduced pressure to give the title compound (4.65 g, yield 93%) as a colorless solid.
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:6][C@:5]([O:9][C@H:10]2[O:15][CH:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]([OH:19])[CH:11]2[OH:20])([CH2:7][OH:8])[CH:4]([OH:21])[C@H:3]1[OH:22].[Al]>O>[CH2:16]([OH:17])[C@H:14]1[O:15][C@H:10]([O:9][C@:5]2([CH2:7][OH:8])[O:6][C@H:2]([CH2:1][OH:23])[C@@H:3]([OH:22])[C@@H:4]2[OH:21])[C@H:11]([OH:20])[C@@H:12]([OH:19])[C@@H:13]1[OH:18]
Reactant: OCC1O[C@H](O[C@]2(CO)O[C@H](CO)[C@H](O)C2O)C(O)[C@@H](O)[C@@H]1O
Agent: [Al]
Solvent: O
Product: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Reaction time: 0.17 h

Procedure:
A Sucrose/Lake red dye (Opalux Red AS-1662-D, available from Colorcon, West Point, Pa.) solution was prepared by mixing 966.3 g of sucrose NF into 414.7 g of purified water in a stainless steel container using a magnetic stir bar. The container was covered with aluminum foil and heated to about 60—about 65° C. with continued mixing. The solution was mixed for an additional 20 minutes at about 60—about 65° C. at which time the solution was visually clear. 9.2 g of lake red dye was added to the sucrose NF solution, the foil replaced, and mixing continued for 10 minutes while maintaining temperature between about 60—about 65° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][S:17](Cl)(=[O:19])=[O:18].CO.O>N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([O:15][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Solvent: O
Solvent: CO
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OS(C)(=O)=O)CC1
Reaction time: 0.25 h

Procedure:
A solution of Intermediate 35 (90.3 g) in pyridine (415 ml) was added dropwise with methanesulfonyl chloride (42.4 ml) with stirring and ice cooling over 15 minutes and stirred with ice cooling for 30 minutes and at room temperature for 20 minutes. The reaction mixture was added with methanol (54.2 ml) to terminate the reaction, stirred at room temperature for 2.5 hours, further added with water (540 ml) and stirred at room temperature for 1 hour and with ice cooling for 1 hour. The deposited precipitates were collected by filtration, washed with water and then dried at 40° C. under reduced pressure to obtain the title compound (105 g).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([C:10]1[C:11](=[O:49])[N:12]2[C:16](=[CH:17][C:18]=1[C@:19]([CH2:43][CH3:44])([O:25][C:26]([C@H:28]1[CH2:32][CH2:31][CH2:30][N:29]1[S:33]([C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=1)(=[O:35])=[O:34])=[O:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]1([O:48][CH2:47][CH2:46][O:45]1)[CH2:14][CH2:13]2)#[N:9]>[Ni].C(O)(=O)C>[C:1]([NH:9][CH2:8][C:10]1[C:11](=[O:49])[N:12]2[C:16](=[CH:17][C:18]=1[C@:19]([CH2:43][CH3:44])([O:25][C:26]([C@H:28]1[CH2:32][CH2:31][CH2:30][N:29]1[S:33]([C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=1)(=[O:34])=[O:35])=[O:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]1([O:45][CH2:46][CH2:47][O:48]1)[CH2:14][CH2:13]2)(=[O:3])[CH3:2]
Reactant: CCOC(=O)[C@@](CC)(OC(=O)[C@H]1CCCN1S(=O)(=O)c1ccc(C)cc1)c1cc2n(c(=O)c1C#N)CCC21OCCO1
Reactant: CC(=O)OC(C)=O
Agent: [Ni]
Solvent: CC(=O)O
Product: CCOC(=O)[C@@](CC)(OC(=O)[C@H]1CCCN1S(=O)(=O)c1ccc(C)cc1)c1cc2n(c(=O)c1CNC(C)=O)CCC21OCCO1

Procedure:
To a mixed solvent which was composed of 20 ml of acetic acid and 50 ml of acetic anhydride and containing 6 g of Raney nickel, 2.00 g of the compound (XIII) obtained in the above procedure (3) was added. While exposing the reaction system to light from a tungsten lamp, the compound (XIII) was reduced for 2 hours under a hydrogen gas stream. After removal of Raney nickel by filtration, the filtrate was concentrated. The residue was subjected to column chromatography on silica gel and then developed by a 50:1 mixed solvent of chloroform and methanol. A fraction containing the intended product was concentrated to drynes,s thereby obtaining 2.15 g of the title compound in an amorphous form.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:36])[C:5]([CH3:35])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:31]C(=O)C)=[C:17]([CH:30]=2)[C:18]([NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.Cl>[CH3:1][O:2][C:3]1[C:4](=[O:36])[C:5]([CH3:35])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:31])=[C:17]([CH:30]=2)[C:18]([NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(C(=O)O)cc3)c2)=C(C)C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc(C(=O)O)cc3)c2)=C(C)C1=O
Yield: 76.8 %

Procedure:
N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-aminobenzoic acid (0.070 g, 0.142 mmol) was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (1.5 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with a 2N hydrochloric acid solution and the aqueous layer was rendered acidic (pH=1 to 2) and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from methanol to obtain the titled compound (0.049 g, 0.109 mmol, 77%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]4[C:34]5[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=5)[N:28]([CH3:36])[N:27]=4)[N:24]=3)[N:19]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:18]=2)=[O:16])[CH2:9]1)=O)(C)(C)C.C(Cl)(=O)C.C1COCC1>CO>[NH:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]4[C:34]5[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=5)[N:28]([CH3:36])[N:27]=4)[N:24]=3)[N:19]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:18]=2)=[O:16])[CH2:9]1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Solvent: CC(=O)Cl
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@@H]2CCCNC2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 88.4 %

Procedure:
In a round-bottomed flask, (R)-3-{[2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (138 mg, 0.22 mmol) was suspended in methanol (2 ml). The reaction was cooled to 0° C. and acetyl chloride (0.30 ml, 4.22 mmol) was added dropwise over 10 min. The resultant bright yellow suspension was stirred at room temperature for 50 min. THF (1 ml) and methanol (1 ml) were added and stirred was continued for 1 h at room temperature then the solvent was evaporated at room temperature. The residue was suspended in dichloromethane and washed with saturated Na2CO3-solution. The aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to afford 105 mg (90%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (R)-piperidin-3-ylamide as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][OH:11])[C:5]([NH2:12])=[C:4]([Cl:13])[N:3]=1.[C:14]([O-])([O-])=[O:15].[K+].[K+].ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O>C(#N)C>[NH2:1][C:2]1[N:7]=[C:6]2[C:5]([NH:12][C:14](=[O:15])[N:8]2[CH2:9][CH2:10][OH:11])=[C:4]([Cl:13])[N:3]=1
Reactant: Nc1nc(Cl)c(N)c(NCCO)n1
Reactant: O=C([O-])[O-]
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: [K+]
Solvent: CC#N
Product: Nc1nc(Cl)c2[nH]c(=O)n(CCO)c2n1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A mixture of 2-[(2,5-diamino-6-chloro-pyrimidin-4-yl)amino]ethanol obtained in step 1 (10.0 g, 49.26 mmol) in acetonitrile (400 ml) were cooled to 0° C. To this reaction mixture K2CO3 (20.39 gm, 147.7 mmol) and 4-nitrophenyl chloroformate (19.8 g, 98.52 mmol)was added and stirred at 25-27° C. for 24 hours. This reaction mixture was filtered and washed with acetonitrile (300 ml) and diethyl ether (300 ml) respectively. Solid obtained was dried to obtain crude 2-amino-6-chloro-9-(2-hydroxyethyl)-7H-purin-8-one as a yellow solid. Small amount of crude material was purified by column chromatography to obtain pure product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:5]2[CH:4]=1)#[N:2].C(Cl)(=O)C(Cl)=O.[CH2:21]([N:28]1[C:36]2[CH:35]=[CH:34][CH:33]=[C:32]([NH2:37])[C:31]=2[CH:30]=[N:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH2:21]([N:28]1[C:36]2[C:31](=[C:32]([NH:37][C:12]([C:9]3[N:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]4=[N:11][CH:10]=3)=[O:14])[CH:33]=[CH:34][CH:35]=2)[CH:30]=[N:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Nc1cccc2c1cnn2Cc1ccccc1
Reactant: N#Cc1ccn2c(C(=O)O)cnc2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1ccn2c(C(=O)Nc3cccc4c3cnn4Cc3ccccc3)cnc2c1
Reaction time: 0.08 h
Yield: 65.1 %

Procedure:
To a solution of 7-cyanoimidazo[1,2-a]pyridine-3-carboxylic acid (0.0527 g, 0.282 mmol) in 0.200 mL of CH2Cl2 was added a drop of DMF followed by oxalyl chloride (1.1 equivalents, 2M CH2Cl2). The reaction was stirred for 5 minutes until bubbling ceased. 1-Benzyl-1H-indazol-4-amine (0.0629 g, 0.282 mmol) was added as a solution in 0.600 mL of CH2Cl2 followed by DIEA (1.2 equivalents). The reaction was stirred at ambient temperature overnight. The reaction was concentrated and the solids were washed with Et2O, water, 2M Na2CO3, water, and finally with Et2O again to provided the desired product as a beige solid 0.072 g (65%). MS (ES+APCI) m/z=393 (M+H).
Reaction SMILES: COC(C)(C)C.O.[C:8]([O:11][CH:12]([O:16][C:17]([CH3:19])=[S:18])[CH:13]([CH3:15])[CH3:14])(=[O:10])[CH3:9]>CCCCCC>[C:8]([O:11][C@@H:12]([O:16][C:17]([CH3:19])=[S:18])[CH:13]([CH3:15])[CH3:14])(=[O:10])[CH3:9]
Reactant: CC(=O)OC(OC(C)=S)C(C)C
Solvent: CCCCCC
Solvent: COC(C)(C)C
Solvent: O
Product: CC(=O)O[C@@H](OC(C)=S)C(C)C
Reaction time: 7 h
Yield: 32 %

Procedure:
Twenty (20) mL of methyl-tert-butyl ether (MTBE) and 0.2 mL of water were shaken for 4 hrs until the solution was clear at which time 1 g of 2-methyl-1-methylthiocarbonyloxypropyl acetate (2f) was added, followed by 1.32 g of PLE/MPEG (60 mg/1 g). The mixture was shaken on an orbital shaker for 7 hrs. Hexane was added and the mixture was filtered through CELITE® 545 pad. The organic solution was washed with water, aqueous sodium bicarbonate (NaHCO3) solution and brine, and dried over anhydrous sodium sulfate (Na2SO4). After evaporation of solvent, 0.32 g (64% yield) of the title compound (17) was obtained having an enantiomeric excess of 64% e.e. The absolute configuration was determined by independent stereospecific synthesis and by derivatization to a compound having known stereochemistry.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:45])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[C:35]([CH2:36][O:37]C3CCCCO3)=[CH:34][O:33][N:32]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][N:14]([CH3:15])[C:12]1[C:11]([C:17]([F:19])([F:18])[F:20])=[CH:10][C:9]2[NH:21][C:22](=[O:45])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[C:35]([CH2:36][OH:37])=[CH:34][O:33][N:32]=4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3nocc3COC3CCCCO3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3nocc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[5-dimethylamino-2-(3-oxo-3-{3-[4-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-3-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example M61) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (50 mg).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].C([CH:8]([C:22]([O-:24])=O)[C:9]([C:19]([O-:21])=O)([OH:18])[C:10](CC)(CC)[C:11]([O-:13])=O)C>CO>[CH2:1]([NH:5][C:11](=[O:13])[CH2:10][C:9]([CH2:8][C:22]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:24])([C:19]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:21])[OH:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: CCC(C(=O)[O-])C(O)(C(=O)[O-])C(CC)(CC)C(=O)[O-]
Solvent: CO
Product: CCCCNC(=O)CC(O)(CC(=O)NCCCC)C(=O)NCCCC
Temperature: 25 °C
Reaction time: 72 h
Yield: 58 %

Procedure:
N,N′,N″-tri-n-butylcitramide was prepared by the reaction of n-butylamine with triethylcitrate. To a round-bottomed flask were added triethylcitrate (31.485 g; 0.1140 mole, 1 eq) and methanol (40 mL). To this solution, n-butylamine (24.999 g; 3.00 eq) was slowly poured. The clear light yellow solution stirred for 3 days at room temperature prior to the removal of methanol via rotary evaporation at 60° C. The resulting crude tacky solid was triturated using diethylether, collected via filtration and dried in vacuo to give a white powder with a slight amine odor (23.95 g; 58% yield).
Reaction SMILES: Cl[CH2:2][CH:3]=[CH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:9]=1.[NH:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23]>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]2[N:9]=[C:5]([CH:4]=[CH:3][CH2:2][N:19]3[C:20](=[O:22])[CH2:21][NH:17][C:18]3=[O:23])[S:6][CH:7]=2)=[CH:11][CH:12]=1
Reactant: O=C1CNC(=O)N1
Reactant: Fc1ccc(-c2csc(C=CCCl)n2)cc1
Product: O=C1CNC(=O)N1CC=Cc1nc(-c2ccc(F)cc2)cs1

Procedure:
The compound was prepared analogously to example 3e) from 92 mg (0.36 mmol) of 2-(3-chloropropenyl)-4-(4-fluorophenyl)thiazole and 54.4 mg (0.54 mmol) of imidazolidine-2,4-dione. Yield: 31 mg (27%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:17]([CH3:19])=[O:18])[C:15]=2[OH:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:20]N1C(=O)CCC1=O.O>C(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:20][C:13]1[S:12][C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=2)=[C:15]([OH:16])[C:14]=1[C:17]([CH3:19])=[O:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(=O)c1c(Br)sc(-c2ccc(C(C)(C)C)cc2)c1O
Yield: 85.5 %

Procedure:
2-(4-t-butylphenyl)-3-hydroxy-4-methylcarbonylthiophene (2.66 g, 9.7 mmol), N-bromosuccinimide (1.73 g, 9.7 mmol) and benzoyl peroxide (153 mg, 0.63 mmol) were heated with reflux for 2 hours in 65 ml of chloroform. Water was added, and the reaction solution was extracted three times with chloroform, and the organic layer was washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. The obtained organic layer was concentrated, and then purified with a silica gel column chromatography (n-hexane/chloroform=3/2) to obtain the desired product as a yellow solid (2.93 g, yield 86%).
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][CH2:29][CH2:30]Br)=[C:25]([O:34][CH3:35])[CH:24]=1)(=[O:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].O.O.[C:44]([OH:49])(=[O:48])[C:45]([OH:47])=[O:46]>CCOCC.C1(C)C=CC=CC=1>[OH2:22].[C:44]([OH:49])(=[O:48])[C:45]([OH:47])=[O:46].[C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]2[CH2:9][CH2:10][N:11]([CH2:30][CH2:29][CH2:28][O:27][C:26]3[CH:32]=[CH:33][C:23]([C:20](=[O:22])[CH3:21])=[CH:24][C:25]=3[O:34][CH3:35])[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCBr
Reactant: c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(=C(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 7.5 g (0.03 mole) of 4-diphenylmethylenepiperidine, 6.3 g (0.032 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl bromide, 25 g of potassium carbonate and 150 ml of toluene was heated at reflux for 16 hrs, cooled, filtered and the solvent evaporated at reduced pressure. The residual oil was taken up in benzene, washed with water, dried over magnisium sulfate and then the solvent was evaporated. The free base was dissolved in isopropanol and treated with 3.8 g (0.03 mole) of oxalic acid dihydrate in dry ether. The white salt which separated was recrystallized from an isopropanol-methanol mixture. The product weighed 8.5 g(54%). m.p. 186°-188° C.