Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:9][C:10]1[N:15]=[C:14]([OH:16])[C:13]([C:17]([O:19]CC)=[O:18])=[CH:12][N:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O.[OH-].[Na+]>C(O)C>[CH2:1]([NH:9][C:10]1[N:15]=[C:14]([OH:16])[C:13]([C:17]([OH:19])=[O:18])=[CH:12][N:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCNc1ncc(C(=O)OCC)c(O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCNc1ncc(C(=O)O)c(O)n1

Procedure:
2-n-Octylamino-5-ethoxycarbonyl-4-hydroxypyrimidine (400 mg, 1.4 mmol) was hydrolysed in boiling water (10 ml): ethanol (3 ml) with NaOH (5 mmol, 200 mg).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])(=[O:10])=[O:9])[N:3]=1.[F:18][C:19]([F:27])([F:26])[C:20](=O)[CH2:21][C:22](=O)[CH3:23].O>C(O)(=O)C>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[S:8]([NH:7][C:4]1[N:3]=[C:2]2[N:1]=[C:22]([CH3:23])[CH:21]=[C:20]([C:19]([F:27])([F:26])[F:18])[N:6]2[N:5]=1)(=[O:9])=[O:10]
Reactant: Nc1nc(NS(=O)(=O)c2ccccc2Cl)n[nH]1
Reactant: CC(=O)CC(=O)C(F)(F)F
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(C(F)(F)F)n2nc(NS(=O)(=O)c3ccccc3Cl)nc2n1
Temperature: 25 °C
Yield: 92.5 %

Procedure:
A mixture of 2.19 g (8.00 mmol) of N-(5-amino-1,2,4-triazol-3-yl)-2-chlorobenzenesulfonamide and 1.09 ml (1.38 g, 8.96 mmol) of 1,1,1-trifluoro-2,4-pentanedione in 9 ml of glacial acetic acid was heated at reflux for 21 hours. After cooling to room temperature, the reaction mixture was poured into a mixture of ice and water. The solid which separated was collected by filtration, washed with water and dried to yield 2.90 g (93 percent) of the desired product as a white solid, mp 203°-204.5° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[CH2:24]OS(C)(=O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:30].[K+]>CC(CC)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[CH2:24][I:30])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](COS(C)(=O)=O)N(C(=O)OCc2ccccc2)C1
Reactant: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CI)N(C(=O)OCc2ccccc2)C1

Procedure:
To a solution of (2S,4R)-1-benzyloxycarbonyl-2-methylsulfonyloxymethyl-4-t-butyldimethylsilyloxypyrrolidine (108.5 g) in methylethylketone (1100 ml), potassium iodide (73.5 g) was added, and the resultant mixture was refluxed for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated to remove the solvent. The residue was diluted with ethyl acetate, washed with aqueous sodium chloride solution, aqueous sodium hypochlorite solution and aqueous sodium chloride solution in order and dried over magnesium sulfate. Removal of the solvent gave (2S,4R)-1-benzyloxycarbonyl-2-iodomethyl-4-t-butyldimethylsilyloxypyrrolidine.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:28][N:29]([CH:38]=[O:39])[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]([N:10]2[C@H:14]([C:15](O)=[O:16])[CH2:13][CH2:12][N:11]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.F[B-](F)(F)F.COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[NH2:69][C:70]1[CH:85]=[CH:84][C:73]([C:74]([O:76][CH2:77][C:78]2[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=2)=[O:75])=[CH:72][CH:71]=1>C(#N)C>[CH:1]1([CH2:6][C@H:7]([CH2:28][N:29]([CH:38]=[O:39])[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]([N:10]2[C@H:14]([C:15]([NH:69][C:70]3[CH:85]=[CH:84][C:73]([C:74]([O:76][CH2:77][C:78]4[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=4)=[O:75])=[CH:72][CH:71]=3)=[O:16])[CH2:13][CH2:12][N:11]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Reactant: Nc1ccc(C(=O)OCc2ccccc2)cc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CC#N
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)Nc2ccc(C(=O)OCc3ccccc3)cc2)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a solution of (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (300 mg, 0.558 mmol) in acetonitrile (10 mL) under N2 at 0° C. was added 4-methylmorpholine (123 mg, 2.2 mmol), followed by 4-[4,6-bis(methyloxy)-1,3,5-triazin-2-yl]-4-methylmorpholin-4-ium tetrafluoroborate (366 mg, 1.116 mmol). The mixture was stirred for 1 h and to this mixture was added phenylmethyl 4-aminobenzoate (191 mg, 0.837 mmol). The mixture was stirred at rt overnight. The mixture was concentrated, and the residue was purified by flash column chromatography eluting with petroleum ether/ethyl acetate (5:1 to 3:1) to provide the title compound (330 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([N:38]=[C:39]=[O:40])=[O:37])=[CH:31][CH:30]=1>O1CCCC1>[CH3:25][N:23]([CH2:22][CH:19]1[CH2:20][CH2:21][N:16]([C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:26]=[CH:27][C:2]([NH:1][C:39]([NH:38][C:36](=[O:37])[CH2:35][C:32]4[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=4)=[O:40])=[CH:3][CH:4]=3)[CH:12]=[CH:11][N:10]=2)=[O:15])[CH2:17][CH2:18]1)[CH3:24]
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Reactant: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3)ccn2)CC1
Solvent: C1CCOC1
Product: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3)ccn2)CC1
Reaction time: 72 h
Yield: 36 %

Procedure:
To a solution of 4-(4-aminophenoxy)-2-{[4-(dimethylaminomethyl)piperidin-1-yl]carbonylamino}pyridine (61.8 mg) in tetrahydrofuran (2.0 ml) was added a solution of 2-(4-fluorophenyl)acetyl isocyanate in tetrahydrofuran (0.25 M, 1.7 ml) at room temperature, followed by stirring for 3 days. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate) to provide the titled compound (32.6 mg, 36%) as white powder.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[NH:16][C:15]3[C:14](=[O:17])[N:13]([CH2:18][CH2:19][CH3:20])[C:12](=[O:21])[N:11]([CH2:22][CH2:23][CH3:24])[C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[CH3:25][O:26][CH2:27][CH2:28][NH2:29]>CCO>[CH3:25][O:26][CH2:27][CH2:28][NH:29][C:2]1[N:7]=[CH:6][C:5]([C:8]2[NH:16][C:15]3[C:14](=[O:17])[N:13]([CH2:18][CH2:19][CH3:20])[C:12](=[O:21])[N:11]([CH2:22][CH2:23][CH3:24])[C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COCCN
Reactant: CCCn1c(=O)c2[nH]c(-c3ccc(Cl)nc3)cc2n(CCC)c1=O
Solvent: CCO
Product: CCCn1c(=O)c2[nH]c(-c3ccc(NCCOC)nc3)cc2n(CCC)c1=O
Temperature: 164 °C
Reaction time: 28 h
Yield: 56.7 %

Procedure:
8a (100 mg) was suspended in methoxyethylamine (1.5 g), in EtOH (4 mL) in a pressure tube and stirred at 164° C. for 28 hrs. After cooling to room temperature, the solvent was removed and the solid was purified by column (26 g silica gel, RT Scientific) (CH2Cl2:MeOH=100:0 to 97:3). The fractions were evaporated and washed with ether to give the product 9a (63 mg). The mother liquid was evaporated and afforded another 30 mg of the product.
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:11][C:12](=O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]([CH3:27])([CH3:26])[C:22]([O:24][CH3:25])=[O:23]>C(OCC)(=O)C>[CH3:27][C:21]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]1[N:9]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[S:8][CH:11]=1)([CH3:26])[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)C(C)(C)OCCCCCCCC(=O)CCl
Reactant: NC(=S)c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)OCCCCCCCc1csc(-c2ccccc2)n1
Temperature: 120 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
A mixture of 783 mg of thiobenzamide and 1.0 g methyl 2-(9-chloro-8-oxononyloxy)-2-methylpropionate were stirred for 2 hours at 120° C. The reaction solution was cooled and dissolved in ethyl acetate, washed by adding sodium hydrogencarbonate, washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=9:1) to provide 963 mg of the objective compound as pale yellow oil.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:14]1[O:15][C:16]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[C:17]=2[N:18]=1.O>Cl>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:14]1[O:15][C:16]2[C:17](=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=2)[N:18]=1
Reactant: O=[N+]([O-])c1cccc2oc(-c3c(F)cccc3F)nc12
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Product: Nc1cccc2oc(-c3c(F)cccc3F)nc12
Temperature: 60 °C
Reaction time: 2 h

Procedure:
14.3 g (63.5 mmol; 5 eq.) of tin chloride is added to a solution of 3.5 g (12.7 mmol) of 2-(2,6-difluorophenyl)-4-nitro-1,3-benzoxazole in 60 ml of concentrated hydrochloric acid. The mixture is stirred for 2 hours at 60° C., then, after returning to ambient temperature and the addition of 100 ml of water, is neutralized by a 50% aqueous solution of soda. The precipitate formed is filtered on a Celite bed and washed with ethanol. The resulting solution is concentrated under reduced pressure, then the desired product is extracted 3 times with 50 ml of ethyl acetate. The organic phases are combined, washed twice with 30 ml of a saturated solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. The 2-(2,6-difluorophenyl)-1,3-benzoxazol-4-amine is used without other purification in the following stage.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])=O.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])C=CC=CC=1>CN(C)C=O>[CH2:23]([O:22][C:20]([C:19]([CH3:25])=[CH:1][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])=[O:21])[CH3:24]
Reactant: CCOC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1C(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)=Cc1ccccc1C(=O)O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A mixture of 5.0 g (33.3 mmol) of 2-formylbenzoic acid and 14.5 g (40.0 mmol) of ethyl 2-(triphenylphosphanylidene)propionate in 100 cm3 of dimethylformamide is stirred at a temperature in the region of 20° C. for 1 hour. After removal of the solvent, the residue is dissolved in dichloromethane and then extracted twice with sodium bicarbonate solution. The aqueous phases are combined, washed with dichloromethane and then acidified with aqueous 6N hydrochloric acid solution to a pH of between 1 and 2. After extracting twice with dichloromethane, the organic phases are combined, dried over magnesium sulfate and then concentrated. 2-(2-Ethoxycarbonylpropen-1-yl)benzoic acid is thus obtained in the form of a yellow oil, which is used directly in the following step without further purification
Reaction SMILES: Cl.[CH2:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][C:11]=1[CH2:19][O:20][CH3:21])[CH3:3].[NH2:22][C:23](=[N:42]O)[C:24]1[CH:33]=[C:32]2[C:27]([CH2:28][CH2:29][N:30]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31]2)=[CH:26][CH:25]=1>CCOC(C)=O>[CH2:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10]1[CH:18]=[CH:17][C:13]([C:14]2[O:16][N:22]=[C:23]([C:24]3[CH:33]=[C:32]4[C:27]([CH2:28][CH2:29][N:30]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31]4)=[CH:26][CH:25]=3)[N:42]=2)=[CH:12][C:11]=1[CH2:19][O:20][CH3:21])[CH3:3]
Reactant: CCC1CCCCN1c1ccc(C(=O)O)cc1COC
Reactant: CC(C)(C)OC(=O)CN1CCc2ccc(C(N)=NO)cc2C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCC1CCCCN1c1ccc(-c2nc(-c3ccc4c(c3)CN(CC(=O)OC(C)(C)C)CC4)no2)cc1COC

Procedure:
Title compound was prepared following general procedure 2 starting from Intermediate 22 (188 mg; 0.6 mmol) and Intermediate 5 (174 mg; 0.6 mmol). The reaction mixture was diluted with EtOAc, washed with water and brine and evaporated under vacuum.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1.[Li]CCCC.[C:13](=[O:15])=[O:14]>CCOCC>[Br:7][C:5]1[N:6]=[C:2]([C:13]([OH:15])=[O:14])[S:3][CH:4]=1
Reactant: O=C=O
Reactant: Brc1csc(Br)n1
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C(O)c1nc(Br)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To the solution of 2,4-dibromothiazole (50 g, 207 mmol, 1.0 eq.) in Et2O (1000 ml) was added n-BuLi (90 ml, 2.5 M, 1.1 eq.) at −78° C. dropwise and it was stirred for one hour. The reaction solution was poured into dry CO2 at −78° C. and the reaction mixture was warmed to the room temperature. TLC and LCMS showed the reaction was complete. It was quenched with water (100 ml). The Et2O phase was removed. The aqueous phase was adjusted to pH to 2-3 and extracted with ethyl acetate. The organic phase was dried, filtered and concentrated to obtain 35 g (82% y) of the 4-bromothiazole-2-carboxylic acid.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH2:12]([NH2:17])[CH2:13][CH:14]([CH3:16])[CH3:15]>C(O)C>[CH2:10]([O:9][C:7]([C:3]1[CH2:4][CH2:5][CH2:6][C:2]=1[NH:17][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[O:8])[CH3:11]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: CC(C)CCN
Solvent: CCO
Product: CCOC(=O)C1=C(NCCC(C)C)CCC1
Temperature: 25 °C
Yield: 94.7 %

Procedure:
To a solution of ethyl 2-oxocyclopentanecarboxylate (5.00 mL, 32.1 mmol) in ethanol (50 mL) was added isoamylamine (3.8 mL, 32.3 mmol) at 25° C. The mixture was heated at reflux for 12 h. The reaction mixture was allowed to cool to 25° C. and concentrated in vacuo. The crude material was purified by flash column chromatography (Teledyne Isco RediSep Flash Column; 0-30% ethyl acetate in hexanes) to afford the desired product, 2-(3-methylbutylamino)-cyclopent-1-enecarboxylic acid ethyl ester (6.84 g, 30.4 mmol, 95%), as a yellowish oil. 1H NMR (400 MHz, CDCl3) δ 0.92 (6H, d, J=6.1 Hz), 1.28 (3H, t, J=6.9 Hz), 1.44 (2H, q, J=7.2 Hz), 1.63-1.74 (1H, m), 1.80-1.87 (2H, m), 2.50-2.58 (4H, m), 3.19 (2H, q, J=6.7 Hz), 4.14 (2H, q, J=7.1 Hz), 7.34 (1H, bs).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][C:8]2[O:9][CH:10]=[C:11]([C:13](=[O:15])[CH3:14])[N:12]=2)[N:3]=1.[C:16]1([C:22]2[O:26][CH:25]=[N:24][C:23]=2[C:27](O)=[O:28])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:13]([C:11]1[N:12]=[C:8]([CH2:7][N:4]2[CH:5]=[CH:6][C:2]([NH:1][C:27]([C:23]3[N:24]=[CH:25][O:26][C:22]=3[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:28])=[N:3]2)[O:9][CH:10]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)c1coc(Cn2ccc(N)n2)n1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Product: CC(=O)c1coc(Cn2ccc(NC(=O)c3ncoc3-c3ccccc3)n2)n1

Procedure:
Following general procedure B, starting from 1-[2-(3-amino-pyrazol-1-ylmethyl)-oxazol-4-yl]-ethanone and 5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 01: tR=0.88 min; [M+H]+=377.95.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[O:27][C@@H:28]([CH3:33])[C:29]([O:31]C)=O)[N:20]=[CH:19][N:18]=3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.[NH3:34]>>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[O:27][C@@H:28]([CH3:33])[C:29]([NH2:34])=[O:31])[N:20]=[CH:19][N:18]=3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1
Reactant: N
Reactant: COC(=O)[C@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12
Product: C[C@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12)C(N)=O
Yield: 89 %

Procedure:
Using the same procedure as in Example 5, methyl (2S)-2-[(4-{[1-(1,3-thiazol-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (250 mg, 0.54 mmol) was reacted with ammonia to give the title compound as a white solid (216 mg, 89%); NMR Spectrum 1.67 (d, 3H), 5.14 (q, 1H), 6.04 (s, 2H), 7.02 (d, 1H), 7.36 (d, 1H), 7.56 (br s, 1H), 7.66 (d, 1H), 7.83-7.72 (m, 4H), 7.90 (br s, 1H), 8.19 (s, 1H), 8.53 (s, 2H), 10.82 (br s, 1H); Mass spectrum 446.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH2:4][CH2:3]1.[C:19](O)(=[O:30])[CH2:20][C:21]1[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:23](O)=[O:24].CO>C(O)C>[NH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([N:1]3[C:19](=[O:30])[CH2:20][C:21]4[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:23]3=[O:24])[CH2:3][CH2:4]2)=[CH:11]1
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Reactant: O=C(O)Cc1ccccc1C(=O)O
Solvent: CCO
Solvent: CO
Product: O=C1Cc2ccccc2C(=O)N1C1CCN(CCc2c[nH]c3ccccc23)CC1
Temperature: 25 °C

Procedure:
4-Amino-1-[2-(indol-3-yl)ethyl]piperidine (2.43 g, 0.01 mol) and homophthalic acid (1.80 g, 0.01 mol) were heated at 160° (external temperature) for 3 hours then cooled to room temperature, giving a glass. This was dissolved in refluxing methanol and a small quantity of ethanol then cooled at 5° C. overnight. The title compound was deposited as a tacky solid which was collected and dried (0.82 g, 21.2%). The hydrochloride was formed by treatment of the base overnight with ethereal HCl, m.p. 186°-188°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C>CN(C=O)C>[N:12]1([C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: FC(F)(F)c1ccnc(N2CCNCC2)n1
Yield: 57.9 %

Procedure:
A solution of 2-chloro-4-(trifluoromethyl)pyrimidine (2.0 g, 11 mmol), piperazine (2.8 g, 33 mmol) and triethylamine (3.0 mL, 22 mmol) in DMF (10 mL) was stirred at 100° C. in a sealed tube overnight. After removal of most of the solvent, the residue was purified by column chromatography on silica gel (EtOAc to EtOAc/MeOH/NEt3 9/1/0.5) to give 1.48 g (56%) of desired product. MS calculated for C9H11F3N4: (M+H) 233; found 233.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[S:18]1[CH:22]=[CH:21][C:20]([C:23](Cl)=[O:24])=[CH:19]1>>[S:18]1[CH:22]=[CH:21][C:20]([C:23]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:24])=[CH:19]1
Reactant: O=C(Cl)c1ccsc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccsc4)nc23)CC1
Yield: 64.2 %

Procedure:
Beginning with 1.5 gm (6.5 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 1.2 gm (7.8 mMol) 3-thiophenecarbonyl chloride, 1.42 gm (64%) of the title compound were prepared essentially by the procedure described in Example 4.
Reaction SMILES: [Mg].[CH2:2](Br)[C:3]#[CH:4].[CH:6](=[O:11])[CH2:7][CH2:8][CH2:9][CH3:10]>CCOCC>[OH:11][CH:6]([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][C:3]#[CH:2]
Reactant: C#CCBr
Reactant: CCCCC=O
Agent: [Mg]
Solvent: CCOCC
Product: C#CCC(O)CCCC
Temperature: 30 °C

Procedure:
A suspension of 24.3 g. (1.0 mole) of magnesium in 90 ml of dry ether is stirred at room temperature under nitrogen with 100 mg. of mercuric chloride. The reaction is initiated by the addition of 2 ml. of propargyl bromide and maintained by the dropwise addition of a solution of 119.5 g. (1.0 mole) of propargyl bromide and 107.7 g. (1.25 mole) of valeraldehyde in 300 ml. of dry ether. While the initial reaction is quite vigorous and is maintained at 30°C. only by cooling in an ice bath it may become necessary to heat the mixture to reflux temperature after about a third of the ether solution is added in order to maintain the reaction. After the addition is complete the reaction mixture is refluxed until most of the magnesium is dissolved (several hours) and the reaction mixture is decanted from excess magnesium into 1500 ml. of stirred ice-cold ammonium chloride solution. The ether layer is separated and the aqueous layer is extracted three times with 300 ml. portions of ether. The combined ether extract is washed with saturated sodium chloride solution, dried over magnesium sulfate and filtered. Evaporation of the ether under vacuum leaves about 115 mg. of yellow oil, which is distilled through a 15 cm. Vigreaux column at 18 mm. The fraction boiling at 81°-82°C. is collected (36 g.) and the higher-boiling and lower-boiling distillates may be redistilled to yield additional product. The infrared absorption spectrum shows at most a trace of allene (5.1 μ) and gas-liquid partition chromatography shows a purity of about 98% for the main fraction.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([OH:16])=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:46][C:47]([CH2:49]O)=[O:48].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:46][C:47](=[O:48])[CH3:49])=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(=O)CO
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 47.2 %

Procedure:
A solution of 2-(3,4-difluorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (378 mg, 1 mmol), Ph3P (524 mg, 2 mmol) and acetol (74 mg, 1 mmol) in THF (25 mL) at room temperature was treated dropwise with a solution of DIAD (0.4 mL, 2 mmol) in THF (5 mL). The mixture was stirred at room temperature for 6 hours and concentrated in vacuo. The residue was chromatographed (silica gel, 1:1 hexanes-ethyl acetate) to provide the desired product (yield: 205 mg, 48%). mp 169-170° C.; 1H NMR (300 MHz, DMSO-d6) δ 2.08 (s, 3H), 3.30 (s, 3H), 5.30 (s, 2H), 7.48 (m, 1H), 7.62 (q, J=10 Hz, 1H), 7.75 (m, 1H), 7.94 (d, J=9 Hz, 2H), 8.05 (d, J=9 Hz, 2H), 8.21 (s, 1H); MS (APCI+) m/z 435 (M+H)+, (APCI−) m/z 469 (M+Cl)−; Anal. calc. for C20H16F2N2O5S.0.75H2O: C, 53.62; H, 3.93; N, 6.25. Found: C, 53.26; H, 3.61; N, 6.08.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[F:29][C:30]1[CH:37]=[CH:36][C:33]([NH:34][CH3:35])=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:37]=[CH:36][C:33]([N:34]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:10]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=3)=[CH:5][CH:4]=2)[CH3:35])=[CH:32][CH:31]=1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Reactant: CNc1ccc(F)cc1
Product: CN(Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2C(F)(F)F)cc1)c1ccc(F)cc1
Yield: 78 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and 4-Fluoro-N-methylaniline, the title compound was isolated as a yellow solid in 78% yield (98% purity by HPLC).