Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C[O:3][C:4](=[O:19])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([C:15]([O:17]C)=[O:16])[CH:9]=1)[NH2:6].[CH:20]1([N:26]2[C:30]3[CH:31]=[CH:32][C:33]([C:35](O)=[O:36])=[CH:34][C:29]=3[N:28]=[C:27]2[C:38]2[CH:42]=[CH:41][O:40][CH:39]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[C:4]([CH:5]([NH:6][C:35]([C:33]1[CH:32]=[CH:31][C:30]2[N:26]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:27]([C:38]3[CH:42]=[CH:41][O:40][CH:39]=3)=[N:28][C:29]=2[CH:34]=1)=[O:36])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([CH:9]=1)[C:15]([OH:17])=[O:16])([OH:3])=[O:19]
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Reactant: COC(=O)c1cc(C[C@H](N)C(=O)OC)ccc1O
Agent: Cl
Product: O=C(NC(Cc1ccc(O)c(C(=O)O)c1)C(=O)O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1

Procedure:
Racemic 3-(carbomethoxy)tyrosine methyl ester hydrochloride (example 119) was coupled to the carboxylic acid of example 2 in the usual manner and saponified to give the tile compound of example 121.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([NH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:10][NH2:11])[CH:7]=1.[C:24](N1C=CN=C1)(N1C=CN=C1)=[S:25].[K+].[Br-].CC#N>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([N:8]2[C:9]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:16][CH:17]=3)=[N:10][NH:11][C:24]2=[S:25])[CH:7]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(Cl)cc1NC(=NN)c1ccc(C(F)(F)F)cc1
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1-n1c(-c2ccc(C(F)(F)F)cc2)n[nH]c1=S

Procedure:
N-(5-Chloro-2-methoxyphenyl)-4-(trifluoromethyl)benzene carbohydrazonamide (2.5 g, 7.27 mmol) was dissolved in THF (450 ml) under N2 and 1,1′-thiocarbonyldiimidazole (1.95 g, 11.0 mmol) added. The solution was stirred at reflux for 18 h and solvent removed by rotary evaporation. The residue was taken up in ethyl acetate (400 ml) and washed with 0.1N HCl solution (100 ml), water (100 ml) and brine prior to drying over MgSO4. Recrystallization from acetonitrile gave 1.91 g (68%) mp 275-280° C.; IR(KBr, υ=cm−1) 3080, 3058, 3020, 2916, 1506, 1488, 1322, 1288, 1174, 1130, 1110; 1H NMR (300 MHz, DMSO-d6) δ 3.51 (3H, s), 7.17 (1H, d, J=9.0 Hz), 7.53-7.57 (3H, m), 7.69 (1H, d, J=2.6 Hz), 7.77 (2H, d, J=8.4 Hz.s), 14.29 (1H, s); MS(DCl)m/z: 386(MH+). Anal. calcd. for C16H11ClF3N3OS.0.06 CH3CN: C, 49.87; H, 2.90; N, 11.04. Found: C, 50.03; H, 2.94; N, 11.07.
Reaction SMILES: [CH2:1]([Cl:3])Cl.C(Cl)(=O)C(Cl)=O.[F:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15]([C:21]([NH:23][C@H:24]([C:28]([NH:30][CH:31]([CH:40]([OH:43])[CH2:41][F:42])[CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])=C2>CS(C)=O>[Cl:3][C:1]1[C:18]2[C:17](=[CH:13][CH:12]=[C:11]([F:10])[CH:19]=2)[N:16]([CH3:20])[C:15]=1[C:21]([NH:23][C@H:24]([C:28]([NH:30][CH:31]([C:40](=[O:43])[CH2:41][F:42])[CH2:32][C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22]
Reactant: ClCCl
Reactant: CC(C)[C@H](NC(=O)c1cc2cc(F)ccc2n1C)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Product: CC(C)[C@H](NC(=O)c1c(Cl)c2cc(F)ccc2n1C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CF
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
DMSO (0.60 mL, 8.5 mmol) was added to a methylene chloride solution of oxalyl chloride (2.1 mL, 2.0M, 4.2 mmol, in 15 mL of methylene chloride), and the resultant reaction mixture was stirred for 10 minutes under a nitrogen atmosphere at -78° C. A methylene chloride solution of N-[(5-fluoro-1-methylindole-2-carbonyl)valinyl]-3-amino-4-hydroxy-5-fluoropentanoic acid, t-butyl ester (820 mg, 1.7 mmol, in 8 mL of dry methylene chloride), and DMSO (0.4 mL) were added dropwise to the reaction mixture and stirred for 15 minutes at -78° C. TEA (1.4 mL, 10.2 mmol) was added to the mixture dropwise and the mixture was stirred for 10 minutes at -78° C., then was allowed to warm to room temperature. The reaction mixture was partitioned between ethyl acetate and 5% KHSO4 solution and the aqueous layer was back-extracted with ethyl acetate. The combined ethyl acetate solutions were washed with 5% KHSO4 solution and brine, dried over sodium sulfate, and concentrated to give the title product as a slightly yellow solid. Trituration with ether afforded the title product as a white powder (705 mg, 85%). TLC: (methanol/methylene chloride, 1:9): Rf =0.63. MS for C24H30ClF2N3O5 : MH+ =514/516; (M-H)- =512/514.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:31])[C@@H:10]([NH:25][C@H:26]([C:28](O)=[O:29])[CH3:27])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[CH3:44][S:45]([NH2:48])(=[O:47])=[O:46]>C(Cl)Cl.C([O-])(O)=O.[Na+].CCOC(C)=O>[CH2:1]([O:8][C:9](=[O:31])[C@@H:10]([NH:25][C@@H:26]([CH3:27])[C:28]([NH:48][S:45]([CH3:44])(=[O:47])=[O:46])=[O:29])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: C[C@H](N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)OCc1ccccc1)C(=O)O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@H](N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)OCc1ccccc1)C(=O)NS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
To a solution of (S)-2-((S)-1-carboxy-ethylamino)-3-(3′-chloro-biphenyl-4-yl)-propionic acid benzyl ester (600 mg, 1.37 mmol) in DCM (7 mL) and saturated aqueous NaHCO3 solution (2 mL) was added triphosgene (407 mg, 1.37 mmol). After being stirred for 0.5 hours, the reaction mixture was diluted with EtOAc and stirred for additional 0.5 hours until generation of gas was completed. The organic layer was separated, washed with brine and concentrated. This was dissolved in DCM (7 mL) and methanesulfonamide (195 mg, 2.06 mmol) was added. After being stirred at rt for 1 hour, the reaction mixture was diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4, concentrated and purified by silica gel column chromatography (eluent: 10% MeOH in DCM) to give (S)-3-(3′-chloro-biphenyl-4-yl)-2-((S)-2-methanesulfonylamino-1-methyl-2-oxo-ethylamino)-propionic acid benzyl ester. MS: m/z (MW) 515; HPLC retention time 1.58 min (HPLC condition A).
Reaction SMILES: O[CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[OH2:7]>>[CH3:2][CH:3]([O:4][C:3]([CH2:5][OH:6])=[O:4])[C:5]([OH:6])=[O:7]
Reactant: OCC(O)CO
Reactant: O
Product: CC(OC(=O)CO)C(=O)O

Procedure:
The insulin-loaded PLGA/HP55 nanoparticles are prepared as follows: Insulin (5 mg) is dissolved into 0.1% PVA (1.0 mL, pH=2) or glycerin as an internal stabilizer to form internal water phase (W1), poly (lactic acid-co-glycolic acid) (PLGA) (100 mg) and HP55 (50 mg) are dissolved into 5 mL of an organic solvent (volume ratio of dichloromethane and acetone is 4:1 or 3:1) to form an oil phase (O), respectively. Optionally, a hydrophobic carrier is added to the oil phase (O) before pouring W1 into O. At 25° C., 1 mL W1 is poured into O, and the mixture is ultrasonic for 0.5 min at 60 W to obtain an initial W1/O emulsion. The initial emulsion is poured into an external water phase with 1.0% PVA (10 mL) (W2) quickly, and the mixture is ultrasonic for 4 min at 60 W to obtain a double W1/O/W2 emulsion. The acetone and dichloromethane in the double emulsion are eliminated totally by rotary evaporation (45° C., 451 mbar, 15 min). The residue is centrifuged (10° C., 20,000 rpm, 10 min). Finally, the pH-sensitive nanoparticles are obtained from the precipitate after at least twice of washing by distilled water and freeze drying. The molecular weight of the PVA used in the present invention is from 31,000 to 50,000 daltons. The molecular weight of the hydrophobic polymer or carrier used in the present invention is from 20,000 to 40,000 daltons.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[F:10][C:11]([F:21])([F:20])[C:12](=O)[CH2:13][C:14](OCC)=[O:15]>C(O)C>[C:1]1([N:7]2[C:14]([OH:15])=[CH:13][C:12]([C:11]([F:21])([F:20])[F:10])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: Cl
Solvent: CCO
Product: Oc1cc(C(F)(F)F)nn1-c1ccccc1
Yield: 87.9 %

Procedure:
20 g (184.9 mmoles) of phenylhydrazine and 4 ml of concentrated hydrochloric acid were added to a solution of 34.1 g (184.9 mmoles) of ethyl trifluoroacetoacetate dissolved in 500 ml of ethanol. The mixture was refluxed for 1 hour with heating, to give rise to a reaction. After the completion of the reaction, the reaction mixture was subjected to vacuum distillation to remove the most part of the solvent contained therein. The residue was mixed with water to precipitate crystals. The crystals were collected by filtration, washed with water until the filtrate became neutral, and dried to obtain 37.1 g (yield: 87.9%) of 1-phenyl-3-trifluoromethyl-1H-pyrazol-5-ol as ocherous crystals.
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Na].Br[C:14]1[CH:18]=[CH:17][S:16][CH:15]=1>[Cu]I.O>[CH2:1]([O:11][C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCO
Reactant: Brc1ccsc1
Agent: [Cu]I
Agent: [Na]
Solvent: O
Product: CCCCCCCCCCOc1ccsc1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
3-Decyloxythiophene was synthesized as follows. 1-Decanol (0.51 mol, 80.27 g) was added dropwise to 3.5 g (0.15 mol) of sodium metal. After complete disappearance of sodium, the residual alcohol was removed in vacuum and the remaining solid was dissolved in 20˜30 ml DMF. After the solution was heated to 110° C., 12.2 g (0.075 mol) of 3-bromo-thiophene and 1.0 g (0.00053 mol) of copper (I) iodide were added. After 16 hrs of stirring at 110° C., the mixture was poured into water and extracted with ether three times. The filtrate was concentrated in vacuo and the yellow oily residue was chromatographed on a silica column using hexane as the eluent to yield 15.5 g of yellow liquid (86% yield). Mw=240.4. Element Anal. Calcd for C14H24SO: C, 69.94; H, 10.06; 0, 6.66; S, 13.34. Found: C, 69.90; H, 10.00; 0, 6.64; S, 13.30.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][NH2:9])[CH:5]=[CH:4][CH:3]=1.Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1.C(=O)([O-])O.[Na+]>C(O)C>[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][NH:9][C:11]2[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Cc1cccc(CN)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(CNc2ncccc2[N+](=O)[O-])n1
Reaction time: 3 h
Yield: 51 %

Procedure:
A mixture of 2.44 parts of 6-methyl-2-pyridinemethanamine, 3.2 parts of 2-chloro-3nitropyridine, 1.7 parts of sodium hydrogen carbonate and 120 parts of ethanol was stirred for 3 hours at reflux temperature. The reaction mixture was filtered while hot over diatomaceous earth. After cooling, the precipitate which formed in the tiltrate was filtered off and dried, yielding 2.5 parts (51%) of 6-methyl-N-(3-nitro-2-pyridinyl)-2pyridinemethanamine; mp. 131.7° C. (interm. 5).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][C:24]=1[CH:25]=O>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:25][C:24]2[CH:27]=[C:28]([O:31][C:32]([F:33])([F:34])[F:35])[CH:29]=[CH:30][C:23]=2[O:22][CH3:21])[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: COc1ccc(OC(F)(F)F)cc1C=O
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1ccc(OC(F)(F)F)cc1CN1C(=O)C(C)CC1c1c(OC)cccc1OC

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 2-methoxy-5-(trifluoromethoxy)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.92 min.; [M+H]+: 440.07 g/mol.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH2:12][C:13]([NH2:15])=[S:14]>C(O)C>[CH2:4]([C:3]1[N:12]=[C:13]([NH2:15])[S:14][CH:2]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(CCl)Cc1ccccc1
Reactant: NC(N)=S
Solvent: CCO
Product: Nc1nc(Cc2ccccc2)cs1

Procedure:
10 g of 1-chloro 3-phenyl propan-2-one are added to 3.9 g thiourea in 100 ml ethanol. The mixture is refluxed for 2 hours. After cooling the whole is concentrated under reduced pressure. The residue is taken up in diluted ammonia then extracted with ether. After purifications the so obtained solid is converted into its hydrochloride which melts at 127°. The yield is=79%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]3[CH:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:12]=[N:13][N:7]3[C:6]=2[CH:20]=1.CC[C:23]([O-:25])=[O:24].Cl.[OH-].[Na+]>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]3[CH:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:12]([C:23]([OH:25])=[O:24])=[N:13][N:7]3[C:6]=2[CH:20]=1
Reactant: CCC(=O)[O-]
Reactant: Fc1ccc2c(c1)N1N=CC(c3ccccc3)C1CO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1=NN2c3cc(F)ccc3OCC2C1c1ccccc1

Procedure:
A solution of the racemic ester (1-6) (0.5 g, 1.5 mmol) in EtOH (10 mL) was treated with 12N HCl (10 mL) and heated at reflux for 8 h. The reaction was cooled to room temperature and neutralized with 3N NaOH and the mixture extracted with EtOAc (50 mL). The organic solution was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was dissolved in MeCN (0.5 mL) and purified by reverse phase HPLC (YMC J-sphere H80 20×50 mm; eluted with 5-95% MeCN/water+0.1% TFA) to provide racemic (3-1). 1H NMR (500 MHz, CDCl3) δ 7.33 (m, 6H), 7.02 (m, 1H), 6.85 (m, 1H), 4.33 (m, 2H), 4.22 (m, 1H), 3.64 (m, 1H) ppm.
Reaction SMILES: [CH:1]1([C:4]2[C:9]([CH:10]3[CH2:12][CH2:11]3)=[CH:8][C:7]([CH2:13][OH:14])=[C:6]([O:15][CH:16]([CH3:18])[CH3:17])[CH:5]=2)[CH2:3][CH2:2]1>[O-2].[O-2].[Mn+4].C1(C)C=CC=CC=1>[CH:1]1([C:4]2[C:9]([CH:10]3[CH2:12][CH2:11]3)=[CH:8][C:7]([CH:13]=[O:14])=[C:6]([O:15][CH:16]([CH3:18])[CH3:17])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC(C)Oc1cc(C2CC2)c(C2CC2)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CC(C)Oc1cc(C2CC2)c(C2CC2)cc1C=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
Manganese dioxide (14.7 g) was added at room temperature to a toluene (80 mL) solution of (4,5-dicyclopropyl-2-isopropoxyphenyl)methanol (5.22 g), and the mixture was stirred at 80° C. for 1 hour in a nitrogen atmosphere. The reaction mixture was filtered through celite, and then, the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (4.88 g).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])=[N:13][C:12]=2[C:24]([NH2:26])=[O:25])=[CH:7][CH:6]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(N(CC)CC)C>CS(C)=O>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[C:14]1[O:15][C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:31]3[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]3)=[CH:6][CH:7]=2)=[C:12]([C:24]([NH2:26])=[O:25])[N:13]=1
Reactant: CN1CCNCC1
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(OCCCl)cc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1CCN(CCOc2ccc(-c3oc(-c4c(F)cccc4F)nc3C(N)=O)cc2)CC1
Temperature: 150 °C
Reaction time: 0.42 h
Yield: 10.2 %

Procedure:
To a solution of 5-(4-(2-chloroethoxy)phenyl)-2-(2,6-difluorophenyl)oxazole-4-carboxamide (0.020 g, 0.053 mmol) in DMSO (1 ml) were added N-methylpiperazine (11 μl, 0.106 mmol) and triethylamine (12 μl, 0.106 mmol). The reaction was heated to 150° C. via microwave irradiation and held at that temperature for 25 minutes. Purification was performed by preparative HPLC to afford 2-(2,6-difluorophenyl)-5-(4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)oxazole-4-carboxamide (0.0024 g, 0.0054 mmol, 10%) as an off white powder. 1H NMR (CD3OD) δ 2.57 (3H, s), 2.76-2.96 (10H, m), 4.24 (2H, t), 7.06 (2H, m), 7.22 (2H, m), 7.64 (1H, m), 8.26 (2H, m). LCMS (2) 2.25 min; m/z (ES+) 443.
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][S:36]([NH2:39])(=[O:38])=[O:37])=[CH:31][CH:30]=1>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:39][S:36]([CH2:35][C:32]3[CH:31]=[CH:30][C:29]([F:28])=[CH:34][CH:33]=3)(=[O:37])=[O:38])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NS(=O)(=O)Cc1ccc(F)cc1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)Cc2ccc(F)cc2)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and [(4-fluorophenyl)methyl]-sulfonamide (Synlett, 1997, 375) in accordance with Procedure 1, Method B described hereinabove. Yield (32%); 1H NMR (d6-DMSO) δ 11.63 (br s, 1H), 7.53 (d, J=15.7 Hz, 1H), 7.40–7.10 (m, 16H), 6.87 (d, J=8.1 Hz, 2H), 6.41 (d, J=15.7 Hz, 1H), 4.72 (s, 2H), 2.37 (q, J=7.4 Hz, 2H), 0.83 (t, J=7.4 Hz, 3H); APcI m/z: 526 (M+H+).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:32]2[CH2:35][CH2:34][CH2:33]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:15][CH2:16]2)[CH:8]=[C:7]([CH:32]2[CH2:35][CH2:34][CH2:33]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCN3C(=O)c4ccccc4C3=O)CC2)n1
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCN)CC2)n1
Yield: 68.8 %

Procedure:
2.4 g of 2-{4-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-butyl}-isoindole-1,3-dione (5.05 mmol) and 1.0 g of hydrazine hydrate (20.2 mmol) were dissolved in 20 ml of ethanol and heated to reflux for 1 h. The precipitate was filtered and the filtrate extracted with water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated to dryness to yield 1.2 g of the title compound.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:23]=[C:22]([CH2:24][N:25]4[CH2:28][CH:27]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:26]4)[S:21][C:9]=3[N:10]=[C:11]([NH:13][C:14]3[C:15]([NH2:20])=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:35][CH:36]([F:42])[C:37](OCC)=O>O1CCOCC1>[F:35][CH:36]([F:42])[C:37]1[N:13]([C:11]2[N:12]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[C:8]3[N:23]=[C:22]([CH2:24][N:25]4[CH2:28][CH:27]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:26]4)[S:21][C:9]=3[N:10]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]=1
Reactant: Nc1ccccc1Nc1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)sc2n1
Reactant: CCOC(=O)C(F)F
Solvent: C1COCCO1
Product: FC(F)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)sc2n1
Temperature: 100 °C
Yield: 34.2 %

Procedure:
A mixture of N-[7-morpholin-4-yl-2-(3-morpholin-4-ylazetidin-1-ylmethyl)thiazolo[5,4-d]pyrimidin-5-yl]benzene-1,2-diamine (65 mg, 0.14 mmol) and ethyl difluoroacetate (0.3 mL, 2.8 mmol) in 1,4-dioxane (0.5 mL) was heated at 100° C. for 3 days. The reaction mixture was cooled to ambient temperature and loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by reversed phase HPLC (Phenomenex Luna C-18, 20 mM Et3N in water on a gradient of 20 mM Et3N in acetonitrile 30:70 to 2:98) to afford 184 as a white solid (26 mg, 35%). LCMS (Method G): RT=8.03 min, M+H+=543. 1 H NMR (CDCl3, 400 MHz) δ 8.29 (d, J=8.1 Hz, 1 H); 7.91 (d, J=7.8 Hz, 1 H); 7.60 (t, J=53.8 Hz, 1 H); 7.45-7.37 (m, 2 H); 4.43 (m, 4 H); 4.02 (s, 2 H); 3.89 (t, J=4.7 Hz, 4 H); 3.74 (t, J=4.5 Hz, 4 H); 3.69 (t, J=6.2 Hz, 2 H); 3.21-3.07 (m, 3 H) and 2.37 (m, 4 H)
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:11])[NH:5][C:6]([CH3:10])=[CH:7][C:8]=1[CH3:9])#[N:2].F[B-](F)(F)F.[CH2:17]([O+](CC)CC)[CH3:18]>ClCCl>[C:1]([C:3]1[C:4]([O:11][CH2:17][CH3:18])=[N:5][C:6]([CH3:10])=[CH:7][C:8]=1[CH3:9])#[N:2]
Reactant: CC[O+](CC)CC
Reactant: Cc1cc(C)c(C#N)c(=O)[nH]1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOc1nc(C)cc(C)c1C#N

Procedure:
3-Cyano-2-ethoxy-4,6-dimethylpyridine was prepared by reacting 3-cyano-4,6-dimethylpyrid-2-one with triethyloxonium tetrafluoroborate in dichloromethane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16](Cl)=[C:11]3[C:10]([I:18])=[N:9]2)=[CH:5][CH:4]=1.C([O-])(=[O:23])C.[Cs+].CN(C=O)C>O>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][CH:15]=[C:16]([OH:23])[C:11]=3[C:10]([I:18])=[N:9]2)=[CH:5][CH:4]=1
Reactant: CC(=O)[O-]
Reactant: COc1ccc(Cn2nc(I)c3c(Cl)ccnc32)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2nc(I)c3c(O)ccnc32)cc1
Temperature: 100 °C
Yield: 33.4 %

Procedure:
A mixture of 1-(4-methoxybenzyl)-4-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine (7.00 g, 17.52 mmol, obtained from Example 84, Step D), cesium acetate (33.62 g, 175.2 mmol) and DMF (175 mL) was heated to 100° C. for 12 hours. The reaction was cooled to room temperature, diluted with water (50 mL), extracted with EtOAc (100 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (5% MeOH in CH2Cl2) to afford the product (2.23 g, 79% yield) as a light orange solid. LRMS (APCI pos) m/e 381.9 (M+H).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([NH2:18])(=[O:17])=[O:16])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:19](=O)([O:27]C1C=CC=CC=1)[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>CN(C)C=O>[C:9]1([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH:18][C:19](=[O:27])[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:16])=[O:17]
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Reactant: NS(=O)(=O)c1ccccc1-c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NS(=O)(=O)c1ccccc1-c1ccccc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
Sodium hydride (2.6 g) was added to dry dimethylformamide (200 ml), and at less than 10° C., a solution of 2-phenylbenzenesulfonamide (23.3 g) in dimethylformamide (50 ml) was added. The mixture was then stirred at room temperature for 1 hour, and diphenyl carbonate (21.4 g) was added at room temperature. The mixture was further stirred at room temperature for 1 hour. Then, after the whole mixture was added to ice water, the mixture was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was dehydrated, and ethyl acetate was distilled off under reduced pressure to give phenyl N-(2-biphenylylsulfonyl)carbamate (35 g) as a solidified desired compound represented by the following formula. mp. 114°-117° C. ##STR11##
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:4](C)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH3:12])=[CH:7][CH:6]=2.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[CH:27]O)[C:22](OCC)=[O:23])=[CH:17][CH:16]=1>>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[C:22](=[O:23])[N:2]([CH3:1])[C:3]3[NH:4][C:5]4[C:10]([C:11]=3[CH:27]=2)=[CH:9][C:8]([CH3:12])=[CH:7][CH:6]=4)=[CH:19][CH:20]=1
Reactant: CNc1cc2cc(C)ccc2n1C
Reactant: CCOC(=O)C(=CO)c1ccc(Br)cc1
Product: Cc1ccc2[nH]c3c(cc(-c4ccc(Br)cc4)c(=O)n3C)c2c1

Procedure:
This compound is prepared according to the usual methods by reaction of N,1,5-trimethyl-1H-indole-2-amine with ethyl 2-(4-bromophenyl)-3-hydroxy-2-propenoate.