Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B#B.[CH2:3]([N:6]([CH2:20][CH2:21][CH3:22])[C:7](=O)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:4][CH3:5].CO>O1CCCC1>[CH2:20]([N:6]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:3][CH2:4][CH3:5])[CH2:21][CH3:22]
Reactant: CCCN(CCC)C(=O)Cc1ccc(OC)c(OC)c1
Agent: B#B
Solvent: CO
Solvent: C1CCOC1
Product: CCCN(CCC)CCc1ccc(OC)c(OC)c1

Procedure:
To 200 ml. (0.20 mole) of a 1M solution of diborane in tetrahydrofuran cooled in an ice bath was added dropwise a solution of 27.8 g. (0.10 mole) of N,N-di-(n-propyl)-3,4-dimethoxyphenylacetamide in about 200 ml. of anhydrous tetrahydrofuran, under argon. The mixture was refluxed for one and one-quarter hours, cooled and methanol added carefully. When the bubbling subsided the reaction mixture was evaporated in vacuo. The residue was dissolved in methanol, ethereal hydrogen chloride was added and the mixture evaporated in vacuo slowly. This residue was dissolved in water, washed with ether, basified and extracted with ether. The dried solution was evaporated to yield N,N-di-(n-propyl)-3,4-dimethoxyphenethylamine.
Reaction SMILES: C([Mg]Cl)(C)C.[CH2:6]([N:13]1[C:17]([C:18]2[CH:19]=[CH:20][C:21]3[O:26][CH2:25][CH2:24][CH2:23][C:22]=3[CH:27]=2)=[C:16](Br)[C:15]([C:29]([F:32])([F:31])[F:30])=[N:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[C:34](=[O:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36]>O1CCCC1.O>[CH2:6]([N:13]1[C:17]([C:18]2[CH:19]=[CH:20][C:21]3[O:26][CH2:25][CH2:24][CH2:23][C:22]=3[CH:27]=2)=[C:16]([C:34](=[O:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:15]([C:29]([F:32])([F:31])[F:30])=[N:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: FC(F)(F)c1nn(Cc2ccccc2)c(-c2ccc3c(c2)CCCO3)c1Br
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1c(C(F)(F)F)nn(Cc2ccccc2)c1-c1ccc2c(c1)CCCO2
Temperature: -20 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
Under nitrogen, isopropyl magnesium chloride 2M in tetrahydrofuran (0.30 mL, 0.59 mmol) was added dropwise to a solution of 1-benzyl-4-bromo-5-(3,4-dihydro-2H-1-benzopyran-6-yl)-3-(trifluoromethyl)-1H-pyrazole (49d) (200 mg, 0.46 mmol) in anhydrous tetrahydrofuran (1.0 mL), previously cooled to −20° C. After 2 hour stirring at the same temperature, ethyl chlorooxoacetate (87 μL, 0.78 mmol) was dropwise added. The mixture was stirred at −20° C. for 60 minutes before being poured in water (2 mL). The mixture was extracted with ethyl acetate (2×3 mL) and the organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (cyclohexane/ethyl acetate 75/25) to provide the desired keto-ester (49e) (80 mg, 0.17 mmol, 38%)
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:21]=[C:22]([O:28][CH3:29])[C:23]([O:26][CH3:27])=[CH:24][CH:25]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[CH3:27][O:26][C:23]1[CH:24]=[C:25]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)[CH:20]=[CH:21][C:22]=1[O:28][CH3:29]
Reactant: COc1ccc(Br)cc1OC
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(-c2cccc3[nH]ccc23)cc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (10 g, 41.1 mmol), and 4-bromoveratrole (8.93 g, 41.1 mmol) in THF (140 mL) were added Palladium catalyst Pd(PPh3)4 (1.43 g, 1.23 mmol) and the freshly prepared sodium hydroxide solution (5.08 g in 58 mL of water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 80° C. oil bath for overnight. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed with brine, and dried over Na2SO4. After filtration, the solvents were evaporated, and the crude product was purified by a silica gel column to give 7.47 g (72%) of 4-(3,4-dimethoxy-phenyl)-1H-indole.
Reaction SMILES: [N:1]1([S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16](O)=[O:17])(=[O:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:33]=[CH:32][C:27]2[N:28]=[C:29]([NH2:31])[S:30][C:26]=2[CH:25]=1>>[N:1]1([S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([NH:31][C:29]2[S:30][C:26]3[CH:25]=[C:24]([O:23][CH3:22])[CH:33]=[CH:32][C:27]=3[N:28]=2)=[O:17])(=[O:11])=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCc3ccccc32)c1
Reactant: COc1ccc2nc(N)sc2c1
Product: COc1ccc2nc(NC(=O)c3cccc(S(=O)(=O)N4CCc5ccccc54)c3)sc2c1

Procedure:
3-(indolin-1-ylsulfonyl)benzoic acid (3) (200 mg, 0.66 mmol) and 6-methoxybenzo[d]thiazol-2-amine (99 mg, 0.55 mmol) using method C. The residue was purified using flash chromatography eluting with 0-40% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give 3-(indolin-1-ylsulfonyl)-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide as an off-white solid. Yield: 89 mg (35%). 1H-NMR: 8.57 (s, 1H), 8.37 (d, J=8 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.77-7.66 (m, 2H), 7.63 (d, J=2.5 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.22 (t, J=7.5 Hz, 1H), 7.16 (d, J=7.5 Hz, 1H), 7.07 (dd, J=8.5, 2.5, 1H), 6.99 (dt, J=7.5, 7.5, 1.0 Hz, 1H), 4.02 (t, J=8.5 Hz, 2H), 3.83 (s, 3H), 2.92 (t, J=8.5 Hz, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:9]#[N:10])=[CH:5][CH:6]=[CH:7][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:30]([C:32]1[CH:50]=[CH:49][C:35]([CH2:36][N:37]2[C:41]([CH2:42][OH:43])=[C:40]([Cl:44])[N:39]=[C:38]2[CH2:45][CH2:46][CH2:47][CH3:48])=[CH:34][CH:33]=1)=O.C[O-].[Na+]>CN(C)C=O.O>[C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1/[CH:2]=[CH:30]/[C:32]1[CH:33]=[CH:34][C:35]([CH2:36][N:37]2[C:41]([CH2:42][OH:43])=[C:40]([Cl:44])[N:39]=[C:38]2[CH2:45][CH2:46][CH2:47][CH3:48])=[CH:49][CH:50]=1)#[N:10]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(C=O)cc1
Reactant: N#Cc1ccccc1CBr
Agent: C[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(/C=C/c2ccccc2C#N)cc1
Reaction time: 3 h
Yield: 22.2 %

Procedure:
To a solution of 0.98 g of α-bromo-o-tolunitrile in 25 mL of dimethylformamide at 25° was added 1.40 g of triphenylphosphine. The mixture was stirred at 80° for 3 hours, then treated with 1.53 g of 1-(4-formylbenzyl)-2-butyl-4-chloro-5-hydroxymethylimidazole, followed immediately by 0.54 g of sodium methoxide, and the mixture was diluted with water and extracted with benzene. The organic phases were combined and washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography on silica gel (elution: 0-20% ethyl acetate/benzene) afforded 0.45 g of 1-[(2'-cyano-trans-stilben-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole; NMR (200 MHz, CDCl3): δ8.01 (d, 1h); 7.85 (d, 1h); 7.73 (t, 1h); 7.47 (t, 1h); 7.44 (AB, 2H, J=16.3); 7.38 (A2B2, 4H); 5.28 (s, 2H); 5.24 (t, 1H); 4.34 (d, 2H); 2.49 (t, 2H); 1.47 (quint., 2H); 1.24 (sext., 2H); 0.79 (t, 3H).
Reaction SMILES: Cl.[N:2]1([CH:8]2[CH2:20][CH2:19][C:18]3[C:10](=[CH:11][C:12]4[C:13]([CH:17]=3)=[N:14][O:15][N:16]=4)[CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:22][CH2:23][C:24]1[CH:33]=[CH:32][C:27]2[C:28](=[O:31])[O:29][CH2:30][C:26]=2[CH:25]=1.C(N(CC)CC)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[N:14]1[O:15][N:16]=[C:12]2[CH:11]=[C:10]3[C:18]([CH2:19][CH2:20][CH:8]([N:2]4[CH2:3][CH2:4][N:5]([CH2:22][CH2:23][C:24]5[CH:33]=[CH:32][C:27]6[C:28](=[O:31])[O:29][CH2:30][C:26]=6[CH:25]=5)[CH2:6][CH2:7]4)[CH2:9]3)=[CH:17][C:13]=12
Reactant: O=C1OCc2cc(CCBr)ccc21
Reactant: c1c2c(cc3nonc13)CC(N1CCNCC1)CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1OCc2cc(CCN3CCN(C4CCc5cc6nonc6cc5C4)CC3)ccc21
Temperature: 55 °C

Procedure:
To a solution of 6-Piperazin-1-yl-5,6,7,8-tetrahydronaphtho[2,3-c][1,2,5]oxadiazole hydrochloride (20 mg, 0.068 mmol), 5-(2-bromoethyl)-2-benzofuran-1(3H)-one (33 mg, 0.14 mmol), and tetrabutylammonium iodide (2.5 mg, 6.8 umol) in DMF (2 mL) was added triethylamine (0.028 mL, 0.20 mmol). The mixture was heated to 55° C. for 6 hours. LC showed formation of the desired product, which was separated by mass-directed HPLC. LC-MS (IE, m/z): 419 [M+1]+. (0.21 μM)
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](O)=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[F:21].C(N1C=CN=C1)([N:24]1C=CN=C1)=O.C(=O)=O.N>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH2:24])=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[F:21]
Reactant: CN1Cc2c(C(=O)O)ncn2-c2ccc(F)c(Cl)c2C1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Agent: O=C=O
Solvent: CN(C)C=O
Product: CN1Cc2c(C(N)=O)ncn2-c2ccc(F)c(Cl)c2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
19.8 g (0.0639 mol) of 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid were suspended in 100 ml of N,N-dimethylformamide while gassing with argon and treated portionwise at room temperature with 10.9 g (0.0671 mol) of 1,1'-carbonyldiimidazole. After the CO2 evolution had finished the beige suspension was stirred at 50° for 30 min., cooled and treated dropwise at a temperature below 25° within about 10 min. with 20 ml of 25% ammonia. After stirring for 15 minutes the brownish solution obtained was poured into 600 ml of ice-water. The mixture was stirred at room temperature for 30 min. and filtered, whereupon the crystals were rinsed with a total of 200 ml of water. After drying there were obtained 14.4 g (73%) of 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide as beige crystals; m.p. 292°-294°.
Reaction SMILES: [OH:1]O.[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([Cl:14])[C:5]=1[N:15]1[C:19]([CH3:20])=[C:18]([S:21][CH3:22])[C:17]([CH:23]=[N:24][OH:25])=[N:16]1>FC(F)(F)C(O)=O>[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:7]=[C:6]([Cl:14])[C:5]=1[N:15]1[C:19]([CH3:20])=[C:18]([S:21]([CH3:22])=[O:1])[C:17]([CH:23]=[N:24][OH:25])=[N:16]1
Reactant: CSc1c(C=NO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C
Reactant: OO
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(S(C)=O)c(C=NO)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
30% Hydrogen peroxide solution (0.32 ml) was added to a solution of 1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-methyl-4-methylthio-1H-pyrazole-3-carboxaldehyde oxime (0.8 g) in trifluoroacetic acid at 20° C. The reaction solution was partitioned between water and dichloromethane and the organic layer dried (magnesium sulfate), evaporated and flash-chromatographed on silica gel, eluting with dichloromethane/ethyl acetate (3:1) to give 1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-methyl-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde oxime (0.29 g), m.p. 210-214° C. Compound 30 and 1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-methyl-4-methylsulfonyl-1H-pyrazole-3-carboxaldehyde oxime (0.2 g), m.p. 211-2120° C. Compound 31.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[C:13]([F:22])=[C:14]([F:21])[C:15]4[N:16]=[C:17]([CH3:20])[O:18][C:19]=4[C:11]=3[NH:10][C:9]2=[O:23])=[C:4]([F:24])[CH:3]=1.[CH:25]1([S:28](Cl)(=[O:30])=[O:29])[CH2:27][CH2:26]1.[H-].[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[C:13]([F:22])=[C:14]([F:21])[C:15]4[N:16]=[C:17]([CH3:20])[O:18][C:19]=4[C:11]=3[N:10]([S:28]([CH:25]3[CH2:27][CH2:26]3)(=[O:30])=[O:29])[C:9]2=[O:23])=[C:4]([F:24])[CH:3]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Cc1nc2c(F)c(F)c3c([nH]c(=O)n3-c3ccc(Br)cc3F)c2o1
Agent: [H-]
Agent: [Na+]
Product: Cc1nc2c(F)c(F)c3c(c2o1)n(S(=O)(=O)C1CC1)c(=O)n3-c1ccc(Br)cc1F
Yield: 42.1 %

Procedure:
Intermediate I-26a was prepared from 6-(4-bromo-2-fluoro-phenyl)-4,5-difluoro-2-methyl-6,8-dihydro-imidazo[4′,5′:3,4]benzo[1,2-d]oxazol-7-one (I-17a: 200 mg, 0.52 mmol), cyclopropanesulfonyl chloride (111 mg, 0.781 mmol) and NaH (31.2 mg, 0.781 mmol) using procedures analogous to those described above for Intermediate I-19a to afford 110 mg of the product (42.1% yield). H1NMR (CDCl3, 300 MHz): δ 7.52-7.39 (m, 3H), 3.35-3.24 (m, 1H), 2.72 (s, 3H), 1.75-1.60 (m, 2H), 1.35-1.25 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[CH:24][CH:23]=[C:22]3Cl)=[CH:4][N:3]=1.O.[CH3:31][O:32][C:33]1[C:38](B(O)O)=[CH:37][CH:36]=[CH:35][N:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].O1CCOCC1>[Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([C:19]2[CH:28]=[C:27]3[C:26](=[CH:21][CH:20]=2)[N:25]=[CH:24][CH:23]=[C:22]3[C:38]2[C:33]([O:32][CH3:31])=[N:34][CH:35]=[CH:36][CH:37]=2)=[CH:4][N:3]=1
Reactant: COc1ncccc1B(O)O
Reactant: O=S(=O)(Nc1cc(-c2ccc3nccc(Cl)c3c2)cnc1Cl)c1ccc(F)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ncccc1-c1ccnc2ccc(-c3cnc(Cl)c(NS(=O)(=O)c4ccc(F)cc4)c3)cc12
Reaction time: 0.33 h

Procedure:
(Some starting materials may be obtained from Frontier Scientific, Inc., Logan, Utah) To a 5 mL CEM microwave tube was added N-(2-chloro-5-(4-chloroquinolin-6-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (0.07 g, 0.2 mmol), 2-methoxypyridine-3-boronic acid hydrate (0.07 g, 0.5 mmol), sodium carbonate (0.2 mL, 0.5 mmol), Pd fibrecat PPh (20% wt, 15 mg), and dioxane (3 mL). The vial was sealed and placed into CEM microwave for 20 min. at 120° C., with 100 watts of power. LC/MS showed a desired product mass as a major peak. The reaction mixture was partitioned between DCM/water. The aqueous layer was extracted with DCM (2×10 mL). The combined organic layers were washed with water, brine, dried over MgSO4 and concentrated. The crude product was purified using SiO2 (12 g) chromatography with hexanes:acetone=80%:20% as the solvent system to afford the desired product as light yellow solid (25 mg). MS (ESI pos. ion) m/z: calc'd for C26H18ClFN4O3S: 520.1; found: 521.3 (M+1). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.95 (s, 3 H) 7.06-7.19 (m, 3 H) 7.42 (d, J=4.53 Hz, 1 H) 7.67 (dd, J=7.31, 1.90 Hz, 1 H) 7.72 (d, J=1.90 Hz, 1 H) 7.75-7.82 (m, 2 H) 7.90 (dd, J=8.77, 2.05 Hz, 1 H) 8.20 (d, J=2.34 Hz, 1 H) 8.31 (d, J=8.77 Hz, 1 H) 8.34 (d, J=2.19 Hz, 1 H) 8.40 (dd, J=5.04, 1.97 Hz, 1 H) 9.03 (d, J=4.38 Hz, 1 H).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.CN(C)C=O.[CH3:12][O:13][C:14]([C:16]1[S:17][C:18]([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[N:26]([CH:30]([CH3:32])[CH3:31])[CH:25]=C3)=[CH:19][CH:20]=1)=[O:15]>ClCCl>[CH3:12][O:13][C:14]([C:16]1[S:17][C:18]([C:21]2[CH:29]=[C:28]3[C:27](=[CH:23][CH:22]=2)[N:26]([CH:30]([CH3:32])[CH3:31])[CH:25]=[C:2]3[CH:1]=[O:5])=[CH:19][CH:20]=1)=[O:15]
Reactant: COC(=O)c1ccc(-c2ccc3c(ccn3C(C)C)c2)s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc3c(c2)c(C=O)cn3C(C)C)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
To anhydrous dichloromethane (30 mL) was added oxalyl chloride (0.1 mL, 1.2 mmol). N,N-dimethylformamide (0.1 mL, 1.2 mmol) was added at 0° C., and stirred for 30 min at 0° C. To this reaction solution was added 5-(1-isopropyl-indol-5-yl)thiophene-2-carboxylic acid methyl ester (0.3 g, 1.0 mmol) obtained in Preparation 32, which was then stirred for 1 h at room temperature. The solvent was removed, tetrahydrofuran (30 mL) and 20% aqueous ammonium acetate solution (30 mL) were added to the residue, and the mixture was heated for 30 min while being stirred under reflux. The reaction solution was cooled, ethyl acetate was added, and the mixture was washed with aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting solid was filtered, washed with ethyl acetate and dried to give the title compound (0.32 g, 99% Yield).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5]Br)[CH3:2].[OH:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1>CN1CCCC1=O.C(OCC)C>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1)[CH3:2]
Reactant: CCOC(CBr)OCC
Reactant: O=Cc1ccc(O)cc1
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: CCOC(COc1ccc(C=O)cc1)OCC
Yield: 96.6 %

Procedure:
Bromoacetaldehyde-diethyl-acetal (98.5 g, 0.5 m) and p-hydroxybenzaldehyde (76.4 g, 0.63 m) were dissolved in N-methylpyrrolidone (250 cm3) and heated at 120° for 12 hours. The reaction mixture was cooled, diluted with diethyl ether and the ether layer was extracted four times with 5% sodium hydroxide solution to remove excess of p-hydroxybenzaldehyde. The ether was removed and the product distilled under reduced pressure to give 115 g (97%) of p-formylphenoxy-acetaldehyde-diethyl-acetal, b. 139°-140°/1.5 mbs. Acetylbenzene-sulphonic acid (sodium salt, 40 g, 0.18 m) was dispersed in a mixture of methanol (400 cm3) and 10% aqueous sodium hydroxide (150 cm3).
Reaction SMILES: Br[CH:2]([CH3:16])[C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:8]([O:10][CH3:11])=[O:9])=O.Cl.[N:18]1([C:23](=[NH:25])[NH2:24])[CH2:22][CH2:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.O>[CH3:15][C:14]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[C:3]1[NH:25][C:23]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:24][C:2]=1[CH3:16]
Reactant: N=C(N)N1CCCC1
Reactant: COC(=O)c1ccc(C)c(C(=O)C(C)Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(-c2[nH]c(N3CCCC3)nc2C)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 43.9 %

Procedure:
Into a 50-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methyl 3-(2-bromopropanoyl)-4-methylbenzoate (compound 197.2, 500.0 mg, 1.75 mmol) in N,N-dimethylformamide (15 mL). Pyrrolidine-1-carboximidamide hydrochloride (compound 197.1, 260.8 mg, 1.75 mmol) was treated with K2CO3, then added to the reaction. The reaction mixture was stirred for 1 h at 50° C. The reaction mixture was diluted with 30 mL of H2O. The aqueous phase was extracted with 3×30 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with PE/EtOAc (1:1)˜EtOAc/methanol (15:1) as eluent to furnish 230.0 mg (44%) of the title compound as a dark blue solid.
Reaction SMILES: [CH:1]([C:4]1[NH:5][CH:6]=[C:7]([C:9]([CH3:20])([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[CH3:10])[N:8]=1)([CH3:3])[CH3:2].[C:21](=O)([O-])[O-].[K+].[K+].IC>C1COCC1>[CH:1]([C:4]1[N:5]([CH3:21])[CH:6]=[C:7]([C:9]([CH3:10])([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[CH3:20])[N:8]=1)([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)c1nc(C(C)(C)c2cccc([N+](=O)[O-])c2)c[nH]1
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)c1nc(C(C)(C)c2cccc([N+](=O)[O-])c2)cn1C
Temperature: 50 °C
Yield: 54.4 %

Procedure:
To a solution of 2-isopropyl-4-[1-methyl-1-(3-nitro-phenyl)-ethyl]-1H-imidazole (0.35 g, 1.28 mmol) in THF (2 mL) was added potassium carbonate (0.21 g, 1.5 mmol) and iodomethane (0.12 mL, 1.92 mmol). The mixture was heated at 50° C. for 5 h then concentrated in vacuo. The residue was partitioned between water and DCM then the organic phase was dried over sodium sulfate and evaporated to afford 2-isopropyl-1-methyl-4-[1-methyl-1-(3-nitro-phenyl)-ethyl]-1H-imidazole (0.2 g, 56%) as colourless semisolid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[C:31](F)=[CH:30][CH:29]=CC=3F)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.ClC1N=C(C2[S:45]C(C(C)C)=NC=2C2C=C(C=CC=2)N)C=CN=1.S1C=CC=C1S(Cl)(=O)=O>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:14])[CH3:15])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[S:45][CH:29]=[CH:30][CH:31]=3)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)c1nc(-c2cccc(N)c2)c(-c2ccnc(Cl)n2)s1
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Agent: O=S(=O)(Cl)c1cccs1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccs3)c2)c(-c2ccnc(Cl)n2)s1
Yield: 87.8 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14, using 3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline (600 mg, 1.8 mmol) and thiophene-2-sulfonyl chloride (331 mg, 1.1 mmol) the title compound was obtained (760 mg, 87.8% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.27 (d, J=5.3 Hz, 1H), 7.51-7.57 (m, 2H), 7.29-7.38 (m, 2H), 7.20-7.27 (m, 2H), 7.13-7.17 (br, 1H), 6.98-7.03 (m, 1H), 6.88 (d, J=5.3 Hz, 1H), 3.27-3.37 (m, 1H), 1.43 (d, J=7.1 Hz, 6H). MS (ES+): 477 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][C:3]=1[CH3:21].[F:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=O)[O:31]C2C=CC=CC=2)=[CH:25][C:24]=1[C:39]([F:42])([F:41])[F:40].CCN(C(C)C)C(C)C>C1COCC1>[F:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:1][C:2]2[CH:20]=[CH:19][C:5]([O:6][C:7]3[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([CH:16]4[CH2:17][CH2:18]4)=[O:15])[CH:8]=3)=[CH:4][C:3]=2[CH3:21])=[O:31])=[CH:25][C:24]=1[C:39]([F:40])([F:41])[F:42]
Reactant: O=C(Nc1ccc(F)c(C(F)(F)F)c1)Oc1ccccc1
Reactant: Cc1cc(Oc2cc(NC(=O)C3CC3)ncn2)ccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(Oc2cc(NC(=O)C3CC3)ncn2)ccc1NC(=O)Nc1ccc(F)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
Add N-[6-(4-amino-3-methyl-phenoxy)pyrimidin-4-yl]cyclopropanecarboxamide (99 mg, 0.35 mmol), phenyl N-[4-fluoro-3-(trifluoromethyl)phenyl]carbamate (100 mg, 0.35 mmol) and DIEA (135 mg, 1.05 mmol) in THF (4 mL), stir at 80° C. for 2 hrs, Remove the volatiles, suspend the residue in DCM, filter and collect the solid to get the target compound (132 mg, 77%). MS: (M+1): 490.3.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[C:4]([C:18]([F:21])=[CH:19][CH:20]=1)[C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=2)[NH:9][CH:8]=1)=[O:6].[N:23]1([S:28](Cl)(=[O:30])=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1.Cl>O1CCCC1.N1C=CC=CC=1>[C:16]([C:13]1[CH:14]=[C:15]2[C:7]([C:5]([C:4]3[C:3]([F:22])=[C:2]([NH:1][S:28]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)(=[O:30])=[O:29])[CH:20]=[CH:19][C:18]=3[F:21])=[O:6])=[CH:8][NH:9][C:10]2=[N:11][CH:12]=1)#[N:17]
Reactant: O=S(=O)(Cl)N1CCCC1
Reactant: N#Cc1cnc2[nH]cc(C(=O)c3c(F)ccc(N)c3F)c2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: N#Cc1cnc2[nH]cc(C(=O)c3c(F)ccc(NS(=O)(=O)N4CCCC4)c3F)c2c1
Temperature: 60 °C
Reaction time: 48 h
Yield: 24.7 %

Procedure:
To 3-(3-amino-2,6-difluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (28, 354 mg, 1.19 mmol) in 9.5 mL of tetrahydrofuran, 0.84 mL of pyridine was added. Pyrrolidine-1-sulfonyl chloride (31, 403 mg, 2.37 mmol) was added and the solution was stirred at 60° C. for 48 hours. The reaction mixture was poured into 1 M aqueous hydrochloric acid and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The crude material was purified by silica gel column chromatography eluting with ethyl acetate and hexane. Appropriate fractions were combined and the solvent removed under reduced pressure to provide the desired compound (P-0006, 127 mg). MS(ESI)[M+H+]+=432.1.