Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:16][C:17]1[C:21]2[C:22]([OH:30])=[C:23]([CH2:27][CH2:28][CH3:29])[CH:24]=[C:25]([Cl:26])[C:20]=2[O:19][CH:18]=1>C(Cl)CCl>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:1]([C:18]2[O:19][C:20]3[C:25]([Cl:26])=[CH:24][C:23]([CH2:27][CH2:28][CH3:29])=[C:22]([O:30][C:1](=[O:10])[C:2]4[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=4)[C:21]=3[C:17]=2[CH3:16])=[O:10])=[CH:3][CH:4]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCCc1cc(Cl)c2occ(C)c2c1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCCc1cc(Cl)c2oc(C(=O)c3ccc(OC)cc3)c(C)c2c1OC(=O)c1ccc(OC)cc1
Reaction time: 0.17 h
Yield: 77.9 %

Procedure:
A solution of p-anisoyl chloride (3.5 gm; 20.5 mmoles) in ethylene dichloride (10 mL) was added slowly to a cooled suspension of aluminium chloride (4.0 gm; 30 mmoles) in ethylene dichloride (100 mL). After stirring for a period of 10 minutes, 3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (1.14 gm; 5 mmoles) in dichloroethylene (5 mL) was added over a period of 2 minutes. The reaction mixture was stirred at room temperature for 1 hour. It was cooled with an ice bath and ice was added slowly. When the vigorous reaction subsided, the organic layer was separated and the aqueous phase was extracted with methylene chloride. The organic phases were combined, dried (Na2SO4), and concentrated in vacuo. The residue was chromatographed on silica gel and eluted with 10% ethylacetate in hexane to yield 1.92 gm (78%) of 2-(p-methoxybenzoyl)-3-methyl-4-(p-methoxybenzoyloxy)-5-propyl-7-chlorobenzofuran, mp.103°-105° C.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH:19]1([CH2:25][C:26](Cl)=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C1COCC1>[CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:26](=[O:27])[CH2:25][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CC1CCCCC1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(CC1CCCCC1)N1C(=O)OCC1Cc1ccccc1
Reaction time: 0.5 h

Procedure:
Thionyl chloride (20.0 mL) was added dropwise to cyclohexyl acetic acid (10.0 g, 70 mmol). After cessation of gas evolution, the reaction mixture was heated to reflux overnight. The reaction mixture was then concentrated in vacuo to yield cyclohexyl acetyl chloride. To a solution of (S)-(−)-4-benzyl-2-oxazolidinone (11.6 g, 65 mmol) in THF (130 mL) at −60° C. was added 1.6 M n-butyl lithium (42 mL, 67 mmol), dropwise, and the reaction mixture was stirred for 0.5 h. To the resulting solution was then added the cyclohexylacetyl chloride, and the resulting mixture was stirred at 0° C. for 2 h. The reaction was quenched with aqueous saturated NaHCO3 solution and extracted with ethyl acetate. The organic layer was dried (MgSO4) and concentrated until a slurry was formed. The slurry was filtered and washed with cold diethyl ether. The filtrate was re-concentrated to yield a solid. The combined solid, 4-benzyl-3-(2-cyclohexyl-acetyl)-oxazolidin-2-one, was dried in vacuo.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14]3=[N:15][C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[C:18]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:17]=4[N:13]3[CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:4]([CH3:28])[CH:3]=1.C([Li])CCC.[CH3:34][S:35]SC>O1CCCC1.[Cl-].[NH4+]>[Cl:22][C:21]1[C:16]2[N:15]=[C:14]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([S:35][CH3:34])=[CH:3][C:4]=4[CH3:28])[CH2:9][CH2:10][CH2:11][CH2:12][N:13]3[C:17]=2[C:18]([CH:23]([CH2:24][CH3:25])[CH2:26][CH3:27])=[CH:19][CH:20]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ccc(Br)cc1C
Reactant: CSSC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ccc(SC)cc1C
Reaction time: 0.33 h
Yield: 53.7 %

Procedure:
To a solution of 1-(4-bromo-2-methylphenyl)-10-chloro-7-(1-ethylpropyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazole (572 mg, 1.24 mmol) in tetrahydrofuran (10 mL) was added n-butyllithium (1.60 M solution in n-hexane, 0.85 mL, 1.36 mmol) at −78° C., and the mixture was stirred for 20 min. To the mixture was added dimethyl disulfide (0.34 mL, 3.72 mmol), and the mixture was stirred at −78° C. for 30 min, at 0° C. for 1 hr. The mixture was diluted with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 5-25% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was washed with n-hexane to give the title compound as a colorless powder (285 mg, 0.666 mmol, 54%).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[C:10](Cl)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4].[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:19]=1[CH2:20][OH:21]>>[CH2:1]([N:5]1[C:9]2=[C:10]([O:21][CH2:20][C:19]3[C:18]([F:17])=[CH:25][CH:24]=[CH:23][C:22]=3[F:26])[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4]
Reactant: OCc1c(F)cccc1F
Reactant: CC=CCn1c(C)c(C)c2cnnc(Cl)c21
Product: CC=CCn1c(C)c(C)c2cnnc(OCc3c(F)cccc3F)c21
Yield: 58.3 %

Procedure:
The title compound (cis/trans=22/78) was prepared as a white powder in 58.3% yield in a similar procedure to that described in Example 1 by using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine (cis/trans=24/76) and 2,6-difluorobenzyl alcohol.
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)=[C:12]([N+:23]([O-:25])=[O:24])[CH:11]=1.N1C=CN=C1>CN(C)C=O>[C:1]([Si:5]([O:22][C:18]1[CH:17]=[C:16]([C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][C:12]=2[N+:23]([O-:25])=[O:24])[CH:21]=[CH:20][CH:19]=1)([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1cc(Cl)ccc1-c1cccc(O)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(-c2ccc(Cl)cc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 93.3 %

Procedure:
tert-Butyldimethylchlorosilane (0.82 g, 5.44 mmol) was added at room temperature to a solution of 4′-chloro-2′-nitro-biphenyl-3-ol (1.05 g, 4.21 mmol) and imidazole (0.58, 8.52 mmol) in anhydrous N,N-dimethylformamide (30 mL) and the resulting mixture was stirred at room temperature for 4 days. The reaction mixture was then partitioned between water and ethyl acetate, the organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified on a silica gel plug (hexane/EtOAc, 90/10) to give 1.43 g (94% yield) of tert-butyl-(4′-chloro-2′-nitro-biphenyl-3-yloxy)-dimethyl-silane as a yellow oil.
Reaction SMILES: B#B.[Cl:3][C:4]1[CH:15]=[CH:14][C:7](OC(C)C(O)=O)=[CH:6][CH:5]=1.[O:16]1C[CH2:19][CH2:18][CH2:17]1>>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH:18]([CH3:19])[CH2:17][OH:16])=[CH:14][CH:15]=1
Reactant: C1CCOC1
Reactant: CC(Oc1ccc(Cl)cc1)C(=O)O
Agent: B#B
Product: CC(CO)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 833 ml. of a chilled solution (0° C.) of 1M diborane in tetrahydrofuran is added dropwise a solution of 96 g. of 2-(p-chlorophenoxy)propionic acid in 500 ml. of tetrahydrofuran. The reaction mixture is stirred for 2 days at room temperature and then poured onto 2 kg. of ice/water. The resulting mixture is extracted with diethyl ether and the extract is washed with water and dried over MgSO4. The solvent is removed under vacuum and the residual liquid is distilled to give 83 g. (b.p. 116°-120° C./0.1 mm.) of product.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([OH:38])=[C:21]([C:31]([NH:33][CH2:34][CH2:35][O:36][CH3:37])=[O:32])[C:22](=[O:30])[N:23]3[CH2:26][C:27]([OH:29])=O)=[N:18][CH:17]=2)=[CH:11][CH:10]=1.C(N(CC)CC)C.[CH:46]1([NH2:50])[CH2:49][CH2:48][CH2:47]1>CN(C=O)C>[CH:46]1([NH:50][C:27](=[O:29])[CH2:26][N:23]2[C:24]3[C:19](=[N:18][CH:17]=[C:16]([CH2:15][C:12]4[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=4)[CH:25]=3)[C:20]([OH:38])=[C:21]([C:31]([NH:33][CH2:34][CH2:35][O:36][CH3:37])=[O:32])[C:22]2=[O:30])[CH2:49][CH2:48][CH2:47]1
Reactant: NC1CCC1
Reactant: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)O)c1=O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)NC2CCC2)c1=O

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluroniuum hexafluorophosphate (57 mg, 0.15 mmol) was added to a mixture of [7-[(4-fluorophenyl)methyl]-4-hydroxy-3-({[2-(methyloxy)ethyl]amino}carbonyl)-2-oxo-1,5-naphthyridine-1(2H)-yl]acetic acid, the title compound in Example 171 (50 mg, 0.12 mmol), triethylamine (0.02 mL, 0.15 mmol) and cyclobutylamine (0.012 mL, 0.15 mmol) in DMF (1 mL) at rt. After 1 h, the mixture was diluted with H2O (4 mL) and the title compound was collected by filtration to give a white solid: 1H NMR (d6-DMSO) δ 10.22 (1H, m), 8.54 (1H, s), 8.42 (1H, m), 7.75 (1H, s), 7.31 (2H, m), 7.10 (2H, m), 4.81 (2H, s), 4.13 (1H, m), 4.10 (2H, s), 3.52 (4H, m), 3.27 (3H, s), 2.09 (2H, m), 1.84 (2H, m), 1.59 (2H, m); HRMS calcd for C25H27FN4O5+H+: 483.2044. Found: 483.2049.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:34]([O:35][CH3:36])=[CH:33][C:7]2[CH2:8][C:9](=O)[N:10]([CH2:13][CH2:14][CH2:15][N:16]([CH3:31])[CH:17]3[CH2:26][CH2:25][C:24]4[C:19](=[CH:20][C:21]([O:29][CH3:30])=[C:22]([O:27][CH3:28])[CH:23]=4)[CH2:18]3)[CH2:11][CH2:12][C:6]=2[CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C(OCC)C>[CH3:36][O:35][C:34]1[C:4]([O:3][CH3:2])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][N:16]([CH3:31])[CH:17]3[CH2:26][CH2:25][C:24]4[C:19](=[CH:20][C:21]([O:29][CH3:30])=[C:22]([O:27][CH3:28])[CH:23]=4)[CH2:18]3)[CH2:9][CH2:8][C:7]=2[CH:33]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C1CCc3cc(OC)c(OC)cc3C1)CC2
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: COc1cc2c(cc1OC)CCN(CCCN(C)C1CCc3cc(OC)c(OC)cc3C1)CC2

Procedure:
Here, 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-[N-methyl-N-(6,7-dimethoxy-1,2,3,4-tetrahydronaphth-2-yl)-amino]-propane hydrochloride (1.4 g, 0.0027 mol) is added to a suspension of lithium aluminum hydride (0.24 g, 0.0062 mol) in diethyl ether (50 ml) and refluxed for 7 hours. Then water and 15% sodium hydroxide solution are added, the mixture is concentrated in vacuo and purified over silica gel (50 g) (32-63 μm) with methylene chloride and increasing amounts of ethanol (up to 15%) as eluant. Yield: 0.6 g. Mp: 92°-93° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])=[O:12])=[CH:9][N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:5]2=[N:6][CH:7]=1.Cl.[CH3:28][N:29]1[CH:33]=[C:32]([NH2:34])[CH:31]=[N:30]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>CN(C=O)C.C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:16][CH2:15][C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([NH:34][C:32]3[CH:31]=[N:30][N:29]([CH3:28])[CH:33]=3)[N:3]=2)[N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:9]=1)=[O:12])([CH3:18])[CH3:17]
Reactant: Cn1cc(N)cn1
Reactant: CC(C)(CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)CO)cn3COCC[Si](C)(C)C)cn1
Temperature: 140 °C
Yield: 18 %

Procedure:
A mixture of 2-bromo-N-(1-hydroxy-2-methylpropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (150 mg, 338 mol), 1-methyl-1H-pyrazol-4-amine hydrochloride (67.8 mg, 526 mol), BINAP (10.5 mg, 16.9 mol), palladium (II) acetate (19.0 mg, 84.6 mol) and sodium tert-butoxide (81.3 mg, 846 mol) in DMF (1 mL) and toluene (500 L) was heated in a microwave at 140° C. for 20 min. The reaction mixture was diluted with water then extracted into ethyl acetate (3×). The combined organic extracts were washed with brine then dried over magnesium sulfate. Purification by chromatography (silica, 20-65% of a 10:89.5:0.5 methanol:dichloromethane:ammonium hydroxide solution in dichloromethane) gave N-(1-hydroxy-2-methylpropan-2-yl)-2-(1-methyl-1H-pyrazol-4-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (28 mg, 60.9 mol, 18%) as a light yellow solid. (EI/CI) m/z: 460.3 [M+H].
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:9][C:10]1[C:11]([NH:16][C:17]([NH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[S:18])=[N:12][CH:13]=[CH:14][CH:15]=1>>[CH3:9][C:10]1[C:11]([NH:16][C:17]([NH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[S:18])=[N:12][CH:13]=[CH:14][CH:15]=1.[CH3:1][C:2]1[C:3]2[N:4]([N:12]=[C:11]([NH2:16])[N:8]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1N
Agent: CCOC(=O)NC(=S)Nc1ncccc1C
Product: Cc1cccn2nc(N)nc12

Procedure:
N-(3-methyl-2-pyridinyl)-N′-carboethoxy-thiourea was prepared from 3-methyl-pyridin-2-ylamine (3.93 g, 0.0363 mol) in a manner analogous to Example 2a. Product was isolated as a yellow solid. 265b) 8-Methyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from N-(3-methyl-2-pyridinyl)-N′-carboethoxy-thiourea (8.6 g, 36 mmol) in a manner analogous to Example 2b. Product was isolated as an off-white solid (3.96 g, 74%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.36 (d, J=6.6 Hz, 1H), 7.21 (d, J=6.8 Hz, 1H), 6.78 (dd, J=6.8 Hz, 6.8 Hz, 1H), 5.96 (bs, 2H), 2.39 (s, 3H). MS=149.0 (MH)+. 265c) (4-Methanesulfonyl-phenyl)-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine was prepared from 8-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (500 mg, 3.37 mmol) and 1-bromo-4-methanesulfonyl-benzene (973 mg, 1.23 mmol) in a manner analogous to Example 2d. Product was isolated as an off-white solid (0.369 g, 36%). MP=227-230° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 10.35 (s, 1H), 8.67 (d, J=6.9 Hz, 1H), 7.88 (d, J=8.9 Hz, 2H), 7.82 (d, J=8.9 Hz, 2H), 7.42 (d, J=7.1 Hz, 1H0, 6.99 (dd, J=7.1 Hz, 7.1 Hz, 1H), 3.14 (s, 3H). MS=303 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11](B3OC(C)(C)C(C)(C)O3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:23]1[C:32]([N:33]([CH3:37])[CH:34]([CH3:36])[CH3:35])=[N:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:38]([O:40][CH3:41])=[O:39])[CH:29]=2)[N:24]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([C:23]3[C:32]([N:33]([CH3:37])[CH:34]([CH3:35])[CH3:36])=[N:31][C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:38]([O:40][CH3:41])=[O:39])[CH:29]=4)[N:24]=3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)OB(c2ccc(-c3ccc(F)cc3)o2)OC1(C)C
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc(-c4ccc(F)cc4)o3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 0.67 h
Yield: 70.1 %

Procedure:
To a solution of 2-[5-(4-fluorophenyl)furan-2-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (442 mg, crude) in dioxane (5.5 mL) and water (3 drops) was added methyl 2-chloro-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (150 mg, 0.51 mmol), K3PO4 (324.9 mg, 1.53 mmol) and Pd(PPh3)4 (29.5 mg, 0.03 mmol) with stirring for 40 min at 90° C. in an oil bath maintained under an inert atmosphere of nitrogen. The reaction mixture was concentrated under reduced pressure to give the residue, which was purified via silica gel chromatography (2% ethyl acetate in petroleum ether) to afford methyl 2-[5-(4-fluorophenyl)furan-2-yl]-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate as light yellow solid (150 mg, 55%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[S:5][C:4]=1[C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:49][C:50]1[CH:51]=[C:52]([NH:57][C:58](=[O:70])[C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([C:65]([C:68]#[N:69])([CH3:67])[CH3:66])[CH:60]=2)[CH:53]=[CH:54][C:55]=1[CH3:56]>CN(C=O)C>[C:68]([C:65]([C:61]1[CH:60]=[C:59]([CH:64]=[CH:63][CH:62]=1)[C:58]([NH:57][C:52]1[CH:53]=[CH:54][C:55]([CH3:56])=[C:50]([NH:49][C:12]([C:4]2[S:5][C:6]3=[N:7][CH:8]=[CH:9][N:10]=[C:11]3[C:3]=2[NH:2][CH3:1])=[O:14])[CH:51]=1)=[O:70])([CH3:67])[CH3:66])#[N:69]
Reactant: CNc1c(C(=O)O)sc2nccnc12
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNc1c(C(=O)Nc2cc(NC(=O)c3cccc(C(C)(C)C#N)c3)ccc2C)sc2nccnc12
Temperature: 75 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
A solution of 7-(methylamino)thieno[2,3-b]pyrazine-6-carboxylic acid 12 (1.6 g, 7.65 mmol), HATU (3.20 g, 8.41 mmol) and DIPEA (3.79 mL, 22.94 mmol) in DMF (20 mL) was stirred at rt for 30 min. N-(3-amino-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide hydrochloride 6 (2.52 g, 7.65 mmol) was added and stirred overnight at 75° C. Quenched in ice/water and the resulting precipitate was collected. Purification by chromatography (10-20% EtOAc in CH2Cl2), co-evaporate with acetonitrile (2×), stirred in water at 70° C. for 1 h and filtrated to give the title compound N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-7-(methylamino)thieno[2,3-b]pyrazine-6-carboxamide 13 (2.06 g, 55.6%). 1H-NMR (400 MHz, DMSO-d6) 1.76 (s, 6H), 2.22 (s, 3H), 3.41 (d, J=5.5 Hz, 3H), 7.26 (d, J=8.6 Hz, 1H), 7.60 (t, J=7.8 Hz, 2H), 7.75 (d, J=7.8 Hz, 1H), 7.82 (d, J=1.9 Hz), 1H), 7.94 (d, J=7.8 Hz, 2H), 8.05 (m, 1H), 8.73 (d, J=2.3 Hz, 1H), 8.77 (d, J=2.3 Hz, 1H), 9.55 (br s, 1H), 10.31 (br s, 1H). (m/z)=485 (M+H)+.
Reaction SMILES: I[C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH2:9][C:10]3[CH:27]=[CH:26][C:13]4[N:14]=[C:15]([NH:17][C@@H:18]5[CH2:23][CH2:22][CH2:21][C@@H:20]([OH:24])[C@H:19]5[OH:25])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[CH:30](B1OC(C)(C)C(C)(C)O1)=[CH2:31].C([O-])([O-])=O.[K+].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH:30]([C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH2:9][C:10]3[CH:27]=[CH:26][C:13]4[N:14]=[C:15]([NH:17][C@@H:18]5[CH2:23][CH2:22][CH2:21][C@@H:20]([OH:24])[C@H:19]5[OH:25])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1)=[CH2:31]
Reactant: O[C@@H]1[C@H](O)CCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(I)ccc43)cc2s1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1ccc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCC[C@@H](O)[C@H]3O)sc2c1
Temperature: 100 °C
Yield: 5.9 %

Procedure:
A suspension of (1R,2S,3R)-3-((6-((5-iodo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol (120 mg, 0.2 mmol), vinylboronic acid pinacol ester (71 mg, 0.5 mmol), and K2CO3 (64 mg, 0.5 mmol) in 6:1 dioxane:water (3.5 mL) was purged with argon for 5 min. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (19 mg, 0.02 mmol) was added to the mixture, the mixture was purged with argon for an additional 5 min and then heated in a sealed tube at 100° C. for 6 h. The mixture was cooled to rt and partitioned between EtOAc (150 mL) and 0.5 M aq K2CO3 (100 mL). The organic layer was separated and washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford the nearly pure compound. This was further purified by silica gel flash chromatography, eluting isocratically with 5% MeOH in CH2Cl2, to afford (1R,2S,3R)-3-((6-((5-vinyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol (5 mg, 5%) as a white powder. 1H NMR (500 MHz, MeOH-d4) δ 8.28 (br s, 1H), 7.69 (s, 1H), 7.54 (m, 1H), 7.41-7.43 (m, 2H), 7.37 (d, J=8.1 Hz, 1H), 7.22 (m, 1H), 6.81-6.86 (m, 2H), 5.76 (d, J=17.7 Hz, 1H), 5.49 (s, 2H), 5.19 (d, J=11.1 Hz, 1H), 3.99-4.02 (m, 2H), 3.50 (m, 1H), 2.08 (m, 1H), 1.72-1.85 (m, 2H), 1.48-1.55 (m, 2H), 1.28-1.39 (m, 2H); LCMS (ESI) m/z 421 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27]I)=[CH:21][C:20]=2[F:29])=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[C:5]([NH:7][O:8][CH2:9][CH2:10][O:11]C=C)=[O:6].[CH3:30][NH2:31]>>[F:1][C:2]1[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][NH:31][CH3:30])=[CH:21][C:20]=2[F:29])=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: C=COCCONC(=O)c1ccc(F)c(F)c1Nc1ccc(CCCI)cc1F
Reactant: CN
Product: CNCCCc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Yield: 32 %

Procedure:
The product of Example 15, Step E, 3,4-Difluoro-2-[2-fluoro-4-(3-iodopropyl)anilino]-N-[2-(vinyloxy)ethoxy]benzamide was reacted with methylamine and then deprotected according to the general procedure of Example 15, Step F, to afford 3,4-difluoro-2-{2-fluoro-4-[3-(methylamino)propyl] anilino}-N-(2-hydroxyethoxy)benzamide as a pale brown solid (32%); m.p. (Et2O) 112–116° C. 1H NMR [400 MHz, (CD3)2SO] δ 9.61 (v br s, 1 H), 7.57–7.50 (m, 1 H), 7.02–6.94 (m, 1H), 6.93 (dd, J=12.4, 1.5 Hz, 1 H), 6.79 (dd, J=8.3, 1.5 Hz, 1 H), 6.65 (ddd, J=8.8, 8.8, 5.9 Hz, 1 H), 3.80 (t, J=4.9 Hz, 2 H), 3.54 (t, J=4.9 Hz, 2 H), 2.66 (t, J=7.3 Hz, 2 H), 2.52 (t, J=7.6 Hz, 2 H), 2.41 (s, 3 H), 1.73 (q, J=7.5 Hz, 2 H). Not all exchangeable protons were observed. Anal. calcd. for C19H22F3N3O3.0.5H2O: C, 56.2; H, 5.7; N, 10.3. Found C, 56.2; H, 5.6; N, 10.2.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[I:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1.O>C1COCC1.ClCCl>[CH2:1]([NH:3][C:9](=[O:10])[C:8]1[CH:12]=[CH:13][C:5]([I:4])=[CH:6][CH:7]=1)[CH3:2]
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CCN
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCNC(=O)c1ccc(I)cc1
Reaction time: 1 h

Procedure:
90 ml (45 mmol) of a 0.5N solution of ethylamine in THF were introduced into a round-bottomed flask and a solution of 4 g (15 mmol) of 4-iodobenzoyl chloride in 20 ml of dichloromethane was added dropwise. Stirring was carried out at room temperature for one hour and the reaction mixture was poured into water and extracted with ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with dichloromethane. After evaporating the solvents, 3.41 g (82%) of the expected amide was recovered.
Reaction SMILES: [NH2:1][C:2]1[C:9]([Br:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.Cl[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][O-].[K+].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(O)C>[Br:10][C:9]1[C:2]2[N:3]([C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:1]=2)[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=1
Reactant: CCOC(=O)C(Cl)=C[O-]
Reactant: N#Cc1cnc(N)c(Br)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cnc2c(Br)cc(C#N)cn12
Yield: 46 %

Procedure:
A mixture of 6-amino-5-bromonicotinonitrile (6.3 g), potassium 2-chloro-3-ethoxy-3-oxoprop-1-en-1-olate (15 g), sulfuric acid (2.2 mL) and ethanol (160 mL) was heated with reflux for 30 hr. To the reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.3 g).