Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[CH2:12][N:13]([CH3:40])[C:14](=[O:39])[N:15]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]5)=[C:18]([C:35]([F:38])([F:37])[F:36])[CH:17]=4)[C:5]=3[C:4]=2[CH:3]=1.[N:41]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[C:43](B(O)O)[CH:42]=1.CC(C1C=C(C(C)C)C(C2C(P(C(C)(C)C)C(C)(C)C)=CC=CC=2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[CH3:40][N:13]1[CH2:12][C:6]2[CH:7]=[N:8][C:9]3[CH:10]=[CH:11][C:2]([C:43]4[CH:42]=[N:41][C:50]5[C:45]([CH:44]=4)=[CH:46][CH:47]=[CH:48][CH:49]=5)=[CH:3][C:4]=3[C:5]=2[N:15]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:26][CH2:27]3)=[C:18]([C:35]([F:36])([F:38])[F:37])[CH:17]=2)[C:14]1=[O:39]
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: CN1Cc2cnc3ccc(Cl)cc3c2N(c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)c(C(F)(F)F)c2)C1=O
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN1Cc2cnc3ccc(-c4cnc5ccccc5c4)cc3c2N(c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)c(C(F)(F)F)c2)C1=O
Temperature: 25 °C
Yield: 47.9 %

Procedure:
To a solution of tert-butyl 4-(4-(9-chloro-3-methyl-2-oxo-3,4-dihydropyrimido[5,4-c]quinolin-1(2H)-yl)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate (57 mg, 0.1 mmol) and quinolin-3-ylboronic acid (26 mg, 0.15 mmol) in 1,4-dioxane (2 mL) at room temperature was added bischloroditriphenylphosphine (4 mg, 0.005 mmol), tert-butyl xphos (4 mg, 0.01 mmol), and Na2CO3 (0.3 mL, 0.3 mmol). The resultant solution was heated to 100° C. for 12 h before cooling to room temperature. The reaction mixture was filtered through celite. The solvent was removed in vacuo and the resulting crude residue was purified by flash column chromatography to afford the title product 32 mg (47%). LC-MS: (M+H)=668.38
Reaction SMILES: BrC1C=CC(C2C=CC(CC=O)=CN=2)=CC=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH:31]=[CH:32][O:33]C)=[CH:26][N:25]=2)=[CH:20][CH:19]=1>>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH:32]=[O:33])=[CH:26][N:25]=2)=[CH:22][CH:23]=1
Reactant: COC=CCc1ccc(-c2ccc(Br)cc2)nc1
Agent: O=CCc1ccc(-c2ccc(Br)cc2)nc1
Product: O=CCCc1ccc(-c2ccc(Br)cc2)nc1

Procedure:
[2-(p-Bromophenyl)-5-pyridyl]acetaldehyde is converted in an analogous manner to paragraph (a) into 2-(p-bromophenyl)-5-(3-methoxy-2-propenyl)pyridine and this is then hydrolyzed in an analogous manner to paragraph (b) to give 3-[2-(p-bromophenyl)-5-pyridyl]propionaldehyde.
Reaction SMILES: [N+](C1C=CC=CC=1C(NC([NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[N:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=2)=[C:14]([Cl:26])[CH:13]=1)=O)=O)([O-])=O.ClC1N=CC(Cl)=CN=1.NC1C=CC(O)=C(Cl)C=1.C(=O)([O-])[O-].[K+].[K+]>O.CS(C)=O>[Cl:26][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[O:18][C:19]1[N:20]=[CH:21][C:22]([Cl:25])=[CH:23][N:24]=1)[NH2:11]
Reactant: O=C(NC(=O)c1ccccc1[N+](=O)[O-])Nc1ccc(Oc2ncc(Cl)cn2)c(Cl)c1
Agent: Clc1cnc(Cl)nc1
Agent: Nc1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ncc(Cl)cn2)c(Cl)c1

Procedure:
N-(2-nitrobenzoyl)-N'-[3-chloro-4-(5-chloro-2-pyrimidinyloxy)phenyl]urea (1) Into a flask, 1.50 g of 2,5-dichloropyrimidine, 1.45 g of 4-amino-2-chlorophenol, 2.76 g of potassium carbonate and 15 ml of dimethylsulfoxide, were introduced, and reacted in a nitrogen atmosphere at 100° C. for 1.5 hours under stirring. After the completion of the reaction, the product was poured into water, and extracted with diethyl ether. The extract was washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and then the solvent was distilled off. The crude product thereby obtained was purified and isolated by silica gel column chromatography to obtain 2.20 g of 3-chloro-4-(5-chloro-2-pyrimidinyloxy)aniline having a melting point of from 95 to 96° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:36]1[CH:40]=[CH:39][C:38]([CH2:41][C:42](O)=[O:43])=[CH:37]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C1COCC1.C(Cl)Cl>[CH3:34][N:33]([CH3:35])[CH2:32][CH2:31][O:30][C:26]1[CH:25]=[C:24]([NH:23][C:19]2[N:18]=[C:17]([C:16]3[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:42](=[O:43])[CH2:41][C:38]5[CH:39]=[CH:40][S:36][CH:37]=5)[CH:7]=[CH:6][CH:5]=4)=[N:9][N:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=34)[CH:22]=[CH:21][N:20]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CN(C)CCOc1cccc(Nc2nccc(-c3c(-c4cccc(N)c4)nn4ccccc34)n2)c1
Reactant: O=C(O)Cc1ccsc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)CCOc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)Cc5ccsc5)c4)nn4ccccc34)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-{[2-(dimethylamino)ethyl]oxy}phenyl)-2-pyrimidinamine (140 mg, 0.3 mmol) in THF were added 3-thienylacetic acid (51 mg, 0.36 mmol), TEA (125 μL, 0.9 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (136 mg, 0.36 mmol). The reaction was stirred overnight at rt, after which the reaction mixture was diluted with DCM, washed with 5% aqueous Na2CO3, dried over Na2SO4, and adsorbed onto silica gel. The crude product was purified by column chromatography and lyophilized to generate the title compound in 72% yield. 1H NMR (400 MHz, d6-DMSO) δ 10.27 (s, 1H), 9.55 (s, 1H), 8.83 (d, J=6.7 Hz, 1H), 8.51 (d, J=8.8 Hz, 1H), 8.26 (d, J=5.1 Hz, 1H), 7.89 (s, 1H), 7.76 (d, J=8.1 Hz, 1H), 7.40-7.53 (m, 4H), 7.26-7.31 (m, 3H), 7.08-7.18 (m, 3H), 6.53 (d, J=8.2 Hz, 1H), 6.48 (d, J=5.3 Hz, 1H), 3.99 (t, J=5.7 Hz, 2H), 3.66 (s, 2H), 2.58 (t, J=5.9 Hz, 2H), 2.18 (s, 6H). ES-LC/MS m/z=588 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=[O:4].O[CH2:14][CH:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O.C(O)CCC>[Br:1][CH2:2][C:3]1([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=2[Cl:12])[O:22][CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][O:4]1
Reactant: OCC(O)c1ccccc1
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Solvent: c1ccccc1
Solvent: O
Product: Clc1ccc(C2(CBr)OCC(c3ccccc3)O2)c(Cl)c1

Procedure:
A mixture of 13.4 parts of 2-bromo-2',4'-dichloroacetophenone, 8.4 parts of α-(hydroxymethyl)benzyl alcohol, 1.15 parts of p-toluenesulfonic acid, 160 parts of benzene and 140 parts of n-butanol is stirred and refluxed for 48 hours with a water-separator. The solvent is removed in vacuo. The residue is purified by column-chromatography over silica gel, using chloroform as eluent. The pure fractions are collected and the eluent is evaporated, yielding 2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-phenyl-1,3-dioxolane as residue.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH:15](C)[CH2:16][N:17]4C(=O)C5=CC=CC=C5C4=O)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:29]3[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=3[F:36])[C:6]=2[CH:37]=1.O.NN.[CH2:41](O)C>>[NH2:17][CH:16]([CH3:41])[CH2:15][C:12]1[N:11]2[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:37][C:6]=3[C:7]([C:29]3[C:30]([F:36])=[CH:31][CH:32]=[CH:33][C:34]=3[F:35])=[N:8][CH2:9][C:10]2=[N:14][N:13]=1
Reactant: CCO
Reactant: CC(CN1C(=O)c2ccccc2C1=O)c1nnc2n1-c1ccc(Cl)cc1C(c1c(F)cccc1F)=NC2
Agent: NN
Solvent: O
Product: CC(N)Cc1nnc2n1-c1ccc(Cl)cc1C(c1c(F)cccc1F)=NC2

Procedure:
In the manner given in Example 21, a solution of N-[2-[8-chloro-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepin-1-yl]propyl]phthalimide in ethanol is heated with hydrazine hydrate to give 1-(2-aminopropyl)-8-chloro-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[C:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:8]([CH3:17])=[CH:7][C:6]=1[NH:18][C:19]1[N:24]=[C:23]2[NH:25][N:26]=[C:27]([CH3:28])[C:22]2=[C:21]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])[N:20]=1)([CH3:3])[CH3:2].Br[CH2:43][CH2:44][OH:45].C(N(CC)CC)C>>[CH:1]([O:4][C:5]1[C:6]([NH:18][C:19]2[N:24]=[C:23]3[NH:25][N:26]=[C:27]([CH3:28])[C:22]3=[C:21]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])[N:20]=2)=[CH:7][C:8]([CH3:17])=[C:9]([CH:11]2[CH2:16][CH2:15][N:14]([CH2:43][CH2:44][OH:45])[CH2:13][CH2:12]2)[CH:10]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3c(C)n[nH]c3n2)c(OC(C)C)cc1C1CCNCC1
Reactant: OCCBr
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3c(C)n[nH]c3n2)c(OC(C)C)cc1C1CCN(CCO)CC1
Temperature: 100 °C

Procedure:
The mixture of N6-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (20 mg, 0.035 mmol), 2-bromoethanol (0.1 N in DMF, 0.070 mmol, 0.70 mL) and triethylamine (0.1 N in DMF, 0.18 mmol, 1.75 mL) was heated at 100° C. for 10 min. The resulting reaction mixture was purified by RP-HPLC to afford 2-(4-(5-isopropoxy-4-(4-(2-(isopropylsulfonyl)phenylamino)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-2-methylphenyl)piperidin-1-yl)ethanol. MS (ES+): 622.3 (MH+).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[N:19]([CH2:22][C@@H:23]([C:32]1[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[C:38]2[C:33]=1[CH:34]=[CH:35][C:36](=[O:50])[NH:37]2)[O:24][Si](C(C)(C)C)(C)C)=[N+:20]=[N-:21]>C1COCC1>[N:19]([CH2:22][C@@H:23]([C:32]1[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[C:38]2[C:33]=1[CH:34]=[CH:35][C:36](=[O:50])[NH:37]2)[OH:24])=[N+:20]=[N-:21]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN=[N+]=[N-])c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: [N-]=[N+]=NC[C@H](O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Yield: 91.9 %

Procedure:
A 1.0 M (THF) solution of TBAF (0.443 mL, 0.443 mmol) was added to a stirring solution of Intermediate 1 (200 mg, 0.443 mmol) in THF (4 mL) at rt. The resulting mixture was stirred over night then concentrated. Chromatography (1:3, Hexanes/EtOAc) afforded the title compound (137 mg, 92%) as an off-white solid. ES/MS calcd. for C18H17N4O3+ 337.1. Found m/z=337.2 (M+H)+.
Reaction SMILES: C[N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([Cl:55])[C:31]=1[NH:32][C:33]1[C:42]2[C:37](=[C:38]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][C:51](O)=[O:52])[C:39]([O:43][CH3:44])=[CH:40][CH:41]=2)[O:36][C:35](=[O:54])[CH:34]=1.[NH4+].[OH-]>CS(C)=O>[Cl:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([Cl:55])[C:31]=1[NH:32][C:33]1[C:42]2[C:37](=[C:38]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][C:51]([NH2:2])=[O:52])[C:39]([O:43][CH3:44])=[CH:40][CH:41]=2)[O:36][C:35](=[O:54])[CH:34]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCC(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCC(N)=O
Reaction time: 1 h

Procedure:
HATU (100 mg, 0.26 mmol) was added to a solution of 6-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-2H-chromen-8-yloxy)hexanoic acid (100 mg, 0.21 mmol, Example 44) and DMSO (2 mL). After 1 h, 28% NH4OH solution (0.4 mL, 2.9 mmol) was added. After an additional hour, the reaction was concentrated and purified by reverse-phase HPLC (1:4→7:3; acetonitrile:water) to give 6-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-2H-chromen-8-yloxy)hexanamide: 1H NMR (400 MHz, DMSO-d6): δ 9.51 (s, 1H), 8.81 (s, 2H), 7.94 (d, 1H), 7.21 (br, 1H), 7.20 (d, 1H), 6.67 (br, 1H), 4.63 (s, 1H), 3.97 (t, 2H), 3.92 (s, 3H), 2.05 (t, 2H), 1.67 (m, 2H), 1.52 (m, 2H), 1.44 (m, 2H); MS (ESI): 465.8.
Reaction SMILES: [CH3:1][NH:2][S:3](/[CH:6]=[CH:7]/[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1)(=[O:5])=[O:4].Cl.[H][H]>[Pd].CN(C)C=O>[CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1)(=[O:4])=[O:5]
Reactant: CNS(=O)(=O)/C=C/c1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CN(C)C=O
Product: CNS(=O)(=O)CCc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 73.9 %

Procedure:
A solution of the product of stage (i) (5.78 g) in a mixture of ethanolic hydrogen chloride [prepared by adding acetyl chloride (1.71 g, 21.8 mmol) to IMS ethanol (400 ml) with stirring] and dimethylformamide (300 ml; added to the above to dissolve the starting material) was hydrogenated at room temperature and atmospheric pressure, using 10% palladium on carbon (5.00 g, 50% w/w with water) as the catalyst until uptake of hydrogen ceased. The mixture was filtered and the filtrate was evaporated to give a solid. The solid was partitioned between 2N sodium carbonate (60 ml) and ethyl acetate (200 ml) and the mixture was heated until the solid had dissolved. The phases were separated, the aqueous phase was extracted with ethyl acetate (200 ml) and the combined organic phases were washed with saturated brine (100 ml), dried (Na2SO4) and evaporated to give a gum. The gum was crystallised from ethyl acetate (60 ml) to give the title compound (4.30 g) as crystals, with m.p. 170°-171°
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[Li]CCCC.[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C>C1COCC1.CCCCCC>[F:13][C:2]([F:1])([F:12])[C:3]1[C:8]2[S:9][C:10]([B:19]([OH:24])[OH:20])=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1cccc2ccsc12
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1cc2cccc(C(F)(F)F)c2s1
Temperature: -30 °C
Reaction time: 0.17 h

Procedure:
To a solution of 7-trifluoromethyl-benzo[b]thiophene (0.52 g, 0.0026 mol) in THF (30 mL) at −78° C. was added 2.5 M of n-BuLi in hexane (1.4 mL). The reaction was then slowly warmed up to −30° C. over 30 min. and stirred at this temperature for 10 min prior to recooling to −78° C. and treatment with triisopropyl borate (0.7255 g, 0.0038 mol). The reaction was then slowly warmed up to 0° C. then was quenched with saturated ammonium chloride and the solvent removed in vacuo. To the residue was added aqueous sodium hydroxide (10 mL, 2N solution) followed by water (30 mL) then this mixture was extracted with DCM. The aqueous solution was acidified using dilute sulfuric acid (2N solution), filtered and the residue dried in vacuo to yield 7-trifluoromethylbenzo[b]thiophen-2-boronic acid. 1H NMR (400 MHz, MeOD) δ ppm 7.55 (1 H, t, J=7.45 Hz), 7.75 (1 H, d, J=7.07 Hz), 8.02 (1 H, s) and 8.17 (1 H, d, J=7.83 Hz).
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:43]([O:50][C:51]1[CH:52]=[C:53]2[C:58](=[CH:59][CH:60]=1)[N:57]=[CH:56][C:55](Br)=[CH:54]2)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.[CH3:62][N:63]1[CH2:69][CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1.CC([O-])(C)C.[K+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:43]([O:50][C:51]1[CH:52]=[C:53]2[C:58](=[CH:59][CH:60]=1)[N:57]=[CH:56][C:55]([N:66]1[CH2:67][CH2:68][CH2:69][N:63]([CH3:62])[CH2:64][CH2:65]1)=[CH:54]2)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CN1CCCNCC1
Reactant: Brc1cnc2ccc(OCc3ccccc3)cc2c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CN1CCCN(c2cnc3ccc(OCc4ccccc4)cc3c2)CC1
Temperature: 110 °C
Reaction time: 3 h
Yield: 57.9 %

Procedure:
A mixture of Pd2(dba)3 (72.9 mg, 0.080 mmol), xantphos (101 mg, 0.175 mmol), intermediate B (500 mg, 1.591 mmol), 1-methyl-1,4-diazepane (1.1) (182 mg, 1.591 mmol) and KOtBu (357 mg, 3.18 mmol) in toluene (10 ml) was bubbling with nitrogen for 15 min. The reaction was stirred at 110° C. for 3 hr under nitrogen atmosphere. The reaction mixture was filtered and concentrated. The crude product was purified by chromatography to give the title compound (320 mg, yield 58%). LCMS (method N): [M+H]+=348, tR=1.75 min.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[N:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][C@@H:22]([CH2:32][Cl:33])[C:12]2=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14]2)C1C=CC=CC=1.C([O-])=O.[NH4+]>O1CCCC1.[C].[Pd]>[C:28]([O:27][C:25]([N:24]1[C:11]2[C:12](=[C:13]3[C:17](=[C:9]([OH:8])[CH:10]=2)[NH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14]3)[C@H:22]([CH2:32][Cl:33])[CH2:23]1)=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: COC(=O)c1cc2c3c(cc(OCc4ccccc4)c2[nH]1)N(C(=O)OC(C)(C)C)C[C@H]3CCl
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)c1cc2c3c(cc(O)c2[nH]1)N(C(=O)OC(C)(C)C)C[C@H]3CCl
Reaction time: 1 h
Yield: 95.1 %

Procedure:
150.7 mg (0.32 mmole) of methyl (1S)-5-benzyloxy-3-t-butoxycarbonyl-1-chloromethyl-1,2,3,6-tetrahydropyrrolo[3,2-e]indole-7-carboxylate and 90 mg of 10% palladium carbon were suspended in 4 ml of tetrahydrofuran, and 1 ml of 25% ammonium formate aqueous solution was added dropwise under ice-cold condition, followed by stirring for 1 hour. The resulting reaction mixture was extracted with ethyl acetate, the obtained organic layer was dried over anhydrous sodium sulfate, and filtrated, followed by concentration to give a residue. The residue was then purified by silica gel column chromatography using an eluate of hexane:ethyl acetate (1:1), followed by crystallization with hexane to give 115.9 mg of methyl (1S)-3-t-butoxycarbonyl-1-chloromethyl-5-hydroxy-1,2,3,6-tetrahydropyrrolo[3,2-e]indole-7-carboxylate. Yield, 95%. NMR (CDCl3) δ: 1.58 (9H, s), 3.54 (1H, t, J=9.8 Hz), 3.87-3.94 (2H, m), 3.96 (3H, s), 4.06 (1H, m), 4.17 (1H, dd, J=9.3, 11.7 Hz), 6.36 (1H, brs), 7.08 (1H, s), 7.64 (1H, brs), 9.23 (1H, brs). [α]D25 =-42.6° (c 0.21, methanol).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=2[S:5][C:6]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:11][CH:10]=1.O1CCCC1.O.[OH-].[Li+].Cl>O.CO>[Cl:1][C:2]1[C:3]2[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=2[S:5][C:6]=1[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][CH:14]=1
Reactant: COC(=O)CCc1ccc(OCc2sc3ccccc3c2Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)CCc1ccc(OCc2sc3ccccc3c2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
A mixture of methyl 4-[(3-chlorobenzo[b]thien-2-yl) methoxy]benzenepropanoate (1.5 g, 4.0 mmol), tetrahydrofuran (20 mL), methanol (5 mL), water (2 mL) and lithium hydroxide monohydrate (0.34 g, 8.0 mmol) was stirred overnight at room temperature. The reaction mixture was neutralized with 0.5N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3:1) to give the title compound (1.3 g, yield 94%).
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[NH2:23][C:24]1[C:25]([CH3:30])=[CH:26][CH:27]=[CH:28][CH:29]=1>>[C:25]1([CH3:30])[C:24]([NH:23][C:2]2[C:3]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Reactant: Cc1ccccc1N
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Nc3ccccc3C)nc2c1
Yield: 37 %

Procedure:
Methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (300 mg, 0.95 mmol) was stirred in o-toluidine (10 mL) at 145° C. for 3 days in an oil bath. The reaction mixture was concentrated in vacuo to give a residue, which was purified by a silica gel column chromatography (1% ethyl acetate in petroleum ether) to afford methyl 3-(o-toluidino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a light yellow solid (145 mg, 37%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:12][C:13]([N:15]2[CH2:20][CH2:19][N:18](CC3C=CC=CC=3)[CH2:17][CH2:16]2)=[O:14])[C:6]([O:10][CH3:11])=[N:7][C:8]=1[CH3:9])[CH3:2].C(O)C>[Pd].C(O)(=O)C>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:12][C:13]([N:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)=[O:14])[C:6]([O:10][CH3:11])=[N:7][C:8]=1[CH3:9])[CH3:2]
Reactant: CCc1cc(NC(=O)N2CCN(Cc3ccccc3)CC2)c(OC)nc1C
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCc1cc(NC(=O)N2CCNCC2)c(OC)nc1C
Reaction time: 4 h
Yield: 93.5 %

Procedure:
After 1-[(5-ethyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-benzyl piperazine (1.71 g, 4.61 mmol) was added the solution of 30 ml of ethanol and 10 ml of glacial acetic acid in the presence of 5% Pd/C, the reaction mixture were stirred under hydrogen gas(40 psi) for 4 hours and extracted with dichloromethane. The mixture was dried with anhydrous magnesium sulfate, filtrated, concentrated and chromatographed to obtain 1.2 g of white solid of the titled compound.
Reaction SMILES: Cl.Cl.[C:3]([N:6]1[CH2:11][CH2:10][N:9]([NH2:12])[CH2:8][CH2:7]1)(=[O:5])[CH3:4].C(N(CC)CC)C.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](Cl)=[O:26]>ClCCl.C(OCC)(=O)C>[C:3]([N:6]1[CH2:11][CH2:10][N:9]([NH:12][C:25]([C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)=[O:26])[CH2:8][CH2:7]1)(=[O:5])[CH3:4]
Reactant: CC(=O)N1CCN(N)CC1
Reactant: O=C(Cl)c1cccs1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(NC(=O)c2cccs2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-acetyl-4-aminopiperazine dihydrochloride (250 mg) and triethylamine (0.65 ml) in dichloromethane (9 ml) was added 2-thiophenecarbonyl chloride (0.19 ml) at 0° C. The mixture was stirred at ambient temperature for 1 hour, diluted with ethyl acetate and washed with water (×2). The organic layer was separated, dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography eluting with a mixture of methanol and ethyl acetate (1:10) to give crystals. Recrystallization from ethanol gave N-(4-acetyl-1-piperazinyl)thiophene-2-carboxamide (256 mg).
Reaction SMILES: [NH3:1].C(O)C.Cl.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:19][CH2:20][CH2:21]Cl)[C:14](=[NH:18])OCC)=[C:9]([C:23]([F:26])([F:25])[F:24])[CH:8]=1>>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:19][CH2:20][CH2:21][NH:1][C:14]2=[NH:18])=[C:9]([C:23]([F:26])([F:25])[F:24])[CH:8]=1
Reactant: N
Reactant: CCOC(=N)C(CCCCl)c1ccc(Br)cc1C(F)(F)F
Agent: Cl
Solvent: CCO
Product: N=C1NCCCC1c1ccc(Br)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 192 h

Procedure:
A saturated ammonia-ethanol solution (2.5 mL) was added to ethyl 2-(4-bromo-2-trifluoromethylphenyl)-5-chloropentanimidate hydrochloride obtained in Preparation Example 3-1 (500 mg), and the mixture was stirred at room temperature for eight days. The insoluble matter was removed by filtration and then the filtrate was concentrated under reduced pressure. Methylene chloride and a 1 N sodium hydroxide solution were added to the resulting residue, and the organic layer was separated. The aqueous layer was reextracted with methylene chloride. The combined organic layers were dried over anhydrous potassium carbonate and concentrated under reduced pressure to obtain 320 mg of the title compound. The property values of the compound are as follows.