Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([O:29][CH3:30])=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][C:11]3[CH:27]=[CH:26][C:14]4[N:15]=[C:16]([NH:18][C@@H:19]5[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]5[OH:25])[S:17][C:13]=4[CH:12]=3)[C:6]=2[CH:28]=1.[CH3:31][N:32](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].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]>[OH:25][C@@H:20]1[CH2:21][CH2:22][CH2:23][CH2:24][C@H:19]1[NH:18][C:16]1[S:17][C:13]2[CH:12]=[C:11]([CH2:10][N:7]3[C:6]4[CH:28]=[C:2]([C:31]#[N:32])[C:3]([O:29][CH3:30])=[CH:4][C:5]=4[N:9]=[CH:8]3)[CH:27]=[CH:26][C:14]=2[N:15]=1
Reactant: COc1cc2ncn(Cc3ccc4nc(N[C@@H]5CCCC[C@H]5O)sc4c3)c2cc1Br
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1cc2ncn(Cc3ccc4nc(N[C@@H]5CCCC[C@H]5O)sc4c3)c2cc1C#N
Temperature: 110 °C
Yield: 41 %

Procedure:
To a suspension of (1R,2R)-2-((6-((6-bromo-5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (50 mg, 0.1 mmol) from Step 5 of Example 47 in DMF (1.5 mL) was added zinc cyanide (24 mg, 0.2 mmol). Argon was bubbled into the mixture for 5 min followed by the addition of 1,1′-bis(diphenylphosphino)ferrocene (9 mg, 0.02 mmol) and tris(dibenzylideneacetone)dipalladium (9 mg, 0.01 mmol). Argon was bubbled into the mixture for an additional 5 min. The reaction vessel was sealed and the mixture was heated at 110° C. for 15 h. The mixture was cooled to rt and argon was again bubbled into the mixture for 5 min. Additional zinc cyanide (24 mg, 0.2 mmol), 1,1′-Bis(diphenylphosphino)ferrocene (9 mg, 0.02 mmol) and tris(dibenzylideneacetone)dipalladium (9 mg, 0.01 mmol) were added to the mixture, and the reaction vessel was resealed and heated for 5 h. The mixture was cooled to rt, filtered, and the filtrate 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 1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-5-methoxy-1H-benzo[d]imidazole-6-carbonitrile (18 mg, 41%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.12 (s, 1H), 8.01 (d, J=7.3 Hz, 1H), 7.70 (d, J=0.9 Hz, 1H), 7.43 (s, 1H), 7.20-7.34 (m, 2H), 5.46 (s, 2H), 4.76 (d, J=4.9 Hz, 1H), 3.90 (s, 3H), 3.51 (m, 1H), 3.33 (m, 1H), 2.03 (m, 1H), 1.87 (m, 1H), 1.57-1.67 (m, 2H), 1.15-1.34 (m, 4H). LCMS (ESI) m/z 434 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][NH:9][C:10](=[O:11])[C:6]=2[CH:5]=[C:4]([CH3:12])[N:3]=1.Cl[CH2:14][C:15]1[CH:16]=[C:17]([CH3:27])[C:18]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[N:19][CH:20]=1.[H-].[Na+].O>CC(N(C)C)=O>[Cl:1][C:2]1[C:7]2[CH2:8][N:9]([CH2:14][C:15]3[CH:20]=[N:19][C:18]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[C:17]([CH3:27])[CH:16]=3)[C:10](=[O:11])[C:6]=2[CH:5]=[C:4]([CH3:12])[N:3]=1
Reactant: Cc1cc2c(c(Cl)n1)CNC2=O
Reactant: Cc1cc(CCl)cnc1OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc2c(c(Cl)n1)CN(Cc1cnc(OCC(F)(F)F)c(C)c1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.7 %

Procedure:
A mixture of 4-chloro-6-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (91 mg, 0.50 mmol, Step-1), 5-(chloromethyl)-3-methyl-2-(2,2,2-trifluoroethoxy)pyridine (119 mg, 0.50 mmol, Step-3 in Amine-3) and sodium hydride (40 mg, 0.99 mmol) in DMA (1.7 mL) is stirred for 1 hour at rt. The reaction mixture is poured into water and extracted with EtOAc. The organic layer is dried over sodium sulfate. After filtration, the filtrate and volatiles are removed. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (2:1) to give 65 mg (34% yield) of the title compound as colorless oil.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13](=O)[NH:14][CH:15]=[N:16]3)=[CH:11][C:10]=2[O:20][CH3:21])[CH:5]=[CH:4][N:3]=[CH:2]1.S(Cl)([Cl:24])=O>>[Cl:24][C:13]1[C:12]2[C:17](=[CH:18][C:9]([O:8][CH2:7][CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[C:10]([O:20][CH3:21])[CH:11]=2)[N:16]=[CH:15][N:14]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCn1ccnc1
Product: COc1cc2c(Cl)ncnc2cc1OCCn1ccnc1

Procedure:
Using a procedure analogous to the one described for the synthesis of Example 23, 7-(2-(imidazol-1-yl)ethoxy)-6-methoxy-3,4-dihydroquinazoline-4-one (286 mg, 1 mmol) was reacted with thionyl chloride (50 ml) to give 4-chloro-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline which was then reacted with 5,7-diaza-6-methyloxindole (440 mg, 3 mmol) and sodium hydride (120 mg, 3 mmol) to give 4-(5,7-diaza-6-methyloxindol-3-yl)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline hydrochloride (80 mg, 15%).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH:12]([B-](F)(F)F)=[CH2:13].[K+].ClCCl.C(N(CC)CC)C>C(O)CC>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([CH:12]=[CH2:13])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: C=C[B-](F)(F)F
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCCO
Solvent: ClCCl
Product: C=Cc1cccn2nc(Cl)nc12
Temperature: 90 °C

Procedure:
To a suspension of 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (0.50 g, 2.2 mmol), potassium vinyltrifluoroborate (0.34 g, 2.6 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (1:1) (35 mg, 0.043 mmol) in 1-propanol (10 mL) was added triethylamine (0.30 mL, 2.2 mmol). The mixture was heated at 90° C. for 6 hours under an atmosphere of nitrogen. The mixture was cooled to room temperature and the volatiles were evaporated under reduced pressure. The residue was diluted with dichloromethane (50 mL) and filtered through a plug of diatomaceous earth. The filtrate was washed with 2N Hydrochloric acid (2×10 mL) and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and evaporated. The residue was purified via chromatography (silica gel column 24 g and 0%→2% methanol: dichloromethane). 2-Chloro-8-vinyl-[1,2,4]triazolo[1,5-a]pyridine was isolated as a white solid (0.336 g, 87%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.40 (d, J=6.8 Hz, 1H), 7.53 (d, J=7.3 Hz, 1H), 7.08-6.94 (m, 2H), 6.59 (d, J=17.6 Hz, 1H), 5.70 (d, J=11.2 Hz, 1H). MS=180, 182 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=1)[C:10]([CH3:25])([CH3:24])[CH:9]2O)=[O:5])[CH3:2].FC(F)(F)C(O)=O>C([SiH](CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[C:18]([F:23])[CH:19]=[C:20]([F:22])[CH:21]=1)[C:10]([CH3:24])([CH3:25])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cc(F)cc(F)c1)N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(F)cc(F)c1)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
To a mixture of 2-(3,5-difluoro-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (5.34 g, 14.8 mmol) and triethylsilane (20 mL) at 25° C. was added trifluoroacetic acid (5 mL) dropwise. The resulting mixture was stirred at 25° C. for 1 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with saturated aqueous sodium bicarbonate solution (2×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company)(10% ethyl acetate/hexanes) to afford 2-(3,5-difluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (2.0 g, 41%) as a white solid: LC/MS m/e calcd for C20H21F2NO2 (M+H)+: 346.4, observed: 346.1.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1([CH3:23])[NH:21][C:20](=[O:22])[CH2:19][NH:18]1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([N:18]1[CH2:19][C:20](=[O:22])[NH:21][C:17]1([CH3:23])[CH3:16])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)NCC(=O)N1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC1(C)NC(=O)CN1C(=O)CNC(=O)OCc1ccccc1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
To an ice-cold solution of N-(benzyloxycarbonyl) glycine (9 g) and 2,2-dimethyl-4-imidazolidinone (5 g) in tetrahydrofuran (THF) (150 ml) a solution of dicyclohexylcarbodiimide (DCC) (9 g) in THF (50 ml) was added dropwise. After stirring for 3 hours at 20° C., the precipitate was filtered off, the filtrate was evaporated to dryness and the residue was crystallized from 2-propanol affording 12 g of the title compound, m.p. 135°-136° C.
Reaction SMILES: [CH:1]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:9][C:10]1[C:15]([F:16])=[C:14]([C:17](O)=[O:18])[C:13]([F:20])=[C:12]([F:21])[C:11]=1[CH3:22]>>[CH:1]1([NH:8][C:17](=[O:18])[C:14]2[C:13]([F:20])=[C:12]([F:21])[C:11]([CH3:22])=[C:10]([F:9])[C:15]=2[F:16])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(F)c(F)c(C(=O)O)c(F)c1F
Reactant: NC1CCCCCC1
Product: Cc1c(F)c(F)c(C(=O)NC2CCCCCC2)c(F)c1F

Procedure:
Prepared in a similar manner to Example 162 using cycloheptylamine and 2,3,5,6-tetrafluoro-p-toluic acid (94%). 1H NMR (CDCl3) δ 1.53 (m, 6H), 1.57 (m, 4H), 2.03 (m, 2H) 2.28 (m, 3H), 4.17 (m, 1H), 5.85 (bs, 1H). MS (304.1, M+H) m.p. 164-165° C.
Reaction SMILES: Cl.[S:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[C:3]1C(O)=O.Br.[OH-].[Na+]>>[S:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1
Reactant: O=C(O)c1cc2c(s1)CCNC2
Agent: Br
Agent: Cl
Agent: [Na+]
Product: c1cc2c(s1)CCNC2

Procedure:
4,5,6,7-Tetrahydro-thieno[3,2-c]pyridine-2-carboxylic acid hydrochloride (260 mg, 1.2 mmol) was mixed with 47% hydrogen bromide aqueous solution (3 ml) and heated under reflux for 4 hours. The reaction solution was returned to room temperature and alkalified by adding sodium hydroxide aqueous solution (5 N), and the reaction product was extracted with diethyl ether, washed with saturated brine and then dried with anhydrous magnesium sulfate. By evaporating the solvent from the organic layer under a reduced pressure, 160 mg (1.1 mmol, 95% in yield) of the title compound was obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:28][C:29]([CH3:34])([CH3:33])[CH2:30][CH:31]=O.[BH4-].[Na+]>CO>[CH3:28][C:29]([CH3:34])([CH3:33])[CH2:30][CH2:31][N:25]1[CH2:26][CH2:27][CH:22]([O:21][C:16]2[N:15]=[CH:14][N:13]=[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[C:17]=2[N+:18]([O-:20])=[O:19])[CH2:23][CH2:24]1
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Reactant: CC(C)(C)CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)CCN1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Compound A2 (0.20 mmol, 80 mg), and 3,3-dimethyl-butyraldehyde (0.24 mmol, 30 μL) were dissolved in methanol (2 mL) and stirred for 5 minutes at room temperature. Then, added sodium borohydride (0.25 mmol, 8.7 mg) and stirred for 10 minutes at room temperature. The reaction mixture was quenched with saturated ammonium chloride solution (1 mL) followed by an extraction with dichloromethane. Removal of organic solvent in vacuo and purification by prep-LCMS provided Compound A7 as a yellow solid (12 mg, 13%). 1H NMR (400 MHz, CDCl3) δ (ppm): 10.17 (s, 1H), 8.36 (s, 1H), 7.90 (d, 2H), 7.78 (d, 2H), 5.71 (s broad, 1H), 3.51 (d, 2H), 3.08 (m, 2H), 2.97 (m, 5H), 2.38 (m, 2H), 2.14 (m, 2H), 1.60 (m, 2H), 0.85 (s, 9H). LCMS (ESI), m/z 478.3 (M+H+, 100%).
Reaction SMILES: [S:1]([OH:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[N:16]=[N:15][CH:14]=1>O.C(O)C>[Cl:23][C:19]1[CH:18]=[C:17]2[C:22]([C:13]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([S:1]([OH:11])(=[O:10])=[O:2])=[CH:8][CH:7]=3)=[CH:14][N:15]=[N:16]2)=[CH:21][CH:20]=1
Reactant: Clc1ccc2c(Cl)cnnc2c1
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: O=S(=O)(O)c1ccc(Nc2cnnc3cc(Cl)ccc23)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
Sulphanilic acid (1.95 g) in water (75 ml) and ethanol (10 ml) at 70° C. was treated with 4,7-dichlorocinnoline (2.2 g) and ethanol (10 ml) was added. The resultant green suspension was stirred vigorously overnight at 70° C. The mixture was cooled, and the solid was filtered, washed with water and dried at room temperature to give 3.45 g of the title compound as the monohydrate, melting point greater than 280° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([CH:34]1[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[CH:34]1([S:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:6]2[CH:5]=[CH:4][C:3]([C:17]3[CH:22]=[N:21][C:20]([NH2:23])=[N:19][CH:18]=3)=[C:2]([F:1])[CH:7]=2)(=[O:32])=[O:33])[CH2:36][CH2:35]1
Reactant: O=S(=O)(c1ccccc1Br)C1CC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3ccccc3S(=O)(=O)C3CC3)cc2F)cn1

Procedure:
The title compound was prepared using methods analogous to those described in Example 376 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and 1-bromo-2-(cyclopropylsulfonyl)benzene. MS (ESI): mass calcd. for C19H16FN3O2S, 369.10; m/z found, 370.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J=1.5, 2H), 8.14 (dd, J=7.9, 1.5, 1H), 7.70-7.63 (m, 1H), 7.62-7.54 (m, 1H), 7.45 (m, 1H), 7.41-7.28 (m, 3H), 5.23 (s, 2H), 2.19-2.06 (m, 1H), 1.16-1.07 (m, 2H), 0.93-0.81 (m, 2H).
Reaction SMILES: C1(S([C:10]([CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[OH:14])([F:12])[F:11])(=O)=O)C=CC=CC=1.[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1.CC([O-])(C)C.[K+]>CN(C=O)C>[F:11][C:10]([F:12])([CH:26]([C:25]1[CH:28]=[CH:29][C:22]([Cl:21])=[CH:23][CH:24]=1)[OH:27])[CH:13]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[OH:14]
Reactant: O=S(=O)(c1ccccc1)C(F)(F)C(O)c1ccccc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(c1ccccc1)C(F)(F)C(O)c1ccc(Cl)cc1
Reaction time: 8 h
Yield: 76 %

Procedure:
Into the mixture of PhSO2CF2CH(OH)Ph (120 mg, 0.4 mmol) and 4-chlorobenzaldehyde (113 mg, 0.8 mmol) in DMF (3 mL) at −50° C., was added t-BuOK (90 mg, 0.8 mmol) in 2 mL DMF. The reaction mixture was stirred at −50° C. to RT overnight. The reaction was then quenched with cold NaCl aqueous solution, followed by extraction with Et2O (20 mL×3). After drying over MgSO4 and solvent removal, the product 2,2-Difluoro-1-phenyl-3-(4′-chlorophenyl)-1,3-propanediol was obtained by chromatography as a white solid, 76% yield. For anti-isomer: 1H NMR (CDCl3): δ 3.22 (m, 2H); 5.04 (td, J=11.0 Hz, 2H); 7.36 (m, 9H). 13C NMR (CDCl3): δ 72.9 (t, J=29 Hz); 73.8 (t, J=29 Hz); 118.7 (t, J=259 Hz); 127.6; 128.6; 129.0; 134.3; 134.8. 19F NMR(CDCl3): δ −118.2˜120.1 (m).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1>CN(C=O)C.CO.CCOC(C)=O.[Pt]=O>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1
Reactant: NC(=O)Cc1ccccc1C#Cc1nc(Cl)ncc1Cl
Agent: O=[Pt]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: NC(=O)Cc1ccccc1CCc1nc(Cl)ncc1Cl

Procedure:
A solution of 2-(2-((2,5-dichloropyrimidin-4-yl)ethynyl)phenyl)acetamide (A138) (1.2 g, 4.0 mmol) in DMF (40 mL) and MeOH (8 mL) was stirred with platinum(II)oxide (0.27 g, 1.2 mmol) under an atmosphere of hydrogen for 144 hours at ambient temperature. The reaction mixture was diluted with EtOAc and filtered through a plug of Celite. The solvents were removed in vacuo and the crude residue was purified by silica gel column chromatography (Combiflash Rf, 0-10% MeOH in DCM) to give the title compound (A139) as a light yellow solid (0.63 g, 51%). LCMS-C: rt 4.82 min; m/z 310 [M+H]+.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17]CC)=O)[C:11](=O)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH:28]([NH2:30])[NH2:29])[CH2:23][CH2:22]1>C[O-].[Na+].CO>[CH2:2]([N:9]1[CH2:14][CH2:13][CH:12]2[C:11](=[N:30][C:28]([CH2:27][N:24]3[CH2:25][CH2:26][O:21][CH2:22][CH2:23]3)=[N:29][C:15]2=[O:17])[CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Reactant: NC(N)CN1CCOCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C1N=C(CN2CCOCC2)N=C2CN(Cc3ccccc3)CCC12
Temperature: 100 °C
Reaction time: 4 h

Procedure:
Ethyl N-benzyl-3-oxo-4-piperidinecarboxylate hydrochloride (2.98 g, 10 mmol) and 2-Morpholinoethane-1,1-diamine (˜20 mmol) were dissolved in the solution of sodium methoxide in methanol (12 mL, 25% wt) and stirred at 100° C. in a sealed tube for 4 h. Solvent was removed in vacuo, residue was dissolved in water (100 mL) and was extracted by CHCl3 and i-PrOH (3:1, 5×80 mL), dried over sodium sulfate. Solvent was removed in vacuo, brown solid residue was directly gone to next step.
Reaction SMILES: [Li]CCCC.Br[C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[C:12]([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>CCOCC.C1COCC1>[C:15]([O:14][C:12]([N:19]1[CH2:24][CH2:23][C:22]([OH:25])([C:7]2[S:8][CH:9]=[CH:10][N:11]=2)[CH2:21][CH2:20]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Brc1nccs1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2nccs2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−78° C.) and stirred solution of n-BuLi (2.6 mL, 1.05 eq., 10.0 M in hexanes) in dry Et2O (20 mL) was added dropwise a solution of 2-bromothiazole (4.0 g, 24.4 mmol) in THF (10 mL) over a 10 minute period. After the yellow mixture had been stirred at −78° C. for 30 minutes, a solution of 1-Boc-4-piperidone (4.9 g, 1 eq.) in THF (20 mL) was added slowly. The mixture was then continued to stir for another 30 minutes before the reaction was quenched by addition of water (5 mL). The mixture was warmed to room temperature and extracted with EtOAc. The organic phase was separated, washed with brine and dried over Na2SO4. After removal of the solvent, the crude product was purified on silica gel (45% EtOAc in hexanes) to afford the desired product as a thick oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]3[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=3)([CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[Na+].[C:27]1([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>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].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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]3[CH:19]=[CH:18][C:17]([N:36]4[CH2:37][CH2:38][N:33]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH2:34][CH2:35]4)=[CH:16][CH:15]=3)([CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CC2CC2(c2ccc(Br)cc2)C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC2CC2(c2ccc(N3CCN(c4ccccc4)CC3)cc2)C1
Temperature: 120 °C
Yield: 40.3 %

Procedure:
To a solution of 1-(4-bromo-phenyl)-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (2 g, 5.91 mmol) in anhydrous toluene (20 mL) were added Pd2(dba)3 (27 mg, 0.029 mmol), BINAP (36 mg, 0.059 mmol), sodium tert-butoxide (230 mg, 2.4 mmol) and 1-phenyl piperazine (1.05 g, 6.5 mmol) and reaction mixture was refluxed at 120° C. for 2 days. After the completion of reaction as confirmed by the TLC, excess solvent was evaporated under reduced pressure to afford crude compound which was purified by column chromatography (silica gel 0.8:9.2 EtOAc:Pet. ether) to afford pure title compound, (1.0 g, 2.38 mmol, 40%) as a thick gel.
Reaction SMILES: [F:1][C:2]1(F)[CH2:12][CH2:11][CH:5]2[C:6]([O:8][C:9](=[O:10])[CH:4]2[CH2:3]1)=[O:7].ClCl>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1
Reactant: O=C1OC(=O)C2CC(F)(F)CCC12
Agent: ClCl
Product: O=C1OC(=O)c2cc(F)ccc21
Yield: 80 %

Procedure:
The procedure of Example III was repeated except that the feed was 4,4-difluorohexahydrophthalic anhydride, the vapor temperature was 240° C., reaction temperature was 255° C., the organic rate was 0.5 grams/minute, and the chlorine rate was 183 ml/min. The product, 4-fluorophthalic anhydride, was produced in 80% yield and 90% purity.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][CH3:44])=[C:37]([C:45]#[N:46])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1.C(O)C.O>[C:45]([C:37]1[CH:36]=[CH:35][C:40]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:39][C:38]=1[O:41][CH2:42][CH2:43][CH3:44])#[N:46]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCCOc1ccc(OB([O-])[O-])cc1C#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCCOc1cc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)ccc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (400 mg) was added toluene/ethanol/water (10/1/1, 13.2 ml) and then were added 3-cyano-4-propoxyphenyl borate (205 mg) and potassium carbonate (234 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture were added palladium acetate (8.6 mg) and tris(2-methylphenyl)phosphine (22.4 mg), and the mixture was refluxed for 18 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate/THF, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give 7-(4-cyano-3-propoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 94) (243 mg).
Reaction SMILES: [CH3:1][C:2]1[CH2:6][CH2:5][C:4](=O)[CH:3]=1.[C:8]1([Li])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Li].BrC1C=CC=CC=1.[NH4+].[Cl-]>CCOCC>[CH3:1][C:2]1[CH2:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:3]=1
Reactant: CC1=CC(=O)CC1
Reactant: [Li]c1ccccc1
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: Brc1ccccc1
Solvent: CCOCC
Product: CC1=CC(c2ccccc2)=CC1
Reaction time: 4 h

Procedure:
A solution of 25 g (0.26 mol) of 3-methyl-2cyclopenten-1-one in 100 mL of ether was added at −78° C. under argon atmosphere to a solution of phenyl litium in 200 mL of ether, previous prepared from 5.76 g (0.83 mol) of lithium and 44 mL (0.42 mol) of bromobenzene. The reaction mixture was stirred for 4 h and then treated with a 10% aq. solution of NH4Cl. The organic phase was collected, washed with water, dried with MgSO4 and concentrated. The residue was distilled at 54° C./1 mmHg. Yield 24.37 g (60%).