Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([C:27]([NH:29][N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[O:28])[CH:18]=[N:19][C:20]=2[O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:11][CH:10]=1.C(N(CC)C(C)C)(C)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([C:27]([NH:29][N:30]3[CH2:31][CH2:32][N:33]([S:46]([CH3:45])(=[O:48])=[O:47])[CH2:34][CH2:35]3)=[O:28])[CH:18]=[N:19][C:20]=2[O:21][CH2:22][C:23]([F:24])([F:26])[F:25])=[CH:11][CH:10]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NN1CCNCC1)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCN(NC(=O)c2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
5-(4-Chlorophenyl)-N-(piperazin-1-yl)-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxamide 2,2,2-trifluoroacetate (1:1) (100 mg, 189 μmol) was combined with dichloromethane (5 mL) to give a white suspension. N,N-Diisopropylethylamine (122 mg, 165 μl, 945 μmol) and methanesulfonyl chloride (23.8 mg, 16.1 μl, 208 μmol) were added successively at 0° C. The reaction mixture was stirred for 1 h at 0° C. and subsequently concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 20 g, 0% to 100% ethyl acetate in n-heptane). Recrystallization from ethyl acetate and n-heptane afforded the title compound (50 mg, 54%) as off-white solid; LC-MS (UV peak area/ESI) 98.0%, 493.0916 (M+H)+.
Reaction SMILES: [K].[SH:2][C:3]1[NH:7][N:6]=[N:5][CH:4]=1.CC(O[CH2:12][C:13]1[CH2:22][S:21][C@@H:16]2[C@H:17]([NH2:20])[C:18](=[O:19])[N:15]2[C:14]=1[C:23]([OH:25])=[O:24])=O.C([O-])(O)=O.[Na+].P([O-])([O-])([O-])=O.OP(O)(O)=O>>[NH2:20][CH:17]1[C:18](=[O:19])[N:15]2[C:14]([C:23]([OH:25])=[O:24])=[C:13]([CH2:12][S:2][C:3]3[NH:7][N:6]=[N:5][CH:4]=3)[CH2:22][S:21][C@H:16]12
Reactant: Sc1cnn[nH]1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=C([O-])O
Agent: O=P(O)(O)O
Agent: O=P([O-])([O-])[O-]
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3cnn[nH]3)CS[C@H]12
Temperature: 55 °C
Reaction time: 2 h

Procedure:
Ten grams (0.075 mole) of 5-mercapto-1,2,3-triazole potassium salt was added to a stirred slurry of 19 g. (0.07 mole) of purified 7-aminocephalosporanic acid and 5.9 g. (0.07 mole) of NaHCO3 in 350 ml. of 0.1 M phosphate buffer (pH 6.4) and the mixture heated and stirred at 55° C. for 31/2 hours under a nitrogen atmosphere. The resulting solution was cooled to 22° C. and adjusted to pH 5.5 with 40% H3PO4. The resulting precipitate was filtered off, washed with cold water (50 ml.) and air dried. The yield of 7-amino-3-(1,2,3-triazole-5-ylthiomethyl)-3-cephem-4-carboxylic acid was 8 g., dec. pt. 230° C. IR analysis showed some decomposition of the β-lactam ring but it was used "as is" for the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:5]=1[C:6](=[O:21])[CH:7]1[CH:12]([C:13]2=[O:18])[CH2:11][C:10]([CH3:19])=[C:9]([CH3:20])[CH2:8]1)([O-])=O.[S-2].[Na+].[Na+]>O>[NH2:1][C:4]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:5]=1[C:6](=[O:21])[C:7]1[CH:8]=[C:9]([CH3:20])[C:10]([CH3:19])=[CH:11][C:12]=1[C:13]2=[O:18]
Reactant: CC1=C(C)CC2C(=O)c3c(cccc3[N+](=O)[O-])C(=O)C2C1
Agent: [Na+]
Agent: [S-2]
Solvent: O
Product: Cc1cc2c(cc1C)C(=O)c1c(N)cccc1C2=O
Temperature: 90 °C

Procedure:
To 5.0 parts of 5-nitro-2,3-dimethyl-1,4,4a,9a-tetrahydroanthraquinone there was added 100 parts of water and then, with stirring at 90°C, 20 parts of a 10 wt % aqueous sodium sulfide. The reaction mixture thus formed was maintained at 90° - 95°C for 1 hour and, after cooled to 25°C, filtered to recover crystals. The crystals were washed with water and dried under reduced pressure to obtain 4.5 parts of 5-amino-2,3-dimethylanthraquinone of a melting point of 222°C.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[F:25][C:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[CH:28][C:27]=1[NH:41][C:42]1[S:43][C:44]2[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=2[N:46]=1>>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:30]3[CH:29]=[CH:28][C:27]([NH:41][C:42]4[S:43][C:44]5[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=5[N:46]=4)=[C:26]([F:25])[CH:31]=3)[C:10]=12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: CC1(C)OB(c2ccc(Nc3nc4ccccc4s3)c(F)c2)OC1(C)C
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6ccccc6s5)c(F)c4)c4c(N)ncnc43)CC2)CC1

Procedure:
Cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-1,3-benzothiazol-2-amine was prepared from cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.100 g, 0.227 mmol) and N2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzothiazol-2-amine (0.105 g, 0.283 mmol) in a manner similar to that used for cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-dlpyrimidin-3-yl}-2-fluorophenyl)-1,3-benzoxazol-2-amine. The compound was formed as an off-white powder (0.051 g, 41%): 1H NMR (DMSO-d6, 400 MHz) δ 10.51 (s, 1H), 8.80 (m, 1H), 8.24 (s, 1H), 7.85 (d, 1H), 7.65 (d, 1H), 7.51 (m, 2H), 7.36 (t, 1H), 7.20 (t, 1H), 4.82 (m, 1H), 3.51-2.25 (m, 14H), 2.15-2.10 (m, 2H), 1.80-1.50 (m, 4H); RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) tr=7.63 min., 100%; m/z 558 (MH+).
Reaction SMILES: C(NC(C)C)(C)C.[Li].C(NC(C)C)(C)C.C([Li])CCC.[C:21]1([CH3:39])[CH:26]=[CH:25][C:24]([S:27]([N:30]2[C:34]3=[N:35][CH:36]=[CH:37][CH:38]=[C:33]3[CH:32]=[CH:31]2)(=[O:29])=[O:28])=[CH:23][CH:22]=1.Cl.[O:41]1CCC[CH2:42]1>CN(C)C=O>[C:21]1([CH3:39])[CH:22]=[CH:23][C:24]([S:27]([N:30]2[C:34]3=[N:35][CH:36]=[CH:37][CH:38]=[C:33]3[CH:32]=[C:31]2[CH:42]=[O:41])(=[O:29])=[O:28])=[CH:25][CH:26]=1
Reactant: C1CCOC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3cccnc32)cc1
Agent: Cl
Agent: [Li]
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: Cc1ccc(S(=O)(=O)n2c(C=O)cc3cccnc32)cc1
Temperature: -75 °C
Reaction time: 3 h

Procedure:
A solution of lithium diisopropylamine {prepared by treating a solution of diisopropylamine (33.6 mL) in tetrahydrofuran (250 mL) with butyl lithium in hexanes (70.4 mL, 2.5M) at −35° C., at −75° C., was treated dropwise with a solution of 1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine [40 g, Reference Example 9(a)] in dry tetrahydrofuran (250 mL) at −75° C. whilst maintaining the reaction temperature below −60° C. After stirring at −75° C. for 3 hours the reaction mixture was allowed to warm to 5° C. over 2 hours then recooled to −75° C. and then treated with dimethylformamide(62 mL). The reaction mixture was left to warm to room temperature over 1 hour then poured into hydrochloric acid (800 mL, 1%) and then evaporated to remove the tetrahydrofuran. The resulting suspension was filtered and the solid was washed with water, then dried and then was subjected to flash column chromatography on silica eluting with dichloromethane to give the title compound (24.37 g) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1C=CC(Br)=[CH:10][N:9]=1.C(=O)([O-])O.[Na+].CO.CNC.[Br:25][C:26]1[CH:27]=[CH:28][C:29]([CH:32]=[CH2:33])=[N:30][CH:31]=1>O1CCOCC1.O.C(O)(=O)C>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:32][CH2:33][N:9]([CH3:10])[CH3:8])=[N:30][CH:31]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C=Cc1ccc(Br)cn1
Agent: CNC
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CC(=O)O
Product: CN(C)CCc1ccc(Br)cn1
Temperature: 80 °C
Reaction time: 3 h
Yield: 22 %

Procedure:
A vinylboronic acid anhydride pyridine complex (86.2 mg (0.36 mmol), 39.3 mg (0.05 mmol) of a [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex, and 209.0 mg (1.5 mmol) of potassium carbonate were added to a solution of 241.2 mg (1.0 mmol) of 2,5-dibromopyridine in dioxane-water (4 ml, 3:1), and the mixture was stirred at 80° C. for 3 hr. A saturated aqueous sodium hydrogencarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation to give 208.4 mg of a crude product of 5-bromo-2-vinylpyridine. A 2.0 M dimethylamine methanol solution (5 ml, 10 mmol) was added to a solution of 208.4 mg of the crude product of 5-bromo-2-vinyl pyridine in acetic acid (1.4 ml), and the mixture was stirred at 80° C. overnight and at 90° C. for two nights. A saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was removed by distillation, and the residue was then purified by column chromatography on silica gel (hexane:ethyl acetate=10:1, chloroform:methanol=10:1) to give 49.7 mg (two steps, yield 22%) of the title compound.
Reaction SMILES: Cl.Cl.Cl.[N:4]1([CH2:8][CH2:9][N:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([CH3:22])[CH:16]=3)[N:12]=[C:11]2[CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:7][CH2:6][CH2:5]1.Cl[C:30]1[N:35]=[CH:34][N:33]=[C:32]([NH2:36])[C:31]=1[CH:37]1[CH2:39][CH2:38]1>>[N:4]1([CH2:8][CH2:9][N:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([CH3:22])[CH:16]=3)[N:12]=[C:11]2[CH:23]2[CH2:24][CH2:25][N:26]([C:30]3[N:35]=[CH:34][N:33]=[C:32]([NH2:36])[C:31]=3[CH:37]3[CH2:39][CH2:38]3)[CH2:27][CH2:28]2)[CH2:5][CH2:6][CH2:7]1
Reactant: Cc1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccc1F
Reactant: Nc1ncnc(Cl)c1C1CC1
Agent: Cl
Product: Cc1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4C4CC4)CC3)n2)ccc1F

Procedure:
The title compound was prepared according to the procedure described for the preparation of compound “1” by using 4-[1-(2-azetidin-1-yl-ethyl)-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidine trihydrochloride and 6-chloro-5-cyclopropyl-pyrimidin-4-ylamine as the starting materials. LC-MS (M+H=476, obsd=476). 1H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.66-7.56 (m, 1H), 7.55-7.49 (m, 1H), 7.47 (s, 1H), 7.07 (t, J=9.1 Hz, 1H), 6.16 (s, 2H), 4.19 (d, J=13.0 Hz, 2H), 3.88 (t, J=6.3 Hz, 2H), 3.11 (t, J=6.9 Hz, 4H), 3.05-2.86 (m, 3H), 2.69 (t, J=6.2 Hz, 2H), 2.26 (s, 3H), 1.92 (ddt, J=26.3, 10.1, 5.7 Hz, 6H), 1.49 (q, J=6.9 Hz, 1H), 1.09-0.95 (m, 2H), 0.43 (d, J=5.2 Hz, 2H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]=[CH:27][CH3:28])[CH2:23][CH2:22][C:21]([C:29](O)=[O:30])=[CH:20][C:19]=3[CH:32]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.[CH3:37][N:38]([CH:40]=O)[CH3:39]>>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]=[CH:27][CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:24][C:18]4[CH:19]=[CH:32][C:15]([CH2:40][N:38]([CH3:37])[CH:39]5[CH2:7][CH2:6][O:5][CH2:1][CH2:2]5)=[CH:16][CH:17]=4)=[O:30])=[CH:20][C:19]=3[CH:32]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)C=O
Reactant: CC=CCN1CCC(C(=O)O)=Cc2cc(-c3ccc(OCCOCCCC)cc3)ccc21
Solvent: O=S(Cl)Cl
Product: CC=CCN1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(-c3ccc(OCCOCCCC)cc3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In DMF (3.9 ml) was dissolved 7-[4-(2-butoxyethoxy)phenyl)-1-crotyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.20 g). To the solution was added thionyl chloride (82 μl), and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and a solution of the resulting residue in THF was added dropwise to a solution of 4-[methyl(tetrahydropyranyl-4-yl)aminomethyl]aniline (111 mg) and triethylamine (0.31 ml) in THF (3.3 ml) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (ethyl acetate/ethanol=4/1), which was recrystallized from isopropyl ether/ethyl acetate to give 7-[4-(2-butoxyethoxy)phenyl]-1-crotyl-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 83) (9 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH2:8][C@H:9]3[CH2:22][C@H:10]3[C:11]=2[N:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[N:13]=1)=[O:5])C.[OH-].[Na+]>CO.C1COCC1>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[N:12]1[C:11]2[C@@H:10]3[CH2:22][C@@H:9]3[CH2:8][C:7]=2[C:6]([C:4]([OH:5])=[O:3])=[N:13]1
Reactant: CCOC(=O)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Temperature: 23 °C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
To a solution of (1aR,5aR)-2-(2,4-difluoro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester (17.4 g, 57.2 mmol) in methanol (100 mL) and THF (100 mL) was added a 2.0 M aqueous solution of sodium hydroxide (86 mL, 172 mmol). The resulting orange solution was stirred at 23° C. for 3 h. The organic solvents were removed under reduced pressure. The remaining aqueous solution was diluted to 150 mL with water and then acidified to pH 2 by addition of 6 M HCl while stirring vigorously. The precipitate was collected by filtration, rinsed with water, and then dried under reduced pressure to give the title compound as a tan solid (15.62 g). LCMS m/z=277.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.41 (td, J=4.6, 3.4 Hz, 1H), 1.15 (td, J=7.8, 4.7 Hz, 1H), 2.16-2.21 (m, 1H), 2.23-2.29 (m, 1H), 2.76 (d, J=16.2 Hz, 1H), 2.90 (dd, J=16.4, 6.2 Hz, 1H), 7.27-7.32 (m, 1H), 7.56-7.62 (m, 1H), 7.75 (td, J=9.0, 5.9 Hz, 1H), 12.93 (bs, 1H).
Reaction SMILES: P(Br)(Br)([Br:3])=O.[CH:6]1([CH2:9][N:10]2[CH:15]=[CH:14][C:13](O)=[C:12]([C:17]([F:20])([F:19])[F:18])[C:11]2=[O:21])[CH2:8][CH2:7]1>CN(C=O)C>[Br:3][C:13]1[CH:14]=[CH:15][N:10]([CH2:9][CH:6]2[CH2:8][CH2:7]2)[C:11](=[O:21])[C:12]=1[C:17]([F:20])([F:19])[F:18]
Reactant: O=c1c(C(F)(F)F)c(O)ccn1CC1CC1
Reactant: O=P(Br)(Br)Br
Solvent: CN(C)C=O
Product: O=c1c(C(F)(F)F)c(Br)ccn1CC1CC1
Temperature: 110 °C
Yield: 42 %

Procedure:
Phosphorus oxybromide (7.03 g, 24.5 mmol) was added to a solution of intermediate D8 (2.60 g, 11.1 mmol) in DMF (50 ml) and the mixture was heated at 110° C. for 1 hour. After cooling in an ice bath the solution was partitioned between water and EtOAc. After three extractions with EtOAc the combined organic fractions were dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate D9 (1.38 g, 42%).
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3].[CH2:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]CC>>[CH2:1]([NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])/[CH:2]=[CH:3]\[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: C=CCNC(=O)OC(C)(C)C
Reactant: C=CCCCCCCCCCCCCCC
Product: CCCCCCCCCCCCCC/C=C\CNC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
Following the allylic amide CM general procedure, tert-butyl allylcarbamate (4.40 mg, 0.0280 mmol) was treated with 1-hexadecene (64.5 mg, 0.290 mmol), 5.0 mol % of in situ-generated complex 2 (75.0 μL, 0.02 M, 1.50 μmol), and allowed to stir under vacuum for 1 h. Z-selectivity could not be determined from 400 MHz 1H NMR spectrum of unpurified product. The resulting brown oil was purified by silica gel chromatography (96:2:2 hexanes:EtOAc:CH2Cl2) to afford 19f (8.30 mg, 0.0230 mmol, 84.0% yield, 81% Z isomer) as a white, crystalline solid. M.P. 42-46° C.; IR (neat): 3353 (br), 2922 (s), 2853 (s), 1700 (s), 1501 (m), 1457 (m), 1390 (m), 1365 (m), 1247 (m), 1170 (s), 1046 (w), 1023 (w); 1H NMR (400 MHz, CDCI3): 5.60-5.34 (overlapping Z/E 2H, m), 4.45 (overlapping Z/E, 1H, br d, J=15.6 Hz), 3.74 (E, 1H, br s), 3.66 (Z, 1H, br s), 2.06-1.96 (overlapping Z/E, 2H, m), 1.43 (overlapping Z/E, 9H, s), 1.41-1.24 (overlapping Z/E, 24H, m), 0.86 (overlapping Z/E, 3H, t, J=7.8 Hz); 13C NMR (100 MHz, CDCl3): 156.0, 155.9, 133.4, 126.3, 125.9, 79.4, 77.4, 32.4, 32.1, 29.9, 29.8 29.8, 29.8, 29.7, 29.7, 29.5, 29.4, 29.3, 28.6, 27.5, 22.8, 19.2, 14.3; HRMS (ESI+) [M+Na]+ calcd for C22H43NO2Na: 376.3191, found: 376.3184.
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.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][C:49]([S:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])=[CH:48][CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH3:31][N:24]([CH2:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14]([C:8]2[CH2:9][CH2:10][S:11](=[O:13])(=[O:12])[C:5]3[CH:4]=[CH:3][C:2]([C:46]4[CH:51]=[CH:50][C:49]([S:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])=[CH:48][CH:47]=4)=[CH:32][C:6]=3[CH:7]=2)=[O:15])=[CH:18][CH:19]=1)[CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCCCCSc1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCCSc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.6 %

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 (310 mg) was added toluene/ethanol/water (10/1/1, 6.0 ml) and then were added 4-(pentylthio)phenyl borate (182 mg) and potassium carbonate (181 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (34 mg), and the mixture was stirred at 100° C. for 12 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 N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-(4-pentylthiophenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 78) (161 mg).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[CH3:13][CH:14]([NH2:17])[CH2:15][CH3:16]>>[CH:14]([NH:17][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1)([CH2:15][CH3:16])[CH3:13]
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Reactant: CCC(C)N
Product: CCC(C)Nc1nc(SC)nc(Cl)c1C=O

Procedure:
Prepared as described above in Example 2 starting from 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 2-butylamine to give the title compound 4-sec-butylamino-6-chloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 0.87 (m, 3H), 1.18 (m, 3H), 1.20 (m, 2H), 2.51 (s, 3H), 4.24 (m, 1H), 9.12 (br s, 1H), 10.18 (s, 1H). LC MS (m/e)=260 (MH+).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].Cl[C:6](=[O:11])[C:7]([O:9][CH3:10])=[O:8].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19][CH3:20]>C(Cl)(Cl)Cl>[CH3:10][O:9][C:7](=[O:8])[C:6]([C:17]1[CH:16]=[CH:15][C:14]([S:19][CH3:20])=[C:13]([Cl:12])[CH:18]=1)=[O:11]
Reactant: COC(=O)C(=O)Cl
Reactant: CSc1ccccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: COC(=O)C(=O)c1ccc(SC)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
A solution of aluminum trichloride (54.9 g, 412 mmol) in chloroform (180 mL) under argon was cooled to 0° C. and then treated dropwise with a solution of methyl chlorooxoacetate (24.3 mL, 264 mmol) in chloroform (180 mL). The reaction mixture was stirred at 0° C. for 30 min and then was treated dropwise with a solution of 2-chlorothioanisole (39.4 g, 247 mmol) in chloroform (180 mL). The reaction mixture turned red in color. The resulting reaction mixture was allowed to warm to 25° C. where it was stirred for 4 h. The reaction mixture was then slowly poured onto ice (700 mL). The resulting yellow mixture was stirred for 15 min and then was filtered through celite to remove the aluminum salts. The filtrate was then extracted with methylene chloride (3×50 mL). The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution (1×50 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo to afford (3-chloro-4-methylsulfanyl-phenyl)-oxo-acetic acid methyl ester (36.4 g, 60%) as a light yellow oil: EI-HRMS m/e calcd for C10H9ClSO3 (M+) 243.9961, found 243.9958.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=4)=[C:15](Br)[C:16]3=[O:19])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[F:54][C:55]([F:66])([F:65])[C:56]1[CH:61]=[CH:60][C:59](B(O)O)=[CH:58][CH:57]=1>>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=4)=[C:15]([C:59]4[CH:60]=[CH:61][C:56]([C:55]([F:66])([F:65])[F:54])=[CH:57][CH:58]=4)[C:16]3=[O:19])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1
Reactant: O=C1C(Br)=C(c2ccc(Cl)cc2)c2ccc(OCCN3CCOCC3)cc21
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: O=C1C(c2ccc(C(F)(F)F)cc2)=C(c2ccc(Cl)cc2)c2ccc(OCCN3CCOCC3)cc21
Yield: 14 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 6-(2-morpholinoethoxy)-2-bromo-3-(4-chlorophenyl)-1H-inden-1-one obtained in Step 6 of Example 28 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 4-(trifluoromethyl)phenyboronic acid instead of 3-pyridinylboronic acid, and being purified by prep HPLC (CH3CN/H2O=7:3) to obtain the title compound (14%).
Reaction SMILES: [CH2:1](OC(CCCCCCNC1C2C(=C(OC)C(OC)=C(OC)C=2)N=CN=1)=O)[CH3:2].C(OC(CCNC1C2C(=C(OC)C(OC)=C(OC)C=2)N=CN=1)=O)C.C(OC(CCCCNC1C2C(=C(OC)C(OC)=C(OC)C=2)N=CN=1)=O)C.C(OC(CCCCCCCNC1C2C(=C(OC)C(OC)=C(OC)C=2)N=CN=1)=O)C.C(CCCCCNC1C2C(=CC=C(Cl)C=2)N=CN=1)(O)=O.[C:128]([CH2:131][NH:132][C:133]1[C:142]2[C:137](=[C:138]([O:147][CH3:148])[C:139]([O:145][CH3:146])=[C:140]([O:143][CH3:144])[CH:141]=2)[N:136]=[CH:135][N:134]=1)([OH:130])=[O:129]>>[CH2:1]([O:129][C:128]([CH2:131][NH:132][C:133]1[C:142]2[C:137](=[C:138]([O:147][CH3:148])[C:139]([O:145][CH3:146])=[C:140]([O:143][CH3:144])[CH:141]=2)[N:136]=[CH:135][N:134]=1)=[O:130])[CH3:2]
Reactant: CCOC(=O)CCCCCCNc1ncnc2c(OC)c(OC)c(OC)cc12
Reactant: COc1cc2c(NCC(=O)O)ncnc2c(OC)c1OC
Agent: CCOC(=O)CCCCCCCNc1ncnc2c(OC)c(OC)c(OC)cc12
Agent: CCOC(=O)CCCCNc1ncnc2c(OC)c(OC)c(OC)cc12
Agent: CCOC(=O)CCNc1ncnc2c(OC)c(OC)c(OC)cc12
Product: CCOC(=O)CNc1ncnc2c(OC)c(OC)c(OC)cc12

Procedure:
4-(6-ethoxycarbonylhexyl)amino-6,7,8-trimethoxy-quinazoline; 4-(2-ethoxycarbonylethyl)amino-6,7,8-trimethoxy-quinazoline; 4-(4-ethoxycarbonylbutyl)amino-6,7,8-trimethoxy-quinazoline; 4-(7-ethoxycarbonylheptyl)amino-6,7,8-trimethoxy-quinazoline; 4-(5-carboxypentyl)amino-6-chloroquinazoline; and 4-(carboxymethyl)amino-6,7,8-trimethoxy-quinazoline.