Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[N:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30]O)=[CH:23][CH:22]=1>CN(C)C=O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:30][CH2:29][CH2:28][CH2:27][C:24]2[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=2)=[CH:7][CH:6]=1
Reactant: OCCCCc1ccncc1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)C(=O)c1ccc(OCCCCc2ccncc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 30.9 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (1.086 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.261 g), stirred for 15 minutes and treated with the mesylate prepared from 0.906 g of 4-pyridinebutanol. The mixture was heated under argon at 60° C. for 4 hours. The cooled mixture was treated with glacial acetic acid (2 drops) and the volatiles were removed under vacuum. The residue was mixed with dichloromethane and dilute cold sodium bicarbonate solution. The dichloromethane extracts were dried (Na2SO4), filtered, and evaporated to give crude product. The material was purified by HPLC (hexane-acetone; 2: 1) to provide 0.58 g of alpha-oxo-4-[4-(4-pyridinyl)butoxy]benzeneacetic acid methyl ester as a colorless oil whose NMR was compatible with the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](B(O)O)[CH:5]=[CH:4][N:3]=1.Br[C:12]1[CH:13]=[C:14]2[C:18](=[C:19]([C:21]([NH2:23])=[O:22])[CH:20]=1)[NH:17][CH:16]=[C:15]2[CH:24]1[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]1.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>[Cl:1][C:2]1[CH:7]=[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([C:21]([NH2:23])=[O:22])[CH:20]=2)[NH:17][CH:16]=[C:15]3[CH:24]2[CH2:25][CH2:26][S:27](=[O:30])(=[O:31])[CH2:28][CH2:29]2)[CH:5]=[CH:4][N:3]=1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Reactant: OB(O)c1ccnc(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)c1cc(-c2ccnc(Cl)c2)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Temperature: 100 °C
Yield: 19.6 %

Procedure:
To a mixture of (2-chloro-4-pyridinyl)boronic acid (0.095 g, 0.606 mmol), 5-bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide (0.075 g, 0.202 mmol) and potassium carbonate (0.168 g, 1.212 mmol) was added 1,4-dioxane (0.898 mL)/water (0.449 mL). The mixture was degassed with nitrogen and PdCl2(dppf) (0.015 g, 0.020 mmol) was added. The reaction mixture was heated in a microwave oven at 100° C. for 5 minutes on ‘high’ absorption setting. LCMS of crude reaction mixture shows the desired m/z and some unreacted starting material (very close ret. times). The reaction mixture was filtered through a Thiol SPE cartridge (500 mg) eluting with 1:1 MeOH/DCM (10 mL). The filtrate was purified with RP-HPLC (XBridge Column, 0.1% NH4OH). The fractions containing the desired compound are combined and concentrated to give 5-(2-chloro-4-pyridinyl)-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide (0.016 g, 19.61%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.COC1C=CC=C2C=1CC[C@H](C)N2>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]2[C:11]=1[NH:10][C@@H:9]([CH3:12])[CH2:8][CH2:7]2
Reactant: COc1ccc(F)c2nc(C)ccc12
Agent: COc1cccc2c1CC[C@H](C)N2
Product: COc1ccc(F)c2c1CC[C@H](C)N2

Procedure:
(S)-8-Fluoro-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline was synthesized from 8-fluoro-5-methoxy-2-methylquinoline according to the procedures described above for (2S)-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline (Intermediate 1). MS (ESI, pos. ion) m/z 196 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]2[C:5]([N:6]=[C:7]3[C:12](=[C:13]2[C:16]([F:19])([F:18])[CH3:17])[CH:11]=[CH:10][CH:9]=[N:8]3)=[CH:4][CH:3]=1.[C-:20]#[N:21].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[N:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]([C:20]#[N:21])([C:16]([F:19])([F:18])[CH3:17])[C:14]=2[CH:15]=1
Reactant: [C-]#N
Reactant: CC(F)(F)c1c2cc(Cl)ccc2nc2ncccc12
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(F)(F)C1(C#N)c2cc(Cl)ccc2Nc2ncccc21
Reaction time: 15 h
Yield: 70 %

Procedure:
Method NN: To a stirred solution of 7-chloro-9-(1,1-difluoroethyl)-4-azaacridine (47) (1.440 g, 5.167 mmol) in anhydrous DMF (25 mL) at room temperature was added NaCN (533 mg, 10.334 mmol). After 15 h at room temperature, the reaction was quenched with 1:1 saturated aqueous NaHCO3/H2O (50 mL), and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Flash chromatography (20%-40% EtOAc-hexane, gradient elution) furnished 49 (1.106 g, 70% yield) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1.Br[C:13]1[N:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[C:7]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH:21]3[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]3)=[CH:17][N:18]=2)=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(Br)nc2)CC1
Reactant: Cc1ccc(B(O)O)c(F)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccc(-c2ccc(OCC3CCN(C(=O)OC(C)(C)C)CC3)cn2)c(F)n1

Procedure:
1,1-Dimethylethyl 4-{[(2′-fluoro-6′-methyl-2,3′-bipyridin-5-yl)oxy]methyl}-1-piperidinecarboxylate (0.21 g, 72%) was prepared as an off-white solid from 2-fluoro-6-picoline-3-boronic acid (0.14 g, 0.87 mmol), 1,1-dimethylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 76, Step 1, 0.27 g, 0.72 mmol), 2M Na2CO3 (2.5 mL) and PdCl2(PPh3)2 (26 mg, 0.04 mmol) DME (8 mL) in a manner similar to Example 21, Step 3. The crude material was purified by chromatography on a silica gel column eluted with 1:10 acetone/CH2Cl2 to give 1,1-dimethylethyl 4-{[(2′-fluoro-6′-methyl-2,3′-bipyridin-5-yl)oxy]methyl}-1-piperidine carboxylate as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.45-8.35 (m, 2H), 7.81 (d, 1H, J=8.0 Hz), 7.30-7.25 (m, 1H), 7.15-7.10 (m, 1H), 4.16 (bs, 2H), 3.88 (d, 2H, J=6.4 Hz), 2.80-2.65 (m, 2H), 2.53 (s, 3H), 2.10-1.90 (m, 1H), 1.90-1.80 (m, 2H), 1.45 (s, 9H), 1.35-1.20 (m, 2H); LRMS (ESI), m/z 402 (M+H).
Reaction SMILES: [OH:1][C@@H:2]([CH2:26][NH:27][S:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)(=[O:30])=[O:29])[C@@H:3]([NH:5][C:6](=[O:25])[O:7][C@H:8]([CH2:13][N:14]1[C:18]2[CH:19]=[C:20]([Cl:24])[C:21]([Cl:23])=[CH:22][C:17]=2[N:16]=[CH:15]1)[C:9]([CH3:12])([CH3:11])[CH3:10])[CH3:4].O[C@H](CNS(C1C=CC=CN=1)(=O)=O)[C@@H](NC(=O)O[C@H](CN1C2C=C(Cl)C(Cl)=CC=2N=C1)C(C)(C)C)C.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>[CH3:4][C@H:3]([NH:5][C:6](=[O:25])[O:7][C@H:8]([CH2:13][N:14]1[C:18]2[CH:19]=[C:20]([Cl:24])[C:21]([Cl:23])=[CH:22][C:17]=2[N:16]=[CH:15]1)[C:9]([CH3:10])([CH3:12])[CH3:11])[C:2](=[O:1])[CH2:26][NH:27][S:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)(=[O:29])=[O:30]
Reactant: C[C@H](NC(=O)O[C@H](Cn1cnc2cc(Cl)c(Cl)cc21)C(C)(C)C)[C@@H](O)CNS(=O)(=O)c1ccccn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: C[C@H](NC(=O)O[C@H](Cn1cnc2cc(Cl)c(Cl)cc21)C(C)(C)C)[C@H](O)CNS(=O)(=O)c1ccccn1
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: C[C@H](NC(=O)O[C@H](Cn1cnc2cc(Cl)c(Cl)cc21)C(C)(C)C)C(=O)CNS(=O)(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 50 %

Procedure:
To a solution of 0.13 g (0.23 mmol) of (1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl (1S,2S)-2-hydroxy-1-methyl-3-[(2-pyridinylsulfonyl)amino]propylcarbamate & (1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl (1S,2R)-2-hydroxy-1-methyl-3-[(2-pyridinylsulfonyl)amino]propylcarbamate in 6 mL of chloroform was added 42 mg (0.1 mmol) of Dess-Martin periodinane, and the reaction mixture was stirred at room temperature for 1.25 h. The mixture was diluted with ethyl acetate and saturated aqueous sodium thiosulfate solution. The layers were mixed vigorously, and then a saturated aqueous sodium bicarbonate solution was added. The layers were separated, and the organic extract was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography eluting with a methanol:chloroform solution (1:9) to yield 64 mg (50%) of (1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl (1S)-1-methyl-2-oxo-3-[(2-pyridinylsulfonyl)amino]propylcarbamate ES-LCMS m/z 556 (M+H)+ retention time=3.66 min. HRMS C23H27Cl2N5O5S m/z 556.1188 (M+H)Cal; 556.1193 (M+H)Obs.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:23]=[CH:24][C:25]([CH2:26][N:34]3[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]3)=[CH:28][CH:29]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(F)cc2)cc1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(C3Nc4cccc5c(=O)[nH]nc(c45)C3c3ccc(F)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.2 %

Procedure:
A mixture of 4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (150 mg, 0.39 mmol), N-methylpiperazine (117 mg, 1.17 mmol) and acetic acid (117 mg, 1.95 mmol) in dichloromethane (20 mL) was stirred at room temperature overnight. Then the mixture was cooled to 0° C. and sodium triacetoxyborohydride (124 mg, 0.58 mmol) was added. After the addition, the mixture was stirred at room temperature for 5 h. Dichloromethane was removed under reduced pressure. The crude product was purified by prep-HPLC to give the title compound (48 mg, yield 22%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 3.02 (s, 3H), 3.60-3.81 (m, 8H), 4.36-4.38 (d, J=7.6 Hz, 1H), 4.47 (s, 2H), 4.80-4.82 (d, J=7.6 Hz, 1H), 6.93-6.97 (m, 214), 7.12-7.15 (m, 2H), 7.22-7.24 (m, 1H), 7.43-7.45 (m, 214), 7.52-7.57 (m, 3H), 7.64-7.68 (m, 1H). LC-MS (ESI) m/z: 470 (M+1)+.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1>>[CH:18]([N:13]1[C:12]([C:34]2[CH:35]=[C:30]([CH3:29])[CH:31]=[CH:32][CH:33]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:19])[CH3:20]
Reactant: Cc1cccc(B(O)O)c1
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Product: Cc1cccc(-c2c3c(nn2C(C)C)CCNCC3)c1
Yield: 17.4 %

Procedure:
The title compound (24 mg) was prepared according to Example 189 using 219 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 209 mg of 3-methylphenylboronic acid. MS (ESI): exact mass calculated for C17H23N3, 269.19; found, m/z 270.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.44-7.41 (m, 1H), 7.34-7.33 (m, 1H), 7.13-7.10 (m, 2H), 4.37 (m, 1H), 3.42-3.40 (m, 2H), 3.19-3.17 (m, 2H), 2.78-2.76 (m, 2H), 2.42 (s, 3H), 1.38 (d, J=6.7 Hz, 6H).
Reaction SMILES: [Si:1]([O:8][CH:9]1[C:17]2[C:12](=[C:13]([CH3:34])[C:14]([CH:18]([OH:33])[C:19]([N:22]3[CH2:32][CH2:31][C:25]4([C:29](=[O:30])[NH:28][CH2:27][CH2:26]4)[CH2:24][CH2:23]3)([CH3:21])[CH3:20])=[CH:15][CH:16]=2)[CH2:11][O:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].FC(F)(F)S(O[C:41]1[CH2:42][O:43][C:44](=[O:47])[C:45]=1[CH3:46])(=O)=O.C(=O)([O-])[O-].[K+].[K+].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.O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Si:1]([O:8][CH:9]1[C:17]2[C:12](=[C:13]([CH3:34])[C:14]([CH:18]([OH:33])[C:19]([N:22]3[CH2:23][CH2:24][C:25]4([C:29](=[O:30])[N:28]([C:41]5[CH2:42][O:43][C:44](=[O:47])[C:45]=5[CH3:46])[CH2:27][CH2:26]4)[CH2:31][CH2:32]3)([CH3:21])[CH3:20])=[CH:15][CH:16]=2)[CH2:11][O:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: Cc1c(C(O)C(C)(C)N2CCC3(CCNC3=O)CC2)ccc2c1COC2O[Si](C)(C)C(C)(C)C
Reactant: CC1=C(OS(=O)(=O)C(F)(F)F)COC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Solvent: Cc1ccccc1
Product: CC1=C(N2CCC3(CCN(C(C)(C)C(O)c4ccc5c(c4C)COC5O[Si](C)(C)C(C)(C)C)CC3)C2=O)COC1=O
Temperature: 70 °C

Procedure:
To a mixture of 8-(1-(1-((tert-butyldimethylsilyl)oxy)-4-methyl-1,3-dihydroisobenzofuran-5-yl)-1-hydroxy-2-methylpropan-2-yl)-2,8-diazaspiro[4.5]decan-1-one (1.35 g, 2.76 mmol), 4-methyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (I-9) (0.884 g, 3.59 mmol) in toluene (40 mL) was added potassium carbonate (0.764 g, 5.52 mmol), Xantphos (0.320 g, 0.552 mmol), and water (0.149 mL, 8.29 mmol). The mixture was flushed with nitrogen for 20 min before addition of palladium (II) acetate (0.062 g, 0.276 mmol). The resulting mixture was heated at 70° C. overnight. After filtration the filtrate was concentrated and the residue was purified on silica gel column using methanol/methylene chloride as eluting solvents to give the title compound. LC/MS: (M+1−114)+: 471.22.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](Cl)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)CCC.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>O1CCOCC1.O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Clc1ncnc2c1CCN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: c1ccc(CN2CCc3c(ncnc3-c3ccccn3)C2)cc1
Temperature: 25 °C
Yield: 38.9 %

Procedure:
Part C: To a solution of 7-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (4.75 g, 18.3 mmol) in 1,4-dioxane (80 mL) at 25° C. was added sequentially 2-(tributylstannyl)pyridine (98%, 5.95 mL, 18.3 mmol), tri-2-furylphosphine (0.85 g, 3.66 mmol), and palladium (II) acetate (0.205 g, 0.914 mmol). The resulting mixture was heated slowly to reflux over ˜0.25 h and then was stirred at reflux for 5.0 h. After cooling to room temperature the mixture was diluted with water and ethyl acetate, and the mixture filtered. The phases were separated, and the organic phase washed with water and brine, dried over anhyd. sodium sulfate, filtered, and concentrated. Column chromatography (elution: 0-5% 2M ammonia in methanol/chloroform) afforded 7-benzyl-4-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (2.15 g, 39%) as a red oil; Mass Spec.: m/c: 303.15 (M+H)+ [calc'd: 303.15]; 1H NMR (500 MHz, CDCl3) δ 9.02 (s, 1H), 8.68 (m, 1H), 8.01 (m, 1H), 7.83 (m, 1H), 7.42-7.27 (m, 6H), 3.80 (m, 4H), 3.31 (m, 2H), 2.80 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[Cu][C:13]#[N:14].[C-]#N.[Na+]>CN(C=O)C.O>[O:9]=[C:7]1[NH:6][C:5]2[CH:10]=[CH:11][C:2]([C:13]#[N:14])=[CH:3][C:4]=2[O:8]1
Reactant: N#C[Cu]
Reactant: O=c1[nH]c2ccc(Br)cc2o1
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2[nH]c(=O)oc2c1
Temperature: 150 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
A mixture of 6-bromo-1,3-benzoxazol-2(3H)-one (2 g; 9.34 mmol) and copper (I) cyanide (1.42 g; 15.86 mmol) in 6 ml DMF is heated at 150° C. under nitrogen atmosphere for 22 hr. After cooling to room temperature, a solution of 1.55 g (31.6 mmol) of sodium cyanide in 32 ml water is added followed by 1 hr stirring. The system is extracted thoroughly with ethyl acetate, washed with brine, dried and concentrated in vacuo to provide 1.5 g (93% yield) of the title compound enough pure as to prosecute the synthesis.
Reaction SMILES: [C:1]([C:5]([C:8](Cl)([Cl:10])[Cl:9])([F:7])[F:6])(Cl)([Cl:3])[Cl:2].C(C(C(Cl)(Cl)Cl)(F)F)(Cl)Cl>>[CH:1]([C:5]([CH:8]([Cl:10])[Cl:9])([F:7])[F:6])([Cl:3])[Cl:2]
Reactant: FC(F)(C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Agent: FC(F)(C(Cl)Cl)C(Cl)(Cl)Cl
Product: FC(F)(C(Cl)Cl)C(Cl)Cl

Procedure:
The reaction was conducted and the product was analyzed in the same manner as in Example 1-1 except that 34 g (0.12 mol) of CCl3CF2CCl3 was used. As a result, it was found that the conversion was 84%, and CHCl2CF2CCl3 formed at a selectivity of 46% and CHCl2CF2CHCl2 formed at a selectivity of 44%.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].Cl[C:15]1[CH:32]=[C:19]2[C:20]3[C:25]([CH2:26][CH2:27][N:18]2[C:17](=[O:33])[N:16]=1)=[CH:24][C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=3>CC(O)C>[CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[N:6]=[C:15]1[CH:32]=[C:19]2[C:20]3[C:25]([CH2:26][CH2:27][N:18]2[C:17](=[O:33])[NH:16]1)=[CH:24][C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=3)([CH3:13])[CH3:12]
Reactant: COc1cc2c(cc1OC)-c1cc(Cl)nc(=O)n1CC2
Reactant: CC(C)c1cccc(C(C)C)c1N
Solvent: CC(C)O
Product: COc1cc2c(cc1OC)-c1cc(=Nc3c(C(C)C)cccc3C(C)C)[nH]c(=O)n1CC2
Temperature: 25 °C
Yield: 78.7 %

Procedure:
2,6-Diisopropylaniline (9.62 ml, 51 mmol) and 2-chloro-9,10-dimethoxy-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-4-one (5 g, 17 mmol) were suspended in propan-2-ol (400 ml) and heated at reflux, under nitrogen, for 4 days. After cooling to room temperature, the solution was concentrated in vacuo and the residue purified by flash column chromatography [dichloromethane/methanol (98:2-96:4)] to afford the title compound (5.8 g, 79%) as a yellow/orange solid.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH:10]1([C:13]2[NH:17][N:16]=[C:15]([NH2:18])[CH:14]=2)[CH2:12][CH2:11]1.C(N(C(C)C)CC)(C)C>C(O)CCC>[Br:1][C:2]1[C:3]([NH:18][C:15]2[CH:14]=[C:13]([CH:10]3[CH2:12][CH2:11]3)[NH:17][N:16]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Clc1ncc(Br)c(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 80 °C
Yield: 74.3 %

Procedure:
A mixture of 5-bromo-2,4-dichloropyrimidine (15.4 g, 67.6 mmol), 5-cyclopropyl-1H-pyrazol-3-ylamine (10.0 g, 81.3 mmol) and diisopropylethylamine (17 mL, 102 mmol) in 1-butanol (150 mL) was heated to 80° C. for 1 h. The solid that formed was collected by filtration and washed with acetonitrile to give the desired product (15.8 g, 75%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]([NH:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([Cl:16])=[CH:11][C:10]=1[C:17]#[C:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])=[O:7])[CH3:2].[H-].[Na+]>CS(C)=O>[CH2:1]([O:3][C:4]([C:5]1[C:6](=[O:7])[NH:8][C:9]2[C:10]([C:17]=1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])=[CH:11][C:12]([Cl:16])=[CH:13][C:14]=2[F:15])=[O:26])[CH3:2]
Reactant: CCOC(=O)CC(=O)Nc1c(F)cc(Cl)cc1C#Cc1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)c1c(Cc2ccccc2Cl)c2cc(Cl)cc(F)c2[nH]c1=O

Procedure:
The title compound was prepared in analogy to example 29 step B from N-[4-Chloro-2-(2-chloro-phenylethynyl)-6-fluoro-phenyl]-malonamic acid ethyl ester (217 mg, 0.55 mmol) and NaH (33 mg, 0.83 mmol) in DMSO. Off white solid (120 mg, 55%). MS (ESI): 394 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[F:15])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[CH2:18]([CH:20]1[O:22][CH2:21]1)Br>CN(C)C=O>[F:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[F:15])[N:7]([CH2:18][CH:20]3[CH2:21][O:22]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: BrCC1CO1
Reactant: Fc1cccc2[nH]c3cccc(F)c3c12
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Fc1cccc2c1c1c(F)cccc1n2CC1CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
To a stirred solution of 4,5-difluoro-9H-carbazole (0.270 g, 1.3 mmol) in N,N-dimethylformamide (5 mL) at 0° C. was added 85% potassium hydroxide (0.105 g, 1.6 mmol) and the mixture was stirred for 1 hr. Epibromohydrin (0.220 mL, 2.7 mmol) was added and the mixture was slowly warmed to room temperature and stirred for 4 hrs. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (10-50% methylene chloride/hexanes) to afford the desired product as a white solid (0.315 g, 91%). 1H NMR (300 MHz, CDCl3) δ 7.45 (tt, 2H, J=8.1, 2.4 Hz), 7.25 (d, 2H, J=8.1 Hz), 6.99 (dt, 2H, J=9.9, 4.2 Hz), 4.68 (dd, 1H, J=15.9, 3.0 Hz), 4.38 (dd, 1H, J=15.9, 5.1 Hz), 3.37 (m, 1H), 2.85 (t, 1H, J=4.5 Hz), 2.57 (dd, 1H, J=4.5, 2.4 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][N:7]=1.Cl[C:17]1[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[N:18]=1.CC(CC(C)C)=O.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:12][C:9]1[CH:8]=[N:7][C:6]([O:5][C:4]2[CH:13]=[CH:14][CH:15]=[C:2]([O:1][C:17]3[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[N:18]=3)[CH:3]=2)=[N:11][CH:10]=1
Reactant: Oc1cccc(Oc2ncc(Cl)cn2)c1
Reactant: Cc1cc(C)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: Cc1cc(C)nc(Oc2cccc(Oc3ncc(Cl)cn3)c2)n1
Yield: 39.7 %

Procedure:
A mixture of 2-(3-hydroxyphenoxy)-5-chloropyrimidine (2.22 g), 2-chloro-4,6-dimethylpyrimidine (1.43 g), isobutyl methyl ketone (25 ml) and anhydrous potassium carbonate (1.52 g) was heated under reflux for a period of 48 hours. The reaction mixture was diluted with water and the aqueous mixture was extracted with chloroform. The chloroform extract was dried and the solvent was removed by distillation under reduced pressure to give a pale yellow solid. The solid was recrystallised from ethanol to give the title compound (1.3 g), m.p. 142° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:30]3[CH2:35][CH2:34][CH2:33][CH2:32][NH:31]3)=[N:9][C:10]=2[C:11]2[CH:29]=[CH:28][C:14]([C:15]([NH:17][C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH:36]([S:38](Cl)(=[O:40])=[O:39])=[CH2:37]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:30]3[CH2:35][CH2:34][CH2:33][CH2:32][N:31]3[S:38]([CH:36]=[CH2:37])(=[O:40])=[O:39])=[N:9][C:10]=2[C:11]2[CH:29]=[CH:28][C:14]([C:15]([NH:17][C:18]3[CH:23]=[C:22]([C:24]([F:25])([F:27])[F:26])[CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c([C@@H]3CCCCN3)nc(-c3ccc(C(=O)Nc4cc(C(F)(F)F)ccn4)cc3)c12
Reactant: C=CS(=O)(=O)Cl
Product: C=CS(=O)(=O)N1CCCC[C@H]1c1nc(-c2ccc(C(=O)Nc3cc(C(F)(F)F)ccn3)cc2)c2c(N)nccn12
Yield: 20.5 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 1, from (S)-4-(8-amino-3-(piperidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (intermediate 25) and ethenesulfonyl chloride prepared according to procedures described by King et. al. in Can. J. Chem. 66 (1988) pp 1109-1116, to afford the title compound (6.1 mg, 20.5%). Data: UPLC(B) Rt: 1.24 min; m/z 572.2 (M+H)+.