Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[S:23][CH:22]=[N:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[CH:27](=O)[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[S:23][CH:22]=[N:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:27]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cncs3)CC2)c1[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc3c(N4CCN(Cc5cncs5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 85 °C

Procedure:
To a mixture of 5-bromo-3-nitro-4-(4-(thiazol-5-ylmethyl)piperazin-1-yl)pyridin-2-amine (0.060 g, 0.15 mmol, 1 eq), EtOH (2.6 mL) and DMF (0.35 mL), p-anisaldehyde (0.022 g, 0.165 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.45 mL, 0.45 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aq NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v 94:6). The title compound was obtained after trituration with diethyl ether as a off-white solid (0.02 g, 27%); 1H-NMR (500 Mz, DMSO-d6): δ 2.61-2.69 (m, 4H, piperazine N(CH2)2), 3.61-3.67 (m, 4H, piperazine N(CH2)2), 3.84 (s, 3H, OMe), 3.86 (s, 2H, NCH2), 7.10 (d, J=9.0 Hz, 2H, ArH, C6H4), 7.82 (s, 1H, thiazole 4-H), 8.13 (d, J=9.0 Hz, 2H, ArH, C6H4), 8.20 (s, 1H, imidazo[4,5-b]pyridine 5-H), 9.05 (s, 1H, thiazole 2-H), 13.20-13.50 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z): Rt=3.34 min—485/487 [(M+H+), Br isotopic pattern, 100%]. ESI-HRMS: Found: 485.0760, calculated for C21H22BrN6OS (M+H)+: 485.0759.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][O:14][CH3:15])[C:8](=O)[CH2:7][CH2:6]2.CC1C=CC(N=[CH:25][C:26]2[C:27]([NH2:35])=[CH:28][C:29]3[O:33][CH2:32][O:31][C:30]=3[CH:34]=2)=CC=1>>[CH3:15][O:14][CH2:13][O:12][C:11]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[CH2:6][C:7]3[C:8]([C:9]=2[CH:10]=1)=[N:35][C:27]1[CH:28]=[C:29]2[O:33][CH2:32][O:31][C:30]2=[CH:34][C:26]=1[CH:25]=3
Reactant: Cc1ccc(N=Cc2cc3c(cc2N)OCO3)cc1
Reactant: COCOc1cc2c(cc1OC)CCC2=O
Product: COCOc1cc2c(cc1OC)Cc1cc3cc4c(cc3nc1-2)OCO4

Procedure:
Using the procedure of Example 1, 5-methoxy-6-methoxymethoxyindan-1-one (452 mg, 2.03 mmol) is reacted with 6[[(4-methylphenyl)imino]methyl]-1,3-benzodioxol-5-amine (517 mg, 2.03 mmol) to yields 7-methoxymethoxy-8-methoxy-10H-1,3-dioxolo[4,5-g]indeno[1,2-b]quinoline. This material is used directly in part (B) without further isolation or purification except for the few milligrams need for NMR and mass spectral studies.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.Cl.[F:27][C:28]1[CH:29]=[C:30]([CH:35]=[CH:36][C:37]=1[N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[C:31]([NH:33][CH3:34])=[O:32].CCN(C(C)C)C(C)C>C(#N)CC.CS(C)=O>[F:27][C:28]1[CH:29]=[C:30]([CH:35]=[CH:36][C:37]=1[N:38]1[CH2:39][CH2:40][N:41]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]4[C:7](=[O:17])[NH:6][C:5]=3[CH:4]=2)[CH2:42][CH2:43]1)[C:31]([NH:33][CH3:34])=[O:32]
Reactant: CNC(=O)c1ccc(N2CCNCC2)c(F)c1
Reactant: O=C1Nc2cc(CO)cnc2N2CCCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CCC#N
Product: CNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)c(F)c1
Temperature: 90 °C
Yield: 33.2 %

Procedure:
To a suspension of (S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (129 mg, 0.553 mmol) in propiononitrile (1.2 mL) was added ((cyanomethyl)trimethylphosphonium iodide (161 mg, 0.664 mmol)) and 3-fluoro-N-methyl-4-(piperazin-1-yl)benzamide hydrochloride (151 mg, 0.553 mmol) and DIEA (290 μl, 1.659 mmol)). The vial was heated to 90° C. for 16 hours. The crude r×n was cooled to RT, DMSO (1 ml) was added, and purified via HPLC (55-90, basic). The fractions were collected, concentrated until a precipitate was visible and filtered. The solids were washed with water and collected to retrieve the product as a white solid (83 mg, 33% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.48 (s, 1H), 8.33 (d, J=4.5 Hz, 1H), 7.45-7.70 (m, 3H), 6.88-7.10 (m, 2H), 4.50 (d, J=12.9 Hz, 1H), 3.83 (dd, J=11.1, 2.5 Hz, 1H), 3.36 (s, 2H), 3.08 (br. s., 4H), 2.75 (d, J=4.5 Hz, 3H), 2.56-2.64 (m, 1H), 2.50 (br. s., 4H), 1.97-2.12 (m, 1H), 1.85 (d, J=11.1 Hz, 1H), 1.63 (d, J=11.9 Hz, 1H), 1.29-1.57 (m, 3H). [M+H] calc'd for C24H29FN6O2, 453; found, 453.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[H-].[Na+].[CH:14]([O:17][P:18]([CH2:24][O:25][C@@H:26]([CH3:33])[CH2:27]OS(C)(=O)=O)([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])([CH3:16])[CH3:15]>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:33][C@@H:26]([O:25][CH2:24][P:18]([O:20][CH:21]([CH3:23])[CH3:22])([O:17][CH:14]([CH3:16])[CH3:15])=[O:19])[CH3:27])=[C:4]([Cl:11])[N:3]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: CC(C)OP(=O)(CO[C@@H](C)COS(C)(=O)=O)OC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OP(=O)(CO[C@@H](C)Cn1cnc2c(Cl)nc(N)nc21)OC(C)C
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
2-Amino-6-chloropurine (1.40 g, 8.3 mmol) was added portionwise to a slurry of sodium hydride (0.25 g, 80% dispersion in oil, 8.3 mmol) in dimethylformamide (50 mL) at room temperature. Vigorous bubbling was noted during the addition. After 30 minutes, the clear, yellow solution was treated with a solution of (S)-2-O-[(diisopropylphosphono)methyl]-1-O-methanesulfonyl-1,2-propanediol (2.50 g, 7.5 mmol) in dimethylformamide (5 mL), and the reaction mixture was heated to 100° C. After 5 hours, the mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel (20:1, 2% to 4% to 8% methanol/methylene chloride) to provide 1.89 g (62%) of the title compound as a viscous pale yellow oil.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH:30]4[CH2:32][CH2:31]4)=[CH:28][C:27]([C:33]([F:36])([F:35])[F:34])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:12]([F:37])[CH:11]=1>>[CH:30]1([C:29]2[C:24]([N:21]3[CH2:20][CH2:19][N:18]([C:16]([C:13]4[CH:14]=[CH:15][C:10]([N:7]5[C@H:3]([CH2:2][OH:1])[CH2:4][CH2:5][C:6]5=[O:8])=[CH:11][C:12]=4[F:37])=[O:17])[CH2:23][CH2:22]3)=[N:25][CH:26]=[C:27]([C:33]([F:35])([F:36])[F:34])[CH:28]=2)[CH2:32][CH2:31]1
Reactant: O=C(c1ccc(Br)cc1F)N1CCN(c2ncc(C(F)(F)F)cc2C2CC2)CC1
Reactant: O=C1CC[C@@H](CO)N1
Product: O=C(c1ccc(N2C(=O)CC[C@H]2CO)cc1F)N1CCN(c2ncc(C(F)(F)F)cc2C2CC2)CC1

Procedure:
Using (S)-5-hydroxymethylpyrrolidin-2-one and (4-bromo-2-fluorophenyl)[4-(3-cyclopropyl-5-trifluoromethylpyridin-2-yl)piperazin-1-yl]methanone (945 mg) described in Preparation Example 123 and by the reaction and treatment in the same manner as in Example 1, the title compound (371 mg) was obtained.
Reaction SMILES: C[Si](Cl)(C)C.[I-].[Na+].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[C:21]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])(O)[CH2:22][CH2:23][CH2:24][CH2:25][C:19]=3[N:18]=[C:17]2[C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:11][CH:10]=1>C(#N)C>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]2[C:20]3[CH:21]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:22][CH2:23][CH2:24][CH2:25][C:19]=3[N:18]=[C:17]2[C:33]([CH3:34])([CH3:36])[CH3:35])=[CH:13][CH:14]=1
Reactant: CCOC(=O)CC1(O)CCCCc2nc(C(C)(C)C)n(Cc3ccc(Cl)cc3)c21
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)CC1CCCCc2nc(C(C)(C)C)n(Cc3ccc(Cl)cc3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.4 %

Procedure:
A mixture of TMSCl (0.513 mL), sodium iodide (601 mg) and acetonitrile (9 ml) was added to a stirred suspension of Intermediate 15 (420 mg) in acetonitrile (3 ml). The RM was stirred at room temp under nitrogen overnight. The reaction mixture was partitioned between EtOAc (50 ml) and sat. NaHCO3 aq. sol.: water (1:1, 50 ml). The two phases were separated and the aqueous phase was extracted again with EtOAc (50 ml). The phases were separated; the organic extracts were combined, dried (hydrophobic frit) and concentrated under vacuum. The residue was purified by reverse phase chromatography using an acetonitrile—0.1% NH3:water—with an amonium carbonate buffer modifier (pH=10) 5%-35% gradient. The desired fractions were combined and concentrated under vacuum. The mixture was purified by MDAP (Method B). The desired fractions were combined and concentrated under nitrogen blowdown to give the title compound (22 mg). LC/MS MH+ 403 Rt 1.09 min (2 minute run).
Reaction SMILES: [F:1][C:2]1([F:15])[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([NH2:12])[C:5]=2[O:4][C:3]1([F:14])[F:13].[C:16]([O:20][C:21](=[O:29])[N:22]([CH2:26][CH2:27]Cl)[CH2:23][CH2:24]Cl)([CH3:19])([CH3:18])[CH3:17].[H-].[Na+]>CN(C=O)C>[C:16]([O:20][C:21]([N:22]1[CH2:26][CH2:27][N:12]([C:11]2[C:5]3[O:4][C:3]([F:13])([F:14])[C:2]([F:1])([F:15])[O:7][C:6]=3[CH:8]=[CH:9][CH:10]=2)[CH2:24][CH2:23]1)=[O:29])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: Nc1cccc2c1OC(F)(F)C(F)(F)O2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2OC(F)(F)C(F)(F)O3)CC1
Reaction time: 1 h
Yield: 33.1 %

Procedure:
An intermediate compound, 1-(2,2,3,3-Tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazine, was produced as follows: To the mixture of 2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-5-ylamine (8.9 g, 40 mmol) and bis-(2-chloro-ethyl)-carbamic acid tert-butyl ester (14.5 g, 60 mmol) in DMF (200 mL) was added NaH (3.2 g, 60% oil dispersion, 80 mmol) at 0° C. and the resulting mixture was stirred at the same temperature for 1.0 h. No reaction was observed by TLC. The mixture was further stirred at room temperature for 4.0 h until LCMS indicated the starting material disappeared. The reaction was quenched with aq. NH4Cl, extracted with EtOAc, washed with brine, dried and concentrated. The residue was purified by flash chromatography (Et3N:EtOAc:heptane/1:10:100) to afford 4-(2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazine-1-carboxylic acid tert-butyl ester (5.2 g, 33%) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[CH3:16][NH:17][C:18]([NH2:20])=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.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]>[CH3:16][N:17]1[C:4](=[O:6])[C:3]2[C:2](=[CH:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=2)[NH:20][C:18]1=[O:19]
Reactant: COC(=O)c1ccc(C(=O)OC)c(Br)c1
Reactant: CNC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(=O)n(C)c(=O)[nH]c2c1
Temperature: 100 °C
Reaction time: 48 h
Yield: 69.6 %

Procedure:
To a solution of dimethyl 2-bromoterephthalate (0.25 g, 0.92 mmol) and methylurea (88.2 mg, 1.19 mmol) in 1,4-dioxane (7 mL) was added cesium carbonate (0.60 g, 1.83 mmol). 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (53.0 mg, 0.092 mmol) was then added followed by tris(dibenzylideneacetone)dipalladium (42 mg, 0.046 mmol). The reaction mixture was heated to 100° C. and stirred for 2 d. The mixture was then cooled to rt and concentrated. Water was added and the remaining solid was filtered. The collected solid was then washed with DCM (3×) to afford methyl 3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (0.15 g, 70%). LC-MS: (FA) ES+ 235; 1H NMR (400 MHz, DMSO) δ 11.63 (s, 1H), 8.05 (d, J=8.2 Hz, 1H), 7.77 (d, J=1.4 Hz, 1H), 7.71 (dd, J=8.2, 1.5 Hz, 1H), 3.89 (s, 3H), 3.26 (s, 3H).
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[C:5]([CH3:16])=[C:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:3]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC>[CH3:16][C:5]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[C:2]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:3][C:4]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1cc(Br)n(S(=O)(=O)c2cccnc2)c1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1cc(-c2ccccc2)n(S(=O)(=O)c2cccnc2)c1C
Temperature: 80 °C
Reaction time: 0.67 h
Yield: 106.6 %

Procedure:
A suspension of ethyl 5-bromo-2-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate (2.26 g), phenylboronic acid (1.54 g), dichloro[bis(triphenylphosphine)]palladium (211 mg) and sodium carbonate (1.91 g) in 1,2-dimethoxyethane (20 mL)-water (10 mL) was stirred at 80° C. for 40 min. After cooling, the reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The organic layer was separated from the filtrate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→6:4) to give the title compound as a colorless oil (yield 2.39 g, about 100%).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[CH2:6][O:7][CH2:8][C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][OH:19])=[CH:10][CH3:11].N1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].O=O.[BH4-].[Na+]>CCOCC.FC(F)(F)C([O-])=O.[Pd+2].FC(F)(F)C([O-])=O.C1(C)C=CC=CC=1>[F:1][C:2]([F:27])([F:28])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:24])([F:26])[F:25])[CH:22]=1)[CH2:6][O:7][CH2:8][C:9]1([CH:10]=[CH2:11])[C:12]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:18][O:19]1
Reactant: CC=C(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1CO
Agent: [Pd+2]
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C=CC1(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)OCc2ccccc21
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A flask was charged with (2-(1-(3,5-bis(trifluoromethyl)benzyloxy)but-2-en-2-yl)phenyl)methanol (1.22 g, 3.0 mmol), palladium trifluoroacetate (50.2 mg, 0.15 mmol), pyridine (0.049 mL, 0.60 mmol), sodium carbonate (160 mg, 1.5 mmol), molecular sieves (3 A, 1.5 g), and toluene (16 mL). The mixture was stirred under a balloon of oxygen, and was heated at 80° C. for 3 h. The reaction was cooled to room temperature, diluted with ether, and filtered through celite. The organics were washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. To aid in separation of the aldehyde byproduct (via oxidation of the alcohol), the following procedure was used to convert it back to starting material. The crude mixture was dissolved in ethanol (6 mL) and treated with sodium borohydride (30 mg, 0.79 mmol). The mixture was stirred at room temperature for 10 min. The mixture was cooled to 0° C., quenched by addition of saturated ammonium chloride, diluted with ether, washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (2.5%-->30% EtOAc/Hex) gave 828 mg (68%) as a colorless oil. 1H-NMR (CDCl3, 300 MHz) δ 7.79 (s, 1H), 7.70 (s, 2H), 7.33 (m, 2H), 7.25 (m, 2H), 6.17 (dd, J=17.1, 10.7 Hz, 1H), 5.44 (dd, J=17.1, 1.5 Hz, 1H), 5.24 (dd, J=10.7, 1.2 Hz, 1H), 5.20 (qAB, JAB=12.2 Hz, 2H), 4.70 (qAB, JAB=13.4 Hz, 2H), 3.83 (qAB, JAB=10.4 Hz, 2H); 13C-NMR (CDCl3, 126 MHz) δ 141.4, 141.0, 139.6, 138.2, 131.7 (q, J=33.6 Hz), 128.2, 127.5, 127.2, 123.5 (q, J=273 Hz), 121.9, 121.4, 121.3, 115.0, 90.1, 76.1, 72.4, 72.0. Mass spec.: 425.12 (MNa)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:27])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21][N:22]([CH3:24])[CH3:23])=[N:19][N:18]=[C:17]1[CH2:25]O.CS(OS(C)(=O)=O)(=O)=O.[CH2:37]([NH2:40])[CH:38]=[CH2:39]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:27])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21][N:22]([CH3:24])[CH3:23])=[N:19][N:18]=[C:17]1[CH2:25][NH:40][CH2:37][CH:38]=[CH2:39]
Reactant: C=CCN
Reactant: CN(C)Cc1nnc(CO)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Agent: CS(=O)(=O)OS(C)(=O)=O
Product: C=CCNCc1nnc(CN(C)C)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 47, 2',5-dichloro-2-[3-(hydroxymethyl)-5-[(dimethylamino)methyl]-4H-1,2,4-triazol-4-yl]benzophenone is treated first with methanesulfonic anhydride followed by allylamine to give 2',5-dichloro-2-[3-[(allylamino)methyl]-5-[(dimethylamino)methyl]-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)(=[O:13])=[O:12].[Cl:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([Cl:28])[C:26]=1Cl>>[Cl:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([Cl:28])[C:26]=1[N:17]1[CH2:18][CH2:19][CH:14]([S:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)(=[O:12])=[O:13])[CH2:15][CH2:16]1
Reactant: O=S(=O)(c1ccc2ccccc2c1)C1CCNCC1
Reactant: Clc1cncc(Cl)c1Cl
Product: O=S(=O)(c1ccc2ccccc2c1)C1CCN(c2c(Cl)cncc2Cl)CC1
Yield: 12.1 %

Procedure:
Using the procedure from Example 7A, Step 7E, 4-(2-naphthylsulfonyl)piperidine (130 mg, 0.51 mmol) was reacted with 3,4,5-trichloropyridine (182 mg, 1.0 mmol) to afford the title compound (26 mg), a white solid, in 12% yield.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:18])[C:4]2[CH2:13][S:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[C:5]=2[O:6][C:7]=1C#N.Cl.[OH-:20].[Na+]>CO>[CH3:1][CH:2]1[C:7](=[O:20])[O:6][C:5]2[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[S:12][CH2:13][C:4]=2[C:3]1=[O:18]
Reactant: [OH-]
Reactant: Cc1c(C#N)oc2c(c1=O)CSc1ccccc1-2
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC1C(=O)OC2=C(CSc3ccccc32)C1=O

Procedure:
A solution of 3-methyl-4-oxo-4H,5H-[1]benzothiopyrano[4,3-b]pyran-2-carbonitrile (0.255 g, 1 mmole, described in Example 6) in 2.5N aqueous sodium hydroxide (10 ml) and methanol (5 ml) is refluxed overnight. The solution is acidified with hydrochloric acid. The precipitate is collected and dissolved in IN aqueous sodium hydroxide. The solution is washed with chloroform and acidified with hydrochloric acid. The precipitate is collected and crystallized from methanol to give the title compound (0.070 g), mp 275°-277° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[CH2:9]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)[CH2:10][C:11]#[CH:12]>>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]#[C:11][CH2:10][CH2:9][C:13]2[S:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)=[N:3][CH:4]=1
Reactant: C#CCCc1nc2ccccc2s1
Reactant: Fc1ccc(Br)nc1
Product: Fc1ccc(C#CCCc2nc3ccccc3s2)nc1
Yield: 47.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-5-fluoro-pyridine (103 mg, 0.59 mmol) and 2-but-3-ynyl-benzo[d]thiazole (110 mg, 0.59 mmol, Example 35(A)). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 78 mg (0.28 mmol, 47%) of 2-(4-(5-fluoropyridin-2-yl)but-3-ynyl)benzo[d]thiazole as a white solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:11]=3[N:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[CH:30][C:31]([N:34]3[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]3)=[N:32][CH:33]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.C(OCC)(=O)C.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>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:28]2[CH:33]=[N:32][C:31]([N:34]3[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]3)=[CH:30][CH:29]=2)=[CH:3][C:4]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: COc1ccc2[nH]c(-c3cc(I)cnc3N)nc2c1
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: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2nc(-c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cnc3N)[nH]c2c1
Temperature: 25 °C

Procedure:
128.87 mg (0.273 mmol) of 5-iodo-3-(5-methoxy-1H-benzimidazol-2-yl)pyridin-2-ylamine and 191.38 mg (0.492 mmol) of tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine-1-carboxylate are suspended in 2.5 ml of N,N-dimethylformamide in a nitrogen-filled microwave vessel, and 0.6 ml (1.2 mmol) of 2M sodium carbonate solution and 31.5 mg (0.027 mmol) of tetrakis(triphenylphosphine)palladium(0) are added. The reaction solution is irradiated with microwaves for 30 min at 120° C. in the Biotage SmithSynthesizer. The reaction mixture is cooled to room temperature and diluted with water/ethyl acetate and filtered. The aqueous phase is extracted a further 2× with ethyl acetate, and the combined organic phases are dried using sodium sulfate, filtered and evaporated to dryness. The residue is purified by means of RP-HPLC, giving tert-butyl 4-[6′-amino-5′-(6-methoxy-1H-benzimidazol-2-yl)-[3,3′]bipyridinyl-6-yl]-piperazine-1-carboxylate.
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1.[CH2:19]([NH2:22])[CH2:20][OH:21].CCN(C(C)C)C(C)C>CCCCO>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]2[N:8]=[CH:3][N:4]=[C:5]([NH:22][CH2:19][CH2:20][OH:21])[CH:6]=2)=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(Nc2ccnc(Cl)n2)cc1
Reactant: NCCO
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: O=[N+]([O-])c1ccc(Nc2cc(NCCO)ncn2)cc1
Temperature: 200 °C
Yield: 94 %

Procedure:
74 mg of chloro-N-(4-nitrophenyl)pyrimidin-4-amine hydrochloride, 23 mg of 2-ethanolamine and 84 mg of DIPEA were dissolved in 1 mL of n-BuOH and charged into a microwave vial and the vial obtained was heated to 200° C. for 60 minutes under microwave irradiation. The reaction was monitored by TLC. The crude product was obtained by evaporating n-BuOH. Purification was carried out by column chromatography using EtOAc: MeOH=10:1. Pure 2-(6-(4-nitrophenylamino)pyrimidin-4-ylamino)ethan-1-ol in the form of a colorless solid was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:20](I)[CH3:21]>CN(C)C=O>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6])[CH3:21]
Reactant: COC(=O)c1ccc(OC)c(O)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)OC)ccc1OC
Temperature: 100 °C
Reaction time: 5.5 h
Yield: 55.4 %

Procedure:
A mixture of 24.3 g (134 mmol) of methyl 3-hydroxy-4-methoxybenzoate, 36.8 g (267 mmol) of anhyd potassium carbonate and 31.4 g (201 mmol) of ethyl iodide in 500 mL of dimethylformamide was stirred at 100° C. for 5.5 h. An additional amount of ethyl iodide (31.4 g) and potassium carbonate (18.4 g) was added and heating was continued for 2 h more. The reaction was filtered and volatile material was removed from the filtrate in vacuo. The residue was slurried with water and filtered to collect the product which was washed with water and dried. Recrystallization from heptane gave 15.6 g of methyl 3-ethoxy-4-methoxybenzoate as white crystals: mass spectrum (electrospray, m/e): M+H 210.9.