Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][CH:11]([CH2:13][CH2:14][CH3:15])[C:10](=[O:16])[N:9]([CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[NH2:67][CH:68]1[CH2:73][CH2:72][N:71]([CH3:74])[CH2:70][CH2:69]1>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][CH:11]([CH2:13][CH2:14][CH3:15])[C:10](=[O:16])[N:9]([CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:67][CH:68]5[CH2:73][CH2:72][N:71]([CH3:74])[CH2:70][CH2:69]5)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCCC1CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC1CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3OC)ncc2N(C)C1=O
Reaction time: 0.08 h
Yield: 76.9 %

Procedure:
A mixture of 0.200 g (0.00044 mole) of (rac)-4-(9-cyclopentyl-5-methyl-7-propyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl amino)-3-methoxy-benzoic acid (I-16), 0.200 g (0.00053 mole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.230 mL (0.0013 mole) of ethyldiisopropyl amine and 2 mL of dimethylformamide was stirred for 5 minutes and then 0.075 g (0.00066 mole) of 4-amino-1-methyl-piperidine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase silica gel chromatography, eluting with an acetonitrile-water gradient (20:80-100:0) to give 0.186 g of (rac)-4-(9-cyclopentyl-5-methyl-7-propyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-17) as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:5]([C:19]2[CH:24]=[CH:23][C:22]([S:25](C)(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[N:4]1)[CH3:2].C([Mg]Cl)CCC.C(B(CC)CC)C.C([O-])(=O)C.[Na+].[NH2:47]OS(O)(=O)=O>C1COCC1.O>[CH2:1]([N:3]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:5]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([NH2:47])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[N:4]1)[CH3:2]
Reactant: CCn1nc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)c1C(F)(F)F
Reactant: NOS(=O)(=O)O
Agent: CC(=O)[O-]
Agent: CCB(CC)CC
Agent: CCCC[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: CCn1nc(-c2ccc(S(N)(=O)=O)cc2)c(-c2ccc(F)cc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
1-Ethyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole (0.45 g, 1.0 mmol) was dissolved in 5 mL dry THF under nitrogen and treated with 0.9 mL of a 1.0M solution of n-butyl magnesium chloride in THF at 0° C. for 10 minutes and warmed to 25° C. for 30 minutes. A solution of triethylborane in THF (2.5 mL, 1.0M) was added and the mixture was stirred at 25° C. for 2 hours and at reflux for 24 hours. After cooling to 25° C., a mixture of water (1.2 mL), sodium acetate (0.90 g) and hydroxylamine-O-sulfonic acid (0.62 g) was added and the reaction stirred at 25° C. for 18 hours. The mixture was partitioned between water and ethyl acetate, and the organic layer washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. Chromatographic purification on silica gel eluting with methyl t-butyl ether/toluene (5/95) gave 4-[1-ethyl-4-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzenesulfonamide as a white solid (0.25 g, 62% yield). Elemental analysis for C18H15N3F4SO2Calc'd: C, 52.30, H, 3.66, N, 10.16, S, 7.76. Found: C, 52.36, H, 3.72, N, 9.98, S, 7.90.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=[CH:14][CH:13]=3)[CH2:7][C:6]=2[CH:22]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[N:36]([CH3:40])[N:35]=[CH:34]3)O1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.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]>[CH3:40][N:36]1[C:37]2[C:33](=[CH:32][C:31]([C:2]3[CH:3]=[CH:4][C:5]4[O:11][CH2:10][CH2:9][N:8]([C:12]5[C:21]6[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=6)[N:15]=[CH:14][CH:13]=5)[CH2:7][C:6]=4[CH:22]=3)=[CH:39][CH:38]=2)[CH:34]=[N:35]1
Reactant: Brc1ccc2c(c1)CN(c1ccnc3ccccc13)CCO2
Reactant: Cn1ncc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: Cn1ncc2cc(-c3ccc4c(c3)CN(c3ccnc5ccccc35)CCO4)ccc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 10 %

Procedure:
A mixture of 7-bromo-4-quinolin-4-yl-2,3,4,5-tetrahydro-1,4-benzoxazepine (206 mg, 0.58 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-methyl-1H-indazole (158 mg (0.58 mmol) (reagent preparation 50), potassium carbonate (320 mg, 2.32 mmol), and dichloro[1,1-bis(diphenylphosphino]ferrocenepalladium (II) dichloromethane adduct (50 mg, 0.06 mmol) in dimethoxyethane (4.0 mL) and water (1.0 mL) was degassed with nitrogen, and then stirred at 100° C. for 1 h. The reaction mixture was cooled to room temperature and partitioned between water and ethyl acetate. The mixture was filtered through celite and then the layers were separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography on silica ((2S)-100% ethyl acetate in hexanes) afforded the title Compound (23 mg, 10% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): 8.63 d, 1H), 8.11 (s, 1H), 8.03 (m, 2H), 7.95 (d, 1H), 7.75 (m, 3H), 7.70 (m, 1H), 7.61 (dd, 1H), 7.51 (m, 1H), 7.11 (d, 1H), 7.02 (d, 1H), 4.61 (s, 2H), 4.39 (m, 2H), 4.09 (s, 3H), 3.84 (m, 2H); MS (EI) for C26H22N4O: 407 (MH+).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([OH:25])=O)=[CH:17][CH:16]=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:25])=[CH:17][CH:16]=1
Reactant: C1CCNCC1
Reactant: O=C(O)COc1ccc(-c2ccccc2F)nc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1ccc(-c2ccccc2F)nc1)N1CCCCC1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.277 mmol) of [6-(2-fluoro-phenyl)-pyridin-3-yloxy]-acetic acid trifluoroacetic acid salt and 47.1 mg (0.554 mmol) of piperidine. Yield: 72 mg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:22])[C:10]([CH3:24])([CH3:23])[N:9]=1.[Cl:25]Cl>Cl.C(O)=O.ClCCCl>[Cl:25][C:18]1[C:13]2[NH:12][C:11](=[O:22])[C:10]([CH3:24])([CH3:23])[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:14]=2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=1
Reactant: CC1(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc2NC1=O
Reactant: ClCl
Agent: Cl
Solvent: O=CO
Solvent: ClCCCl
Product: CC1(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])cc(Cl)c2NC1=O
Temperature: 25 °C
Reaction time: 168 h

Procedure:
A solution of 160 g (0.49 mol) of 5-(o-fluorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one in 400 ml of concentrated hydrochloric acid and 400 ml of formic acid is treated while stirring with a solution of 46 g of chlorine gas in 400 ml of 1,2-dichloroethane. The reaction mixture, which consists of two phases, is stirred at room temperature, whereby after 3 days a further 25 g of chlorine gas in 200 ml of 1,2-dichloroethane are added and after 5 days a further 5 g of chlorine gas in 40 ml of 1,2-dichloroethane are added. After 7 days, the mixture is concentrated, treated with ice-water, made alkaline with aqueous ammonia and extracted four times with methylene chloride. The organic extract is concentrated and treated with 600 ml of isopropanol. Subsequently, the residual methylene chloride is removed on a steam-bath and the product is left to crystallise. There is obtained 9-chloro-5-(o-fluorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one of melting point 174°-175°.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[C:11]3[C:25]([O:27]CC)=[O:26])=[CH:4][C:3]=2[O:2]1.OC1(C2C=CC3OCOC=3C=2)C2C(=CC=CC=2)C(C2C=CC=CC=2)=C1C(OCC)=O.C([SiH](CC)CC)C.B(F)(F)F.CCOCC.Cl>C(Cl)Cl>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:11]3[C:25]([OH:27])=[O:26])=[CH:4][C:3]=2[O:2]1
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1c1ccc2c(c1)OCO2
Agent: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1(O)c1ccc2c(c1)OCO2
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(O)C1C(c2ccccc2)c2ccccc2C1c1ccc2c(c1)OCO2
Reaction time: 0.25 h
Yield: 100 %

Procedure:
Ethyl (RS)-1-(3,4-Methylenedioxyphenyl)-3-phenylindene-2-carboxylate. To a solution of ethyl (1RS)-1-hydroxy-1-(3,4-methylenedioxyphenyl)-3-phenylindene-2-carboxylate (1.03 g, 2.58 mmol) in CH2Cl2 (40 mL) was added triethylsilane (0.49 ml, 3.07 mmol), followed by boron trifluoride etherate (1.55 ml, 12.6 mmol). The reaction mixture was allowed to stir for 15 min, at which time was added slowly 3M HCl. The mixture was extracted with EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3 and saturated aqueous NaCl. The solvent was removed in vacuo to provide the title compound (1.00 g, 100%) as a mixture of Δ1 and Δ2 double bond isomers.
Reaction SMILES: [Br-].[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][Zn+])#[N:3].Cl[C:10]1[N:15]=[N:14][C:13]([NH:16][C:17](=[O:30])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=2)=[CH:12][CH:11]=1.CCOC(C)=O.Cl>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C:10]1[N:15]=[N:14][C:13]([NH:16][C:17](=[O:30])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:27])[F:28])[CH:20]=2)=[CH:12][CH:11]=1)#[N:3]
Reactant: O=C(Cc1cccc(OC(F)(F)F)c1)Nc1ccc(Cl)nn1
Reactant: N#CCCCC[Zn+]
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: CCOC(C)=O
Product: N#CCCCCc1ccc(NC(=O)Cc2cccc(OC(F)(F)F)c2)nn1
Reaction time: 4 h

Procedure:
4-Cyanobutylzinc bromide solution (3.0 equiv., 0.50 mol, 1.0 L) was charged into an argon gas purged 5000 mL 3 neck round bottom flask. Argon(g) purge for 5 minutes followed by the addition of 1117 (1.0 equiv., 0.167 mol, 55.3 g) and NiCl2(dppp) (0.15 equiv., 0.0251 mol, 13.6 g) under a blanket of argon(g). The reaction usually goes to completion after 4 hours (TLC: 1:1 hexanes-ethyl acetate). EtOAc (15 vol., 832 mL) added to deep red solution. Water (15 vol., 832 mL) was added, thick slurry formed. 1N HCl added until slurry breaks to pale blue layer (˜6 vol., 333 mL). Transferred to separatory funnel and organic layer was washed with 1N HCl (2×500 mL), dried (MgSO4) and concentrated by rotary evaporation (bath ≦30° C.) to a solid reddish oil. Oil dissolved in dichloromethane (15 vol., 832 mL), silica gel (100 g) was slurried into red solution, this was concentrated by rotary evaporation (bath ≦30° C.) to a solid reddish powder. Loaded onto a bed of silica gel (5 cm×11 cm), flushed with 25% hexanes in ethyl acetate (3 L), combined organics concentrated by rotary evaporation (bath ≦30° C.). Dried under high vacuum to a constant weight to afford N-(6-(4-cyanobutyl)pyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide 1118: yield of 58.2 g (92%). 1H NMR (300 MHz, DMSO-d6) δ 11.41 (s, 1H), 8.28 (d, J=9.2 Hz, 1H), 7.65 (d, J=9.2 Hz, 1H), 7.52-7.27 (m, 4H), 3.89 (s, 2H), 2.92 (t, J=7.5 Hz, 2H), 2.56 (t, J=7.0 Hz, 2H), 1.80 (m, 2H), 1.61 (m, 2H).
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:24])([F:23])[C:5]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)([OH:10])[C:6]([F:9])([F:8])[F:7].C(N(CC)CC)C.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([S:40](Cl)(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=1>C(Cl)Cl>[F:24][C:4]([F:3])([F:23])[C:5]([C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:22][CH2:21][N:20]([S:40]([C:36]3[CH:37]=[CH:38][CH:39]=[C:34]([O:33][CH3:32])[CH:35]=3)(=[O:42])=[O:41])[CH2:19][CH2:18]2)=[CH:15][CH:16]=1)([OH:10])[C:6]([F:9])([F:8])[F:7]
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(S(=O)(=O)N2CCN(c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 48.2 %

Procedure:
A 25-mL round-bottomed flask was cooled to 0° C. and charged with 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydrochloride (200 mg, 0.5 mmol, Example 91, Step 1), CH2Cl2 (5 mL) and triethylamine (0.35 mL, 2.5 mmol). 3-Methoxybenzenesulfonyl chloride (113 mg, 0.55 mmol, Sigma-Aldrich, St. Louis, Mo.) was added. After 10 min at 0° C., the reaction was concentrated onto silica gel and purified via column chromatography (40 g silica gel, 0 to 100% hexanes in EtOAc) to give 1,1,1,3,3,3-hexafluoro-2-(4-(4-((3-methoxyphenyl)sulfonyl)-1-piperazinyl)phenyl)-2-propanol (120 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3]1.Br[CH:18]=[C:19]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[Cl:28])[CH3:20].N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Cu]I>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1/[C:19](/[CH3:20])=[CH:18]/[N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:16])=[CH:11][C:12]=2[C:13]2[CH2:14][CH2:15][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1=2
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Reactant: CC(=CBr)c1ccc(Cl)cc1Cl
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CCN(C)CC2)c1ccc(Cl)cc1Cl
Temperature: 85 °C

Procedure:
3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (214 mg, 1 mmol), 1-(1-bromoprop-1-en-2-yl)-2,4-dichlorobenzene (318 mg, 1.2 mmol), L-proline (0.2 mmol), CuI (19 mg, 0.1 mmol) and potassium phosphate tribasic (424 mg, 2 mmol) in DMF was stirred at RT and purged with nitrogen. The reaction mixture was heated at 85° C. overnight. An additional 1 eq. of reagents was added and the mixture heated for an additional 24 h. The DMF was evaporated and the residue was poured into water. The precipitate obtained was filtered and purified by silica gel chromatography (100-200-mesh) using 0-5% MeOH:DCM as eluant followed by reverse phase HPLC to separate the isomers. 1H NMR (CDCl3, TFA salt) δ (ppm): 7.35 (s, 1H), 7.18 (m, 2H), 7.05 (d, 1H), 6.98 (d, 1H), 6.70 (m, 2H), 3.60 (m, 2H), 3.10 (m, 5H), 2.90 (s, 3H), 2.60 (m, 1H), 2.42 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]([C:22]([NH2:24])=[O:23])=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:11]=2)[N:8]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.CCN(C(C)C)C(C)C.Cl.Cl.[F:47][C:48]1([F:56])[CH2:53][CH2:52][CH2:51][C@@H:50]([NH2:54])[C@H:49]1[NH2:55].C(O)(C(F)(F)F)=O.Cl>CN1C(=O)CCC1>[NH2:55][C@H:49]1[C:48]([F:56])([F:47])[CH2:53][CH2:52][CH2:51][C@H:50]1[NH:54][C:3]1[N:4]=[N:5][C:6]([C:22]([NH2:24])=[O:23])=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:11]=2)[N:8]=1
Reactant: N[C@@H]1CCCC(F)(F)[C@@H]1N
Reactant: CSc1nnc(C(N)=O)c(Nc2cccc(-c3ncccn3)c2)n1
Agent: Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1nnc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1cccc(-c2ncccn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
3-(Methylthio)-5-(3-(pyrimidin-2-yl)phenylamino)-1,2,4-triazine-6-carboxamide (40 mg, 0.12 mmol) was dissolved in 4 mL NMP. To it was added mCPBA (77%) (108 mg, 0.48 mmol). The mixture was stirred at RT for 1 h. To it was added DIEA (0.21 mL, 1.20 mmol) and (1R,2R)-3,3-difluorocyclohexane-1,2-diamine dihydrochloride (53 mg, 0.24 mmol). The mixture was stirred at 80° C. for 1 h. It was cooled to RT, acidified with TFA (0.3 mL) and subjected to reverse phase preparative HPLC to isolate the title compound (35 mg) as HCl salt. MS found for C20H21F2N9O as (M+H)+ 442.5. UV: λ=240 nm. Proton NMR: (CD3OD) δ 8.94-8.92 (3H, m), 8.41 (1H, d, J=8.0 Hz), 7.79 (1H, d, J=8.0 Hz), 7.64 (1H, t, J=8.0 Hz), 7.45 (1H, t, J=4.8 Hz), 4.90 (1H, m), 4.13 (1H, m), 2.24-1.82 (6H, m) ppm.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:12]4[S:19][C:18]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[CH:17][C:13]=4[N:14]=[CH:15][N:16]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Br:26]N1C(=O)CCC1=O>C(Cl)Cl>[Br:26][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([NH:10][C:11]3[C:12]4[S:19][C:18]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[CH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH:5]=2)[NH:1][CH:2]=1
Reactant: c1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Brc1c[nH]c2ccc(Nc3ncnc4cc(-c5ccccc5)sc34)cc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 17 %

Procedure:
To a solution of (1H-Indol-5-yl)-(6-phenyl-thieno[3,2-d]pyrimidin-4-yl)-amine (150 mg, 0.438 mmol) in methylene chloride was added N-bromosuccinimide (86 mg, 0.482 mmol). The reaction mixture was stirred for 2 days at room temperature and then concentrated in vacuo. The orange residue was chromatographed by preparative reverse-phase HPLC using a 200 nM acetate buffer and acetonitrile gradient to afford pure product (17% yield). RP18-HPLC RT: 6.377 minutes; API MS: 371.2 (M+1); MP: 201-203° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([CH:19]([OH:25])[CH2:20][O:21][CH2:22][CH2:23]Cl)[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[K+].[CH3:28][NH:29][CH3:30].C(O)C>C(OCC)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([CH:19]([OH:25])[CH2:20][O:21][CH2:22][CH2:23][N:29]([CH3:30])[CH3:28])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: OC(COCCCl)c1ccc2cc(OCc3ccccc3)ccc2c1
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Product: CN(C)CCOCC(O)c1ccc2cc(OCc3ccccc3)ccc2c1

Procedure:
A mixture of 4.5 g of 1-(6-benzyloxy-2-naphthyl)-2-(2-chloroethoxy)ethanol, 1 g of potassium iodide, 10 ml of a 50% aqueous dimethylamine solution and 20 ml of ethanol was refluxed for 3 hours. To the reaction mixture was added 10 ml of a 50% aqueous dimethylamine solution. The resulting mixture was further refluxed for 6 hours. The reaction mixture was cooled and concentrated to about a half volume under reduced pressure. To the concentrate were added 100 ml of ethyl acetate and 100 ml of water. The mixture was adjusted to pH 10.5 with potassium carbonate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. To the residue thus obtained was added 30 ml of diethyl ether. The resulting crystals were collected by filtration and dried to obtain 3.9 g of 1-(6-benzyloxy-2 -naphthyl)-2-[2-(N,N-dimethylamino)ethoxy]ethanol (compound No. 284).
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]1[S:11][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[N:9][C:8]=1[CH3:16].[Cl:17][S:18](O)(=[O:20])=[O:19].P(Cl)(Cl)(Cl)(Cl)Cl.[Cl-].[P+]=O>C(Cl)Cl>[C:13]([NH:12][C:10]1[S:11][C:7]([C:6]2[CH:5]=[C:4]([S:18]([Cl:17])(=[O:20])=[O:19])[S:3][C:2]=2[Br:1])=[C:8]([CH3:16])[N:9]=1)(=[O:15])[CH3:14]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)Nc1nc(C)c(-c2ccsc2Br)s1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=[P+]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of N-[5-(2-bromo-thiophen-3-yl)-4-methyl-thiazol-2-yl]-acetamide obtained in Step II, as describe above (1100 mg; 3.47 mmol; 1 eq), in DCM (60 ml) is cooled to 0° C. with an ice bath. The reaction is degassed with nitrogen and chlorosulfonic acid (1.16 ml; 17.3 mmol; 5 eq) dissolved in DCM (30 ml) is added dropwise. The reaction mixture is stirred at 0° C. for 15 minutes. Phosphorus pentachloride (1444 mg; 6.94 mmol; 2 eq) is added followed directly by phosphorus oxide chloride (1.3 ml; 13.9 mmol; 4 eq). The reaction is stirred for an additional 2 hours at room temperature. Then the reaction mixture is poured into a beaker with crushed ice and directly transferred in a separated funnel. It is extracted with 2 portions EtOAc. The organic layer is dried over MgSO4, affording the title compound (1440 mg; quantitative yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH:8]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][N:11]=2)[CH3:9])[CH:2]=1.O.[OH-].[Li+].O1CCCC1.Cl>O.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH:8]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][N:11]=2)[CH3:9])[CH:2]=1
Reactant: COC(=O)c1ccc(C(C)Oc2cccnc2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(Oc1cccnc1)c1ccc(C(=O)O)cn1
Temperature: 20 °C
Reaction time: 4 h
Yield: 96.6 %

Procedure:
A mixture of methyl 6-(1-(pyridin-3-yloxy)ethyl)nicotinate (600 mg, 2.33 mmol), lithium hydroxide monohydrate (420 mg, 10 mmol), tetrahydrofuran (6 mL), methanol (2 mL) and water (2 mL) was stirred at 20° C. for 4 hours. The mixture was acidified to pH=1 with concentrated hydrochloric acid and then extracted with dichloromethane (10 mL×3). The combined organic phase was separated, dried by sodium sulfate and then filtered. The filtrate was concentrated in vacuo to give 6-(1-(pyridin-3-yloxy)ethyl)nicotinic acid (550 mg, 97%).
Reaction SMILES: [CH:1]1([PH:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:14](Br)[CH2:15]Br>>[CH2:8]([P:7]([CH:15]1[CH2:14][CH2:10][CH2:11][CH2:12][CH2:13]1)[CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:9][P:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: BrCCBr
Reactant: C1CCC(PC2CCCCC2)CC1
Product: C1CCC(P(CCP(C2CCCCC2)C2CCCCC2)C2CCCCC2)CC1

Procedure:
Dicyclohexyl phosphine (40 g, 0.2 mole) was reacted with ethylene dibromide (18 g, 0.1 mole) for 2 hours at 90°-100° C. to form ethylenebis(dicyclohexylphosphine). The phosphine compound was then oxidized with 25 g of 30% hydrogen peroxide to give the phosphine oxide. The crude product was recrystallized from isopropanol/water to give 20 grams of the subject compound, m.p. 199°-201° C.