Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([S:17][C:18]4[CH:19]=[CH:20][C:21]([N+:25]([O-])=O)=[C:22]([CH:24]=4)[NH2:23])=[N:15][N:16]=3)[N:13]=2)=[CH:4][CH:3]=1.O.N>C(O)(=O)C.[Zn]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11]3[N:12]([C:14]([S:17][C:18]4[CH:24]=[C:22]([NH2:23])[C:21]([NH2:25])=[CH:20][CH:19]=4)=[N:15][N:16]=3)[N:13]=2)=[CH:4][CH:3]=1
Reactant: Nc1cc(Sc2nnc3ccc(-c4ccc(F)cc4)nn23)ccc1[N+](=O)[O-]
Agent: N
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(Sc2nnc3n2N=C(c2ccc(F)cc2)CC3)cc1N
Temperature: 20 °C
Reaction time: 1 h
Yield: 215.3 %

Procedure:
422 mg of zinc(0) are added to a solution of 240 mg of 5-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-2-nitroaniline in 13 cm3 of acetic acid and the resulting mixture is stirred for 1 h at 20° C. 30 cm3 of water are then added to the reaction mixture, which is changed to an alkaline medium by adding 16 cm3 of an aqueous solution of ammonia at 28%. The mixture obtained is extracted with ethyl acetate. The resulting organic phase is washed successively with a saturated aqueous solution of sodium hydrogen carbonate and with a saturated aqueous solution of sodium chloride and is then dried over magnesium sulphate, filtered and evaporated to dryness. The residue is made into a paste in ether, filtered, and then dried under vacuum at 20° C. 479 mg of 4-{[6-(4-fluorophenyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}benzene-1,2-diamine are thus obtained, the characteristics of which are as follows:
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:25].Br[CH2:30][C:31]([O:33][CH3:34])=[O:32]>CN(C=O)C.C(OCC)(=O)C>[F:28][C:2]([F:27])([F:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:25]
Reactant: COC(=O)CBr
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1C(F)(F)F
Reaction time: 0.25 h
Yield: 66.7 %

Procedure:
40% Methanolic Triton B (0.18 mL, 0.4 mM) was added to a solution of the 9-[(2-trifluoromethylphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (120 mg, 0.31 mM) in 5 mL DMF at room temperature. After 15 minutes, methyl bromoacetate (98.5 mg, 0.62 mM) was added and the resultant mixture stirred at room temperature for 4.5 hours. The mixture was diluted with ethyl acetate, washed four times with H2O, 1 N HCl, H2O, sat. NaHCO3, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate/THF) to afford 95 mg (67%) of the {9-[(2-trifluoromethylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (CDCl3) δ7.7 (d, 1H, J=8 Hz), 7.5-7.2 (m, 6H), 6.95 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 6.45 (d, 1H, J=8 Hz), 6.3 (br s, 1H), 6.1 (br s, 1H), 5.7 (s, 2H), 4.9 (s, 2H), and 3.9 (s, 3H). IR (CHCl3, cm−1) 1763 and 1674. MS (ES) m/e 457.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[N:4][N:3]=1.[Cl:13][CH:14]([Cl:33])[C:15]([NH:17][C@H:18]([CH2:31][F:32])[C@H:19]([OH:30])[C:20]1[CH:25]=[CH:24][C:23]([Sn](C)(C)C)=[CH:22][CH:21]=1)=[O:16]>>[Cl:13][CH:14]([Cl:33])[C:15]([NH:17][C@H:18]([CH2:31][F:32])[C@H:19]([OH:30])[C:20]1[CH:21]=[CH:22][C:23]([C:2]2[S:6][C:5]([CH2:7][NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[N:4][N:3]=2)=[CH:24][CH:25]=1)=[O:16]
Reactant: CS(=O)(=O)NCc1nnc(Br)s1
Reactant: C[Sn](C)(C)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Product: CS(=O)(=O)NCc1nnc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)s1

Procedure:
Following the general procedure of Example 9—Step 2 and making non-critical variations but using N-((5-bromo-1,3,4-thiadiazol-2-yl)methyl)methane-sulfonamide and 2,2-dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(trimethyl-stannyl)phenyl)-propan-2-yl)acetamide the title compound is obtained (11.8 mg): 1H NMR (400 MHz, DMSO-d6) 3.0 (s, 3H), 4.2-4.4 (m, 1.5H), 4.45 (t, 1H), 4.55-4.6 (m, 0.5H), 4.65 (d, 2H), 4.7-4.75 (m, 0.5H), 4.95 (bt, 0.5H), 6.1 (d, 1H), 6.5 (s, 1H), 7.5 (d, 2H), 7.95 (d, 2H), 8.15 (t, 1H), 8.6 (d, 1H). m/z (C1) M+H 471.
Reaction SMILES: Br[C:2]1[C:3]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[N:4][N:5]2[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=12.[CH3:25][S:26][C:27]1[N:32]=[C:31]([Sn](CCCC)(CCCC)CCCC)[CH:30]=[CH:29][N:28]=1>O1CCOCC1.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.[Ag-]=O>[F:14][C:11]([F:12])([F:13])[C:9]1[CH:8]=[CH:7][C:6]2[N:5]([N:4]=[C:3]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:19][CH:20]=3)[C:2]=2[C:31]2[CH:30]=[CH:29][N:28]=[C:27]([S:26][CH3:25])[N:32]=2)[CH:10]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(SC)n1
Reactant: FC(F)(F)c1ccc(-c2nn3cc(C(F)(F)F)ccc3c2Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=[Ag-]
Solvent: C1COCCO1
Product: CSc1nccc(-c2c(-c3ccc(C(F)(F)F)cc3)nn3cc(C(F)(F)F)ccc23)n1

Procedure:
A mixture of 3-bromo-6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridine (0.82 g), 2-(methylthio)-4-(tributylstannyl)pyrimidine (0.83 g), dichlorobis(triphenylphosphine)palladium (0.14 g) and silver (I) oxide (0.43 g) in 1,4-dioxane (10 mL) was heated to reflux for 18 h. The mixture was cooled, filtered and the filtrate concentrated to dryness. The residue was purified by chromatography eluting with an increasing gradient from cyclohexane to cyclohexane-diethylether (94:6) to give, after concentration to dryness of the appropriate fractions, the title compound as a cream solid (0.46 g); 1H NMR (d6-DMSO) δ 9.58(1H, s), 8.50(1H, d), 8.46(1H, d), 7.90(2H, d), 7.84 (2H, d), 7.82(1H, dd), 6.94(1H, d), 2.43(3H, s); m/z 455 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([C:13]([O:15][CH3:16])=[O:14])[C:10](O)=[O:11])[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:19])=O.CN(C)C=O>ClCCCl>[Cl:19][C:10]([CH:9]([CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:11]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)C(Cc1cccc(Cl)c1)C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)C(Cc1cccc(Cl)c1)C(=O)Cl
Temperature: 40 °C
Reaction time: 7 h

Procedure:
A total of 8.0 g of the residue containing 3-(3-chlorophenyl)-2-methoxycarbonylpropionic acid prepared in Step B of Example 1 was dissolved in 32.8 g of 1,2-dichloroethane under nitrogen atmosphere, and 11.8 g of thionyl chloride and 0.05 g of dimethylformamide were added thereto, followed by stirring at 40° C. for 7 hours. The resulting mixture was concentrated under reduced pressure to remove 1,2-dichloroethane and unreacted thionyl chloride to thereby yield 7.98 g of methyl 2-chloroformyl-3-(3-chlorophenyl)-propionate.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[C:12](=[O:20])[C:13]([C:15]([O:17][CH2:18]C)=[O:16])=[CH:14][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][NH:6]3.[CH3:21]OS(OC)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[C:12](=[O:20])[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:21]
Reactant: CCOC(=O)c1cn2c3c(c(F)ccc3c1=O)CCN2
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cn2c3c(c(F)ccc3c1=O)CCN2C
Temperature: 120 °C
Reaction time: 1 h
Yield: 45.9 %

Procedure:
To 1.24 g (4.5 mmol) of the compound (189) obtained in Example 62, 8 ml (87 mmol) of dimethylsulfate was added, and the solution was heated at 120° C. for 3 hours. After air-cooling, the solution was added to 70 ml of ice/water to which 12 g (87 mmol) of anhydrous potassium carbonate was added, and the solution was stirred for 1 hour. The solution was extracted with 100 ml of chloroform, and after drying over magnesium sulfate, the solvent was removed by distillation. The residue was separated by column chromatography (silica gel 40 g, eluent solvent; chloroform:methanol=100:1) to obtain 571 mg of the subject compound (190) in a 46% yield.
Reaction SMILES: [C:1]1([CH2:7][C:8]([N:10]=[C:11]=[S:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[CH:42]=[CH:41][C:17]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]([N:28]3[CH2:33][CH2:32][CH:31]([N:34]4[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]4)[CH2:30][CH2:29]3)=[O:27])[CH:20]=2)=[C:16]([F:43])[CH:15]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1.C(O)C>[F:43][C:16]1[CH:15]=[C:14]([NH:13][C:11]([NH:10][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[S:12])[CH:42]=[CH:41][C:17]=1[O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]([N:28]2[CH2:29][CH2:30][CH:31]([N:34]3[CH2:35][CH2:36][CH:37]([OH:40])[CH2:38][CH2:39]3)[CH2:32][CH2:33]2)=[O:27])[CH:20]=1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCC(O)CC4)CC3)c2)c(F)c1
Reactant: O=C(Cc1ccccc1)N=C=S
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCC(O)CC4)CC3)c2)c(F)c1
Reaction time: 1 h
Yield: 57 %

Procedure:
After adding a solution of 2-phenylacetyl isothiocyanate in toluene (0.2 M, 4.0 ml) to a solution of 4-(4-amino-2-fluorophenoxy)-2-{[4-(4-hydroxypiperidin-1-yl)piperidin-1-yl]carbonylamino}pyridine (164 mg) and (+)-10-camphorsulfonic acid (85 mg) in ethanol (4.0 ml) at room temperature, the mixture was stirred for 1 hour. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine in that order and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:methanol=98:2 to 95:5) to provide the title compound (127 mg, 57%) as white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=C(SC)C=C2OC1C=CC(NC(C2(C(NC3C=CC(F)=CC=3)=O)CC2)=O)=CC=1F.CS[C:43]([S:54][CH3:55])=[C:44]1[C:49](=[O:50])[O:48][C:47]([CH3:52])([CH3:51])[O:46][C:45]1=[O:53].COC1C=C(C=CC=1OC)N>CCO>[CH3:14][O:13][C:12]1[CH:11]=[C:10]([NH:9][C:43]([S:54][CH3:55])=[C:44]2[C:49](=[O:50])[O:48][C:47]([CH3:52])([CH3:51])[O:46][C:45]2=[O:53])[CH:5]=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CSC(SC)=C1C(=O)OC(C)(C)OC1=O
Reactant: COc1cc2nc(SC)cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)c2cc1OC
Agent: COc1ccc(N)cc1OC
Solvent: CCO
Product: COc1ccc(NC(SC)=C2C(=O)OC(C)(C)OC2=O)cc1OC
Yield: 83 %

Procedure:
Synthesis of N-(4-{[6,7-bis(methyloxy)-2-(methylthio)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide Commercially available 5-(bis-methylsulfanyl-methylene)-2,2-dimethyl-[1,3]dioxane-4,6-dione (3.5 g, 14 mmol) and 3,4-dimethoxyaniline (2.2 g, 14 mmol) were reflux in EtOH (20 mL) for 2 hours. The EtOH was removed under reduced pressure and EtOAc was added to the residue. The product was filtered and washed with cold EtOAc (3×). 5-[(3,4-dimethoxy-phenylamino)-methylsulfanyl-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione was obtained as a white solid (1.7 g, 47% yield) and used without further purification. LCMS: m/z 352 (M−H)−.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[F:13][C:14]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:15]=1[OH:24].C([O-])([O-])=O.[K+].[K+].C(#N)C>O>[F:13][C:14]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:15]=1[O:24][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: N#Cc1cc([N+](=O)[O-])ccc1Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.2 %

Procedure:
In a 250 ml single-neck flask equipped with a magnetic stirrer and a reflux condenser fitted with a nitrogen bubbler were placed 9.59 g (0.0525 moles) of 2-chloro-5-nitrobenzonitrile, 9.96 g (0.0541 moles) of 2,3,4,5,6-pentafluorophenol, 7.56 g (0.0541 moles) of anhydrous K2CO3, and 75 ml of acetonitrile. The mixture was heated to reflux and held there for 3 hrs. The reaction mixture was then cooled to room temperature and diluted with 150 ml of deionized water. The product separated as a crystalline solid. The solid was filtered off, washed thoroughly with water, and air-dried. The air-dried solid was recrystallized from 200 ml of absolute ethanol to give 9.91 g (57% yield) of purified 2-(2,3,4,5,6-pentafluorophenoxy)-5-nitrobenzonitrile, mp 127.5°-129° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH2:29]O)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:19](=[O:20])[C:18]3[CH:21]=[CH:22][C:23]([N+:24]([O-:26])=[O:25])=[C:16]4[C:17]=3[C:12](=[CH:13][CH:14]=[CH:15]4)[C:11]2=[O:27])=[CH:6][CH:5]=1)[CH3:2].P(Br)(Br)[Br:32]>C(Cl)(Cl)Cl>[Br:32][CH2:29][CH2:28][N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:19](=[O:20])[C:18]3[CH:21]=[CH:22][C:23]([N+:24]([O-:26])=[O:25])=[C:16]4[C:17]=3[C:12](=[CH:13][CH:14]=[CH:15]4)[C:11]2=[O:27])=[CH:6][CH:5]=1
Reactant: BrP(Br)Br
Reactant: CCN(CCO)c1ccc(N2C(=O)c3cccc4c([N+](=O)[O-])ccc(c34)C2=O)cc1
Solvent: ClC(Cl)Cl
Product: CCN(CCBr)c1ccc(N2C(=O)c3cccc4c([N+](=O)[O-])ccc(c34)C2=O)cc1

Procedure:
1.5 g (3.7 mmol) of 2-{4-[ethyl(2-hydroxyethyl)amino]phenyl}-6-nitro-1H-benzo[de]isoquinolin-1,3(2H)-dione was dissolved in 80 mL of chloroform and heated to a boil. Then, 10.7 mL (11.1 mmol) of phosphorus tribromide was added dropwise within 20 minutes, and the solution was heated at reflux for an additional 2 hours. The mixture was then poured onto ice, and the aqueous phase was extracted with chloroform. The combined organic phases were dried over magnesium sulfate. The purification was performed by column chromatography on silica gel with toluene as the developing solvent. Yield: 0.90 g (52% of the theoretical), dark-red powder. 1H-NMR (d6DMSO/300 MHz): δ=1.12 (t, J=8.1 Hz, 3H), 1.86 (q, 2H), 3.58 (t, J=6.9 Hz, 2H), 4.01 (t, J=6.9 Hz, 2H), 6.96 (d, J=4.2 Hz, 2H, phenyl), 7.83 (d, J=7.6 Hz, 1H, naphthalene), 7.95 (d, J=4.4 Hz, 2H, phenyl), 8.33 (d, J=8.1 Hz, 1H, naphthalene), 8.52 (d, J=8.8 Hz, 1H, naphthalene), 8.67 (d, J=8.0 Hz, 1H, naphthalene), 9.13 (d, J=8.6 Hz, 1H, naphthalene).
Reaction SMILES: C1COCC1.[NH2:6][C:7]1[C:12]2=[C:13]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:30]=4[F:39])=[O:27])=[C:21]([F:40])[CH:20]=3)[C:14]([CH2:16][O:17][CH3:18])=[CH:15][N:11]2[N:10]=[CH:9][N:8]=1.[Br:41]N1C(C)(C)C(=O)N(Br)C1=O.[O-]S([O-])=O.[Na+].[Na+]>CCOC(C)=O>[NH2:6][C:7]1[C:12]2=[C:13]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=[CH:31][C:30]=4[F:39])=[O:27])=[C:21]([F:40])[CH:20]=3)[C:14]([CH2:16][O:17][CH3:18])=[C:15]([Br:41])[N:11]2[N:10]=[CH:9][N:8]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: COCc1cn2ncnc(N)c2c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)c(F)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)c(F)c2)c2c(N)ncnn2c1Br
Temperature: -40 °C
Reaction time: 1 h
Yield: 107 %

Procedure:
To a solution of THF (500 mL) was added 1-{4-[4-amino-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea (2.29 g, 4.65 mmol). The solution was cooled to −40° C. and then 1,3-dibromo-5,5-dimethylhydantoin (665 mg, 2.33 mmol) was added in two batches 20 min apart. The reaction was stirred at −40° C. for 1 h and then allowed to warm to rt over the following 2 h. Aq saturated Na2SO3 was added to the reaction followed by EtOAc. The layers were separated and the aqueous layer was back extracted with EtOAc. The organic layer was washed with 1 N NaOH and water, dried (Na2SO4), filtered and evaporated to yield 2.83 g crude (107%) of the desired product. MS [M+H]+=571; LCMS RT=3.54.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:22])[CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[CH:11][CH:10]=1.[OH-].[Na+].Cl>ClCCl>[O:22]=[C:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5])=[CH:10][CH:11]=1)[CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Reactant: CCCCC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCCC(=O)Nc1ccc(C(=O)CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.9 %

Procedure:
To a 2-dram vial was added pentanoyl chloride (0.040 mL, 0.00033 mol), 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.051 g, 0.00025 mol) (Example 1, Step (c)), dichloromethane (3 mL), and a 3.6 mmol amine per gram of 4-morpholinomethyl polystyrene resin (0.10 g, 0.00036 mol amine), the vial was tightly capped, and the mixture was shaken at room temperature for approximately 5 hours. To the mixture was added an excess of [Bis(2-aminoethyl)amino-ethyl]amino-methyl polystyrene resin, the vial was tightly capped, and the mixture was shaken at room temperature overnight. The mixture was gravity filtered into a clean 2-dram vial, and the solvent evaporated under a stream of nitrogen. The residue was dissolved in THF (3 mL), 1.0 M NaOH (0.5 mL, 0.0005 mol) was added, and the mixture was shaken overnight. Additional 1.0 M NaOH (0.25 mL, 0.00025 mol) was added, and the mixture was shaken overnight. To the mixture was added 1.0 M HCl (1.0 mL, 0.001 mol), and the two-phase mixture was shaken for 1 hour. The bottom layer was withdrawn by pipet, and the remaining organics were evaporated under a stream of nitrogen. The residue was dried in vacuo to give 0.054 g of 4-oxo-4-(4-pentanoylamino-phenyl)-butyric acid as a pink solid; mp 153-155° C.
Reaction SMILES: [Cl-].[C:2]([C:4]1[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][NH2+:9]1)#[N:3].CCN(CC)CC.[C:27](Cl)(=[O:29])[CH3:28]>C1COCC1>[NH2:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:5]([O:6][CH2:7][C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:27](=[O:29])[CH3:28])[C:4]=1[C:2]#[N:3]
Reactant: N#Cc1c(OC[C@@H]2CCC[NH2+]2)cccc1[N+](=O)[O-]
Reactant: CC(=O)Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCC[C@H]1COc1cccc(N)c1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.1 %

Procedure:
To a suspension of (S)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride (130 mg, 0.46 mmol) (Example 209b) in THF (5 mL) were added Et3N (135 μL, 0.97 mmol) and acetyl chloride (36 μL, 0.50 mmol). The reaction was stirred at rt for 18 h, filtered and diluted with EtOH (20 mL). The resulting solution was hydrogenated (20 Bar) using 10% Pd/C as the catalyst. Upon completion, the reaction mixture was concentrated to provide the title compound (61 mg, 51%) as a clear syrup. MS 260 (MH+).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][C@H:24]1[CH2:29][O:28][CH2:27][CH2:26][NH:25]1>>[CH3:23][C@H:24]1[CH2:29][O:28][CH2:27][CH2:26][N:25]1[C:18]([C:12]1[S:13][C:14]2[CH2:15][CH2:16][O:17][C:8]3[CH:7]=[C:6]([C:4]4[CH:5]=[N:1][NH:2][CH:3]=4)[CH:22]=[CH:21][C:9]=3[C:10]=2[N:11]=1)=[O:19]
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: C[C@H]1COCCN1
Product: C[C@H]1COCCN1C(=O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (S)-3-methylmorpholine (1.2 equiv) to give 138 (14.9 mg, M+1 397.1)
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:12]=[C:13](C=[CH:19][CH:20]=3)C(NC)=O)=[CH:10][C:5]2=[N:4][CH:3]=1.[N:21]1C=CC(B(O)O)=CC=1>>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:20]=[CH:19][N:21]=[CH:13][CH:12]=3)=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: CNC(=O)c1cccc(-c2ccn3c(Br)cnc3c2)c1
Reactant: OB(O)c1ccncc1
Product: Brc1cnc2cc(-c3ccncc3)ccn12

Procedure:
This compound is prepared analogously to 3-(3-Bromo-imidazo[1,2-a]pyridin-7-yl)-N-methyl-benzamide (Intermediate EA) by replacing (3-methylaminocarbonylphenyl)boronic acid (step EA2) with 4-pyridine boronic acid.
Reaction SMILES: Cl[C:2](=[CH2:5])[C:3]#[N:4].Cl.[CH:7]([NH:10][NH2:11])([CH3:9])[CH3:8].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:8][CH:7]([N:10]1[CH:5]=[CH:2][C:3]([NH2:4])=[N:11]1)[CH3:9]
Reactant: C=C(Cl)C#N
Reactant: CC(C)NN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)n1ccc(N)n1
Temperature: 45 °C
Yield: 57.8 %

Procedure:
2-Chloroacrylonitrile (3.41 mL, 42.59 mmol) was added at RT to a stirring solution of N-isopropylhydrazine hydrochloride (4.71 g, 42.6 mmol), potassium carbonate (11.8 g, 85.2 mmol) in water (50 mL). The reaction was warmed to 45° C. for 4 hours before cooling back to RT. The aqueous layer was then extracted with ethyl acetate (5×30 mL) and the combined organic layers were dried (MgSO4), treated with activated charcoal, filtered and evaporated. The residue was purified by chromatography, eluting with 67%-100% ethyl acetate in hexanes, to afford the title compound (3.08 g, 58%) as a 6:1 mixture of authentic product to regioisomeric product as an oil. The material was used without further purification. 1H NMR δ (CDCl3): 1.42 (m, 6H), 3.58 (br. s, 2H), 4.25 (sept, 1H), 5.58 (d, 1H), 7.15 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]#[N:19])=[CH:10][CH:9]=2)[C:5]2[CH:20]=[C:21]([OH:38])[C:22]([O:24][CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)=[CH:23][C:4]=2[N:3]=1.[CH2:39]([O:46][C:47]([N:49]1[CH2:54][CH2:53][CH:52](O)[CH2:51][CH2:50]1)=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]#[N:19])=[CH:10][CH:9]=2)[C:5]2[CH:20]=[C:21]([O:38][CH:52]3[CH2:53][CH2:54][N:49]([C:47]([O:46][CH2:39][C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)=[O:48])[CH2:50][CH2:51]3)[C:22]([O:24][CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:27][CH2:26]3)=[CH:23][C:4]=2[N:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Reactant: Cc1nc2cc(OC3CCN(C(=O)OC(C)(C)C)CC3)c(O)cc2n1Cc1ccc(C#N)c2ccccc12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc2cc(OC3CCN(C(=O)OC(C)(C)C)CC3)c(OC3CCN(C(=O)OCc4ccccc4)CC3)cc2n1Cc1ccc(C#N)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2-methyl-6-hydroxy-5-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-cyanonaphth-1-yl)methylbenzimidazole (2.8 g) in THF (50 mL) was first added N-benzyloxycarbonyl-4-hydroxypiperidine (1.7 g), PPh3 (1.9 g), and then DEAD (1.2 mL) in a dropwise fashion. After stirring at ambient temperature for 1 hour the solvent was removed and the residue was separated by silica gel chromatography (hexane/ethyl acetate, gradient) to afford 2-methyl-6-(N-(benzyloxycarbonyl)piperidin-4-yloxy)-5-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-cyanonaphth-1-yl)methylbenzimidazole.