Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([S:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14]/[C:13]/1=[CH:18]\[C:19]1[N:20]=[N:21][N:22]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH:23]=1)(=[O:10])[CH3:9].Br[CH:34]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[F:46])[C:35]([CH:37]1[CH2:39][CH2:38]1)=[O:36].C(N(CC)CC)C.[Cl-].[Na+]>C(#N)C>[C:8]([S:11][CH:12]1[CH2:17][CH2:16][N:15]([CH:34]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[F:46])[C:35]([CH:37]2[CH2:38][CH2:39]2)=[O:36])[CH2:14]/[C:13]/1=[CH:18]\[C:19]1[N:20]=[N:21][N:22]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[CH:23]=1)(=[O:10])[CH3:9]
Reactant: O=C(C1CC1)C(Br)c1ccccc1F
Reactant: COc1ccc(Cn2cc(/C=C3\CNCCC3SC(C)=O)nn2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1ccc(Cn2cc(/C=C3\CN(C(C(=O)C4CC4)c4ccccc4F)CCC3SC(C)=O)nn2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.9 %

Procedure:
To a solution of (E)-4-(acetylsulfanyl)-3-{[1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl]methylidene}piperidine hydrogen trifluoroacetate (6.03 g) in acetonitrile (100 ml) were added 2-bromo-2-(2-fluorophenyl)-1-cyclopropylethanone (5.0 g) and triethylamine (3.5 ml). The resulting mixture was stirred at room temperature for 15 minutes. Then, the reaction was stopped by addition of a saturated aqueous sodium chloride solution, and the products were extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The residue was purified by chromatography on silica gel using a mixture of hexane, ethyl acetate and dichloromethane (1:1:1) as the eluent to afford the title compound as a pale yellow amorphous solid (5.11 g, yield: 75%).
Reaction SMILES: O1CCOCC1.[CH:7]1([NH:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18](=[O:33])[C:19]([O:29][CH2:30][C:31]#[N:32])=[CH:20][N:21]3[CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:16][C:15]=2[F:34])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C([Sn]([N:48]=[N+:49]=[N-:50])(CCCC)CCCC)CCC.[OH-].[Na+]>CCOCC>[CH:7]1([NH:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18](=[O:33])[C:19]([O:29][CH2:30][C:31]4[NH:50][N:49]=[N:48][N:32]=4)=[CH:20][N:21]3[CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:16][C:15]=2[F:34])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#CCOc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=c1c(OCc2nnn[nH]2)cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc12
Temperature: 25 °C

Procedure:
To a 5 ml 1,4-dioxane solution of 300 mg of {[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]oxy}acetonitrile was added 0.8 ml of tributyltin azide, followed by heating under reflux for 2 days. After cooling to room temperature, aqueous 1M sodium hydroxide solution and ether were added, followed by layer separation operation. To the aqueous layer was added 1 M hydrochloric acid, followed by extraction with chloroform and washing with aqueous saturated sodium chloride. After drying over anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure. By adding ether to the resulting residue and collecting the insoluble materials by filtration, 70 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-(1H-tetrazol-5-ylmethoxy)quinolin-4(1H)-one was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:22].O1CCOCC1>CO.C(OCC)(=O)C>[ClH:22].[ClH:22].[O:21]=[S:17]1(=[O:20])[CH2:16][CH2:15][CH:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCS(=O)(=O)CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOC(C)=O
Product: O=S1(=O)CCC(N2CCNCC2)CC1
Yield: 99.5 %

Procedure:
To a stirred solution of 4-(1,1-dioxo-tetrahydro-2H-thiopyran-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (8.02 g, 25 mmol) in methanol at 45° C. (150 mL) was added 4 N hydrochloric acid in 1,4-dioxane (100 mmol, 25 mL, Aldrich). The mixture was stirred at 45° C. for 7 h until thin layer chromatography (5% methanol in ethyl acetate) indicated that the reaction was complete. The solvent was removed under reduced pressure to give 1-(1,1-dioxo-tetrahydro-2H-thiopyran-4-yl)-piperazine dihydrochloride as a white solid (7.24 g, 99.5%). LR-MS: 218 [(M+H)+]
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[C:5]([CH:14]=[CH2:15])[CH:4]=1.C(N(CC)CC)C.[C:23]([C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35](O)=[O:36])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>C(Cl)Cl>[C:23]([C:27]1[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][C:35]([NH:1][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[C:5]([CH:14]=[CH2:15])[CH:4]=2)=[O:36])=[CH:31][CH:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1ccc(CCC(=O)O)cc1
Reactant: C=Cc1cc(CN)ccc1NS(C)(=O)=O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=Cc1cc(CNC(=O)CCc2ccc(C(C)(C)C)cc2)ccc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 73 %

Procedure:
N-[4-(aminomethyl)-2-vinylphenyl]methanesulfonamide (0.23 mol) and was suspended in methylene chloride and treated with triethylamine followed by 3-(4-tert-butyl-phenyl)-propionic acid and DMTMM (40 mg). The resulting mixture was stirred for 2 days at ambient temperature and concentrated under reduced pressure. The crude residue was column-chromatographed (hexane/ethylacetate=3/2) to yield a white solid (73%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:32])=[C:4]([CH:26]=[C:27]([F:31])[C:28]=1[C:29]#[N:30])[C:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]([F:24])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[CH3:25])=[O:6].N1(C2CCCCCCCCCC2)CCCN=CCCCCC1.[C:55](Cl)(=[O:62])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>C(Cl)(Cl)Cl>[C:55]([NH:1][C:2]1[C:3]([F:32])=[C:4]([CH:26]=[C:27]([F:31])[C:28]=1[C:29]#[N:30])[C:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]([F:24])([C:16]([F:18])([F:19])[F:17])[C:20]([F:21])([F:22])[F:23])=[CH:10][C:9]=1[CH3:25])=[O:6])(=[O:62])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cc(F)c(C#N)c(N)c1F
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Solvent: ClC(Cl)Cl
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cc(F)c(C#N)c(NC(=O)c2ccccc2)c1F
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
To a solution of 3-amino-4-cyano-2,5-difluoro-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-benzamide (70 mg, 0.15 mmol) (Example I16) in chloroform (0.75 ml) were added 1,8-diazabicycloundec-7-ene (“DBU”) (49 μl, 0.33 mmol) and benzoyl chloride (17 μl, 0.15 mmol). The reaction mixture was heated in a microwave to 140° C. for 30 minutes. Two further portions of benzoyl chloride (17 μl, 0.15 mmol) were added and heating continued at 140° C. for 30 minutes each time. The reaction mixture was partitioned between water and chloroform. The aqueous phase was extracted twice with chloroform. The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by reverse-phase chromatography (eluent:trifluoroacetic acid/water/acetonitrile 1:4:5 to 1:1:8) to give Compound No. E36 of Table E (0.013 g, 15% yield) as an off-white solid. M.p. 245-248° C. 1H-NMR (400 MHz, CDCl3): 2.28 (6H, s), 7.38 (2H, s), 7.15-8.1 (8H, m) ppm.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH:4]([S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:36]=[CH:35][C:18]([NH:19][C:20]3[N:25]=[C:24]([C:26]4[N:30]([CH:31]([CH3:33])[CH3:32])[C:29]([CH3:34])=[N:28][CH:27]=4)[CH:23]=[CH:22][N:21]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])=[O:7])=[CH2:5]>C1COCC1>[CH3:1][N:2]([CH3:3])[CH2:5][CH2:4][S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:36]=[CH:35][C:18]([NH:19][C:20]3[N:25]=[C:24]([C:26]4[N:30]([CH:31]([CH3:32])[CH3:33])[C:29]([CH3:34])=[N:28][CH:27]=4)[CH:23]=[CH:22][N:21]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)(=[O:7])=[O:8]
Reactant: CNC
Reactant: C=CS(=O)(=O)N1CCN(c2ccc(Nc3nccc(-c4cnc(C)n4C(C)C)n3)cc2)CC1
Solvent: C1CCOC1
Product: Cc1ncc(-c2ccnc(Nc3ccc(N4CCN(S(=O)(=O)CCN(C)C)CC4)cc3)n2)n1C(C)C
Reaction time: 1 h

Procedure:
Dimethylamine (2.0 M) in THF (1.5 ml) was added to a stirred suspension of 2-{4-[4-(vinylsulphonyl)piperazin-1-yl]anilino}-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidine (Example 29; 140 mg 0.3 mmol) in THF (3 ml) at room temperature. Additional dimethylamine solution (0.5 ml) was added after 2 hours. The reaction was stirred for 1 hour then stood overnight. The reaction was evaporated under reduced pressure, triturated with ether and filtered to give the title compound as a yellow solid. (134 mg 89%). NMR: 1.40 (d, 6H), 2.46 (s, 3H), 2.62 (t, 2H), 3.13 (t, 4H), 3.20-3.35 (2H and 4H)[under exchangeables], 5.68 (septuplet, 1H), 6.92 (d, 2H), 6.95 (d, 1H), 7.38 (s, 1H), 7.47 (d, 2H), 8.31 (d, 1H), 9.18 (s, 1H) [+duetero acetic acid: 3.01 (b d, 2H), 3.14 (t, 4H), 3.33 (t, 4H), 3.37 (m, 2H)]; m/z 478.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH2:13])[CH:6]=[C:5]1[C:14]1[S:15][CH:16]=[CH:17][N:18]=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][S:24]([C:20]2[S:19][CH:23]=[CH:22][CH:21]=2)(=[O:26])=[O:25])[CH:6]=[C:5]1[C:14]1[S:15][CH:16]=[CH:17][N:18]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COCn1c(-c2nccs2)cc2cccc(N)c21
Solvent: c1ccncc1
Product: COCn1c(-c2nccs2)cc2cccc(NS(=O)(=O)c3cccs3)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a mixture of 1-(methoxymethyl)-2-(1,3-thiazol-2-yl)-1H-indole-7-amine (1.87 g) and pyridine (10 mL) was added thiophene-2-sulfonyl chloride (1.57 g) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (2.69 g, yield 92%) was obtained as yellow crystals from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio). melting point 95-97° C.
Reaction SMILES: Cl.C1C2C(=CC=CC=2)CCN1CCC[CH2:15][N:16]1[C:25](=[O:26])[C:24]2[CH:27]=[CH:28][CH:29]=[C:22]3[C:23]=2[C:18](=[CH:19][CH:20]=[CH:21]3)[C:17]1=[O:30].[Br:31][CH2:32][CH2:33][CH2:34][CH2:35]CBr.BrCCCCBr>>[Br:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:15][N:16]1[C:17](=[O:30])[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:23]=2[C:24](=[CH:27][CH:28]=[CH:29]3)[C:25]1=[O:26]
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCN1CCc2ccccc2C1
Reactant: BrCCCCCBr
Agent: Cl
Solvent: BrCCCCBr
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCBr

Procedure:
Following the procedure of part (a) of example 39 but substituting 1,5-dibromopentane for the 1,4-dibromobutane, one obtains 2-(5-bromopentyl)-1H-benz[de]isoquinoline-1,3(2H)-dione; m.p. 113°-115°.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.P(OC)(OC)OC.C(O[K])(C)(C)C.[CH:26]([C:28]1[C:36]2[C:31](=[CH:32][C:33]([C:37]#[N:38])=[CH:34][CH:35]=2)[NH:30][N:29]=1)=O.Cl>CN(C=O)C.O>[C:37]([C:33]1[CH:32]=[C:31]2[C:36]([C:28](/[CH:26]=[CH:2]/[C:3]3[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=3)=[N:29][NH:30]2)=[CH:35][CH:34]=1)#[N:38]
Reactant: N#Cc1ccc2c(C=O)n[nH]c2c1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: CC(C)(C)O[K]
Agent: COP(OC)OC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(/C=C/c2n[nH]c3cc(C#N)ccc23)cc1
Temperature: 125 °C
Reaction time: 1.5 h
Yield: 104.3 %

Procedure:
A mixture of methyl 4-(bromomethyl)benzoate (4.58 g, 20 mmol) and trimethyl phosphite (3.54 mL, 30 mmol) was refluxed (oil temp. 125° C.) for 1 h under argon. After cooling to rt, the reaction mixture was diluted with DMF (50 mL) and cooled to 0° C. using ice bath. tBuOK (3.92 g, 35 mmol) was added slowly. After addition, the resulting dark brown solution was stirred for 5 min at 0° C. before a solution of 3-formyl-1H-indazole-6-carbonitrile (2.0 g, 11.7 mmol) in DMF (15 mL) was added dropwise via a pasteur pipette over 5 min. The reaction mixture was then stirred for 90 min at 0° C.; 2N HCl (25 mL) was added slowly over 2 min, followed by H2O (100 mL). The resulting suspension was stirred for 5 min at 0° C. The precipiates collected by suction filtration were rinsed well with H2O and dried to give crude (E)-methyl 4-(2-(6-cyano-1H-indazol-3-yl)vinyl)benzoate (3.70 g) as an orange solid. Trituration with 50 mL of ether, followed by sonication and suction filtration gave pure (E)-methyl 4-(2-(6-cyano-1H-indazol-3-yl)vinyl)benzoate (2.56 g, 72%) as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ 13.83 (s, 1H), 8.43 (d, J=8.8 Hz, 1H), 8.18 (s, 1H), 7.97 (d, J=8.4 Hz, 2H), 7.87 (d, J=8.4 Hz, 2H), 7.76 (d, J=16.4 Hz, 1H), 7.63 (d, J=16.8 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 3.86 (s, 3H); MS ESI 304.1 [M+H]+, calcd for [C18H13N3O2+H]+ 304.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[Cl:10][C:11]1[CH:12]=[C:13](B(O)O)[C:14]([F:17])=[N:15][CH:16]=1.C([O-])(=O)C.[K+]>CCO.O>[Cl:10][C:11]1[CH:12]=[C:13]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=2)[C:14]([F:17])=[N:15][CH:16]=1
Reactant: Cc1nc(N)nc(Cl)n1
Reactant: OB(O)c1cc(Cl)cnc1F
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1nc(N)nc(-c2cc(Cl)cnc2F)n1
Temperature: 100 °C
Yield: 56.3 %

Procedure:
To a 20 mL microwave reaction tube was added 4-chloro-6-methyl-1,3,5-triazin-2-amine (Example 9, 1.00 g, 6.94 mmol), 5-chloro-2-fluoropyridin-3-ylboronic acid (Combi-Blocks, 1.62 g, 9.22 mmol), potassium acetate (Aldrich, 2.07 g, 21.1 mmol) and Am-Phos (Aldrich, 0.247 g, 0.349 mmol) in EtOH (12 mL) and water (1.2 mL). The mixture was degassed by bubbling argon through for 5 min. The tube was heated in an microwave reactor (Biotage) at 100° C. for 20 min. The reaction mixture was partitioned between water (100 mL) and 25% IPA in chloroform with 1% NH4OH (60 mL). The aqueous phase was extracted with 25% IPA in chloroform with 1% NH4OH (2×50 mL). The combined organic phases were washed with saturated aqueous sodium chloride (40 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. Adding DCM to the residue resulted in precipitate formation. The solid was collected via filtration and washed with MeOH to afford 4-(5-chloro-2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.937 g) as a light yellow powder. The filtrate and the wash were combined and concentrated, then purified by column chromatography (eluent: iPrOH (w/10% NH4OH) in CHCl3 0.25% to 6.25%) followed by washing with MeOH to afford additional product (0.149 g) as a white solid. The total yield is 1.08 g (65%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.54 (dd, J=8.02, 2.74 Hz, 1H) 8.46-8.51 (m, 1H) 7.73 (s, 2H) 2.37 (s, 3H). m/z (ESI, positive ion) m/z: 240.1 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:8][C:9]2[C:10]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[NH:22][C:23](=O)[CH2:24][C:25]([F:28])([F:27])[F:26])=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:2]=1.O=P(Cl)(Cl)Cl>O1CCOCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:8][C:9]2[C:10]([N:15]3[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[N:22]=[C:23]3[CH2:24][C:25]([F:28])([F:27])[F:26])=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:2]=1
Reactant: O=C(CC(F)(F)F)Nc1ccccc1Nc1ncccc1CC(c1cccnc1)c1cccnc1
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: FC(F)(F)Cc1nc2ccccc2n1-c1ncccc1CC(c1cccnc1)c1cccnc1
Temperature: 25 °C
Yield: 103.9 %

Procedure:
To a solution of N-(2-{[3-(2,2-dipyridin-3-ylethyl)pyridin-2-yl]amino}phenyl)-3,3,3-trifluoropropanamide (127 mg) in 6 mL of dioxane was added 500 uL of POCl3. Immediate precipitation was observed. The reaction was heated at 100 C for 24 h, giving a sluggish reaction. The reaction was cooled to 0 C and carefully quenched with saturated aqueous sodium bicarbonate. then partitioned between saturated aqueous sodium bicarbonate and CH2Cl2. The aqueous solution was extracted with CH2Cl2 (2×), and the combined organic solutions were dried (Na2SO4) and concentrated. The resulting crude mixture of starting material and desired product was dissolved in 4 mL of dioxane. This solution was added dropwise to 10 mL of POCl3 stirring at 50 C. The mixture was heated at 100 C for 8 h, then cooled to room temperature and concentrated in vacuo. CH2Cl2 was added to the residue, and the resulting solution was cooled to 0 C and neutralized slowly with saturated aqueous sodium bicarbonate, then partitioned between saturated aqueous sodium bicarbonate and CH2Cl2. The aqueous solution was extracted with CH2Cl2 (3×), and the combined organic solutions were dried (Na2SO4) and purified by flash chromatography. A second purification by reverse phase HPLC provided 127 mg of 1-[3-(2,2-dipyridin-3-ylethyl)pyridin-2-yl]-2-(2,2,2-trifluoroethyl)-1H-benzimidazole as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.54 (dd, J=4.6, 1.7 Hz, 1H), 8.43 (d, J=4.4 Hz, 2H), 8.31 (d, J=1.7 Hz, 1H), 8.24 (s, 1H), 7.91 (d, J=8.1 Hz, 1H), 7.69 (dd, J=7.8, 1.5 Hz, 1H), 7.40-7.35 (m, 2H), 7.31-7.28 (m, 1H), 7.22-7.20 (m, 1H), 7.18-7.11 (m, 3H), 6.92 (d, J=8.1 Hz, 1H), 4.08 (t, J=7.8 Hz, 1H), 3.73-3.64 (m, 1H), 3.52-3.43 (m, 1H), 3.29-3.21 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][NH:9][C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:6][N:5]=[C:4]([S:18][CH3:19])[N:3]=1.[C:20]([O:24][C:25](=[O:38])[NH:26][C:27]([CH3:37])([CH3:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH2:35])[CH:30]=1)([CH3:23])([CH3:22])[CH3:21].C(N(CC)C1C=CC=CC=1)C>ClCCl>[C:20]([O:24][C:25](=[O:38])[NH:26][C:27]([CH3:37])([CH3:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:2]2[C:7]([CH2:8][NH:9][C:10]3[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:17])=[CH:6][N:5]=[C:4]([S:18][CH3:19])[N:3]=2)[CH:30]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CSc1ncc(CNc2c(Cl)cccc2Cl)c(Cl)n1
Reactant: CC(C)(Cc1cccc(N)c1)NC(=O)OC(C)(C)C
Solvent: CCN(CC)c1ccccc1
Solvent: ClCCl
Product: CSc1ncc(CNc2c(Cl)cccc2Cl)c(Nc2cccc(CC(C)(C)NC(=O)OC(C)(C)C)c2)n1
Reaction time: 0.5 h
Yield: 38.9 %

Procedure:
A solution of 520 mg (1.6 mmol) of 4-chloro-5-(2,6-dichloroanilinomethyl)-2-methylthiopyrimidine, 420 mg (1.6 mmol) of (2-(3-aminophenyl)-1,1-dimethyl-ethyl)-carbamic acid tert-butyl ester and 250 mg (1.7 mmol) of N,N-diethylaniline in 5 ml of dichloromethane was heated at 80° C. until the solvent had evaporated and then to 120° C. for 30 minutes and then cooled. The product was purified by flash chromatography on silica gel eluting with diethyl ether/isohexane in a ratio 1:1 to give 350 mg (39%) of (2-(3-[5-[(2,6-dichlorophenylamino)-methyl]-2-methylthiopyrimidin-4-yl-amino]-phenyl)-1,1-dimethyl-ethyl)-carbamic acid tert-butyl ester as a white solid. [Mass spectrum (ESI) MH+ =562].
Reaction SMILES: C(OC([NH:8][C@H:9]([CH3:18])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)(C)(C)C.[ClH:19]>C(OCC)(=O)C>[O:11]([CH2:10][C@H:9]([NH2:8])[CH3:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[ClH:19]
Reactant: C[C@H](COc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H](N)COc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
(R)- N-(tert-Butoxycarbonyl)-1-phenoxy-2-propylamine (8.0 g, 33 mmol) was dissolved in ethyl acetate (100 ml). A solution of hydrochloric acid (g) in ethyl acetate (6N, 100 ml) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 20 h during which time a heavy precipitate was formed. The reaction mixture was concentrated to half the original volume before the product was collected by filtration and dried in vacuo to provide the title compound as a white solid hydrochloride (4,3 g, 69%) m.p. 186°-189° C. 1H NMR (DMSO-d6)δ 1.31 (3H, d, --CH3), 3.51-3.60 (1H, m, --CH--), 4.05 (1H, dd, --CH2 a-), 4.12 (1H, dd, --CH2 b-), 6.95-7.00 (3H, m. Ar--H), 7.32 (2H, t, Ar--H).
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].C(N(CC)CC)C.[CH2:12]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)[CH2:13][CH2:14][CH2:15][CH3:16]>C1COCC1.O.CCOC(C)=O>[OH:4][N:3]([CH3:2])[C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:17]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:18][CH:19]=1
Reactant: CCCCCc1ccc(C(=O)Cl)cc1
Reactant: CNO
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCc1ccc(C(=O)N(C)O)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 0° C. solution of N-methylhydroxylamine hydrochloride (793 mg, 2 eq.) in 20 ml of THF:H2O (1:1) with triethylamine (198 ml, 3.0 eq.) was added 4-(n-pentyl) benzoic acid chloride (1.0 ml, 4.75 mmol). The solution was stirred for 0.5 hour at 0° C. then allowed to warm to room temperature and stir overnight. The reaction mixture was diluted with EtOAc and the organic layer was washed with H2O, 1N HCl (2×), and brine, then dried over anhydrous MgSO4. Concentration in vacuo gave a yellow oil which was flash chromatographed in LPS-1 silica gel eluting with (1:1) hexane/EtOAc. Product containing fractions were concentrated in vacuo to yield title product, 380 mg (37%) as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[OH:32])O1>>[NH2:1][C:2]1[N:16]=[CH:15][C:14]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[OH:32])=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Reactant: CC1(C)OB(c2ccccc2O)OC1(C)C
Product: Nc1ncc(-c2ccccc2O)cc1C(=O)Nc1ccncc1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol gives “A73”; method 1: HPLC/MS: 1.16 min, [M+H]=307;
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[OH:35][C:36]1([C:42]([OH:44])=[O:43])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:39]4[CH2:40][CH2:41][C:36]([OH:35])([C:42]([OH:44])=[O:43])[CH2:37][CH2:38]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O=C(O)C1(O)CCNCC1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCC(O)(C(=O)O)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
1-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-4-hydroxypiperidine-4-carboxylic acid was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 4-Hydroxy-piperidine-4-carboxylic acid following General Procedure C.