Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH2:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[N:3]=1.[NH:23]1[CH2:27][CH2:26][C@H:25]([NH2:28])[CH2:24]1>>[NH2:28][C@H:25]1[CH2:26][CH2:27][N:23]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=3[NH:12][C:13](=[O:21])[CH2:14][CH2:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[N:3]=2)[CH2:24]1
Reactant: O=C(CCC1CCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Reactant: N[C@H]1CCNC1
Product: N[C@H]1CCN(c2ccc3c(NC(=O)CCC4CCCC4)c(Cl)ccc3n2)C1
Yield: 69.7 %

Procedure:
Prepared according to the method of example 30, using N-(2,6-dichloro-5-quinolinyl)-cyclopentanepropanamide (Example 62(a)) (500 mg) and (3S)-3-pyrrolidinamine (390 mg). Purification (SiO2, methanol:dichloromethane:ammonium hydroxide solution 7:93:1 as eluant) gave the title compound as a solid (400 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1.[N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[NH:18][C:17]=1[SH:25].[OH-].[Na+]>C(O)C>[CH3:15][O:14][CH2:13][CH2:12][CH2:11][O:10][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][S:25][C:17]2[NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:16]=2)[C:8]=1[CH3:9]
Reactant: COCCCOc1ccnc(CCl)c1C
Reactant: Sc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Yield: 100.5 %

Procedure:
2-Chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine (53.2 g (200 mmol)), denatured ethanol (320 ml), 2-benzimidazole thiol (30.2 g (201 mmol)) and sodium hydroxide (26.8 g (670 mmol)) were added together and reacted for about 2 hours at 50° C. After disappearance of the raw materials had been confirmed by TLC, this solution was concentrated under a reduced pressure and ethyl acetate (430 ml) and water (340 ml) were added thereto, followed by stirring and standing, and the water layer was then separated. The organic layer was washed with 10% aqueous sodium hydroxide solution (110 ml) and water (2×110 ml) and concentrated under a reduced pressure to obtain crude 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole (69.0 g) (HPLC purity 98.7%, yield 101%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH:12]([OH:16])[C:13]#[C:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)C=CC=1.[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CCCCCC>[CH2:1]([O:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH:12]([OH:16])/[CH:13]=[CH:14]\[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CC#CC(O)CC(C)COCc1ccccc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: c1ccc2ncccc2c1
Solvent: CCCCCC
Product: C/C=C\C(O)CC(C)COCc1ccccc1

Procedure:
A mixture of 1 g. (4.31 mmoles) of rac. 1-benzyloxy-2-methylhept-5-yn-4-ol, 0.1 g. of Lindlar catalyst, 0.04 ml. of quinoline and 30 ml. of hexane was stirred in an atmosphere of hydrogen, at room temperature, for 40 minutes during which time approximately one equivalent of hydrogen was taken up. The catalyst was filtered and washed with hexane then the combined filtrate and washes were concentrated in vacuo giving 1.05 g. of oily product. This material was chromatographed on 50 g. of silica gel. Elution with 2:1 parts by volume and 1:1 parts by volume hexane-ether afforded 0.844 g. of a pale yellow oil. Evaporative distillation gave rac. Z-1-benzyloxy-2-methyl-5-hepten-4-ol as a colorless oil, b.p. 113°-123° C. (bath temperature) (0.25 mm Hg.).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=2)[NH:9]S(C(C)(C)C)=O)=[CH:4][CH:3]=1.Cl>CO>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:16]2[C:21]([C:22]([F:25])([F:23])[F:24])=[CH:20][CH:19]=[CH:18][N:17]=2)[NH2:9])=[CH:6][CH:7]=1
Reactant: CC(C)(C)S(=O)NC(c1ccc(I)cc1)c1ncccc1C(F)(F)F
Agent: Cl
Solvent: CO
Product: NC(c1ccc(I)cc1)c1ncccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N-((4-iodophenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide in MeOH (5 mL) was added HCl (2.0 mL, 8.0 mmol) (4.0 M in 1,4-dioxane). The reaction was stirred at rt under N2 for 18 h. The reaction was then concentrated, and the residue was purified by reverse-phase preparative HPLC (Shimadzu) on a Phenomenex Gemini™ column (5 micron, C18, 110 Å, Axia, 100×30 mm) eluting at 45 mL/min with a linear gradient of 10% to 100% MeCN (0.1% TFA) in H2O (0.1% TFA) over 20 minutes. The product-containing fractions were combined, concentrated, dissolved in DCM (5 mL) and extracted with saturated aqueous NaHCO3 (2×5 mL). The organic layer was dried and concentrated to give (4-iodophenyl)(3-(trifluoromethyl)-pyridin-2-yl)methanamine as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]([OH:20])[CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:6][C:7]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].CO[CH:24](OC)[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[O:33][CH3:34].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3]([C@@H:4]1[O:20][CH:24]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=2[O:33][CH3:34])[N:6]([C:7]([NH:9][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:8])[C@H:5]1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:21]
Reactant: COC(=O)C(O)C(NC(=O)NC(C)(C)C)c1ccccc1
Reactant: COc1ccc(C(OC)OC)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1OC(c2ccc(OC)cc2OC)N(C(=O)NC(C)(C)C)[C@H]1c1ccccc1

Procedure:
N-(t-butylaminocarbonyl)-β-phenyl isoserine methyl ester (PREPARATION 1, 68 mg, 0.23 mM) is dissolved in dry THF (5 mL) and the solution treated with 2,4-dimethoxy benzaldehyde dimethyl acetal (70 mg, 0.33 mM) and pyridinium p-toluenesulfonate (6 mg, 0.02 mM) and the mixture warmed to reflux. Approximately 2 mL solvent is boiled away 3 times in a 45 minute period replenishing with 2 mL of fresh THF at which time TLC shows no starting material. The solvent is concentrated under reduced pressure and chromatographed (7 g of silica gel packed in ethyl acetate/1hexane, 1/3; elution with 80 mL ethyl acetate/hexane, 1/3; 45 mL ethyl acetate/hexane, 1/2; 30 mL ethyl acetate/hexane, 2/3 and 30 mL ethyl acetate/hexane, 1/1) to give the title compound: less polar isomer found in fractions 21-31—NMR (CDCl3, TMS) 1.19, 3.82, 3.85, 3.89, 4.68, 4.88, 5.52, 6.46, 6.70 and 7.25-7.50 δ, MS (FAB-High Res.) theory for C24H31N2O6+H=443.2182, found=443.2172; more polar isomer in fractions 33-42—NMR (CDCl3, TMS) 0.99, 3.53, 3.81, 3.88, 4.05, 4.55, 5.45, 6.48, 6.79 and 7.25-7.50 δ; MS (FAB-High Res.) theory for C24H31N2O6+H=443.2182, found=443.2180.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:11][C:12]2[CH:22]=[CH:21][C:15]3[N:16]=[C:17]([S:19][CH3:20])[S:18][C:14]=3[CH:13]=2)[CH:9]=O)=[C:4]([N+:23]([O-])=O)[CH:3]=1>CCO.CC(O)=O.[Fe]>[I:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:11][C:12]3[CH:22]=[CH:21][C:15]4[N:16]=[C:17]([S:19][CH3:20])[S:18][C:14]=4[CH:13]=3)[CH:9]=[N:23][C:4]=2[CH:3]=1
Reactant: CSc1nc2ccc(CN(C=O)c3ccc(I)cc3[N+](=O)[O-])cc2s1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: CSc1nc2ccc(Cn3cnc4cc(I)ccc43)cc2s1
Temperature: 25 °C
Yield: 68 %

Procedure:
A stirred mixture of N-(4-iodo-2-nitrophenyl)-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)formamide and iron powder (16.7 g, 20 mmol) in EtOH (140 mL) and HOAc (60 mL) was heated at reflux for 1 h. The mixture was cooled to rt and filtered, and the filtrate was concentrated under reduced pressure. The residue was partitioned between EtOAc (200 mL) and 0.5 M aq Na2CO3 (100 mL). The organic layer was separated and further washed with brine (100 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to afford 6-((5-iodo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole (5.9 g, 68%) as a yellow solid that did not require further purification. 1H NMR (500 MHz, DMSO-d6) δ 8.44 (s, 1H), 8.03 (d, J=1.0 Hz, 1H), 7.97 (s, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.49 (dd, J=1.4, 8.5 Hz, 1H), 7.37-7.43 (m, 2H), 5.60 (s, 2H), 2.76 (s, 3H); LCMS (ESI) m/z 438 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[CH2:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9](=[O:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16]
Reactant: COC(=O)C(=O)Cc1ccc(N)cc1
Reactant: CCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1ccc(CC(=O)C(=O)OC)cc1

Procedure:
A mixture of 0.10 mole of methyl p-aminophenylpyruvate, 0.10 mole of 1-bromohexadecane, and 0.10 mole of anhydrous potassium carbonate in 40 ml. of hexamethylphosphoramide is heated at 80° C. for 20 hrs. The mixture is then cooled, diluted with water and extracted with ether. The ethereal solution is then evaporated, yielding methyl (4-hexadecylaminophenyl)pyruvate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=O)[CH2:8][CH2:7]2.[CH2:13]([NH2:16])[CH2:14][CH3:15].[BH4-].[Na+]>C1(C)C=CC=CC=1>[CH2:13]([NH:16][CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[CH2:10]1)[CH2:14][CH3:15]
Reactant: CCCN
Reactant: O=C1CCc2cccc(Cl)c2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCNC1CCc2cccc(Cl)c2C1

Procedure:
8-Chloro-2-tetralone (500 mg, 2.78 mMol) in toluene (25 mL) was reacted with propylamine (1.14 mL, 13.9 mMol) and sodium borohydride (500 rag) as described in Example2 to give after purification by flash chromatography (5% methanol in dichloromethane+tr. NH4OH) the title compound as a dark oil (340 mg, 55%). The hydrochloride was formed, and recrystallization (ethanol/diethyl ether) gave a colorless, crystalline solid (m.p.=213°-215° C.).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([OH:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[H-].[Na+].[CH3:40]I>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([O:37][CH3:40])([CH3:35])[CH3:36])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:17][CH:18]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2]
Reactant: CI
Reactant: CCCc1nc(CC)n(-c2ccc(C(C)(C)O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)n(-c2ccc(C(C)(C)OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 0.25 h
Yield: 32 %

Procedure:
To a solution of 4′-({2-ethyl-1-[4-(1-hydroxy-1-methylethyl)phenyl]-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.30 g) in N,N-dimethylformamide (5 mL) was added sodium hydride (0.049 g, 60%), and the mixture was stirred for 15 min. Then methyl iodide (0.076 mL) was added, and the mixture was further stirred for 2 hr. Small pieces of ice were added to the reaction mixture. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.10 g, 32%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:43][O:44][C:45]1[C:46]2[N:59]=[C:58]([NH2:60])[S:57][C:47]=2[C:48]([N:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)=[N:49][CH:50]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:60][C:58]2[S:57][C:47]3[C:48]([N:51]4[CH2:56][CH2:55][O:54][CH2:53][CH2:52]4)=[N:49][CH:50]=[C:45]([O:44][CH3:43])[C:46]=3[N:59]=2)=[O:9])=[CH:5][N:4]=1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Reactant: COc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1ccc(C(=O)Nc2nc3c(OC)cnc(N4CCOCC4)c3s2)cn1

Procedure:
From 6-methoxynicotinic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 402 (M+H+, 100).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[NH:5][C:4]=1C(O)=O)[CH3:2].[H-].[Na+].[CH3:18][C@@H:19]1[CH2:21][O:20]1>C1(OC2C=CC=CC=2)C=CC=CC=1.O1CCCC1>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]([CH2:18][C@H:19]([OH:20])[CH3:21])[CH:4]=1)[CH3:2]
Reactant: C[C@@H]1CO1
Reactant: CCc1c(C(=O)O)[nH]c2ccc(F)cc12
Agent: [H-]
Agent: [Na+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1cn(C[C@@H](C)O)c2ccc(F)cc12
Reaction time: 2 h
Yield: 62 %

Procedure:
A suspension of 1.21 g of 3-ethyl-5-fluoroindole-2-carboxylic acid in 16 ml of diphenyl ether was stirred at 260° for 2 hours and, after cooling to 0°, diluted with 29 ml of tetrahydrofuran. 218 mg of sodium hydride dispersion were added and the mixture was stirred for one hour. Subsequently, 0.61 ml of (R)-methyloxirane was added and the reaction mixture was stirred at room temperature for 90 hours. The mixture was extracted with diethyl ether, water and saturated sodium chloride solution and the organic phase was dried over sodium sulfate. The solvent was removed and the residue was chromatographed over 120 g of silica gel with hexane-toluene (1:2) and subsequently with toluene-ethyl acetate (9:1). 0.8 g (62%) of (R)-1-(3-ethyl-5-fluoro-indol-1-yl)-propan-2-ol was obtained as pale brown crystals with m.p. 65°-67°.
Reaction SMILES: [OH:1][CH:2]([C:34]([CH3:38])([CH3:37])[CH2:35][OH:36])[C:3]([NH:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:9])=O.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[CH2:39]([O:1][CH:2]([C:34]([CH3:38])([CH3:37])[C:35]([O:46][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:36])[CH2:3][NH:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:9])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)NCCCOC(=O)CCNC(=O)C(O)C(C)(C)CO
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NCCCOC(=O)CCNCC(OCc1ccccc1)C(C)(C)C(=O)OCc1ccccc1
Yield: 72.2 %

Procedure:
3-(N-Oleoylamino)propyl 3-[N-(2,4-dihydroxy-3,3-dimethyl-1-oxobutyl)amino]propionate (270 mg) and 281 mg of benzoyl chloride were reacted in the same manner as in Example 36 to obtain 260 mg of the title compound (yield: 69%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=5)[CH:21]=4)=[CH:15][N:14]([S:30]([C:33]4[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=4)(=[O:32])=[O:31])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[N:40]1[CH2:45][CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42][CH2:41]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=5)[CH:21]=4)=[CH:15][N:14]([S:30]([C:33]4[CH:34]=[CH:35][C:36]([CH3:37])=[CH:38][CH:39]=4)(=[O:32])=[O:31])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[N:40]1[CH2:41][CH2:42][NH:43][CH2:44][CH2:45]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)c(F)c4)cnc32)cc1
Yield: 93.2 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(2-fluoro-4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (150 mg, 0.206 mmol) was deprotected in TFA/DCM (1/1 ml) to afford 120 mg (93% yield) of the titled compound. MS: m/z=625.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([O:20][C:21]4[CH:26]=[C:25]([CH2:27][NH:28][C:29](=[O:34])[CH2:30][CH2:31][CH2:32]Br)[N:24]=[CH:23][N:22]=4)=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)=[O:10])=[CH:4][C:3]=1[C:35]([F:38])([F:37])[F:36].[H-].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([O:20][C:21]4[CH:26]=[C:25]([CH2:27][N:28]5[CH2:32][CH2:31][CH2:30][C:29]5=[O:34])[N:24]=[CH:23][N:22]=4)=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)=[O:10])=[CH:4][C:3]=1[C:35]([F:38])([F:37])[F:36]
Reactant: O=C(CCCBr)NCc1cc(Oc2ccc3c(ccn3C(=O)Nc3ccc(F)c(C(F)(F)F)c3)c2)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCCN1Cc1cc(Oc2ccc3c(ccn3C(=O)Nc3ccc(F)c(C(F)(F)F)c3)c2)ncn1
Temperature: 0 °C

Procedure:
5-{6-[(4-Bromo-butyrylamino)-methyl]-pyrimidin-4-yloxy}-indole-1-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide (0.353 g, 0.595 mmol) is dissolved in 10 mL THF and cooled to 0° C. Sodium hydride (63 mg, 1.5 mmol, 60% in mineral oil) is added and the reaction is allowed to warm to room temperature overnight. The reaction is quenched with water and diluted with ethyl acetate. The organic layer is removed, dried, and concentrated and the residue is separated via semi-prep HPLC (C18; 20-100% I/H2O with 0.1% TFA) to provide the title compound. MS (ESI) m/z 514.9 (M+1); 1H NMR (400 m/z, DMSO-d6) δ ppm 10.40 (s, 1 H), 8.68 (d, J=1.01 Hz, 1 H), 8.28 (d, J=9.09 Hz, 1 H), 8.09-8.12 (m, 2 H), 7.99-8.03 (m, 1 H), 7.57 (t, J=9.85 Hz, 1 H), 7.49 (d, J=2.27 Hz, 1 H), 7.15 (dd, J=8.97, 2.40 Hz, 1 H), 6.94 (d, J=1.01 Hz, 1 H), 6.81 (d, J=3.79 Hz, 1 H), 4.45 (s, 2 H), 3.42 (t, J=6.95 Hz, 2 H), 2.29-2.34 (m, 3 H), 2.00 (t, J=7.58 Hz, 2 H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17]([N:20]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:40])[CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([O:29]COC)[CH2:25][CH2:24]3)(=[O:19])=[O:18])[CH:8]=2)[N:3]=1.C[OH:42].Cl.[OH-].[K+]>C(O)(=O)C>[Cl:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[CH2:33][N:20]([CH2:21][CH2:22][N:23]1[CH2:24][CH2:25][CH:26]([OH:29])[CH2:27][CH2:28]1)[S:17]([CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2](=[O:42])[CH:11]=[CH:10]2)(=[O:18])=[O:19]
Reactant: COCOC1CCN(CCN(Cc2ccccc2Cl)S(=O)(=O)CCCCOc2ccc3nc(Cl)ccc3c2)CC1
Reactant: CO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=c1ccc2cc(OCCCCS(=O)(=O)N(CCN3CCC(O)CC3)Cc3ccccc3Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 2.63 g of 2-chloro-6-[4-{N-(2-chlorobenzyl)-N-[2-(4-methoxymethoxy-1-piperidinyl)-ethyl]aminosulfonyl}butoxy]quinoline dissolved in 50 ml of acetic acid was refluxed for 3.5 hours. The solvent was removed by distillation under reduced pressure to obtain crude 6-[4-{N-(2-chlorobenzyl)-N-[2-(4-methoxymethoxy-1-piperidinyl)ethyl]aminosulfonyl}-butoxy]carbostyril. To the substance were added 10 ml of methanol and 10 ml of a 5% aqueous hydrochloric acid solution. The mixture was stirred at room temperature for 1 day and then made alkaline with an aqueous potassium hydroxide solution, followed by extraction with ethyl acetate. The extract was washed with water and dried with magnesium sulfate. The solvent was removed by distillation. The resulting residue was purified by silica gel column chromatography (eluant: 10% methanol/dichloromethane) to obtain 1.4 g of 6-[4-{N-(2-chlorobenzyl)-N-[2-(4-hydroxy-l-piperidinyl)ethyl]-aminosulfonyl}butoxy]carbostyril.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([O:12][CH2:13][CH2:14][C:15]2([CH2:31][CH3:32])[CH2:20][CH2:19][N:18]([C:21]3[S:22][C:23]4[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:24]=4[N:25]=3)[CH2:17][CH2:16]2)[CH:6]=1.[OH-].[Na+].O1CCCC1.Cl>CO>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:33])=[O:2])=[CH:6][C:7]=1[O:12][CH2:13][CH2:14][C:15]1([CH2:31][CH3:32])[CH2:20][CH2:19][N:18]([C:21]2[S:22][C:23]3[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:24]=3[N:25]=2)[CH2:17][CH2:16]1
Reactant: CCC1(CCOc2cc(CC(=O)OC)ccc2Cl)CCN(c2nc3ccc(Cl)cc3s2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC1(CCOc2cc(CC(=O)O)ccc2Cl)CCN(c2nc3ccc(Cl)cc3s2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.9 %

Procedure:
A mixture of [4-Chloro-3-[2-[1-(6-chlorobenzothiazole-2-yl)-4-ethyl piperidine-4-yl]ethoxy]phenyl]acetic acid methyl ester (152 mg), 2N aqueous sodium hydroxide (0.45 mL), tetrahydrofuran (1 mL) and methanol (1 mL) was stirred at room temperature for 2 hours. The reaction solution was neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (53 mg). Yield: 36%.
Reaction SMILES: N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:13]N1C(=O)CCC1=O.[CH3:21][C:22]1[C:31](=[O:32])[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:24]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:23]=1[C:39]1[O:40][CH:41]=[CH:42][N:43]=1>C(Cl)(Cl)(Cl)Cl.O>[Br:13][CH2:21][C:22]1[C:31](=[O:32])[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:24]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:23]=1[C:39]1[O:40][CH:41]=[CH:42][N:43]=1
Reactant: Cc1c(-c2ncco2)n(-c2ccccc2)c2ncccc2c1=O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: O=c1c(CBr)c(-c2ncco2)n(-c2ccccc2)c2ncccc12
Temperature: 90 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
A mixture of 2,2′-azobis(2-methylpropionitrile) (AIBN, 43.4 mg, 0.265 mmol), N-bromosuccinimide (345 mg, 1.94 mmol) and 3-methyl-2-oxazol-2-yl-1-phenyl-1H-[1,8]naphthyridin-4-one (535 mg, 1.76 mmol) in carbon tetrachloride (22.0 mL) was heated at 90° C. for 2 hr. The reaction was cooled to 25° C. and sat overnight. The reaction was diluted with water (30 mL) and extracted into methylene chloride (2×50 mL). The combined organics were then washed with a saturated aqueous solution of sodium bicarbonate (2×50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in methylene chloride and methanol, treated with silica gel, re-concentrated and dried in vacuo. Flash chromatography (40 g, 15%-40% ethyl acetate-hexanes) gave 3-bromomethyl-2-oxazol-2-yl-1-phenyl-1H-[1,8]naphthyridin-4-one (321.7 mg, 47.7%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH:9][N+:10]([O-])=O)[CH:5]=[CH:4][C:3]=1[C:13]([F:16])([F:15])[F:14].Cl[Si](C)(C)C.[Li+].[BH4-]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH2:10])[CH:5]=[CH:4][C:3]=1[C:13]([F:15])([F:16])[F:14]
Reactant: O=[N+]([O-])C=Cc1ccc(C(F)(F)F)c(F)c1
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCc1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.7 %

Procedure:
2-Fluoro-4-(2-nitro-vinyl)-1-trifluoromethyl-benzene (I-47a: 2.8 g, 11.914 mmol) was reacted with chlorotrimethylsilane (10.328 g, 95.07 mmol), LiBH4 (1.03 g 47.65 mmol) and THF (40 mL). The resulting mixture was stirred at room temperature for 72 hours to afford 2.46 g of the product (100% yield), LCMS: 99.49%, m/z=208.0 (M+1)