Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:19][C:7]=3[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si](C)(C)C)[C:9]=2[CH:10]=1.[CH2:30]([O:37][C:38]1[CH:43]=[CH:42][NH:41][C:40](=[O:44])[CH:39]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C([O-])([O-])=O.[K+].[K+]>[Cu]I.CS(C)=O>[CH2:30]([O:37][C:38]1[CH:43]=[CH:42][N:41]([C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:19][C:7]=4[N:8]([CH2:11][O:12][CH2:13][CH3:14])[C:9]=3[CH:10]=2)[C:40](=[O:44])[CH:39]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(c3ccc(Br)cc3n2COCC[Si](C)(C)C)C1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOCn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Temperature: 130 °C
Reaction time: 8 h
Yield: 14.2 %

Procedure:
To a solution of tert-butyl 7-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (0.66 g, 1.9 mmol) in DMF (8 mL) was added NaH (60% weight dispersion in mineral oil, 113 mg, 2.82 mmol) followed by SEMCl (0.50 mL, 2.8 mmol). The reaction was stirred at room temperature until complete. The reaction was quenched with H2O, and the aqueous mixture was extracted with CH2Cl2. The organic phase was washed with H2O and brine and dried over Na2SO4. After filtration and concentration, the residue was dried under vacuum to give tert-butyl 7-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate, which and used directly in the next step. To a mixture of tert-butyl 7-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (0.75 g, 1.6 mmol), 4-benzyloxypyridone (0.31 g, 1.6 mmol), 8-hydroxyquilinine (34 mg, 0.23 mmol), K2CO3 (0.26 g, 1.9 mmol) and CuI (45 mg, 0.23 mmol) was added DMSO (6 mL). The reaction mixture was degassed and back-filled with N2. The reaction was stirred at 130° C. overnight. The mixture was cooled and filtered through a layer of Celite. The filtrate was diluted with CH2Cl2, washed with H2O and 5% aqueous LiCl and dried over Na2SO4. The organic solution was filtered and concentrated, and the residue was purified by flash column chromatography (silica gel, 5% CH3OH in CH2Cl2) to give the title compound as a yellow oil (0.12 g, 13%): 1H NMR (500 MHz, CDCl3) δ 7.60 (d, J=8.5 Hz, 1H), 7.44-7.37 (m, 6H), 7.31 (d, J=7.5 Hz, 1H), 7.09 (m, 1H), 6.12 (s, 1H), 6.07 (d, J=6.5 Hz, 1H), 5.40 (s, 2H), 5.07 (s, 2H), 4.65 (m, 2H), 3.86 (m, 2H), 3.51 (t, J=8.0 Hz, 2H), 2.73 (m, 2H), 1.53 (s, 9H), 0.89 (t, J=8.0 Hz, 2H), −0.04 (s, 9H); ESI MS m/z 602 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]([NH:30][C:31]2[S:32][C:33]([CH3:40])=[C:34]([C:36]([F:39])([F:38])[F:37])[N:35]=2)([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[O:41]C.B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:27])([F:28])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)([NH:30][C:31]2[S:32][C:33]([CH3:40])=[C:34]([C:36]([F:38])([F:37])[F:39])[N:35]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][C:3]=1[OH:41]
Reactant: COc1cc([C@](Cc2ccccc2)(Nc2nc(C(F)(F)F)c(C)s2)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1sc(N[C@](Cc2ccccc2)(c2cc(F)cc(OC(F)(F)C(F)F)c2)c2ccc(F)c(O)c2)nc1C(F)(F)F
Temperature: -76 °C
Reaction time: 2 h
Yield: 71.7 %

Procedure:
To a solution of (S)-N-(1-(4-fluoro-3-methoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-5-methyl-4-(trifluoromethyl)thiazol-2-amine (28.5 mg, 0.046 mmol) in CH2Cl2 (1 mL) at −76° C. was added BBr3 (460 μL, 1 M in DCM, 0.46 mmol). The reaction mixture was stirred at −76° C. for 2 h and quenched by the addition of MeOH. The reaction mixture was concentrated and the residue was purified by preparative HPLC Phenomenex Luna AXIA S5 30×100 mm Ballistic column 50-100% MeOH (90% in water, 0.1% TFA) gradient over 10 min with flow rate 40 mL/min and UV detection at 220 nm. (S)-2-fluoro-5-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(5-methyl-4-(trifluoromethyl)thiazol-2-ylamino)-2-phenylethyl)phenol eluted at a retention time of 11.09 min and was isolated as a colorless gum (20 mg, 72% yield). LCMS: RT=4.12 min [M+H] 607.2 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm). NMR: 400 MHz 1H (CDCl3) 7.14 ppm, 3H, m; 6.95 ppm, 6H, m; 6.65 ppm, 2H, m; 6.07 ppm, 1H, s; 5.88 ppm, 1H, m; 3.69 ppm, 2H, d, J=1.26 Hz; 3.49 ppm, 1H, s; 2.29 ppm, 3H, q, J=2.19 Hz.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][C:24]([OH:26])=O)[CH:21]=2)[NH:16][CH:15]=1.C(OC(Cl)=O)C(C)C.[CH:35]1([NH2:41])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.Cl>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH:35]1([NH:41][C:24](=[O:26])[CH2:23][C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[CH2:13][CH2:12][N:3]2[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: O=C(O)Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Reactant: NC1CCCCC1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 3-[2-(1,3-dioxo-2H-isoindol-2-yl)ethyl]-1H-indole-5-acetic acid (0.2 g) and triethylamine (0.061 g) in chloroform (10 ml) was treated with isobutylchloroformate (0.08 g) at -5°, resulting red solution stirred at the same temperature for 20 h and cyclohexylamine was added to the resulting anhydride (0.06 g). Reaction was allowed to warm up to ambient temperature and stirred for 1 h then the mixture was poured into dilute hydrochloric acid (2N, 20 ml) extracted with chloroform (3×10 ml), dried (MgSO4), solvent removed and residual oil purified by chromatography (silica Merck, 7734; 10 g; 1% methanol in dichloromethane as eluent). Product was obtained as an oil which on treatment with ethyl acetate/ether gave the title compound as a solid (0.09 g) m.p. 175°-6°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[N:23]=[C:24]=[O:25].Cl>C(Cl)Cl>[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[NH:23][C:24](=[O:25])[N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: CCCCCCCNCCCCCO
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCN(CCCCCO)C(=O)Nc1ccc(F)cc1F
Reaction time: 1 h
Yield: 96.9 %

Procedure:
Part C. To a solution of N-(5-hydroxypentyl)-N-heptylamine (11.65 g, 0.0578 mol) in methylene chloride (75 mL) under a nitrogen atmosphere cooled to 0°, 2,4-difluorophenylisocyanate (8.97 g, 0. 0578 mol) was added slowly. The reaction mixture was stirred for 1 hour, poured into 1 N aqueous HCl (200 mL) and extracted with ethyl acetate (300 mL). The combined organic extracts were washed with water and brine, then dried over magnesium sulfate and was concentrated to give N'-{2,4-difluorophenyl)-N-heptyl-N-5-hydroxypentylurea as a pale yellow oil (20.0 g, 0.056 mol). 1H NMR (CDCl3) δ8.03 (m, 1H), 6.88-6.59 (m, 2H), 6.45 (bs, 1H), 3.68 (t, 2H, J=8.4 Hz), 3.33 (m, 4H), 1.81-1.22 (m, 16H), 0.91 (t,3H, J=6.7 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH:14]([OH:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:17](OCC)(OCC)OCC>C(O)=O>[OH:16][CH:14]([CH3:15])[CH2:13][N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[CH:17]1
Reactant: CC(O)CNc1c(N)cnc2ccccc12
Reactant: CCOC(OCC)OCC
Solvent: O=CO
Product: CC(O)Cn1cnc2cnc3ccccc3c21
Temperature: 150 °C

Procedure:
A mixture of 32.9 g of 3-amino-4-(2-hydroxypropylamino)quinoline in 100 ml of triethyl orthoformate and 10 drops of formic acid was heated at 150° C. for two hours. The mixture was evaporated under vacuum, then 200 ml of water was added and the pH was adjusted to pH 2 to 3 with concentrated hydrochloric acid. The solution was basified with ammonium hydroxide, then with 50 percent sodium hydroxide solution. An oily product eventually solidified and was separated by filtration. Recrystallization from a mixture of hexane and dichloromethane gave an off-white solid 1-(2-hydroxypropyl)-1H-imidazo[4,5-c]quinoline, m.p. 171° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[CH:23]([C:25]1[NH:29][C:28]([CH3:30])=[C:27]([CH2:31][C:32]([NH:34][CH2:35][CH:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)=[O:33])[C:26]=1[CH3:43])=O.N1CCCCC1>>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:25]1[NH:29][C:28]([CH3:30])=[C:27]([CH2:31][C:32]([NH:34][CH2:35][CH:36]2[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH2:41]2)=[O:33])[C:26]=1[CH3:43])(=[O:12])=[O:11]
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CC(=O)NCC1CCN(C)CC1
Solvent: C1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)NCC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 5-(2,6-Dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one (400 mg, 1.12 mmol), 2-(5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)-N-(1-methyl-piperidin-4-ylmethyl)-acetamide (295 mg, 1.2 q.) and piperidine (1.5 eq.) was stirred at rt for 96 hours. The reaction was concentrated and purified on a silica gel column to give the titled compound as a brown solid.
Reaction SMILES: [CH:1]1[CH:8]=[CH:7][C:5](=[O:6])[C:4]([OH:9])=[CH:3][CH:2]=1.[Co:10](Cl)Cl.C([O-])(=O)C.[Na+]>CO.O>[CH:1]1[CH:8]=[CH:7][C:5](=[O:6])[C:4]([OH:9])=[CH:3][CH:2]=1.[Co:10]
Reactant: Cl[Co]Cl
Agent: CC(=O)[O-]
Agent: O=c1cccccc1O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: [Co]

Procedure:
To a solution of tropolone (244 mg) in methanol is added a solution of cobalt (II) chloride (129 mg) in water and then sodium acetate (164 mg). The precipitate is recovered by filtration and recrystallized from ethanol-ethyl acetate to give 206 mg of tropolone cobalt complex as brown powder.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:11](=[O:20])[NH:12][C:13]4[N:14]([N:16]=[C:17]([CH3:19])[CH:18]=4)[C:15]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2].[Na].Cl[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:11](=[O:20])[N:12]([CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[C:13]4[N:14]([N:16]=[C:17]([CH3:19])[CH:18]=4)[C:15]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c1ncc1c(=O)[nH]c3cc(C)nn3c12
Reactant: ClCCN1CCOCC1
Agent: [Na]
Product: CCn1ncc2c1ncc1c(=O)n(CCN3CCOCC3)c3cc(C)nn3c12
Reaction time: 24 h

Procedure:
2.7 g. of 8-ethyl-2-methyl-4H-pyrazolo[1,5-a]pyrazolo-[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one (0.01 mol.) and 0.3 g. of sodium are refluxed for 1 hour in 30 ml. of diethylene glycoldimethylether with stirring. The temperature is lowered to 90° and 2 g. of 1-chloro-2-morpholinoethane are added and stirring is continued for 24 hours. The inorganic precipitate is filtered off, the solvent removed in vacuo and the crystalline product, 8-ethyl-2-methyl-4-(2-morpholino)ethyl-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido-[3,4-e]pyrimidin-5(8H)-one is recrystallized from ethyl acetate, yield 3.1 g. (81%); m.p. 140°-141°.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([OH:14])=O.[C:15]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][C:27]=1[NH2:28])[NH:24][CH:23]=[CH:22]2)([CH3:18])([CH3:17])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[C:15]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][C:27]=1[NH:28][C:12]([C:3]1[C:2](=[O:1])[C:11]3[C:6](=[CH:7][N:8]=[CH:9][CH:10]=3)[NH:5][CH:4]=1)=[O:14])[NH:24][CH:23]=[CH:22]2)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)c1cc2cc[nH]c2cc1N
Reactant: O=C(O)c1c[nH]c2cnccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc2cc[nH]c2cc1NC(=O)c1c[nH]c2cnccc2c1=O
Temperature: 80 °C

Procedure:
To 4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylic acid (48 mg, 0.25 mmol), 5-tert-butyl-1H-indol-6-amine (48 mg, 0.25 mmol) in DMF (1 mL) was added HATU (106 mg, 0.28 mmol), followed by triethylamine (106 μL, 0.76 mmol) and the reaction mixture was heated at 80° C. for 16 h. The reaction mixture was then purified by reverse phase HPLC 10-99% ACN in water to give N-(5-tert-butyl-1H-indol-6-yl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxamide. MS m/z: 361.5 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH:15]=O)[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:17]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][N:27]3[CH2:28][CH2:29][N:24]([CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:25][CH2:26]3)[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=CCCc1cc(-c2ccc(Cl)cc2)no1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Clc1ccc(-c2cc(CCCN3CCN(Cc4ccccc4)CC3)on2)cc1
Yield: 61.2 %

Procedure:
About 2 min after dissolving 3-[3-(4-chlorophenyl)isoxazol-5-yl]propanal (10 mg, 0.04 mmol) and 1-benylpiperazine (7.3, 0.04 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (27 mg, 0.13 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 2 hr and followed the same processes as in Example 1 to obtain 9.7 mg (58.3%) of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:19][CH2:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31].O>CN(C)C=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]2[CH2:19][CH2:20][N:21]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2ccc(F)cc2[nH]1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2ccc(F)cc2n1CCN1C(=O)c2ccccc2C1=O
Reaction time: 0.5 h

Procedure:
A 1.0 g portion of ethyl 6-fluoro-2-indolecarboxylate was dissolved in 50 ml of dimethylformamide, mixed under ice-cooling with a suspension consisting of 0.3 g of 60% sodium hydride and 10 ml of dimethylformamide, stirred at the same temperature for 30 minutes, further mixed with 5.0 g of N-(2-bromoethyl)phthalimide and then stirred for 24 hours while gradually returning to room temperature. After terminating the reaction by adding water, this was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with anhydrous sodium sulfate, and then the solvent was evaporated. The thus obtained residue was applied to a silica gel column chromatography and developed with a hexane-ethyl acetate (9:1) mixed solvent, thereby obtaining 0.74 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:4][C:3]=1[N:14]1[C:18]([CH3:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[N:15]1.[Cl:24]Cl>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][S:10]([CH3:13])(=[O:11])=[O:12])=[CH:4][C:3]=1[N:14]1[C:18]([CH3:19])=[C:17]([Cl:24])[C:16]([C:20]([F:21])([F:22])[F:23])=[N:15]1
Reactant: ClCl
Reactant: Cc1cc(C(F)(F)F)nn1-c1cc(OS(C)(=O)=O)c(Cl)cc1F
Solvent: ClC(Cl)Cl
Product: Cc1c(Cl)c(C(F)(F)F)nn1-c1cc(OS(C)(=O)=O)c(Cl)cc1F
Yield: 98.7 %

Procedure:
Into a solution of 1-(2-fluoro-4-chloro-5-methylsulfonyloxyphenyl)-3-trifluoromethyl-5-methylpyrazole (37.3 g) in chloroform (200 ml) was introduced chlorine gas (7.1 g) at 60° C. for 20 minutes. Removal of the solvent from the reaction solution by distillation in vacuo gave the titled compound (40.2 g) as a pale yellow oil which soon crystallized on standing at room temperature. Recrystallization from a mixture of n-hexane/benzene yielded a white crystalline solid. m.p. 72°-74.5° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.Cl[C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][NH:16]2)=[C:12]([N:19]2[C:23]3[CH:24]=[C:25]([CH3:29])[C:26]([CH3:28])=[CH:27][C:22]=3[N:21]=[CH:20]2)[N:11]=1>>[CH3:28][C:26]1[C:25]([CH3:29])=[CH:24][C:23]2[N:19]([C:12]3[N:11]=[C:10]([NH:1][C@H:2]4[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]4)[N:18]=[C:17]4[C:13]=3[N:14]=[CH:15][NH:16]4)[CH:20]=[N:21][C:22]=2[CH:27]=1
Reactant: Cc1cc2ncn(-c3nc(Cl)nc4[nH]cnc34)c2cc1C
Reactant: N[C@H]1CC[C@H](N)CC1
Product: Cc1cc2ncn(-c3nc(N[C@H]4CC[C@H](N)CC4)nc4[nH]cnc34)c2cc1C
Temperature: 140 °C

Procedure:
570 mg of trans-1,4-diaminocyclohexane are brought to its melting temperature (70° C.), 149 mg of product obtained in stage 1 above are added in a single step, and the mixture is then heated at 140° C. for approximately 18 hours.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C:13]1([CH3:23])[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=O)[C:14]1([CH3:22])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4].Cl.[F:29][C:30]1([F:34])[CH2:33][NH:32][CH2:31]1>>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:25])([CH3:26])[CH3:27])[S:8]/[C:9]/1=[N:10]\[C:11]([C:13]1([CH3:23])[CH2:17][CH2:16][CH:15]([C:18]([N:32]2[CH2:33][C:30]([F:34])([F:29])[CH2:31]2)=[O:20])[C:14]1([CH3:21])[CH3:22])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: FC1(F)CNC1
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1(C)CCC(C(=O)O)C1(C)C
Agent: Cl
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1(C)CCC(C(=O)N2CC(F)(F)C2)C1(C)C

Procedure:
The product from Example 96 and 3,3-difluoroazetidine hydrochloride (Oakwood)) were processed using the method described in Example 99 to afford the title compound. 1H NMR (DMSO-d6) δ 0.51 (s, 3H), 0.90 (t, J=7.3 Hz, 3H), 1.22 (s, 3H), 1.25 (s, 3H), 1.26-1.36 (m, 2H), 1.39-1.48 (m, 1H), 1.57 (s, 9H), 1.57-1.78 (m, 3H), 1.93-2.07 (m, 1H), 2.62-2.67 (m, 2H), 2.72-2.83 (m, 1H), 2.88-2.94 (m, 1H), 4.14-4.37 (m, 2H), 4.41-4.52 (m, 1H), 4.73-4.86 (m, 1H), 8.50 (s, 1H). MS (ESI+) m/z 470 (M+H)+. Anal. calcd. for C24H37F2N3O2S: C, 61.38; H, 7.94; N, 8.95. Found: C, 61.35; H, 7.84; N, 8.96.
Reaction SMILES: N1C2C(=CC=CC=2)C(C2CCC(=O)CC2)=C1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([CH:31]2[CH2:40][CH2:39][C:34]3(OCC[O:35]3)[CH2:33][CH2:32]2)[CH2:27][CH2:26]1>>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([CH:31]2[CH2:40][CH2:39][C:34](=[O:35])[CH2:33][CH2:32]2)[CH2:27][CH2:26]1
Reactant: COc1ccccc1N1CCN(C2CCC3(CC2)OCCO3)CC1
Agent: O=C1CCC(c2c[nH]c3ccccc23)CC1
Product: COc1ccccc1N1CCN(C2CCC(=O)CC2)CC1
Yield: 92.5 %

Procedure:
This compound was prepared in the manner described above for intermediate 3a by replacing 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-1H-indole with 1-(2-methoxy-phenyl)-4-(1,4-dioxa-spiro[4,5]dec-8-yl)-piperazine (5.0 g, 15 mmol) to afford 4.0 g (93%) of the title compound.
Reaction SMILES: [C:1]([C@:5]1([CH3:34])[C@@H:18]2[C@@:9]3([CH2:20][CH2:19][C@:16]4([CH2:17]2)[C@@:11]25[C:27]6[C:22](=[CH:23][CH:24]=[C:25]([OH:29])[C:26]=6[O:28][C@@H:10]32)[CH2:21][C@H:15]4[N:14]([CH2:30][CH:31]2[CH2:33][CH2:32]2)[CH2:13][CH2:12]5)[O:8][CH2:7][O:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:35](S(CCC)=O)[CH2:36]C>>[C:1]([C@:5]1([CH3:34])[C@@H:18]2[C@@:9]3([CH2:20][CH2:19][C@:16]4([CH2:17]2)[C@@:11]25[C:27]6[C:22](=[CH:23][CH:24]=[C:25]([OH:29])[C:26]=6[O:28][C@@H:10]32)[CH2:21][C@H:15]4[N:14]([CH2:30][CH:31]2[CH2:32][CH2:33]2)[CH2:13][CH2:12]5)[O:8][CH:7]([CH2:35][CH3:36])[O:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCS(=O)CCC
Reactant: CC(C)(C)[C@@]1(C)OCO[C@]23CC[C@@]4(C[C@@H]21)[C@H]1Cc2ccc(O)c5c2[C@@]4(CCN1CC1CC1)[C@H]3O5
Product: CCC1O[C@]23CC[C@@]4(C[C@@H]2[C@@](C)(C(C)(C)C)O1)[C@H]1Cc2ccc(O)c5c2[C@@]4(CCN1CC1CC1)[C@H]3O5

Procedure:
The title compound 4 was prepared similar to the procedure described in Example 1 for compound 3 using dipropyl sulfoxide instead of DMSO. After column chromatography, 117 mg (53.7% yield, >99.9 purity) of compound 4 was isolated as an off-white solid as a mixture of two epimers in a 96.1:3.9 ratio.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([F:20])=[CH:16][C:17]=3[F:19])[N:12]=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:10]=2[CH3:27])[CH:5]=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH2:37][CH2:38][O:39][CH2:40][CH:41]=2)O1.C1(P(C2CCCCC2)C2(OC)CC=CC(OC)=C2C2C=CC=CC=2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:39]1[CH2:38][CH:37]=[C:36]([C:2]2[CH:3]=[C:4]([NH:8][C:9]3[C:18]4[C:13](=[CH:14][C:15]([F:20])=[CH:16][C:17]=4[F:19])[N:12]=[C:11]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[C:10]=3[CH3:27])[CH:5]=[N:6][CH:7]=2)[CH2:41][CH2:40]1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cncc(Br)c1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COC1=C(c2ccccc2)C(OC)(P(C2CCCCC2)C2CCCCC2)CC=C1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cncc(C2=CCOCC2)c1
Temperature: 90 °C
Reaction time: 21.5 h

Procedure:
A mixture of N-(5-bromo-3-pyridinyl)-5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine (38.0 mg, 0.089 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (29.1 mg, 0.139 mmol), 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (S-Phos) (7.7 mg, 0.019 mmol), palladium(II) acetate (6.9 mg, 10.24 μmol), and potassium phosphate tribasic (60.4 mg, 0.29 mmol) in DMF (1 mL) and water (0.05 mL) was degassed by nitrogen. The mixture was heated to 90° C. After 21.5 h, the reaction was cooled to rt, then treated with water. After extracting twice with EtOAc, the organic layers were combined and dried over anhydrous magnesium sulfate. After filtration and concentration the residue was purified on basic alumina (0-35% EtOAc in hexanes) to afford an impure yellow residue. The light yellow film was further purified by HPLC (10-60% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution.) The desired fractions were concentrated then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution and once with brine, the solvent was removed under reduced pressure to yield a white solid as N-(5-(3,6-dihydro-2H-pyran-4-yl)-3-pyridinyl)-5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine. 1H NMR (400 MHz, CDCl3) δ ppm 8.76 (1H, m), 8.31 (1H, d, J=1.8 Hz), 8.18 (1H, d, J=2.5 Hz), 7.94 (2H, m), 7.69 (1H, m), 7.38 (1H, dddd, J=7.4, 4.9, 1.3, 0.7 Hz), 7.12 (3H, m), 6.25 (1H, m), 4.33 (2H, q, J=2.7 Hz), 3.94 (2H, t, J=5.5 Hz), 2.51 (2H, td, J=5.0, 2.2 Hz), 2.17 (3H, s). Mass Spectrum (pos.) m/e: 431.1 (M+1).
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8])([CH3:3])[CH3:2].BrBr.[O-:15]S([O-])=O.[Na+].[Na+]>ClCCl>[CH:1]([S:4]([C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8])=[O:15])([CH3:3])[CH3:2]
Reactant: O=S([O-])[O-]
Reactant: CC(C)Sc1ccccc1C=O
Agent: BrBr
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)S(=O)c1ccccc1C=O
Reaction time: 0.33 h

Procedure:
A solution of 2-(isopropylthio)benzaldehyde (0.33 g, 1.83 mmol) in dichloromethane (10 ml) was admixed with aqueous KHCO3 solution (1.18 g in 10 ml of H2O). With vigorous stirring, a solution of bromine (0.310 g, 1.93 mmol) in dichloromethane (1.5 ml) was added dropwise. After continuing to stir for 20 min, a spatula-tip of Na2SO3 was added, and the organic phase was removed, washed with saturated NaCl solution, dried over MgSO4 and filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (3:1 to 1:1 hexane:ethyl acetate). The product precipitated out as a yellowish oil. Yield 0.304 g (85%).