Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6].[CH:14]1[C:19]([CH2:20]O)=[CH:18][CH:17]=[C:16]([Cl:22])[CH:15]=1.C(P(CCCC)CCCC)CCC>O1CCCC1>[Cl:22][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][O:1][C:2]2[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=2)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6])=[CH:14][CH:15]=1
Reactant: CON(C)C(=O)c1cccc(O)c1
Reactant: OCc1ccc(Cl)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CON(C)C(=O)c1cccc(OCc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
1.81 g (10.0 mmol) B5, 1.57 g (11.0 mmol) 4-chlorobenzylic alcohol and 3.03 g (15.0 mmol) tributylphosphine were dissolved in 100 ml tetrahydrofurane and 3.78 g (15.0 mmol) azodicarbonylpiperidine was added at 10° C. The mixture was stirred at room temperature overnight. After removal of the precipitate, the mother liquor was evaporated to dryness and the residue was taken up with ethyl acetate. After filtration and washing with aqueous sodium hydrogen carbonate, 2 N HCl and water, the organic phase was dried over sodium sulfate end the solvent was removed in vacuo. Chromatography of the residue on SiGel (n-heptane/ethyl acetate 2:1) yielded 2.8 g (90%) B8.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][S:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[S:29]([CH3:32])(=[O:31])=[O:30])(=[O:22])=[O:21])[CH:17]=3)[NH:12][N:11]=2)=[CH:4][CH:3]=1.[H][H]>[Pd].CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][S:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[S:29]([CH3:32])(=[O:31])=[O:30])(=[O:22])=[O:21])[CH:17]=3)[NH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(/C=C/c3ccc(F)cc3)c2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(CCc3ccc(F)cc3)c2c1
Yield: 73 %

Procedure:
N-{3-[2-(4-Fluorophenyl)ethyl]-1H-indazol-5-yl}-2-methylsulfonylbenzenesulfonamide can be obtained in the following way: a mixture of 300 mg of N-{3-[(E)-2-(4-fluorophenyl)vinyl]-1H-indazol-5-yl}-2-methylsulfonylbenzenesulfonamide, of 30 mg of 10% palladium-on-charcoal and of 8 ml of dimethylformamide is autoclaved under a pressure of 10 bar of hydrogen and the mixture is stirred at a temperature in the region of 20° C. for 1 hour until complete absorption of hydrogen. The medium is then filtered through a bed of Celite® 535, this is washed with dimethylformamide and the filtrate is concentrated to dryness under reduced pressure. The solid residue is taken up with dichloromethane and the insoluble material is isolated by filtration, washed with dichloromethane and then dried under reduced pressure. 220 mg of N-{3-[2-(4-fluorophenyl)ethyl]-1H-indazol-5-yl}-2-methylsulfonylbenzenesulfonamide is thus obtained in the form of an off-white solid melting at 234° C. (analysis C22H20FN3O4S2 % calculated C, 55.81; H, 4.26; F, 4.01; N, 8.87; O, 13.51; S, 13.54. % found C, 55.80; H, 4.45; F, 3.85; N, 8.97; S, 12.80).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]1.CN1CCOCC1>C(#N)C.C([O-])(O)=O.[Na+]>[N:12]1([C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CN1CCOCC1
Product: COC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 62 %

Procedure:
Benzyl chloroformate (11.0 mL, 0.0768 mol) was added into a solution of methyl piperidine-4-carboxylate (10.0 g, 0.0698 mol) and 4-methylmorpholine (15.4 mL, 0.140 mol) in acetonitrile (20.0 mL). After 30 min, the mixture was diluted with NaHCO3 (7.5%), extracted with ethyl acetate (AcOEt) (3×30 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated to afford 1-benzyl 4-methyl piperidine-1,4-dicarboxylate (12 gram) which was directly used in next step without further purification.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])#[N:4].Br[CH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1.O>CN(C=O)C>[C:3]([CH2:5][CH2:6][CH2:7][CH2:8][C:9]([CH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])#[N:4]
Reactant: C=CCOC(=O)C(CCCCC#N)C(=O)OCC=C
Reactant: COC(=O)c1ccc(CCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)C(CCCCC#N)(CCc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
5.62 g (140 mmol; 60% pure) of sodium hydride are added in portions to a solution of 48.64 g (127.73 mmol) of diallyl 2-(4-cyanobutyl)malonate in 160 ml of dry DMF at 0° C. The reaction solution is then allowed to reach room temperature and is stirred for 90 min. The reaction solution is then cooled to 0° C. again and, after addition of 45.72 g (153.3 mmol) of methyl 4-(2-bromoethyl)benzoate in 80 ml of dry DMF, stirred at this temperature for 45 min. The mixture is then stirred at room temperature overnight. The reaction mixture is mixed with water and extracted with ethyl acetate. After phase separation, the aqueous phase is extracted three more times with 200 ml of ethyl acetate each time. After combining the combined organic phases, the mixture is washed with saturated sodium chloride solution and dried over sodium sulfate, and then the solvent is stripped off in vacuo. The resulting crude product is purified by silica gel chromatography (mobile phase: cyclohexane/ethyl acetate 10:1→100% ethyl acetate). 18.53 g (43.3 mmol, 34% of theory) of a colorless liquid are obtained.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([O:17]C)[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:19])[CH:2]=1.B(Br)(Br)Br.C(Cl)Cl>>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:19])[CH:2]=1
Reactant: COc1cccc2c1cc(C)n2Cc1cccc(-c2ccccc2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc2c(O)cccc2n1Cc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.5 %

Procedure:
A solution of 125 mg (3.8 mmol) of 1-((1,1′-biphenyl)-3-ylmethyl)-2-methyl-4-methoxy-1H-indole is O-demethylated by treating it with 15 mL of 1M BBr3/CH2Cl2. The reaction mixture is stirred at room temperature for 5 hours and concentrated at reduced pressure. The crude product is chromatographed on silica gel and is eluted with 20% EtOAc/hexane to give 1030 mg (87% yield) of 1-((1,1′-biphenyl)-3-ylmethyl)-2-methyl-4-hydroxy-1H-indole.
Reaction SMILES: [N+:1]([C:4]1[C:13]([O:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])([O-])=O.C(OCC)(=O)C>CO.[Ni]>[NH2:1][C:4]1[C:13]([O:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(OC2CCOCC2)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(OC2CCOCC2)c1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.3 %

Procedure:
A mixture of methyl 2-nitro-3-(tetrahydro-2H-pyran-4-yloxy)benzoate (1.3 g, 4.8 mmol) and Raney Ni (0.5 g) in MeOH (30 mL) was stirred under 1 atm of H2 at room temperature for 24 h. TLC (petroleum ether:ethyl acetate=1:1) showed the reaction was complete. The mixture was filtered, the filtrate was concentrated in vacuo. The residue was purified by chromatography (petroleum ether:ethyl acetate=20:1) to give the title compound (0.8 g, 72%) as a colorless oil.
Reaction SMILES: [C:1]1([Li])[CH:16]=[CH:15][CH:14]=[C:13]2[C:2]=1[CH:3]=[C:4]1[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[C:5]12.[Cl-:18].[Cl-].[Cl-].[CH:21]1([Zr+3:26])[CH:25]=[CH:24][CH:23]=[CH:22]1>C1(C)C=CC=CC=1.C(OCC)C>[Cl-:18].[Cl-:18].[C:1]1([Zr+2:26][CH:21]2[CH:25]=[CH:24][CH:23]=[CH:22]2)[CH:16]=[CH:15][CH:14]=[C:13]2[C:2]=1[CH:3]=[C:4]1[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[C:5]12
Reactant: [Li]c1cccc2c1C=C1C2=Nc2ccccc21
Reactant: [Zr+3]C1C=CC=C1
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C1=CC([Zr+2]c2cccc3c2C=C2C3=Nc3ccccc32)C=C1
Reaction time: 8 h

Procedure:
A sample of the indeno[1,2-b]indolyl lithium salt produced above (10 g, 42 mmol) is dissolved in toluene (95 mL) to produce an orange slurry. Diethyl ether (35 mL) is added slowly to give an orange solution. This solution is added over 15 min. at room temperature with stirring to a slurry of cyclopentadienylzirconium trichloride (11 g, 42 mmol) in toluene (190 mL) and diethyl ether (190 mL). The mixture turns deep red and is kept at room temperature overnight. The slurry is filtered to recover a red solid, which is washed with toluene (200 mL) and dried under vacuum to give the catalyst (16.5 g, 78%).
Reaction SMILES: [F:1][C:2]1[C:37]([CH3:38])=[CH:36][C:5]([CH2:6][C@H:7]([CH2:23][CH2:24][CH2:25][CH2:26][NH:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C:8]([N:10]2[C@H](CC3C=CC=CC=3)COC2=O)=[O:9])=[CH:4][C:3]=1[CH3:39].[C-]#N.[K+].Cl.C1C[O:47]CC1.CO>>[F:1][C:2]1[C:37]([CH3:38])=[CH:36][C:5]([CH2:6][C@H:7]([CH2:23][CH2:24][CH2:25][CH2:26][NH:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C:8]([NH:10][OH:47])=[O:9])=[CH:4][C:3]=1[CH3:39]
Reactant: C1CCOC1
Reactant: Cc1cc(C[C@H](CCCCNCc2ccc(F)cc2)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc(C)c1F
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Product: Cc1cc(C[C@H](CCCCNCc2ccc(F)cc2)C(=O)NO)cc(C)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
To a solution of (R)-3-((S)-2-[4-fluoro-3,5-dimethylbenzyl)-6-(4-fluorobenzylamino)-hexanoyl]-4-benzyloxazolidin-2-one (0.030 g, 0.0561 mmol) in 2.5 mL of THF/MeOH/50% NH2OH—H2O (2:2:1), was added KCN (0.001 g, 0.015 mmol). After stirring at room temperature for overnight, the reaction mixture was acidified with concentrated HCl to pH=2 and filtered. The product was isolated by RP-HPLC eluting with 20-100% acetonitrile (0.025% TFA)/water (0.025% TFA) to give the title compound as an off-white solid (0.005 g, 23% yield). LC-MS: tR=4.8 min, m/z 391 (M+H)+, 1H NMR (300 MHz, CD3OD) δ 1.27-1.38 (m, 2H), 1.40-1.57 (m, 2H), 1.58-1.75 (m, 2H), 2.19 (s, 6H), 2.20-2.31 (m, 1H), 2.52-2.66 (m, 1H), 2.70-2.82 (m, 1H), 3.00 (t, J=7.91 Hz, 2H), 4.17 (s, 2H), 6.82 (d, J=6.74 Hz, 2H), 7.20 (t, J=8.64 Hz, 2H), 7.51 (dd, J=8.20, 5.27 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[C:4](Cl)[N:3]=1.[OH:20][C:21]1[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH:29]=[CH2:30])[CH:24]=[CH:25][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[C:4]([O:20][C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH:29]=[CH2:30])[CH:24]=[CH:25][CH:26]=2)[N:3]=1
Reactant: C[Si](C)(C)CCOCn1cnc2c(Cl)nc(Cl)nc21
Reactant: C=CC(=O)Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CC(=O)Nc1cccc(Oc2nc(Cl)nc3c2ncn3COCC[Si](C)(C)C)c1
Temperature: 60 °C
Yield: 84.4 %

Procedure:
To a solution of 2,6-dichloro-9-{[2-(trimethylsilyl)ethoxy]methyl}-9H-purine (1.78 g, 5.58 mmol) and N-(3-hydroxyphenyl)prop-2-enamide (1.00 g, 6.13 mmol) in DMF (28 mL) was added K2CO3 (2.34 g, 16.7 mmol). The reaction was heated to 60° C. for 30 min, at which point LCMS showed consumption of starting material. The mixture was cooled to rt and partitioned between water and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc twice more. The combined organics were washed with water (three times) and brine, dried over Mg2SO4, and filtered. The filtrate was concentrated, and the crude material was purified by flash chromatography on a Biotage 40M column; product was eluted with 0%-40% EtOAc/heptane to yield the title compound (2.10 g, 85% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.35 (s, 1H) 8.69 (s, 1H) 7.74 (t, J=2.02 Hz, 1H) 7.50-7.56 (m, 1H) 7.41-7.48 (m, 1H) 7.05 (ddd, J=7.96, 2.27, 0.88 Hz, 1H) 6.39-6.50 (m, 1H) 6.22-6.32 (m, 1H) 5.75-5.81 (m, 1H) 5.62 (s, 2H) 3.57-3.66 (m, 2H) 0.84-0.91 (m, 2H) −0.05 (s, 9H). m/z (APCI+) for C20H24ClN5O3Si 446.00 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Cl[C:12]([S:14]Cl)=[O:13]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:7][C:12](=[O:13])[S:14][N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)SCl
Reactant: NC(=O)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: O=c1oc(-c2ccc(Cl)cc2)ns1
Temperature: 80 °C

Procedure:
To a solution of 4-chlorobenzamide (0.25 g, 1.60 mmol) in toluene (10 ml) was added chlorocarbonylsulfenyl chloride (0.70 ml, 8.03 mmol). The resulting reaction mixture was refluxed at 80° C. for 3 h. After the completion of the reaction (TLC monitoring), the mixture was concentrated, added diethyl ether and washed twice with water, twice with 5% NaHCO3, again with water, and was dried (Na2SO4), concentrated under vacuum to give the product (crude yield 0.520 g) that was carried forward to the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6](=[O:20])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=4)[NH:12][CH:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:23][N:24]1[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]1.[ClH:37]>C(Cl)Cl.O1CCOCC1>[ClH:37].[ClH:37].[OH:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6](=[O:20])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=4)[NH:12][CH:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1
Reactant: Cc1ccc2[nH]cc(/C=C3\Oc4c(ccc(O)c4CN4CCN(C(=O)OC(C)(C)C)CC4)C3=O)c2c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccc2[nH]cc(/C=C3\Oc4c(ccc(O)c4CN4CCNCC4)C3=O)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
A solution of tert-butyl (Z)-4-({6-hydroxy-2-[(5-methyl-1H-indol-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.030 g, 0.061 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 2 hours. The mixture was azeotroped twice with toluene under reduced pressure, and then the residual solid was suspended in a mixed solvent of methylene chloride and diethyl ether and thereby washed to obtain (Z)-6-hydroxy-2-[(5-methyl-1H-indol-3-yl)methylene]-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one dihydrochloride (0.018 g, 64%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:15](Cl)(=[O:18])[CH2:16][CH3:17].Cl>C1(C)C=CC=CC=1>[C:15]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:18])[CH2:16][CH3:17]
Reactant: Nc1ccc(Br)cc1
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCC(=O)Nc1ccc(Br)cc1
Reaction time: 2 h
Yield: 89.2 %

Procedure:
A solution of 4-bromoaniline (9.0 g, 52.3 mmol) in PhMe (100 mL) and pyridine (8.5 mL, 110 mmol, 2.0 eq.) was cooled in an ice bath and slowly treated with propionyl chloride (5.5 mL, 63 mmol, 1.2 eq.). After 2 h, the reaction mixture was added to 0.1 M HCl and extracted into EtOAc. Concentration followed by recrystallization of the residue from EtOH/water gave N-propionyl-4-bromoaniline (10.64 g, 89%). [M−H]−=278.1 m/z.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][CH2:11][CH2:12]Cl)[CH:5]=[CH:6][C:7]=1[CH3:8].[OH:14][C:15]1([C:21]2[CH:22]=[N:23][C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH3:8])[O:9][CH2:10][CH2:11][CH2:12][N:18]1[CH2:19][CH2:20][C:15]([OH:14])([C:21]2[CH:22]=[N:23][C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:16][CH2:17]1
Reactant: OC1(c2cnc3ccccc3c2)CCNCC1
Reactant: Cc1ccc(OCCCCl)cc1C
Product: Cc1ccc(OCCCN2CCC(O)(c3cnc4ccccc4c3)CC2)cc1C
Yield: 26.5 %

Procedure:
Beginning with 0.218 gm (1.1 mMol) 3-chloropropyl 3,4-dimethylphenyl ether and 0.250 gm (1.1 mMol) 4-hydroxy-4-(quinolin-3-yl)piperidine, 0.114 gm (27%) of the title compound were recovered as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:15]=1[NH2:16].CCN(CC)CC>C1COCC1>[Cl:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([NH:16][C:15]2[C:14]([F:13])=[CH:20][CH:19]=[CH:18][C:17]=2[F:21])[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Reactant: Nc1c(F)cccc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1nc(Cl)c(C=O)c(Nc2c(F)cccc2F)n1
Temperature: 55 °C
Yield: 69.8 %

Procedure:
To a solution of 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde (10.0 g, 44.8 mmol) in THF (250 mL) was added 2,6-difluoroaniline (5.35 mL, 49.3 mmol, 1.1 eq) followed by Et3N (12.6 mL, 89.6 mmol, 2 eq). The reaction mixture was heated to 55° C. for about 22 h before concentrated. The slurry was re-dissolved in DCM (250 mL) and washed with H2O (2×100 mL), then concentrated and further washed with acetone (2×10 mL) to give 9.87 g (70%) of pure 4-chloro-6-[(2,6-difluorophenyl)amino]-2-(methylthio)-5-pyrimidinecarbaldehyde. LC-MS m/z 316 (M+H)+.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][C:22]2[C:25]([CH2:30]Cl)=[C:26]([Cl:29])[CH:27]=[CH:28][C:21]=2[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].O>CN(C=O)C>[CH2:1]([S:8][CH2:30][C:25]1[C:22]2[CH2:23][CH2:24][N:18]([C:16]([O:15][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:17])[CH2:19][CH2:20][C:21]=2[CH:28]=[CH:27][C:26]=1[Cl:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CCl)c2CC1
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSCc3ccccc3)c2CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 161.9 %

Procedure:
Dissolve benzylmercaptan (230 mg, 1.84 mmol) in anhydrous DMF (5 mL). Add sodium hydride (100 mg, 2.5 mmol, 60% dispersion in mineral oil) and stir the mixture for 10 min. Add then a solution of 3-tert-butoxycarbonyl-7-chloro-6-chloromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (550 mg, 1.67 mmol) in anhydrous DMF (1 mL). Stir under nitrogen at room temperature overnight. Pour reaction mixture into water (150 mL) and extract with DCM (3×50 mL). Wash the combined organic extracts with brine, dry over Na2SO4, filter and concentrate in vacuo to afford crude 6-benzylthiomethyl-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil (1.13 g) suitable for use without additional purification.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([C@@H:24]3[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:30][CH2:31][CH2:32][C:33](Cl)=[O:34]>C1COCC1.C(OCC)(=O)C>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([C@@H:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:33](=[O:34])[CH2:32][CH2:31][Cl:30])[CH2:25]3)[N:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)[C:22]=12
Reactant: O=C(Cl)CCCl
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2[C@@H]1CCCNC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2[C@@H]1CCCN(C(=O)CCCl)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
To a solution of (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (6) (0.40 g, 1.04 mmol) and TEA (0.29 mL, 2.08 mmol) in THF (15 mL) cooled to 0° C. was added 3-chloropropanoyl chloride (0.132 g, 2.08 mmol). After stirring 1 hr at 0° C., the reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (50 mL). The organic layer was dried (MgSO4), filtered and concentrated to collect 0.49 g of a white solid. The white solid was subjected to flash chromatography (5% MeOH/EtOAc) to provide 0.31 g (62%) of (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-3-chloropropan-1-one (9) as a white solid. 1H NMR (300 MHz, DMSO) δ 8.25 (s, 1H), 7.64 (d, 2H, J=8.5 Hz), 7.40 (m, 2H), 7.20-7.00 (m, 7H), 4.60 (m, 1H), 4.12-3.10 (m, 6H), 2.94-1.60 (m, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[NH:17][C:16](=O)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][NH2:32]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([NH:32][CH2:31][CH2:30][N:29]([CH3:33])[CH3:28])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)CCN
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(=O)[nH]c3cc(Cl)ccc23)CC1
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCNc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(Cl)cc2n1
Yield: 56.5 %

Procedure:
4-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-7-chloroquinol-2-one (145 mg, 0.4 mmol), sodium hydride (15 mg, 0.6 mmol), N-phenyl(trifluoromethylsulfon)imide (202 mg, 0.56 mmol), and N,N-dimethylethylenediamine (276 μL, 2.4 mmol) are treated according to method E yielding 98 mg of 4-[4-(tert-butoxycarbonyl)piperazin-1-yl]-7-chloro-2-[2-(dimethylamino)ethylamino]quinoline. 38 mg thereof are treated with TFA-CH2Cl2 1:1 (0.6 mL) for 1 h and concentrated. The residue is converted into the title product with 4-fluorophenyl isocyanate (16 μL) and triethylamine (120 μL).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[C:12]([CH:26]=[O:27])=[C:11]([I:28])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:29]([C:33]1[CH:34]=[C:35]([Mg]Br)[CH:36]=[CH:37][CH:38]=1)([CH3:32])([CH3:31])[CH3:30]>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)[C:12]([CH:26]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:38]=3)[OH:27])=[C:11]([I:28])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC1(C)Cc2nc(C3CCCC3)c(C=O)c(I)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reactant: CC(C)(C)c1cccc([Mg]Br)c1
Product: CC1(C)Cc2nc(C3CCCC3)c(C(O)c3cccc(C(C)(C)C)c3)c(I)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-2-cyclopentyl-4-iodo-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 3-tert.-butylphenylmagnesium bromide. The product is obtained as a diastereomic mixture, which is used directly in the next step.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:24][Si:25]([CH3:33])([CH3:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C=O>[C:12]([C:7]1[CH:8]=[C:9]([S:11][CH2:24][Si:25]([CH3:33])([CH3:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: C[Si](C)(CCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(SC[Si](C)(C)c2ccccc2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Mix 2,6-di-t-butyl-4-mercaptophenol (2.4 g, 10mmol), potassium carbonate (1.4 g, 10 mmol), chloromethyldimethylphenylsilane (1.9 g, 10 mmol) and dimethylformamide (50 mL) and stir overnight at room temperature under argon atmosphere. Dilute the mixture with ice-water and extract with ethyl ether. Wash the ethereal layer with water, then brine, filter through flourosil-Na2SO4, and evaporate to an orange oil (3.5 g). Purify the product by first distilling (bp 160°-170° C. @0.1 mm Hg), then subjecting to silica gel chromatography (CCl4 :CHCl3 /1:1) to obtain the title compound as a light yellow oil which slowly crystallizes to a whim waxy solid (2.3 g, 59%).