Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:12](=[O:15])[O:13][CH2:14][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.C([O-])(=O)C.[Na+]>[Pd].C(O)(=O)C>[CH2:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[CH:2][C:11]=2[C:12](=[O:15])[O:13]1
Reactant: O=C1OCc2c1c(Cl)nc1ccccc21
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1OCc2c1cnc1ccccc21
Reaction time: 2 h

Procedure:
A mixture of 4-Chloro-furo[3,4-c]quinolin-3(1H)-one (500 mg), 10% Palladium on carbon (100 mg) and sodium acetate (500 mg) in 20 mL of acetic acid was hydrogenated at atmospheric pressure for 2 h. After filtration through celite, the solvent was removed in vacuo, and the residue was taken up in methylene chloride. After filtration the solvent was removed in vacuo to afford Furo[3,4-c]quinolin-3(1H)-one as a solid.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17][CH3:18])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17]([CH3:18])=[O:31])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: CSc1nc2ccc(Cn3cnc4cc(F)ccc43)cc2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Cn3cnc4cc(F)ccc43)cc2s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a stirred solution of 6-((5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole (0.64 g, 1.9 mmol) from the previous step in DCM (20 mL) at 0° C. was added a solution of meta-chloroperbenzoic acid (0.472 g, 2.3 mmol) in DCM (3 mL). The mixture was stirred at 0° C. for 2 h. The solution was diluted with EtOAc (100 mL) and washed sequentially with saturated aq Na2S2O3, saturated aq NaHCO3, and brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 6-((5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (0.63 g, 94%) as a yellow solid, which was not purified further. 1H NMR (300 MHz, CDCl3) δ 8.02-8.05 (m, 2H), 7.78 (s, 1H), 7.51 (dd, J=9.6, 2.4 Hz, 1H), 7.38 (dd, J=8.4, 1.8 Hz, 1H), 7.20 (m, 1H), 7.00 (dt, J=9.0, 2.4 Hz, 1H), 5.52 (s, 2H), 3.07 (s, 3H); LCMS (ESI) m/z 346 (M+H)+.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:24]=[C:23]([C:25]([NH:27][C:28]3[C:29]([CH3:39])=[C:30]([CH:35]=[CH:36][C:37]=3[CH3:38])[C:31]([O:33][CH3:34])=[O:32])=[O:26])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:24]=[C:23]([C:25]([NH:27][C:28]3[C:29]([CH3:39])=[C:30]([CH:35]=[CH:36][C:37]=3[CH3:38])[C:31]([O:33][CH3:34])=[O:32])=[O:26])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH2:11][CH2:10]1
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCC(O[Si](C)(C)C(C)(C)C)CC3)nc3ccccc23)c1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCC(O)CC3)nc3ccccc23)c1C
Temperature: 25 °C
Reaction time: 14 h
Yield: 26.5 %

Procedure:
To a solution of methyl 3-(2-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)quinoline-4-carboxamido)-2,4-dimethylbenzoate (1.30 g, 0.00087 mol) in THF (2.0 ml) is added Bu4NF 1.0 M in THF (10.0 ml) at 0° C. The reaction mixture is gradually warmed to ambient temperature. After 14 hours, the reaction mixture is diluted with ice-water and extracted with ethyl acetate. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue is purified by flash chromatography (silica gel) with ethyl acetate in hexanes to afford the title compound as a yellow solid (0.10 g, 27%). Mass spectrum (m/z): 434.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=O)[CH2:6][CH2:5]2.[C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:15].CC(O)=O.C([O-])(=O)C.[NH4+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])/[C:7](=[C:16](\[C:14]#[N:15])/[C:17]([O:19][CH2:20][CH3:21])=[O:18])/[CH2:6][CH2:5]2
Reactant: COc1cc2c(cc1Cl)CCC2=O
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(C#N)=C1\CCc2cc(Cl)c(OC)cc21
Temperature: 120 °C
Reaction time: 12 h
Yield: 61.6 %

Procedure:
To the solution of 5-chloro-6-methoxy-2,3-dihydro-1H-inden-1-one (Prep15, 12 g, 61.2 mmol) in toluene (240 ml) was added ethyl cyanoacetate (8.3 g, 73.46 mmol), AcOH (48 ml, 0.8 mol) and ammonium acetate (12 g, 0.16 mol). The mixture was stirred for 12 hours at 120° C., checked by TLC, concentrated, filtered and washed with water and ethanol twice and purified by FC to afford 11 g of title compound (y=62%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[C:7]([CH3:21])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:20])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:19])[C:16]([OH:18])=O)=[O:5])[CH3:2].[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23]>>[CH2:1]([O:3][C:4]([CH:6]=[C:7]([CH3:21])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:20])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:19])[C:16]([N:24]([CH2:25][CH3:26])[CH2:22][CH3:23])=[O:18])=[O:5])[CH3:2]
Reactant: CCNCC
Reactant: CCOC(=O)C=C(C)CCC=C(C)CCC=C(C)C(=O)O
Product: CCOC(=O)C=C(C)CCC=C(C)CCC=C(C)C(=O)N(CC)CC

Procedure:
Starting materials: 11-ethoxycarbonyl-2,6,10-trimethyl-2,6,10-undecatrienoic acid and diethylamine.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][O-:13].[Na+].[Cl-].[NH4+]>CO>[CH3:12][O:13][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C)c([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
A solution of 2-chloro-4-methyl-5-nitropyridine (3.0 g, 17.3 mmol) in methanol (20 mL) was added a solution of sodium methoxide (28% in methanol, 10 mL) dropwise at 0° C. The mixture was warmed to room temperature and stirred for 16 hr. The mixture was neutralized by addition of aqueous ammonium chloride and concentrated in vacuo. The residue was dissolved in water and extracted with ethyl acetate. Organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound (2.84 g, 16.8 mmol, 98%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:24][C:25]2[CH:26]=[N:27][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][CH:30]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:14][CH:15]([CH2:18][C:19]([O:21]CC)=[O:20])[CH2:16][N:17]=1)=[CH:9]2)[CH3:2].O1CCCC1.CO.[OH-].[K+]>O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:24][C:25]2[CH:26]=[N:27][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][CH:30]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:14][CH:15]([CH2:18][C:19]([OH:21])=[O:20])[CH2:16][N:17]=1)=[CH:9]2)[CH3:2]
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OCC)c3[nH]2)S1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCOc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.5 %

Procedure:
To a mixture of ethyl [2-(7-ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetate (0.22 g), tetrahydrofuran (10 mL) and methanol (10 mL) was added a solution of potassium hydroxide (85%, 0.10 g) in water (5 mL). The mixture was stirred at room temperature for 15 h and then partitioned between ethyl acetate and aqueous citric acid solution. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated to give a light yellow amorphous solid, which was crystallized from ethyl acetate-hexane to give the title compound (186 mg, 90%) as light yellow crystals. MS 476 (MH+). mp 208-210° C.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([F:24])=[CH:6][C:7]3[C:17](=[O:18])[C:16]([C:19]([O:21]CC)=[O:20])=[CH:15][N:9]4[CH:10]([CH3:14])[CH2:11][O:12][C:13]=2[C:8]=34)[CH2:3][CH2:2]1.[OH-].[Na+].C(O)C.Cl>C(OCC)(=O)C.O.O1CCOCC1>[CH:1]1([C:4]2[C:5]([F:24])=[CH:6][C:7]3[C:17](=[O:18])[C:16]([C:19]([OH:21])=[O:20])=[CH:15][N:9]4[CH:10]([CH3:14])[CH2:11][O:12][C:13]=2[C:8]=34)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn2c3c(c(C4CC4)c(F)cc3c1=O)OCC2C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC1COc2c(C3CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.4 %

Procedure:
To 250 mg of ethyl 10-cyclopropyl-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylate were added 2.5 ml of a 1N aqueous sodium hydroxide solution, 2.5 ml of ethanol and 2.5 ml of dioxane in this order. The resulting mixture was stirred at room temperature for 1.5 hours. To the reaction mixture were added 10 ml of water and 20 ml of ethyl acetate in this order. The resulting mixture was adjusted to pH 3 with 2N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. Diethyl ether was added to the residue obtained and the resulting crystals were collected by filtration to obtain 200 mg (yield: 87.3%) of 10-cyclopropyl-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][O:6][C:5]2([CH:15]([Br:16])[CH2:14][CH2:13][C:12]3[N:11]([S:17]([C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:10]=[CH:9][C:8]2=3)[O:4]1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.N1C=CC=CC=1>ClCCl>[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33]([O:1][CH2:2][CH:3]2[CH2:7][O:6][C:5]3([CH:15]([Br:16])[CH2:14][CH2:13][C:12]4[N:11]([S:17]([C:20]5[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=5)(=[O:19])=[O:18])[CH:10]=[CH:9][C:8]3=4)[O:4]2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2CCC(Br)C32OCC(CO)O2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2COC3(O2)c2ccn(S(=O)(=O)c4ccc(C)cc4)c2CCC3Br)cc1
Reaction time: 10 h
Yield: 87 %

Procedure:
To a solution of 4'-hydroxymethyl-5-bromo-1-p-toluenesulfonyl-4,5,6,7-tetrahydroindole-4-spiro-[1,3]-dioxolane (100 parts) in dichloromethane (2000 parts) is added a solution of p-toluenesulfonyl chloride (1.1 molar equivalent) and pyridine (1.2 molar equivalents) in dichloromethane (500 parts), and the mixture is kept at room temperature for 10 hours. The mixture is evaporated, and the residue is dissolved in ethyl acetate, washed with water, dried and evaporated to give 4'-p-toluenesulfonyloxymethyl-5-bromo-1-p-toluenesulfonyl-4,5,6,7-tetrahydroindole-4-spiro-[1,3]dioxolane in 87% yield. The physical constants are given in Table I, No. 18.
Reaction SMILES: [C:1](=[O:40])([O:30]C1C=CC([N+]([O-])=O)=CC=1)[O:2][C@@H:3]1[CH2:19][C@@H:18]2[C@@:6]([CH3:29])([C@@H:7]3[C@@H:15]([CH2:16][CH2:17]2)[C@:14]2([OH:20])[C@@:10]([CH3:28])([C@@H:11]([C:21]4[CH:22]=[CH:23][C:24](=[O:27])[O:25][CH:26]=4)[CH2:12][CH2:13]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[N:41]1([CH2:46][CH2:47]O)[CH2:45][CH2:44][CH2:43][CH2:42]1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1](=[O:40])([O:30][CH2:47][CH2:46][N:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1)[O:2][C@@H:3]1[CH2:19][C@@H:18]2[C@@:6]([CH3:29])([C@@H:7]3[C@@H:15]([CH2:16][CH2:17]2)[C@:14]2([OH:20])[C@@:10]([CH3:28])([C@@H:11]([C:21]4[CH:22]=[CH:23][C:24](=[O:27])[O:25][CH:26]=4)[CH2:12][CH2:13]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1
Reactant: OCCN1CCCC1
Reactant: C[C@]12CC[C@H](OC(=O)Oc3ccc([N+](=O)[O-])cc3)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccc(=O)oc3)CC[C@]12O
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@]12CC[C@H](OC(=O)OCCN3CCCC3)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccc(=O)oc3)CC[C@]12O
Yield: 86.1 %

Procedure:
To a solution of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 4-nitrophenyl carbonate (24 mg, 0.044 mmol) in CH2Cl2 was added 2-(pyrrolidin-1-yl)ethanol (50.6 mg, 0.44 mmol, 10 eq), DIEA (22.7 mg, 0.176 mmol, 4 eq) and DMAP (19.7 mg, 0.176 mmol, 4 eq). The resultant mixture was stirred at 40° C. for 16 h and then purified via preparative TLC to afford (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-(pyrrolidin-1-yl)ethyl carbonate (20 mg, 87.0%) as a white solid. LRMS (M+H+) m/z 528.4. 1H NMR (CD3OD, 400 MHz) δ 8.01 (dd, J=10.0, 2.4 Hz, 1H), 7.44 (m, 1H), 6.29 (d, J=10.0 Hz, 1H), 5.00 (m, 1H), 4.35 (t, J=5.4 Hz, 2H), 3.12 (m, 2H), 2.96 (m, 4H), 2.55-2.60 (m, 1H), 1.08-2.15 (m, 25H), 0.99 (s, 3H), 0.73 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[N+:27]([C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=[O:34])([O-:29])=[O:28]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][CH:38]=[C:30]([N+:27]([O-:29])=[O:28])[CH:31]=3)[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Solvent: c1ccncc1
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2OC(=O)c2cccc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
1.2 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are dissolved in 10 ml of pyridine, and 0.66 g of 3-nitrobenzoyl chloride is added thereto. The mixture is stirred at room temperature for one hour. After the reaction, the mixture is poured into ice-water. The crystalline precipitates are collected by filtration and then recrystallized from a mixture of ethyl acetate and n-hexane. 1.26 g of (±)-cis-2-(4-methoxyphenyl)-3-(3-nitrobenzoyloxy)-5-[2-(dimethylamino)-ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained as colorless prisms. Yield: 75%.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([NH:20][C:21]3[C:26]([C:27]4[N:35]=[CH:34][N:33]=[C:32]5[C:28]=4[N:29]=[CH:30][N:31]5C4CCCCO4)=[CH:25][CH:24]=[CH:23][N:22]=3)[C:14]=2[F:42])(=[O:11])=[O:10])=[C:5]([F:43])[CH:4]=1>>[N:35]1[C:27]([C:26]2[C:21]([NH:20][C:15]3[C:14]([F:42])=[C:13]([NH:12][S:9]([C:6]4[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][C:5]=4[F:43])(=[O:11])=[O:10])[CH:18]=[CH:17][C:16]=3[F:19])=[N:22][CH:23]=[CH:24][CH:25]=2)=[C:28]2[C:32]([NH:31][CH:30]=[N:29]2)=[N:33][CH:34]=1
Reactant: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccc(Cl)cc1F
Agent: Cl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3[nH]cnc23)c1F)c1ccc(Cl)cc1F
Reaction time: 2 h
Yield: 88 %

Procedure:
1M aqueous hydrochloric acid solution was added into the 4-chloro-N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-2-fluorobenzenesulfonamide (20 mg, 0.032 mmol) prepared at Step 10 and stirred for 2 hours. After the reaction, the reactant was washed with an aqueous solution of sodium hydrogen carbonate and salt water. After extraction with ethylacetate, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 15 mg of the target compound, N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-4-chloro-2-fluorobenzenesulfonamide (percentage yield: 88%), was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[C:15](C)=[N:14][CH:13]=[N:12]1.[CH3:17]O>[Pd]>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[N:14][C:13]([CH3:17])=[N:12]1)[NH2:8]
Reactant: Cc1ncnn1-c1ccc([N+](=O)[O-])cc1F
Reactant: CO
Agent: [Pd]
Product: Cc1ncn(-c2ccc(N)cc2F)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 93 %

Procedure:
10% Palladium on carbon (2.50 g, 23.5 mmol) was added under an atmosphere of nitrogen to a chilled (ice-water bath) solution of 1-(2-fluoro-4-nitrophenyl)-5-methyl-1H-1,2,4-triazole (15.0 g, 67.5 mmol, from preparation A, step1) dissolved in methanol (400 mL). The flask was repeatedly evacuated and flushed with hydrogen gas (double balloon). The resulting mixture was allowed to warm to rt and left to stir for 72 h under the hydrogen atmosphere. The vessel was subsequently purged with nitrogen gas. The reaction vessel and it contents were chilled (ice-water bath) and an additional portion of 10% Palladium on carbon (2.50 g, 23.5 mmol) was added. The flask was repeatedly evacuated and flushed with hydrogen gas (double balloon). The resulting mixture was allowed to warm to rt and left to stir for 6 h under the hydrogen atmosphere. The vessel was subsequently purged with nitrogen gas. The crude reaction mixture was filtered through a short plug of diatomaceous earth (Celite®). The reaction vessel and the Celite® were rinsed with fresh methanol. The combined filtrates were concentrated in vacuo. The residue was dried under high vacuum overnight to afford 3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (12.1 g, 63.0 mmol, 93% yield) as a blackish/grey solid. LC-MS (M+H)+ 193.2. 1H NMR (500 MHz, CDCl3) δ ppm 8.31 (d, J=2.4 Hz, 1H), 7.47 (t, J=8.7 Hz, 1H), 6.47-6.58 (m, 2H), 3.97 (br. s., 2H), 2.48 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][N:9]([CH3:11])[CH3:10])[CH:5]=[N:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:10][N:9]([CH2:8][C:4]1[CH:3]=[C:2]([NH:19][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[CH:7]=[N:6][CH:5]=1)[CH3:11]
Reactant: CN(C)Cc1cncc(Br)c1
Reactant: COc1ccc(CN)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1ccc(CNc2cncc(CN(C)C)c2)cc1
Temperature: 130 °C
Yield: 42.1 %

Procedure:
In a 25 mL microwave vessel, 1-(5-bromopyridin-3-yl)-N,N-dimethylmethanamine (LIV) (1.27 g, 5.92 mmol), 4-methoxybenzylamine (LV) (0.77 mL, 5.92 mmol), cesium carbonate (2.70 g, 8.29 mmol) and xanthphos (0.17 g, 0.30 mmol) were suspended in xylenes (12.0 mL). The solvent was degassed, and tris(dibenzylideneacetone)dipalladium(0) (0.27 g, 0.30 mmol) was added. The vessel was sealed, and the reaction was heated to 130° C. for 5 h in a microwave reactor. The solvent was decanted away from the solid material and concentrated to a residue. The residue was purified by silica gel chromatography using a 40 g Thomson normal-phase silica gel cartridge (100% CHCl3→3:97 MeOH[7N NH3]:CHCl3) to afford 5-((dimethylamino)methyl)-N-(4-methoxybenzyl)pyridin-3-amine (LVI) (0.68 g, 2.49 mmol, 42% yield) as a yellow solid. 1H NMR (DMSO-d6) δ ppm 7.84 (d, J=3 Hz, 1H), 7.64 (d, J=2 Hz, 1H), 7.27 (d, J=11 Hz, 2H), 6.88 (d, J=11 Hz, 2H), 6.83-6.82 (m, 1H), 6.35 (t, J=8 Hz, 1H), 4.20 (d, J=8 Hz, 2H), 3.72 (s, 3H), 3.24 (s, 2H), 2.08 (s, 6H); ESIMS found for C16H21N3O m/z 272 (M+H).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C(OC([N:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:27]([O:32][CH2:33][CH2:34][OH:35])=[N:28][CH:29]=[CH:30][N:31]=2)[CH2:22][CH2:21]1)=O)(C)(C)C.[C:36]([C:39]1[O:40][C:41]2[C:47](O)=[CH:46][CH:45]=[CH:44][C:42]=2[CH:43]=1)(=[O:38])[CH3:37].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[ClH:68].[NH+]1C=CC=CC=1>C1COCC1.CO.O>[ClH:68].[N:23]1([C:26]2[C:27]([O:32][CH2:33][CH2:34][O:35][C:47]3[C:41]4[O:40][C:39]([C:36](=[O:38])[CH3:37])=[CH:43][C:42]=4[CH:44]=[CH:45][CH:46]=3)=[N:28][CH:29]=[CH:30][N:31]=2)[CH2:22][CH2:21][NH:20][CH2:25][CH2:24]1
Reactant: CC(=O)c1cc2cccc(O)c2o1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cc2cccc(OCCOc3nccnc3N3CCNCC3)c2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
DEAD (0.787 mL, 5.00 mmol) was added to a stirred solution of 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.50 g, 4.63 mmol; prepared in Example 52, Step 2), 2-acetyl-7-hydroxybenzofuran (0.88 g, 5.0 mmol) and PPh3 (1.31 g, 5 0 mmol) in THF (3 mL) under gentle heating. After being stirred for 30 min at room temperature, the reaction mixture was poured into water, extracted with EtOAc, dried (MgSO 4) and concentrated The residue was purified b column chromatography on silica using toluene/EtOAc (7 ·3) as eluent. The pure fractions were combined and treated with CH2Cl2/TFA/H2O (50:45:5; 5 mL) for 30 min at room temperature. The mixture was poured into 0.5 M aqueous HCl and washed with EtOAc. The aqueous layer was alkalinized, by addition of NaOH, to pH 12 and extracted with EtOAc. The organic layer was dried (MgSO4), filtered and concentrated The residue (0.250 g, 0.65 mmol) and pyridinium hydrochloride (0.075 g, 0.65 mmol) was dissolved in MeOH. The mixture was and concentrated and the residue was re-dissolved in EtOH and concentrated three more times to give 0.27 g (14 %) of the title product. Pos-EI-MS shows M+ and 19 ions supporting the stated structure. HRMS m/z calcd for C20H22N4O4 (M)+ 382.1641, found 382.1631.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([CH:19]([CH3:21])[CH3:20])[CH2:4][C@H:5]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH3:29][S:30]([O:1][CH2:2][C@H:3]([CH:19]([CH3:21])[CH3:20])[CH2:4][C@H:5]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:32])=[O:31]
Reactant: CC(C)[C@@H](CO)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@@H](COS(C)(=O)=O)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The solution of 2.84 g of tert-butyl 4(S)-(2(S)-hydroxymethyl-3-methylbutyl)-2,2-dimethyl-oxazolidine-3-carboxylate in 100 ml of dichloromethane is admixed at 0° C. successively with 1.41 ml of triethylamine and 0.76 ml of methanesulphonyl chloride. The reaction mixture is stirred at 0° C. over 1 hour and subsequently concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a slightly yellowish oil. Rf=0.30 (1:2 EtOAc-heptane); Rt=5.03 (gradient I).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[S:13][C:12]([CH:14]=[O:15])=[CH:11][CH:10]=2)[CH:6]=[C:5]([NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[N:4]=1.S([CH2:37][N+:38]#[C-:39])(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CO>[CH3:1][O:2][C:3]1[N:4]=[C:5]([NH:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH:6]=[C:7]([C:9]2[S:13][C:12]([C:14]3[O:15][CH:39]=[N:38][CH:37]=3)=[CH:11][CH:10]=2)[N:8]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COc1ccc(CCNc2cc(-c3ccc(C=O)s3)nc(OC)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1ccc(CCNc2cc(-c3ccc(-c4cnco4)s3)nc(OC)n2)cc1
Temperature: 25 °C
Yield: 72.5 %

Procedure:
A stirred mixture of 5-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carbaldehyde [300 mg, 0.81 mmol, Example 8(b)], tosylmethylisocyanide (174 mg, 0.89 mmol), K2CO3 (246 mg 1.78 mmol) and MeOH (30 mL) is heated at reflux for 4 hours. The mixture is allowed to cool to ambient temperature, concentrated by rotary evaporator to remove the solvent. The residue is partitioned between EtOAc and water. The organic phase is dried over magnesium sulfate, filtered and concentrated. The residual solid is subjected to flash column chromatography on silica gel eluting with EtOAc and cyclohexane to afford [2-methoxy-6-(5-oxazol-5-yl-thiophen-2-yl)-pyrimidin-4-yl]-[2-(4-methoxy-phenyl)-ethyl]-amine [240 mg, 73%, Example 11(a)]. LCMS: RT=8.99 minutes, MS: 409 (M+H). IC50=2.3 nM