Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[OH:12].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[OH:12]
Reactant: COc1ccccc1B(O)O
Reactant: Oc1ncnc2ccc(Br)cc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1-c1ccc2ncnc(O)c2c1
Temperature: 150 °C
Yield: 98.1 %

Procedure:
Preparation D6, Step 2: A mixture of 6-bromoquinazolin-4-ol (227 mg, 1.01 mmol), 2-methoxyphenylboronic acid (307 mg, 2.02 mmol), 2.0 M potassium phosphate (aq) (1.5 mL, 3.0 mmol), and DMF (3 mL) in a 5 mL microwave tube was degassed under vacuum/Ar. A catalytic amount of tetrakis(triphenylphosphine)palladium(0) was added to the tube, the mixture was degassed again, the tube was sealed, and the reaction was heated at 150° C. in the microwave for 30 min. The resulting black mixture was filtered, then concentrated in-vacuo. The residue was taken up in 9:1 ethyl acetate/heptane (50 mL), washed with water (3×20 mL), then brine, then dried over sodium sulfate and concentrated in-vacuo. The residue was purified over silica gel, eluting with 1:1 ethyl acetate/heptane, 100% ethyl acetate, then 9:1 ethyl acetate/methanol, to yield 250 mg of 6-(2-methoxyphenyl)quinazolin-4-ol as a white powder. MS (ES+)=253 (M+H+).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[CH2:26]([O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1)[CH2:27][CH2:28][CH3:29]>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:35](=[O:36])[C:34]2[CH:33]=[CH:32][C:31]([O:30][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:39][CH:38]=2)[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CCCCOc1ccc(C(=O)Cl)cc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOc1ccc(C(=O)N[C@@H]2CCc3cccc(N4CCN(C)CC4)c3C2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (110 mg, 0.41 mmol) and triethylamine (95 μL, 0.69 mmol) in methylene chloride (20 mL) was added dropwise 4-butoxybenzoyl chloride (103 mg, 0.48 mmol) in methylene chloride (5 mL). After the addition the reaction was allowed to stir at ambient temperature for 15 min and was then washed with dilute aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:2) as the eluent. Yield: 150 mg (75%) of the title compound as white crystals: mp 190-191° C.; [α]21D -49° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 421 (0.6, M+).
Reaction SMILES: C([O:8][C:9](=[O:40])[CH2:10][CH:11]([N:23]1[CH:27]=[CH:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)[CH2:24]1)[C:12]([NH:14][C@H:15]1[CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:16]1=[O:22])=[O:13])C1C=CC=CC=1>CCO>[C:31]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:30]=[CH:29][C:28]([N:25]2[CH:26]=[CH:27][N:23]([CH:11]([C:12]([NH:14][C@H:15]3[CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:16]3=[O:22])=[O:13])[CH2:10][C:9]([OH:40])=[O:8])[CH2:24]2)=[CH:33][CH:32]=1
Reactant: O=C(CC(C(=O)N[C@H]1CCCCNC1=O)N1C=CN(c2ccc(-c3ccccc3)cc2)C1)OCc1ccccc1
Solvent: CCO
Product: O=C(O)CC(C(=O)N[C@H]1CCCCNC1=O)N1C=CN(c2ccc(-c3ccccc3)cc2)C1
Reaction time: 1.5 h
Yield: 94 %

Procedure:
According to the procedure described in Example 1(a), a suspension of 3(RS)-(3-biphenyl-4-yl-1H-imidazol-1-yl)-N-(hexahydroazepin-2-on-3(S)-yl)succinamic acid benzyl ester in EtOH was hydrogenolyzed after 90 minutes to provide 779 mg (94%) of 3(RS)-(3-biphenyl-4-yl-1H-imidazol-1-yl)-N-(hexahydroazepin-2-on-3(S)-yl)succinamic acid as a solid. FABMS: 447 (C25H27N4O4; M+H+).
Reaction SMILES: [ClH:1].[NH2:2][CH:3]([CH:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12][C:11]2[CH:20]=[CH:21][CH:22]=[CH:23][C:10]1=2)[C:4]([O:6]CC)=[O:5].[OH-].[K+].C(O)C>O>[ClH:1].[NH2:2][CH:3]([CH:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12][C:11]2[CH:20]=[CH:21][CH:22]=[CH:23][C:10]1=2)[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(N)C1c2ccccc2CCc2ccccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC(C(=O)O)C1c2ccccc2CCc2ccccc21
Yield: 74.4 %

Procedure:
Ethyl α-amino-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-acetate hydrochloride (13 g, 39 mmol) is stirred with 400 mL of 1M ethanolic potassium hydroxide solution at room temperature overnight. Ethanol is stripped and the solid taken up in water, extracted with diethyl ether, and acidified with 1N hydrochloric acid to pH 1. A precipitate is collected by filtration, washed with diethyl ether, dried at 50° C./2 mm Hg to furnish 8.81 g of the title compound; mp >285° C.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.N1C=CC=CC=1.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C(Cl)Cl>[CH2:8]([O:7][C:5]([CH:4]1[CH2:3][CH2:2][N:1]([S:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:26])=[O:25])[CH2:11][CH2:10]1)=[O:6])[CH3:9]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)C1CCNCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1CCN(S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.2 %

Procedure:
A solution of ethyl isonipecotate (15.7 g, 0.1 mol) in methylene chloride (100 mL) at 0° C. was treated with pyridine (10 mL) and then benzenesulfonyl chloride (17.6 g, 0.1 mol). The reaction was warmed to room temperature and stirred at room temperature for 2 hours. The reaction was then poured into 1 N HCl (1 L) and extracted with ethyl acetate (2×500 mL). The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure. The solid was recrystallized from ethyl acetate to give 17 g of product.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26]C)=O)=[C:21]([O:28][C@@H:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[F:37])[CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:38]>CO>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:38])=[O:26])=[C:21]([O:28][C@@H:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[F:37])[CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O[C@H](C)c1ccccc1F
Solvent: CO
Product: C[C@@H](Oc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(N)=O)c1ccccc1F

Procedure:
In a similar manner as described for example A5, 2.50 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-[(1R)-1-(2-fluorophenyl)ethoxy]thiophene-2-carboxylate and 92 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: [C:1]([O:20][CH2:21][C@H:22]([C@H:24]([C@@H:26]([C@@H:28]([CH2:30][O:31][C:32]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[OH:29])[OH:27])[OH:25])[OH:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:53](Br)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>>[C:1]([O:20][CH2:21][C@H:22]([C@H:24]([C@@H:26]([C@@H:28]([CH2:30][O:31][C:32]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[O:29][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[O:27][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[O:25][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[O:23][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O[C@@H]([C@H](O)[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: c1ccc(CO[C@@H]([C@H](OCc2ccccc2)[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)OCc2ccccc2)[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)OCc2ccccc2)cc1
Reaction time: 0.08 h
Yield: 219 %

Procedure:
10.64 g (16 mmol) of 1,6-di-O-trityl-D-mannitol and 3.07 g of NaH (60% oil dispersion) were added into a 250 mL round-bottom flask. The flask was purged with N2 and cooled in a dry ice/isopropanol bath, and then 133 mL of anhydrous DMF was added. After stirring for 5 min, 8.55 mL (72 mmol) of benzyl bromide was added slowly to the reaction mixture. The dry ice/iPrOH bath was removed and the reaction mixture stirred at RT for 3.5 hr and then concentrated under reduced pressure. 400 mL of EtOAc and 300 mL of deionized water were added to the residue. After separation, the water layer was back extracted twice with EtOAc. The combined EtOAc layers were washed three times with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 18 g of desired product (yield: 109%). The product was used directly for the next reaction without further purification. Mass spec analysis (MALDI-TOF): exact mass: 1026.49, obtained: 1050.85 [M+Na]+.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@@H:21]1[CH:26]=[CH:25][C@@H:24]([CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[NH:23][CH2:22]1)S(C1C=CC([N+]([O-])=O)=CC=1[N+]([O-])=O)(=O)=O)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].C1(S)C=CC=CC=1>C(#N)C>[CH2:1]([O:4][NH:5][C@@H:21]1[CH:26]=[CH:25][C@@H:24]([CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:30])[CH3:31])[NH:23][CH2:22]1)[CH:2]=[CH2:3]
Reactant: C=CCON([C@@H]1C=C[C@@H](CO[Si](C)(C)C(C)(C)C)NC1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CC#N
Product: C=CCON[C@@H]1C=C[C@@H](CO[Si](C)(C)C(C)(C)C)NC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 56.7 %

Procedure:
To a stirred suspension of N-(allyloxy)-N-((3R,6S)-6-((tert-butyldimethylsilyloxy)methyl)-1,2,3,6-tetrahydropyridin-3-yl)-2,4-dinitrobenzenesulfonamide (Intermediate 127, 17.50 g, 33.10 mmol) and potassium carbonate (13.73 g, 99.31 mmol) in acetonitrile (700 mL), benzenethiol (5.10 ml, 49.65 mmol) was added. The reaction mixture was stirred at rt for 2.5 hours. LCMS showed the completion of the reaction. The reaction was concentrated, the diluted with EtOAc and filtered through a disposal filter. The filtrate was concentrated and the crude product was purified on silica gel column (0-4% MeOH in DCM) to get the desired product as a yellow oil (5.6 g).
Reaction SMILES: [ClH:1].[C:2]([NH:5][C:6]1[C:7]([F:26])=[CH:8][C:9](N)=[C:10]([CH:24]=1)[O:11][C:12]1[CH:23]=[CH:22][CH:21]=[CH:20][C:13]=1[O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])(=[O:4])[CH3:3].N([O-])=O.[Na+]>[Cu]Cl.O.COC(C)(C)C>[C:2]([NH:5][C:6]1[C:7]([F:26])=[CH:8][C:9]([Cl:1])=[C:10]([CH:24]=1)[O:11][C:12]1[CH:23]=[CH:22][CH:21]=[CH:20][C:13]=1[O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])(=[O:4])[CH3:3]
Reactant: COC(=O)COc1ccccc1Oc1cc(NC(C)=O)c(F)cc1N
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: COC(=O)COc1ccccc1Oc1cc(NC(C)=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 30 ml of concentrated hydrochloric acid was added 2.0 g of methyl [2-(5-acetylamino-2-amino-4-fluorophenoxy)phenoxy]acetate, and the mixture was stirred at room temperature for 1 hour. Then, an aqueous solution consisting of 0.42 g of sodium nitrite and 3 ml of water was added under ice cooling. After stirring at the same temperature for 1 hour, 40 ml of t-butyl methyl ether was added and 0.85 g of copper (I) chloride was added. After stirring for 30 minutes, water was added, and the mixture was extracted with t-butyl methyl ether. The organic layer was washed with water, dried over magnesium sulfate, and then concentrated. The residue was subjected to column chromatography (eluent: hexane/ethyl acetate=2/1) to give 0.52 g of methyl [2-(5-acetylamino-2-chloro-4-fluorophenoxy)phenoxy]acetate.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:36])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:33]=[CH:32][C:18]([C:19]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([CH:29]([F:31])[F:30])[CH:23]=4)=[O:20])=[C:17]([O:34][CH3:35])[CH:16]=3)[N:10]=2)[CH:8]=1.[CH:37]1([C:40](Cl)=[O:41])[CH2:39][CH2:38]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:36][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:40]([CH:37]2[CH2:39][CH2:38]2)=[O:41])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:33]=[CH:32][C:18]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([CH:29]([F:31])[F:30])[CH:23]=3)=[O:20])=[C:17]([O:34][CH3:35])[CH:16]=2)[N:10]=1
Reactant: COc1cc(-n2nc(-c3cc(CN)ccc3Cl)[nH]c2=O)ccc1C(=O)Nc1ccc(F)c(C(F)F)c1
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-n2nc(-c3cc(CNC(=O)C4CC4)ccc3Cl)[nH]c2=O)ccc1C(=O)Nc1ccc(F)c(C(F)F)c1
Yield: 28.4 %

Procedure:
The title compound was prepared by following the procedure as described for step-2 of Intermediate-30, by using 4-(3-(5-(aminomethyl)-2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(3-(difluoromethyl)-4-fluorophenyl)-2-methoxybenzamide (Intermediate-35, 0.050 g, 0.09 mmol), cyclopropylcarbonyl chloride (0.016 g, 0.14 mmol), DIPEA (2.0 mL) and THF (5 mL) to afford 0.015 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.67 (s, 4H), 1.59 (m, 1H), 3.92 (s, 3H), 3.32 (d, J=4.8 Hz, 2H), 7.03-7.33 (m, 1H), 7.35-7.47 (m, 3H), 7.62-7.68 (m, 2H), 7.76-7.84 (m, 2H), 8.09 (m, 2H), 8.70 (m, 1H), 10.28 (s, 1H), 12.69 (brs, 1H); MS (m/z): 586.12 (M+H)+.
Reaction SMILES: Cl[C:2](Cl)(Cl)[C@@H:3]1[O:8][C:7](=[O:9])[C@@H:6]([CH3:10])[C@H:5]([CH3:11])[O:4]1.S(=O)(=O)(O)O.[CH3:19]C(O)C>O>[CH3:10][C@H:6]([C@@H:5]([OH:4])[CH3:11])[C:7]([O:8][CH:3]([CH3:19])[CH3:2])=[O:9]
Reactant: C[C@@H]1O[C@H](C(Cl)(Cl)Cl)OC(=O)[C@H]1C
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)OC(=O)[C@H](C)[C@H](C)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1.0 g of (2S, 5S,6S)-2-trichloromethyl-5,6-dimethyl-1,3-dioxan-4-one produced by a procedure similar to Example 1-(7) were added 0.1 ml of concentrated sulfuric acid and 10 ml of 2-propanol, stirred at room temperature for one hour, and 20 ml of water was added to effect ether extraction. The ether phase was dried over anhydrous sodium sulfate and ether was distilled off followed by distilling the residue to obtain 0.4 g of isopropyl (2R, 3S)-2-methyl-3-hydroxybutanoate of the following formula. ##STR61## (2) Repeating the procedure of Example 5-(1) except that 2-propanol was replaced with 2-butanol, 0.5 g of 1-methylpropyl (2R, 3S)-2-methyl-3-hydroxybutanoate of the following formula was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([NH2:24])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].CO[CH:33]1[CH2:37][CH2:36][CH:35](OC)O1.O>C(O)(=O)C>[C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([N:24]1[CH:33]=[CH:37][CH:36]=[CH:35]1)=[CH:14][CH:13]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC1CCC(OC)O1
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(N)cc12
Solvent: O
Solvent: CC(=O)O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-n3cccc3)cc12
Yield: 66.3 %

Procedure:
A solution of tert-butyl(6-amino-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.41 g, 1 mmol) and 2,5-dimethoxytetrahydrofuran (0.19 ml, 1.5 mmol) in acetic acid (10 ml) was stirred at 80° C. for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[4-butoxy-2-isobutyl-1-oxo-6-(1H-pyrrol-1-yl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.31 g, 67.4%) as crystals.
Reaction SMILES: [C:1]1([CH3:12])[C:2]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:1]1[C:2]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccccc1CBr

Procedure:
A mixture of 100 g of ethyl o-toluate, 100 g of N-bromosuccinimide and 0.3 g of benzoyl peroxide in 1 liter of carbon tetrachloride is heated under reflux for 3 hours with stirring and filtered. The filtrate is washed with 3% aqueous sodium hydroxide and then with water, dried over magnesium sulfate and concentrated under reduced pressure to provide ethyl α-bromo-o-toluate as an oil.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:27])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][O:22][CH2:23][CH3:24])[C:16](Br)=[N:15][C:14]=2[N:13]([CH3:26])[C:11]1=[O:12])(=[O:3])[CH3:2].[S-2:28].[Na+].[Na+]>C(O)C>[C:1]([O:4][C@H:5]([CH3:27])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][O:22][CH2:23][CH3:24])[C:16]([SH:28])=[N:15][C:14]=2[N:13]([CH3:26])[C:11]1=[O:12])(=[O:3])[CH3:2]
Reactant: [S-2]
Reactant: CCOCn1c(Br)nc2c1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n2C
Agent: [Na+]
Solvent: CCO
Product: CCOCn1c(S)nc2c1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n2C
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a stirring solution of (R)-1-(5-acetoxyhexyl)-8-bromo-7-ethoxymethyl-3-methylxanthine (prepared as described above for CT 12440) (1.77 g, 4.0 mmol) in ethanol (100 ml) was added sodium sulfide (4.48 g, 80 mmol). The reaction mixture was stirred at 90° C. for 1 hour. After evaporation of the solvent under reduced pressure, the crude product was purified by flash chromatography on silica gel eluting with ethyl acetate-methanol (7:1) to provide (R)-1-(5-acetoxyhexyl)-7-ethoxymethyl-8-mercapto-3-methylxanthine. This product was dissolved in methanol (100 ml). A solution of hydrogen chloride in ether (1.0 M, 1.0 ml) was added and stirred at room temperature for 24 hours. After evaporation of the solvent under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with ethyl acetate-methanol (4:1) to provide (R)-1-(5-hydroxyhexyl)-7-ethoxymethyl-8-mercapto-3-methylxanthine (610 mg, 51% yield) as a white solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[CH3:11])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:18](Cl)(=[O:20])[CH3:19]>ClCCl>[C:18]([O:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[C:5]([CH3:11])[CH:6]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: Cc1cc(O)ccc1C(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.2 %

Procedure:
4-Isopropyl-3-methylphenol (1.00 g) was dissolved in dichloromethane (10 ml) to prepare a solution. Pyridine (724 mg) and acetyl chloride (615 mg) were added to the solution, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was dried under the reduced pressure to give 4-isopropyl-3-methylphenyl acetate (1.41 g, yield 100%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:17][CH2:18][CH3:19])[CH2:5][CH2:6][NH:7][CH2:8][CH:9]1[O:14][CH:13]([CH3:15])[CH:12]([CH3:16])[CH2:11][O:10]1)[CH3:2].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:32][CH2:33][C:34](Cl)=[O:35]>O>[CH2:1]([O:3][CH:4]([O:17][CH2:18][CH3:19])[CH2:5][CH2:6][N:7]([CH2:8][CH:9]1[O:14][CH:13]([CH3:15])[CH:12]([CH3:16])[CH2:11][O:10]1)[C:34](=[O:35])[CH2:33][Br:32])[CH3:2]
Reactant: O=C(Cl)CBr
Reactant: CCOC(CCNCC1OCC(C)C(C)O1)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(CCN(CC1OCC(C)C(C)O1)C(=O)CBr)OCC

Procedure:
N-(3,3-Diethoxypropyl)-N-(4,5-dimethyl-1,3-dioxan-2-ylmethyl)amine (0.05 mole), benzene (100 ml), water (100 ml) and sodium carbonate (2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is cooled to a temperature of from 5° to 10° C and bromoacetyl chloride (0.05 mole) is added dropwise with stirring. After the addition is completed stirring is continued until the reaction mixture has reached room temperature. After this time the organic phase is separated from the aqueous phase and is washed with water. The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(3,3-diethoxypropyl)-N-(4,5-dimethyl-1,3-dioxan-2-ylmethyl)-α-bromoacetamide as the residue.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[C:9]3[N:17]=[C:16]([C:18]4[CH:19]=[C:20]([NH2:24])[CH:21]=[N:22][CH:23]=4)[CH:15]=[CH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:3][CH2:2]1.[Br:25][C:26]1[CH:31]=[C:30]([Br:32])[CH:29]=[CH:28][C:27]=1[S:33](Cl)(=[O:35])=[O:34]>N1C=CC=CC=1.C(Cl)Cl>[Br:25][C:26]1[CH:31]=[C:30]([Br:32])[CH:29]=[CH:28][C:27]=1[S:33]([NH:24][C:20]1[CH:21]=[N:22][CH:23]=[C:18]([C:16]2[CH:15]=[CH:14][C:10]3[N:11]=[CH:12][N:13]=[C:8]([O:7][CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[C:9]=3[N:17]=2)[CH:19]=1)(=[O:35])=[O:34]
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1Br
Reactant: Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)c1)c1ccc(Br)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
To a solution of 5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-amine (Intermediate 12) (0.0500 g, 0.155 mmol) in pyridine (0.773 ml) was slowly added 2,4-dibromobenzene-1-sulfonyl chloride (0.0620 g, 0.186 mmol) at 0° C. After stirred for 1 hour at room temperature, the reaction mixture was diluted with DCM and quenched with 1N. aq HCl. The combined organic layers were washed brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was recrystallized from EtOAc-Hexane to give 2,4-dibromo-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzenesulfonamide (0.0550 g, 57%) as a purple solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 2.03-2.11 (2H, m), 2.24-2.28 (2H, m), 3.70-3.75 (2H, m), 4.11-4.16 (2H, m), 5.65-5.71 (1H, m), 7.53 (1H, dd, J=2.0, 8.4 Hz), 7.90 (1H, d, J=1.6 Hz), 7.97 (1H, d, J=8.4 Hz), 8.21 (1H, d, J=8.8 Hz), 8.37 (1H, d, J=8.8 Hz), 8.52 (1H, s), 8.59 (1H, d, J=2.8 Hz), 8.84 (1H, s), 9.16 (1H, d, J=2.0 Hz). m/z=622.0 [M+1]+.