Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2](F)(F)[C:3](O)=O.C(O[C:13](=O)[NH:14][C:15]([C:18]1[N:22]([CH3:23])[C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])=[N:20][N:19]=1)([CH3:17])[CH3:16])(C)(C)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:21]1[N:22]([CH3:23])[C:18]([C:15]([N:14]2[CH2:2][C:3]3[C:26](=[CH:25][CH:24]=[CH:29][CH:28]=3)[CH2:13]2)([CH3:16])[CH3:17])=[N:19][N:20]=1
Reactant: Cn1c(-c2ccccc2Cl)nnc1C(C)(C)NC(=O)OC(C)(C)C
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cn1c(-c2ccccc2Cl)nnc1C(C)(C)N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (2 ml) was added to a chloroform (4 ml) solution of tert-Butyl-{1-[5-(2-chlorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1-methylethyl}carbamate (500 mg), followed by stirring at room temperature for 2 hours. The reaction solution and chloroform were added to an aqueous saturated sodium hydrogen carbonate solution and then the organic layer was separated. Furthermore, the organic layer washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered and then the solvent was removed by evaporation under reduced pressure. Potassium carbonate (394 mg) and 1,2-bis(bromomethyl)benzene (376 mg) were added to a DMF (10 ml) solution of the resulting residue, followed by stirring at 60° C. for 14 hours. Distilled water and chloroform were added to the reaction solution and then the organic layer was separated. Furthermore, the organic layer washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered and then the solvent was removed by evaporation under reduced pressure. The resulting crude product was purified by flash chromatography (chloroform:methanol=25:1) to obtain 35 mg of 2-{1-[5-(2-chlorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1-methylethyl} isoindoline (colorless solid).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([O:19][C@H:20]3[CH2:24][N:23]([C:25](=[O:35])[C@@H:26]([NH:31][C:32](=[O:34])O)[C:27]([CH3:30])([CH3:29])[CH3:28])[C@H:22]([C:36]([O:38][CH3:39])=[O:37])[CH2:21]3)=[CH:9][C:10]([N:14]3[CH:18]=[CH:17][CH:16]=[N:15]3)=[N:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:47]([N:51]=C=O)([CH3:50])([CH3:49])[CH3:48]>ClCCl>[CH3:39][O:38][C:36]([C@@H:22]1[CH2:21][C@@H:20]([O:19][C:8]2[C:7]3[C:12](=[CH:13][C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)[N:11]=[C:10]([N:14]3[CH:18]=[CH:17][CH:16]=[N:15]3)[CH:9]=2)[CH2:24][N:23]1[C:25](=[O:35])[C@@H:26]([NH:31][C:32]([NH:51][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:34])[C:27]([CH3:28])([CH3:29])[CH3:30])=[O:37]
Reactant: COC(=O)[C@@H]1C[C@@H](Oc2cc(-n3cccn3)nc3cc(OC)ccc23)CN1C(=O)[C@@H](NC(=O)O)C(C)(C)C
Reactant: CC(C)(C)N=C=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@@H](Oc2cc(-n3cccn3)nc3cc(OC)ccc23)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-1-((2S,4R)-4-(7-methoxy-2-(1H-pyrazol-1-yl)quinolin-4-yloxy)-2-(methoxycarbonyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamic acid hydrochloride (0.165 mmol) in dichloromethane (3.0 mL) was added triethylamine (0.06 mL, 0.413 mmol) and tert-butylisocyanate (0.02 mL, 0.165 mmol) and the reaction mixture was stirred at room temperature. After 16 hours, the reaction mixture was diluted with dichloromethane and washed with 1N HCl, saturated sodium bicarbonate, and brine. The dichloromethane layer was then evaporated to dryness to give (2S,4R)-methyl-1-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-4-(7-methoxy-2-(1H-pyrazol-1-yl)quinolin-4-yloxy)-pyrrolidine-2-carboxylate.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.[S:37]1(=[O:45])(=[O:44])[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]1.[Na].C(O)(=O)C>>[OH:17][C@@H:16]1[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13][C@H:12]1[N:9]1[CH:8]=[N:7][C:6]2[C:10]1=[N:11][C:3]([CH2:2][NH:1][CH:40]1[CH2:41][CH2:42][S:37](=[O:45])(=[O:44])[CH2:38][CH2:39]1)=[N:4][C:5]=2[NH:22][CH2:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Reactant: O=C1CCS(=O)(=O)CC1
Agent: [Na]
Solvent: CC(=O)O
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC4CCS(=O)(=O)CC4)nc32)[C@H](O)[C@@H]1O
Yield: 42.8 %

Procedure:
The title compound was prepared by a similar method to example 6 using (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino}-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (305 mg, 0.60 mmol) (example 1), tetrahydro-1λ6-thiopyran-1,1,4-trione (88 mg, 0.60 mmol), sodium triacetoxyborohydrde (200 mg, 0.90 mmol) and acetic acid (43 mg, 0.72 mmol). The product was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol:ammonia (96:4:0.2) to give the title compound (160 mg) as a foam. MS: 623 (MH+).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH:15]2[CH2:17][C:18]([Cl:21])([C:19]#[N:20])[CH:12]1[CH:13]=[CH:14]2)=O)C1C=CC=CC=1.C(O)(=O)C.[BrH:26]>C(O)(=O)C>[BrH:26].[Cl:21][C:18]1([C:19]#[N:20])[CH2:17][CH:15]2[CH:14]=[CH:13][CH:12]1[NH:11][CH2:16]2
Reactant: N#CC1(Cl)CC2C=CC1N(C(=O)OCc1ccccc1)C2
Agent: Br
Solvent: CC(=O)O
Product: N#CC1(Cl)CC2C=CC1NC2
Reaction time: 0.17 h

Procedure:
5.0 g. (0.0165 moles) of N-benzyloxycarbonyl-7-chloro-7-cyano-2-azabicyclo[2.2.2]oct-5-ene are dissolved in a mixture of 30 ml. of glacial acetic acid and 15 ml. of a 4-5N glacial acetic acid/hydrogen bromide mixture. The reaction mixture is allowed to stand at room temperature for 10 minutes, and is then evaporated. The evaporation residue is crystallized from acetone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[Br:13][CH2:14][CH2:15]Br.[OH-].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:15][CH2:14][Br:13])[CH:8]=2)[CH:3]=1
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: BrCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: BrCCOc1ccc2cc(Br)ccc2c1
Temperature: 100 °C

Procedure:
A round-bottom flask containing 1.0 g (4.5 mmol) of 6-bromo-2-naphthol, 1,2-dibromoethane (135 mmol, 12 mL), potassium hydroxide (5 mL of a 40% solution) and tetrabutylammonium bromide (1.35 mmol, 0.43 g) was heated at 100° C. for 3 h. The reaction mixture was diluted with 150 mL of CH2Cl2 and washed with water and brine, dried over sodium sulfate and concentrated under vacuum to give the desired compound in 100% as a pale brown solid; 1HNMR (300 MHz, CDCl3) δ 3.70 (t, 2H), 4.40 (t, 2H), 7.05-7.90 (m, 6H). MS (DCI) m/z 330 (M+).
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.B.C1COCC1.[Cl:28][CH2:29][C:30]([C:32]1[CH:41]=[C:40]([Cl:42])[C:35]2[N:36]=[C:37]([CH3:39])[O:38][C:34]=2[CH:33]=1)=[O:31]>C1COCC1>[Cl:28][CH2:29][C@H:30]([C:32]1[CH:41]=[C:40]([Cl:42])[C:35]2[N:36]=[C:37]([CH3:39])[O:38][C:34]=2[CH:33]=1)[OH:31]
Reactant: Cc1nc2c(Cl)cc(C(=O)CCl)cc2o1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: C1CCOC1
Product: Cc1nc2c(Cl)cc([C@H](O)CCl)cc2o1
Reaction time: 1 h

Procedure:
To a solution of (S)-Methyl-CBS-oxazaborolidine (1M in toluene, 0.745 mL, 0.745 mmol) and BH3-THF (8 mL, 8 mmol) is added at the same time a solution of BH3-THF (19 mL, 19 mmol) and a solution of 6-Chloroacetyl-4-chloro-2-methyl-benzooxazole (37.98 mmol) in 19 mL of THF. Both solutions are added dropwise over 30 minutes. The solution is stirred for 1 hour and quenched with the slow addition of methanol (50 mL). The solution is concentrated and the residue chromatographed over a short silica gel column (1:1 hexane/ethyl acetate).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][N:10]=[CH:11][CH:12]=2)[S:7]1.C(N(CC)CC)C.[N+:23]([C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)([O-:25])=[O:24]>O1CCCC1>[N+:23]([C:26]1[CH:27]=[CH:28][C:29]([S:32]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:14](=[O:15])[C:13]3[C:8](=[CH:9][N:10]=[CH:11][CH:12]=3)[S:7]2)(=[O:34])=[O:33])=[CH:30][CH:31]=1)([O-:25])=[O:24]
Reactant: O=c1c2ccncc2sn1CCCCO
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=c1c2ccncc2sn1CCCCOS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 4 h

Procedure:
To a stirred solution of 0.73 g of 2-(4-hydroxybutyl)isothiazolo[5,4-c]pyridin-3(2H)-one and 0.8 mL of triethylamine in 50 mL of dry tetrahydrofuran at 0° C. was added 0.63 g of technical grade 4-nitrobenzenesulfonyl chloride. After 4 h, the solution was filtered and concentrated to dryness under reduced pressure. The residue was dissolved in 100 mL of ethyl acetate, washed with 10 mL of saturated sodium carbonate and dried over MgSO4. Concentration under reduced pressure gave 1.4 g of crude 2-(4-(4-nitrobenzenesulfonyloxy)butyl)-isothiazolo[5,4-c]pyridin-3(2H)-one as an oil. The crude product was a mixture of 4-nitrobenzenesulfonate contaminated with a small amount of chloride by NMR, and was used in the next step without further purification.
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[C:11]2=[N:12][C:13]([C@@H:22]([NH:24][C:25]3[C:30]([C:31]#[N:32])=[C:29]([NH2:33])[N:28]=[C:27]([NH2:34])[N:26]=3)[CH3:23])=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:15]=[C:10]2[N:9]([CH3:35])[CH:8]=1)(=O)C.C(=O)(O)[O-].[Na+]>CO>[NH2:34][C:27]1[N:28]=[C:29]([NH2:33])[C:30]([C:31]#[N:32])=[C:25]([NH:24][C@H:22]([C:13]2[N:12]=[C:11]3[C:7]([OH:6])=[CH:8][N:9]([CH3:35])[C:10]3=[CH:15][C:14]=2[N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH3:23])[N:26]=1
Reactant: CC(=O)Oc1cn(C)c2cc(N3CCOCC3)c([C@H](C)Nc3nc(N)nc(N)c3C#N)nc12
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](Nc1nc(N)nc(N)c1C#N)c1nc2c(O)cn(C)c2cc1N1CCOCC1
Reaction time: 0.25 h
Yield: 7 %

Procedure:
1N NaOH was added to a 50 mL pear flask charged with (S)-5-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-1-methyl-6-morpholino-1H-pyrrolo[3,2-b]pyridin-3-yl acetate (3.29 g, 7.29 mmol) in methanol (25 mL). The reaction was complete within about 15 minutes. Saturated sodium bicarbonate solution was added. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified by preparative HPLC (acid mode, 5% to 25% ACN/water gradient). The product-containing fractions were pooled, neutralized with saturated sodium bicarbonate, and then extracted with EtOAc (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound as an off-white solid (210 mg, 7.04%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34 (d, J=6.57 Hz, 3 H), 2.70-2.80 (m, 2 H), 2.96-3.07 (m, 2 H), 3.15 (s, 3 H), 3.63 (d, J=2.53 Hz, 2 H), 3.71-3.88 (m, 4 H), 5.78-5.96 (m, 1 H), 6.07 (s, 1 H), 6.41 (br s, 2 H), 6.60 (s, 2 H), 7.33 (s, 1 H); ESI-MS m/z [M+H]+ calc'd for C19H23N9O2, 410; found 410.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.B([O-])([O-])O[C:19]1[CH:24]=[CH:23][C:22]2[O:25][CH2:26][O:27][C:21]=2[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O>[CH2:26]1[O:27][C:21]2[CH:20]=[CH:19][C:24]([C:2]3[CH:3]=[CH:4][C:5]4[S:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=4[CH:16]=3)=[CH:23][C:22]=2[O:25]1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2SCC1
Reactant: [O-]B([O-])Oc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COC(=O)C1=Cc2cc(-c3ccc4c(c3)OCO4)ccc2SCC1
Yield: 90.8 %

Procedure:
Under argon atmosphere, a mixture of methyl 7-bromo-2,3-dihydro-1-benzothiepine-4-carboxylate (1.5 g), 3,4-methylenedioxyphenyl borate (0.92 g) and potassium carbonate (1.39 g) in toluene/ethanol/water (50/5/5 ml) was stirred at room temperaturel hours. To the mixture was added tetrakistriphenylphosphine palladium (0.29 g), and the mixture was refluxed for 16 hours and cooled. The mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the residue was purified with column chromatography (ethyl acetate/hexane=1:2) to give pale yellow crystals of methyl 7-(3,4-methylenedioxyphenyl)-2,3-dihydro-1-benzo-thiepine-4-carboxylate (1.55 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[C:7](Cl)=[N:8][C:9]([Cl:12])=[N:10][CH:11]=1)[CH3:2].O>C(O)C.[Zn]>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[N:10][C:9]([Cl:12])=[N:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cnc(Cl)nc1Cl
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cc1cnc(Cl)nc1
Temperature: 99.5 °C
Reaction time: 0.17 h
Yield: 61 %

Procedure:
Zinc powder (3.55 g, 54.3 mmol) was added to a solution of (2,4-dichloro-pyrimidin-5-yl)acetic acid ethyl ester (Example 43-(1); 1.57 g, 6.70 mmol) in ethanol (10 mL)-water (8.5 mL), and the mixture was heated while stirring at an external temperature of 96 to 103° C. for 10 minutes. The reaction mixture was cooled to room temperature and then filtered, and the filtrate was concentrated under reduced pressure. Ethyl acetate and water were added to the residue, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=2/1) to give the title compound (820 mg, 61%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[C:19]([O:23][C:24]([N:26]1[CH2:30][CH2:29][C@@H:28]([NH2:31])[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:31][C@@H:28]1[CH2:29][CH2:30][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:27]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Product: CCOC(=O)c1cnc2c(OC)cccc2c1N[C@@H]1CCN(C(=O)OC(C)(C)C)C1

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (266 mg, 1.0 mmol) was treated with (R)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester following general procedure B to afford 4-((R)-1-tert-butoxycarbonyl-pyrrolidin-3-ylamino)-8-methoxy-quinoline-3-carboxylic acid ethyl ester 381 mg). Thus obtained amino-ester (208 mg, 0.5 mmol) was subjected to reaction with 1-chloro-3-isocyanato-benzene according to general procedure C to furnish 3-[(R)-3-(3-chloro-phenyl)-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimido[5,4-c]quinolin-1-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (194 mg). LCMS: m/z 523 [M+1]+.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C@:4]12[CH2:12][CH2:11][C:10]3[C:13]4[CH:14]=[CH:15][C:16]([O:21][CH3:22])=[CH:17][C:18]=4[CH2:19][CH2:20][C:9]=3[C@@H:8]1[CH2:7][CH2:6][C:5]2=[O:23].C(O)(=O)C>C(O)C>[CH3:3][C@:4]12[CH2:12][CH2:11][C:10]3[C:13]4[CH:14]=[CH:15][C:16]([O:21][CH3:22])=[CH:17][C:18]=4[CH2:19][CH2:20][C:9]=3[C@@H:8]1[CH2:7][CH2:6][C@@H:5]2[OH:23]
Reactant: COc1ccc2c(c1)CCC1=C2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCC1=C2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Yield: 44.7 %

Procedure:
Add sodium borohydride (0.5 g.) in ethanol (60 cc.) with stirring to 13-methyl-3-methoxygona-1,3,5(10),8-tetraen-17-one (2.0 g.) in ethanol (150 cc.) at 14°-15°. Leave the mixture at room temperature for 1 hour, acidify with glacial acetic acid and evaporate to dryness under reduced pressure. Treat the residue with water, ether-extract and wash and dry. Evaporate the extracts. Recrystallize the residue from a mixture of methanol (15 cc.) and water (3 cc.) to obtain the title product (0.90 g.), m.p. 110°-2°. A sample sublimes at 110°/10-4 mm. and has an ultra-violet absorption peak at 277 mμ (ε 14,500).
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5].[Na].[BH4-].[Na+].[CH2:15]([NH2:18])[CH2:16][CH3:17]>C(O)C>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH:4]([OH:5])[CH2:3][NH:18][CH2:15][CH2:16][CH3:17])[CH:7]=1
Reactant: CCCN
Reactant: O=C(CBr)c1cccnc1
Agent: Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCNCC(O)c1cccnc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To 1.01 g (3.6 mmol) of 3-bromoacetylpyridine hydrobromide, prepared as described in Example 1, was added 20 ml of absolute ethanol and 0.5 g (13.2 mmol) of sodium boronhydride (NaBH4). The reaction mixture was stirred at 20° C. for 2 hours and filtered. To the filtrate containing 3-pyridyloxirane was added 0.7 ml (8.5 mmol) of n-propylamine and heated at reflux temperature of the reaction mixture for 5 hours. The reaction mixture was then evaporated to a dry residue and to it was added 20 ml of chloroform, a solid portion was filtered off, the filtrate was evaporated and an oil residue formed was purified by column chromatography on silica gel (silica gel 60, mobile phase: CHCl3:ethyl acetate=10:2). This yields 0.33 g (50%) of 1-(3-pyridyl)-2-propylaminoethanol in the form of the oil base (molecular weight: 180.25, gross formula: C10H16N2O)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[C:8]([C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1)([O:10][CH2:11][CH3:12])=[O:9].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:5]1[CH:6]=[CH:7][C:2]([C:17]2[CH:18]=[C:13]([CH:14]=[CH:15][CH:16]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:3][CH:4]=1
Reactant: Brc1ccncc1
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1cccc(-c2ccncc2)c1
Yield: 84.6 %

Procedure:
Part A. A solution of 4-bromopyridine (1.0 g, 5.2 mmol) in acetonitrile-water (10 mL/5 mL) is treated with 3-carboethoxybenzeneboronic acid (0.93 g, 5.2 mmol), sodium carbonate (2.2 g, 21 mmol) and catalytic tetrakis(triphenylphosphine)palladium. The solution is heated to reflux for 12 h., then cooled and extracted with ethyl acetate. The extract is washed with brine, dried over sodium sulfate, filtered and evaporated. The residual material is separated by flash chromatography to afford ethyl 3-pyridin-4-yl-benzoate (1.0 g, 86%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20]C(=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CCC2C(SC(=O)N(C)C)=C(Cl)C=C(Cl)C=2CC1)=O)(C)(C)C.[OH-].[K+].I[CH2:55][CH2:56][O:57][CH:58]([CH3:60])[CH3:59]>CO.[Cl-].[NH4+]>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:55][CH2:56][O:57][CH:58]([CH3:60])[CH3:59])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: CC(C)OCCI
Agent: CN(C)C(=O)Sc1c(Cl)cc(Cl)c2c1CCN(C(=O)OC(C)(C)C)CC2
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: CC(C)OCCSc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Temperature: 57.5 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
To a 4:1 mixture of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 3-tert-butoxycarbonyl-7,9-dichloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (200 mg, 0.52 mmol) in methanol (5 mL) under nitrogen, add potassium hydroxide (0.9 g, 16.1 mmol) at ambient temperature. When the mixture becomes homogenous, heat at 55-60° C. for 2-3 h, until TLC shows the disappearance of starting material. Cool to ambient temperature, add aqueous saturated ammonium chloride, extract three times with diethyl ether, dry over anhydrous MgSO4, and concentrate in vacuo. Dissolve the crude 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine in anhydrous THF (5 mL) under nitrogen and add with stirring 1.0 M potassium t-butoxide in THF (1.0 mL) at ambient temperature. After 10 min, add 2-(2-iodoethoxy)propane (223 mg, 1.04 mmol), and allow the reaction to continue overnight. Dilute with aqueous saturated ammonium chloride, extract the mixture three times with diethyl ether, dry over anhydrous MgSO4, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (12:1) to provide 3-tert-butoxycarbonyl-7-chloro-6-(2-isopropoxy-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a clear oil (127 mg, 63%). Use a method similar to the General Procedure 1-4 to give the title compound as a white solid. MS (ES+) m/z: 300 (M+H)+.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:18][O:19][CH3:20])[C:7]2=[O:21])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:29])C=CC=CC=1>ClCCl>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16]([CH3:17])=[O:29])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:18][O:19][CH3:20])[C:7]2=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COCc1cc2cnc(SC)nc2n(C2CCCC2)c1=O
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: ClCCl
Product: COCc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 53.7 %

Procedure:
8-Cyclopentyl-6-methoxymethyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (4.44 g, 14.54 mmol) and 2-benzenesulfonyl-3-phenyl-oxaziridine (4.94 g, 18.90 mmol) were dissolved in dichloromethane (100 mL) and stirred at ambient temperature for 12 hours. The solvent volume was reduced to approximately 50 mL and was then purified by silica gel chromatography to give 8-cyclopentyl-2-methanesulfinyl-6-methoxymethyl-8H-pyrido[2,3-d]pyrimidin-7-one as an off-white solid (2.51 g, 53.7%). 1H NMR δ(400 MHz, CDCl3) 8.93 (s, 1H), 7.78 (t, J=1.7 Hz, 1H), 5.99 (m, 1H), 4.46 (d, J=1.7 Hz, 1H), 3.53 (s, 3H), 2.96 (s, 3H), 2.23 (m, 2H), 2.12 (m, 2H), 1.93 (m, 2H), 1.69 (m, 2H).
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([NH2:9])[NH:6][N:5]=2)[CH2:3][CH2:2]1.Br[C:11]1[C:12](=[O:19])[N:13]([CH3:18])[CH:14]=[C:15]([Br:17])[CH:16]=1>>[Br:17][C:15]1[CH:16]=[C:11]([NH:9][C:7]2[NH:6][N:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[CH:8]=2)[C:12](=[O:19])[N:13]([CH3:18])[CH:14]=1
Reactant: Nc1cc(C2CC2)n[nH]1
Reactant: Cn1cc(Br)cc(Br)c1=O
Product: Cn1cc(Br)cc(Nc2cc(C3CC3)n[nH]2)c1=O
Yield: 20.7 %

Procedure:
Using the same general procedure as Example 109c, reaction of 3-cyclopropyl-5-amino-1H-pyrazole (500 mg, 4.06 mmol) and 3,5-dibromo-1-methylpyridin-2(1H)-one (1.08 g, 4.06 mmol) afforded a 21% yield (260 mg) of 110a as an off-white solid: mp 203-204° C.; 1H NMR (500 MHz, DMSO-d6) δ 8.20 (s, 1H), 8.02 (d, 1H, J=2.5 Hz), 7.34 (d, 1H, J=2.5 Hz), 5.77 (d, 1H, J=2.1 Hz), 3.48 (s, 3H), 1.84 (m, 1H), 0.90 (m, 4H), 0.63 (m, 4H); MS (ESI+) m/z 309.0 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([O:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:4]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(Cl)Cl>[N:12]1([CH2:11][CH2:10][CH2:9][O:8][C:5]2[CH:4]=[C:3]([CH2:2][CH:21]3[CH2:22][CH2:23][NH:18][CH2:19][CH2:20]3)[O:7][N:6]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C1CCNCC1
Reactant: ClCc1cc(OCCCN2CCCCC2)no1
Solvent: ClCCl
Product: c1c(OCCCN2CCCCC2)noc1CC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
1-[3-(5-Chloromethyl-isoxazol-3-yloxy)-propyl]-piperidine (0.15 g, 0.80 mmol) was dissolved in DCM (5 mL) and piperidine (0.24 mL, 2.4 mmol) was added slowly. The reaction mixture was stirred overnight at rt and then was concentrated to yield the crude product (0.140 g). The crude product was purified (SiO2: 0-5% 2 M NH3 in MeOH/DCM) to give the final product (0.118 g, 47.6%). MS (ESI): exact mass calcd. for C17H29N3O2, 307.23; m/z found 308.4 [M+H]+. 1H NMR (500 MHz, CDCl3): 5.75 (s, 1H), 4.25-4.20 (m, 2H), 3.53 (s, 2H), 2.47-2.31 (m, 10H), 1.98-1.90 (m, 2H), 1.61-1.52 (m, 8H), 1.45-1.35 (m, 4H).