Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:13][CH2:14][O:15][CH2:16][CH3:17].O>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][CH2:13][CH2:14][O:15][CH2:16][CH3:17])=[CH:4][CH:3]=1
Reactant: CCOCCBr
Reactant: OCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCOCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.6 %

Procedure:
In DMF (120 ml) was dissolved 4-bromobenzyl alcohol (15 g). To the mixture was added under ice-cooling 65% sodium hydride (3.0 g), and the mixture was stirred at room temperature for 3 hours. To the mixture was added dropwise at room temperature 2-bromoethylethyl ether (11.4 g), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=10/1) to give 1-bromo-4-[(2-ethoxyethoxy)methyl]benzene (9.0 g). In THF (104 ml) was dissolved 1-bromo-4-[2-ethoxyethoxy)methyl)]benzene (8.7 g). To the mixture was added dropwise at −78° C. 1.6M n-butyllithium/hexane (23 ml), and the mixture was stirred for 1 hour. To the mixture was added dropwise trimethyl borate (8.7 g), and the mixture was stirred for 30 minutes and warmed to room temperature. To the mixture was added 5% sulfuric acid (35 ml), and the mixture was stirred for 15 minutes. The reaction mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=1/2) to give 4-[(2-ethoxyethoxy)methyl]phenyl borate (2.1 g).
Reaction SMILES: F[C:2]1[C:3]([C:8]2([OH:14])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.C(Cl)Cl>[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:2]2[C:3]([C:8]3([OH:14])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:27][CH:26]=1
Reactant: OC1(c2nccnc2F)CCOCC1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: OC1(c2nccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CCOCC1
Temperature: 80 °C

Procedure:
To a solution of 4-(3-fluoropyrazin-2-yl)tetrahydro-2H-pyran-4-ol (0.1 g, 0.505 mmol) in DMSO (1 mL) was added 4-(benzo[d]thiazol-2-ylamino)phenol (0.183 g, 0.757 mmol) and cesium carbonate (0.329 g, 1.009 mmol). The resulting mixture was heated to 80° C. overnight. Reaction mixture was diluted with DCM and washed with alternating washes of water and brine to remove DMSO. Purification by Biotage (0-10% MeOH/DCM) produced product. MS (ESI, pos. ion) m/z: 421.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [N+:1]([NH:4][C:5]([NH2:7])=[NH:6])([O-:3])=[O:2].C[O-].[Na+].[CH:11]([CH:13]([CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)[C:14](OCC)=O)=[O:12]>CO>[N+:1]([NH:4][C:5]1[NH:7][C:11](=[O:12])[C:13]([CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)=[CH:14][N:6]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C(C=O)Cc1cccc2ccccc12
Reactant: N=C(N)N[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1cccc2ccccc12

Procedure:
Nitroguanidine (9.10 g) was added to a solution of sodium methoxide (from 2.22 g sodium) in methanol (100 ml) and the mixture was heated under reflux for 45 minutes, ethyl 2-formyl-3-(1-naphthyl)propionate (16.05 g) was added and the mixture was heated under reflux for 20 hours and evaporated to dryness. The residue was poured into water and the mixture was extracted with chloroform and the pH of the residual aqueous phase was adjusted to 4 with acetic acid. The solid which precipitated was recrystallised from acetic acid to give 2-nitroamino-5-(1-naphthylmethyl)-4-pyrimidone, m.p. 226°-7°.
Reaction SMILES: C([O:8][C:9](=[O:39])[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:38])[CH:18]([C:24]2[CH:33]=[CH:32][C:31]3[C:30]([CH3:35])([CH3:34])[CH2:29][CH2:28][C:27]([CH3:37])([CH3:36])[C:26]=3[CH:25]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][CH:11]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd].CCCCC>[CH3:34][C:30]1([CH3:35])[CH2:29][CH2:28][C:27]([CH3:36])([CH3:37])[C:26]2[CH:25]=[C:24]([CH:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:17]([O:16][C:13]3[CH:12]=[CH:11][C:10]([C:9]([OH:39])=[O:8])=[CH:15][CH:14]=3)=[O:38])[CH:33]=[CH:32][C:31]1=2
Reactant: [H][H]
Reactant: CCCCCC(C(=O)Oc1ccc(C(=O)OCc2ccccc2)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCCCC
Product: CCCCCC(C(=O)Oc1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
403 mg of (RS)-Benzyl-4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-heptanoyloxy]-benzoate in 10 ml of ethyl acetate with 80 mg of palladium on carbon (10% w/w) was subjected to an atmospheric pressure of hydrogen for 1 hour. The mixture was filtered over Celite and washed with about 10 ml ethyl acetate. The solution was evaporated, giving a colorless oil. Trituration in pentane gave a white amorphous solid, 303 mg, m.p. 133-135° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([CH:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1)=[O:11].FC(F)(F)C(O)=O>C(OCC)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3s2)CC1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1nc2ccccc2s1)C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Mix 4-[(2-benzothiazolyl)carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (10.5 g, 30.31 mmol) and trifluoroacetic acid (75 mL) and stir at room temperature for 2 hours. Cool in an ice/water bath and add ethyl ether until a solid begins to precipitate. Stir at 0° C. for 30 minutes, collect the solid by filtration and wash with ethyl ether and recrystallize (methanol/ethyl ether) to give the title compound as a white powder; mp 195°-197° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[N:8][OH:9])=[CH:3][CH:2]=1.C(Cl)(Cl)[Cl:11]>>[OH:9][N:8]=[C:7]([Cl:11])[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: ON=Cc1ccncc1
Reactant: ClC(Cl)Cl
Product: ON=C(Cl)c1ccncc1

Procedure:
4-Pyridinecarboxaldehyde oxime (30.6 g, 0.25 mol) was chlorinated in chloroform (350 ml) as described in Example 1 to produce N-hydroxy-4-pyridine-carboximidoyl chloride which was suspended in ether (500 ml) containing 2-chloroethanethiol (26.9 g, 0.25 mol). With ice bath cooling, triethylamine (5.1 g, 0.5 mol) was added dropwise. After the addition, water was made, the suspended solid, crude 2-chloroethyl N-hydroxy-4-pyridinecarboximidothioate was collected on a filter and dried. This crude ester was added to a solution of sodium ethoxide (from 5.75 g sodium in 500 ml ethanol), and the reaction mixture stirred for 4 hours. Water was added and the product was extracted with ether to give 5,6-dihydro-3-(4-pyridinyl)-1,4,2-oxathiazine, mp 80°-82° C., (found: C, 53.16; H, 4.56; N, 15.07. C8H8N2OS requires C, 53.33; H, 4.48; N, 15.55).
Reaction SMILES: C([NH:4][C:5]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:20][CH:19]=1)(C(OCC)=O)[C:6]([O:8]CC)=[O:7])(=O)C.[ClH:32]>C(O)C>[ClH:32].[NH2:4][CH:5]([CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:23]=1)[C:6]([OH:8])=[O:7]
Reactant: CCCCCCCCc1ccc(CCC(NC(C)=O)(C(=O)OCC)C(=O)OCC)cc1
Agent: Cl
Solvent: CCO
Product: CCCCCCCCc1ccc(CCC(N)C(=O)O)cc1

Procedure:
Diethyl 2-acetamido-2-[2-(4-octylphenyl)ethyl]malonate (20 g) was added to a 5N aqueous hydrochloric acid solution (350 ml) and the mixture was refluxed under heating for 6.5 hours. Ethanol (45 ml) was added to the mixture and the whole mixture was further refluxed under heating for 1.5 hours. The reaction mixture was concentrated under reduced pressure to give the subject compound (20 g). MS: 292(M+).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C:15]([NH2:23])([C:20]([NH2:22])=[O:21])[CH2:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:27]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(OC)OC>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9](=[O:24])[NH:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C:15]1([C:20](=[O:21])[NH:22][C:27]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[N:23]1)[CH2:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)C1(N)Cc2ccc(NC(=O)OCc3ccccc3)cc2C1
Reactant: COC(OC)(OC)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc2c(c1)CC1(C2)N=C(c2ccccc2)NC1=O)OCc1ccccc1

Procedure:
A solution of (±)-benzyl[2-amino-2-(aminocarbonyl)-2,3-dihydro-1H-inden-5-yl]carbamate (described in Intermediate 1, 35.0 mg, 0.108 mmol) and (trimethoxymethyl)benzene (0.022 mL, 0.129 mmol) in toluene (5 mL) was heated at reflux for 7.5 h. The reaction mixture was concentrated under reduced pressure. The crude product was dissolved in DMSO (1 mL) and purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions were combined and concentrated to give the title compound. MS: m/z=412 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([C:12]2[CH:16]=[C:15]([CH:17]=[CH:18][P:19](=[O:26])([O:23]CC)[O:20]CC)[O:14][N:13]=2)=[CH:4][C:3]=1[C:27]([CH3:30])([CH3:29])[CH3:28].C[Si](C)(C)Br.O>ClCCl>[OH:1][C:2]1[C:3]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:4][C:5]([C:12]2[CH:16]=[C:15]([CH:17]=[CH:18][P:19](=[O:20])([OH:23])[OH:26])[O:14][N:13]=2)=[CH:6][C:7]=1[C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CCOP(=O)(C=Cc1cc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)no1)OCC
Agent: C[Si](C)(C)Br
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1cc(-c2cc(C=CP(=O)(O)O)on2)cc(C(C)(C)C)c1O

Procedure:
4.0 g (0.009 mol) of the product from Example 57 were stirred, under a protective gas and at room temperature, in 300 ml of absolute dichloromethane together with 3.9 ml (0.03 mol) of trimethylbromosilane until the reaction was complete (monitoring by TLC). After adding 0.5 ml of water, the mixture was concentrated; the residue was taken up several times in methanol and concentrated under reduced pressure. The oil was stirred with tert-butyl methyl ether until a crystalline residue remained. Yield: 3.0 g.
Reaction SMILES: [C:1]([C:4]1[S:8]/[C:7](=[N:9]\[C:10](=[O:19])[C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2F)/[N:6]([CH2:20][C@H:21]2[CH2:25][CH2:24][CH2:23][O:22]2)[C:5]=1[CH3:26])(=[O:3])[CH3:2].[F:27][C:28]([F:32])([F:31])[CH2:29][OH:30].CC(C)([O-])C.[K+]>O1CCCC1.O>[C:1]([C:4]1[S:8]/[C:7](=[N:9]\[C:10](=[O:19])[C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[O:30][CH2:29][C:28]([F:32])([F:31])[F:27])/[N:6]([CH2:20][C@H:21]2[CH2:25][CH2:24][CH2:23][O:22]2)[C:5]=1[CH3:26])(=[O:3])[CH3:2]
Reactant: OCC(F)(F)F
Reactant: CC(=O)c1s/c(=N\C(=O)c2cc(Cl)ccc2F)n(C[C@H]2CCCO2)c1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1s/c(=N\C(=O)c2cc(Cl)ccc2OCC(F)(F)F)n(C[C@H]2CCCO2)c1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To the solution of the product from Example 280A (360 mg, 0.91 mmol) in tetrahydrofuran (4 mL) was added 2,2,2-trifluoroethanol (227 mg, 2.27 mmol) and a 1.0 M solution of potassium tert-butoxide in tetrahydrofuran (2.27 mL, 2.27 mmol). The reaction mixture was stirred at room temperature for 24 hours. The mixture was diluted with water, and extracted with ethyl acetate. The organic extract was dried (Na2SO4), filtered and concentrated. Purification by reverse phase HPLC afforded the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 1.64-1.75 (m, 1H) 1.90-2.00 (m, 2H) 2.10-2.20 (m, 1H) 2.51 (s, 3H) 2.80 (s, 3H) 3.73 (dd, J=1.59, 7.3 Hz, 1H) 3.88 (dd, J=15.3, 6.7 Hz, 1H) 4.07 (dd, J=13.7, 8.2 Hz, 1H) 4.33-4.41 (m, 1H) 4.47 (dd, J=16.8, 8.2 Hz, 2H) 4.62 (dd, J=13.7, 2.8 Hz, 1H) 7.03 (d, J=8.5 Hz, 1H) 7.39 (dd, J=8.5, 2.8 Hz, 1H) 8.02 (d, J=2.8 Hz, 1H); MS (ESI) m/z 477 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[C:18]([F:20])[C:6]([CH2:7][N:8]([CH3:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[C:5]([F:21])[CH:4]=1)#[N:2].[NH2:22][OH:23]>C(O)C>[F:21][C:5]1[CH:4]=[C:3]([C:1](=[N:22][OH:23])[NH2:2])[CH:19]=[C:18]([F:20])[C:6]=1[CH2:7][N:8]([CH3:17])[CH2:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11]
Reactant: NO
Reactant: CN(CC(=O)OC(C)(C)C)Cc1c(F)cc(C#N)cc1F
Solvent: CCO
Product: CN(CC(=O)OC(C)(C)C)Cc1c(F)cc(C(N)=NO)cc1F

Procedure:
A solution of tert-butyl 2-((4-cyano-2,6-difluorobenzyl)(methyl)amino)acetate (0.281 g, 0.95 mmol) and 50% aqueous hydroxylamine (0.32 mL) in ethanol (1.3 mL) was heated at 75° C. for 18 hours. The solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water, and then the organic phase was passed through a hydrophobic frit. The solvent was evaporated in vacuo to afford the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.22-7.13 (2H, m), 4.81 (2H, br s), 3.91 (2H, s), 3.20 (2H, s), 2.40 (3H, s), 1.48 (9H, s).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:20])[C:5]2[N:6]=[CH:7][N:8]([C@H]3[C@@H](O)[C@@H](O)[C@H](CO)O3)[C:9]=2[N:10]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28]Cl)=[CH:24][CH:23]=1.Cl>CS(C)=O>[NH2:1][C:2]1[NH:3][C:4](=[O:20])[C:5]2[N:6]([CH2:28][C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=3)[CH:7]=[N:8][C:9]=2[N:10]=1
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@@H](CO)[C@H](O)[C@@H]2O)c(=O)[nH]1
Reactant: ClCc1ccc(Cl)cc1
Agent: Cl
Solvent: CS(C)=O
Product: Nc1nc2ncn(Cc3ccc(Cl)cc3)c2c(=O)[nH]1
Temperature: 50 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
To a solution of 2-amino-9-((2R,3S,4R,5S)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1H-purin-6(9H)-one (14 g, 49.47 mmol) in DMSO (50 mL) was added 1-chloro-4-(chloromethyl)benzene (10 g, 62.16 mmol). The reaction was stirred at 50° C. overnight. The mixture was cooled to room temperature and HCl (50 mL, 10% w.w) was added. The reaction was stirred at 70° C. for 2 h. The reaction was cooled and the precipitate was collected and washed with water and ethanol. The product was dried under vacuum to give 2-amino-7-(4-chlorobenzyl)-1H-purin-6(7H)-one (10 g, 74.1% yield) as grey solid. LCMS retention time 0.529 min; LCMS MH+ 276.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.O>[CH2:13]([O:20][C:21]([NH:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCc1c[nH]c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(NCCc1c[nH]c2ccccc12)OCc1ccccc1
Reaction time: 2 h

Procedure:
To a mixture of tryptamine 1.0 g (6.2 mmol) in a mixture of CHCl3 and H2O, was added 1.1 g (6.2 mmol) benzylchloroformate, followed by dropwise addition of sat. NaHCO3 solution to maintain alkaline conditions. The reaction was stirred for 2 hrs. The reaction was extracted with CHCl3 and the organic layer was concentrated to dryness giving a dark yellow oil. The oil was crystallized from ethanol/water to give an off-white crystalline product.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@@H:11]([OH:24])[CH2:12][CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].C(N(CC)CC)C>ClCCl>[CH3:25][S:26]([O:24][C@@H:11]([CH2:12][CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[C@@H:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:10])(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](OCc1ccccc1)[C@@H](O)CCc1cccc2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](OCc1ccccc1)[C@H](CCc1cccc2ccccc12)OS(C)(=O)=O
Temperature: 4 °C
Reaction time: 0.67 h
Yield: 107.4 %

Procedure:
To an ice-cooled solution of (2S,3S)-2-benzyloxy-5-(1-naphthyl)pentan-3-ol (obtained in Preparation 26) (7.43 g) in dichloromethane (100 ml) was added methanesulfonyl chloride (2.15 ml) followed by triethylamine (3.88 ml). The mixture was stirred at 4° C. for 40 min. After being diluted with dichloromethane, the mixture was washed with water and brine, dried and concentrated in vacuo to give (2S,3S)-2-benzyloxy-5-(1-naphthyl)-3-pentyl methanesulfonate (9.92 g, 107.4%) as an oil. The product was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.Br[C:18]1[S:22][C:21]([C:23]#[N:24])=[CH:20][C:19]=1[CH3:25]>>[CH3:1][C:2]1([CH3:16])[O:3][C:4](=[O:15])[NH:5][C:6]2[CH:11]=[CH:10][C:9]([C:18]3[S:22][C:21]([C:23]#[N:24])=[CH:20][C:19]=3[CH3:25])=[CH:8][C:7]1=2
Reactant: Cc1cc(C#N)sc1Br
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Product: Cc1cc(C#N)sc1-c1ccc2c(c1)C(C)(C)OC(=O)N2

Procedure:
5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-4-methylthiophene-2-carbonitrile was prepared, according to the procedure in Example 5 using (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 5-bromo-4-methyl-2-thiophenecarbonitrile, as an off-white solid: mp 195-200° C.; 1H-NMR (DMSO-d6) δ 10.2 (s, 1H), 8.32 (s, 1H), 7.41-7.44 (m, 2H), 7.01 (d, 1H, J=8.8 Hz), 2.28 (s, 3H), 1.64 (s, 6H); MS (APCI) m/z 299 [M+H]+; Anal. Calcd. For C16H14N2O2S; C, 64.41; H, 4.75; N, 8.89. Found: C, 64.64; H, 4.62; N, 9.39.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Cl)=[CH:32][CH:31]=1>O1CCCC1>[CH2:1]([O:3][C:4](=[O:18])[C:5]1([CH2:34][C:33]2[CH:36]=[CH:37][C:30]([Cl:29])=[CH:31][CH:32]=2)[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]1)[CH3:2]
Reactant: ClCc1ccc(Cl)cc1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
A solution of ethyl-N-boc-isonipecotate (51.4 g, 0.2 mole) in tetrahydrofuran (1 L) at -78° C. was treated with a solution of lithium bis (trimethylsilyl)amide in tetrahydrofuran (220 mL of a 1M solution). The solution was stirred at -60° for 15 minutes at which time 4-chlorobenzyl chloride (33.8 g, 0.22 moles) was added and the reaction warmed to room temperature over 1.5 hours. The reaction was concentrated at reduced pressure to one quarter volume and then poured into saturated aqueous sodium bicarbonate (1 L) and extracted with ethyl acetate (2×800 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure. The residue was chromatographed on silica gel with 30% ethyl acetate/hexane as eluent to give 61.3 g.
Reaction SMILES: C(OC1C=CC(C2C=CC(C([NH2:24])(C)C)=CC=2)=CC=1)C1C=CC=CC=1.[N:25]1([CH2:30][CH2:31][CH:32]=O)[CH:29]=[CH:28][N:27]=[CH:26]1>>[N:25]1([CH2:30][CH2:31][CH2:32][NH2:24])[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: O=CCCn1ccnc1
Reactant: CC(C)(N)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Product: NCCCn1ccnc1

Procedure:
In a similar manner to Example 24, 1-(4′-benzyloxybiphenyl-4-yl)-1-methylethylamine (A15) (1.4 g) and 3-(imidazol-1-yl)propionaldehyde (0.72 g) were reacted to give N-1-(4′-benzyloxybiphenyl-4-yl)-1-methylethyl)-3-(imidazol-1-yl)propylamine, m.p. 93-95° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:17]([OH:19])=O)[CH:14]=2)[C@@H:9]1[CH:20]([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([S:25]([C:28]1[CH:33]=[CH:32][C:31]([CH2:34][NH2:35])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH3:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:23]([S:25]([C:28]1[CH:33]=[CH:32][C:31]([CH2:34][NH:35][C:17]([C:13]2[CH:14]=[C:15]3[CH2:16][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C@@H:9]([CH:20]([CH3:21])[CH3:22])[C:10]3=[N:11][CH:12]=2)=[O:19])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH3:24]
Reactant: CC(C)[C@H]1c2ncc(C(=O)O)cc2CN1C(=O)OC(C)(C)C
Reactant: CCS(=O)(=O)c1ccc(CN)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN(C(=O)OC(C)(C)C)[C@H]3C(C)C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 71.5 %

Procedure:
To a solution of (S)-6-(tert-butoxycarbonyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylic acid (83.3 mg, 281 μmol) and (4-(ethylsulfonyl)phenyl)methanamine (67.1 mg, 337 μmol) in DMF (2 mL) at rt was added HATU (160 mg, 421 μmol) and diisopropylethylamine (97.8 μL, 561 μmol). The mixture was stirred at rt for 15 h, at which point it was quenched with saturated aqueous ammonium chloride solution (15 mL). EtOAc (25 mL) was added, then the phases were separated. The organic layer was washed with brine (15 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 50% EtOAc in hexanes, gradient to 100%) to afford 98.0 mg tert-butyl(S)-3-((4-(ethylsulfonyl)benzyl)carbamoyl)-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate, (15), (77%). LC-MS tR=0.92 min in 1 min chromatography, MS (ESI) m/z 488.5 [M+H]+. 1H NMR (CD3OD, 400 MHz, mixture of rotamers): δ 8.94 (d, J=2.0 Hz, 1H), 8.16 (d, J=12.0 Hz, 1H), 7.89 (dd, J=2.0 Hz, 8.4 Hz, 2H), 7.64 (d, J=8.8 Hz, 2H), 4.96 (m, 1H), 4.83 (m, 1H), 4.70 (s, 2H), 4.59 (m, 1H), 3.20 (q, J=7.2 Hz, 2H), 2.56-2.42 (m, 1H), 1.48 (s, 9H), 1.20 (t, J=7.2 Hz, 3H), 1.06 (d, J=7.2 Hz, 1.5H), 1.02 (d, J=6.8 Hz, 1.5H), 0.80 (d, J=6.8 Hz, 1.5H), 0.74 (d, J=6.8 Hz, 1.5H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[N:10][C:11]([Cl:15])=[CH:12][C:13]=1[I:14])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:15][C:11]1[N:10]=[CH:9][C:8]([NH2:7])=[C:13]([I:14])[CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1I
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cnc(Cl)cc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
(6-Chloro-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester (3.67 g, 10.3 mmol) was dissolved in DCM (32 mL) and TFA (8 mL) was added. The reaction mixture was stirred at ambient temperature for 2 h and then evaporated in vacuo. The resultant residue was treated with 5N aqueous sodium hydroxide solution (25 mL), diluted with water (100 mL) and extracted into ethyl acetate (2×100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford the title compound as yellow solid (2.37 g, 90%). 1H NMR (CD3OD, 300 MHz): 7.80 (s, 1H), 7.60 (s, 1H), 4.14 (s, 2H). LCMS (Method B): RT=3.00 min, M+H+=255.
Reaction SMILES: [NH:1]1[C:8](=[O:9])[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[CH3:10]O.[OH-].[Na+].CI>O>[CH3:10][S:3][C:2]1[N:4]=[C:5]([OH:6])[CH:7]=[C:8]([OH:9])[N:1]=1
Reactant: O=C1CC(=O)NC(=S)N1
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: CSc1nc(O)cc(O)n1
Temperature: 41 °C

Procedure:
A quantity (72.07 g., 0.5 mole) of 2-thiobarbituric acid was dissolved in a reaction medium consisting of 500 ml. methanol, 500 ml. water, and 20 g. sodium hydroxide. The medium was heated in order to effect solution. After cooling the solution to 41° C., 142 g. (1.0 mole) methyl iodide was added, with stirring. The reaction mixture was heated at the reflux temperature for 1 hr. The desired 2-(methylthio)-4,6-pyrimidinediol crystallized out as the refluxing continued, and it was recovered on a filter by cooling the reaction mixture to 60° C. and filtering. The initial crop of crystalline product weighed 51.5 g. and had a melting point at >300° C. After refrigerating the mother liquor, an additional 19.08 g. of product was obtained.