Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH3:2][O:3][CH:4]([O:12]C)[C:5]([C:8](OC)=O)=[CH:6]O.S(O)(O)(=O)=O.[CH3:19][S:20][C:21](=[NH:23])[NH2:22]>CO.C(OCC)(=O)C>[CH3:19][S:20][C:21]1[N:23]=[CH:8][C:5]([C:4]([O:3][CH3:2])=[O:12])=[CH:6][N:22]=1
Reactant: CSC(=N)N
Reactant: COC(=O)C(=CO)C(OC)OC
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(SC)nc1
Yield: 76 %

Procedure:
A solution of the sodium salt of 3,3-dimethoxy-2-methoxycarbonylpropen-1-ol (5.0 g, 25 mmol), 2-methyl-2-thiopseudourea sulfate (3.5 g, 25 mmol) in anhydrous methanol (25 mL) was refluxed for 3 hours under anhydrous conditions. The reaction mixture was cooled and diluted with ethyl acetate. The reaction mixture was filtered and the residue was washed with ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography (silica gel) using 25% ethyl acetate in hexane to afford the desired product (3.5 g, 75%) as a white powder. 1H-NMR (d6-DMSO, 400 MHz) δ 9.0 (s, 2H), 3.92 (s, 3H), 2.58 (s, 3H); ES-HRMS m/z 185.041 (M+H C7H8N2O2S requires 185.0379).
Reaction SMILES: IC.[CH3:3][C:4]1[CH:27]=[CH:26][C:7]2[CH:8]([C:18]3[C:19](=[S:25])[NH:20][C:21](=[O:24])[NH:22][CH:23]=3)[C:9]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:10]=3[CH:11]=[CH:12][C:6]=2[CH:5]=1.[C:28](=O)(O)[O-].[Na+]>C(O)C.O>[CH3:3][C:4]1[CH:27]=[CH:26][C:7]2[CH:8]([C:18]3[C:19]([S:25][CH3:28])=[N:20][C:21](=[O:24])[NH:22][CH:23]=3)[C:9]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:10]=3[CH:11]=[CH:12][C:6]=2[CH:5]=1
Reactant: Cc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1c[nH]c(=O)[nH]c1=S
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CI
Solvent: O
Product: CSc1nc(=O)[nH]cc1C1c2ccc(C)cc2C=Cc2cc(C)ccc21
Reaction time: 0.5 h

Procedure:
Iodomethane (0.2 ml) was added to a stirred suspension of the product from step (i) (0.65 g) and sodium bicarbonate (0.4 g) in ethanol (15 ml) and water (4 ml). After stirring for 30 min, the reaction mixture was washed with water, 1M hydrochloric acid, aqueous sodium bicarbonate, water, dried (MgSO4) and evaporated under reduced pressure. The residue was triturated with ether and filtered. Yield 0.49 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][CH:7]=1.C[Si]([C:13]#[N:14])(C)C.C(N(CC)CC)C>CC#N>[F:1][C:2]1[C:3]([C:13]#[N:14])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C#N
Reactant: [O-][n+]1cccc(F)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1ncccc1F

Procedure:
The mixture of 3-fluoro-pyridine 1-oxide (0.99 g, 8.75 mmol), trimethylsilyl cyanide (4.80 ml, 35.0 mmol), and triethyl amine (1.84 ml, 13.2 mmol) in 100 ml of CH3CN was heated at reflux overnight. The solvents were removed, under reduced pressure and the residue was partitioned between EtOAc and saturated NaHCO3. The organic portion was separated, dried with Na2SO4, filtered, condensed, the crude compound as purified by flash column chromatography (10 to 20% of EtOAc in hexanes). The titled compound was obtained as a light yellowish solid. MS (ES+): 123.1 (M+H)+. Calc'd for C6H3FN2—122.10.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[OH:12][CH2:13][CH:14]1[CH2:16][CH2:15]1.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O.O>[Br:1][C:2]1[C:3]([O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Reactant: OCC1CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cnc(OCC2CC2)c(Br)c1
Yield: 59.4 %

Procedure:
A mixture of 3.0 g (13 mmol) 5-Bromo-6-chloro-nicotinic acid, 1.4 g (19 mmol) (hydroxymethyl)cyclopropane and 2.85 g (51 mmol) potassium hydroxide in DMSO (12 mL) was heated under microwave radiation for 6 min to 100° C. 50 mL water and 150 mL citric acid (10%) was added. A solid precipitated, was filtered off, re-dissolved in ethyl acetate and dried with Na2SO4. The product crystallized upon evaporation of the solvent from ethyl acetate/heptane 1:1 to yield 2.1 g (71%) of the title compound as white solid, MS (ISP): 270.3 (M−H).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH:7]1[C:16](=[O:17])[C:15]2[NH:14][CH:13]=[N:12][C:11]=2[N:10]=[C:8]1[NH2:9]>N1C=CC=CC=1>[C:1]([NH:9][C:8]1[NH:7][C:16](=[O:17])[C:15]2[NH:14][CH:13]=[N:12][C:11]=2[N:10]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Reactant: CC(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)C(=O)Nc1nc2nc[nH]c2c(=O)[nH]1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Isobutyryl chloride (2.02 mL, 19.9 mmol) was added dropwise to a stirred suspension of guanine (3.02 g, 20 mmol) and TEA (1.45 mL, 10.4 mmol) in anhydrous pyridine (40 mL). The mixture was stirred for 3 h at 100° C. The reaction was quenched using methanol, and the solid was filtered, washed with methanol and dried in vacuo to give 10: yield 2.67 g (60%); MS (+ESI): m/z 222 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:14]1([C:9]2[CH:8]=[CH:13][CH:12]=[CH:11][C:10]=2[N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: Brc1ccccc1C1CCCCC1
Reactant: C1CNCCN1
Product: c1ccc(N2CCNCC2)c(C2CCCCC2)c1

Procedure:
The title compound was prepared in a manner similar to Preparation 1A except that piperazine was coupled to 1-bromo-2-cyclohexyl-benzene.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:2].C([O:16][C:17]([C:19]1[C:20](Cl)=[N:21][C:22]([S:25][CH3:26])=[N:23][CH:24]=1)=O)C.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:5]1[CH2:6][N:7]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[C:20]2[N:21]=[C:22]([S:25][CH3:26])[N:23]=[CH:24][C:19]=2[C:17]1=[O:16])=[O:13])[CH3:2]
Reactant: CCOC(=O)CCNC1CCCC1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CN(C2CCCC2)c2nc(SC)ncc2C1=O
Reaction time: 16 h

Procedure:
3-Cyclopentylamino-propionic acid ethyl ester (1.0 g, 5.4 mmol) and 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (1.25 g, 5.4 mmol) were combined in DCM (10 mL) and diisopropylethylamine (0.83 g, 6.5 mmol) was added. After 16 h, the solution was partitioned between water and DCM and the organic layer was dried (MgSO4) and concentrated. Chromatography (0-20% EtOAc/hexanes gradient) provided the title compound that was directly carried on to the next step. Sodium (25 wt % dispersion in paraffin wax, 0.25 g, 6.0 mmol) was added to t-butanol (5.0 mL) at rt. After 10 minutes, a solution of 4-[cyclopentyl-(2-ethoxycarbonyl-ethyl)-amino]-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (2.0 g, 5.4 mmol) in 10 mL of toluene was added to the sodium t-butoxide solution and the resulting mixture was heated at 90° C. for 30 minutes. The reaction mixture was then cooled and the solution was adjusted to pH 7 using a 1N HCl solution. The solution was then extracted with EtOAc (2×20 mL) and the organic layer was dried (MgSO4) and concentrated to provide 0.26 g (14%). 1H-NMR (400 MHz, CDCl3:) 5 ppm 12.0 (br s, 1H), 8.20 (s, 1H), 5.10-5.18 (m, 1H), 4.26-4.31 (m, 3H), 3.72 (q, 2H, J=7.0 Hz), 2.50 (s, 3H), 1.63-1.86 (m, 5H), 1.20-1.35 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][OH:13].[N:14]([C:17]1[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=1)=[C:15]=S.Cl.CN(C)CCCN=C=NCC.CN(C)C>O1CCCC1.C(OCC)(=O)C.O>[NH2:8][C:4]1[C:3]2[N:9]([CH2:10][CH2:11][CH2:12][OH:13])[C:15]([NH:14][C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)=[N:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(N)c1NCCCO
Reactant: COc1ncc(N=C=S)c(OC)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ncc(Nc2nc3cccc(N)c3n2CCCO)c(OC)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 14.4 %

Procedure:
To a solution of 3-[(2,6-diaminophenyl)amino]propan-1-ol (Reference Example 115; 363 mg, 2.00 mmol) in tetrahydrofuran (5.0 mL) was added 5-isothiocyanato-2,4-dimethoxypyrimidine (440 mg, 2.20 mmol) portionwise at room temperature. After stirring for 2 hr, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (422 mg, 2.20 mmol) and trimethylamine (0.331 mL, 2.40 mmol) was added. The mixture was warmed to 50° C. and stirred for additional 3 hr. Water and ethyl acetate were added to the mixture and the insoluble materials were filtered off. The filtrate was extracted with ethyl acetate. Organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 0-15% methanol/ethyl acetate gradient mixture. The filtrate was concentrated in vacuo to give the title compound (99 mg, 0.287 mmol, 14%) as a pale yellow amorphous.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:27])=[C:5]([C@@H:10]2[O:15][CH2:14][C@@H:13]3[CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][CH2:19][N:12]3[CH2:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]>>[F:31][C:30]([F:33])([F:32])[C:28]([OH:34])=[O:29].[F:9][C:8]1[C:3]([C:1]#[N:2])=[C:4]([CH3:27])[C:5]([C@@H:10]2[O:15][CH2:14][C@@H:13]3[CH2:16][NH:17][CH2:18][CH2:19][N:12]3[CH2:11]2)=[CH:6][CH:7]=1
Reactant: Cc1c([C@H]2CN3CCN(C(=O)OC(C)(C)C)C[C@H]3CO2)ccc(F)c1C#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1c([C@H]2CN3CCNC[C@H]3CO2)ccc(F)c1C#N

Procedure:
tert-Butyl (3S,9aS)-3-(3-cyano-4-fluoro-2-methylphenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (1.88 g, 5.01 mmol) was treated with 10 mL TFA at RT for 1 h. The TFA was then removed under reduced pressure to yield the title compound. LC-MS: M+1=276: 1H-NMR (600 MHz, DMSO) δ ppm 7.954 (dd, J=8.7, 6.25 Hz, 1H), 7.412 (t, J=8.85 Hz, 1H), 4.939 (dd, J=8.4, 2.75 Hz, 1H), 3.848 (d, J=11.8 Hz, 1H), 3.762 (b, 1H), 3.189-3.536 (m, 8H), 3.072 (d, J=12 Hz, 1H), 2.485 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:6][CH:7]=1.[CH3:25][C:26]([CH3:28])=O.C([BH3-])#N.[Na+]>CO.C(O)(=O)C.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:19][CH2:20][N:21]([CH:26]([CH3:28])[CH3:25])[CH2:22][CH2:23]2)=[N:6][CH:7]=1
Reactant: O=C(Nc1ccc(Cl)cn1)c1ccccc1NCC1CCNCC1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)N1CCC(CNc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
A solution of N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.152 g, 0.4 mmol) in methanol-acetic acid (95:5) (5 mL) was treated with acetone (5 mL) and sodium cyanoborohydride (0.111 g, 1.8 mmol). The reaction mixture was stirred at room temperature for 24 h, then it was diluted with 1 N NaOH until pH 13 and extracted with dichloromethane. The organic extracts were combined, dried with MgSO4, filtered and concentrated in vacuo to provide the title compound (0.158 g, 92%). The crude material was triturated in dichloromethane-hexanes, giving a white powder which was filtered and dried under vacuum at 60° C.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:12][C:11](=O)[CH2:10][CH2:9][N:8]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:4][CH:3]=1.[N+:23](CS(C1C=CC(C)=CC=1)(=O)=O)#[C-:24].CC(C)([O-])C.[K+].O>COCCOC>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:12][CH:11]([C:24]#[N:23])[CH2:10][CH2:9][N:8]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1Cc1ccc(Cl)cc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(C#N)CC1Cc1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 2 h
Yield: 61.3 %

Procedure:
To a solution of tert-butyl 2-(4-chlorobenzyl)-4-oxopiperidine-1-carboxylate (8.737 g, 26.98 mmol) in DME (200 mL) under nitrogen was added simultaneously 1-(isocyanomethyl-sulfonyl)-4-methylbenzene (7.90 g, 40.47 mmol) in 200 mL DME and potassium tert-butoxide (81 mL, 80.94 mmol) over 1 hour so that the temperature never rose above 0° C. The solution was stirred at −20° C. for 2 h and then let to warm to room temperature overnight. Water (200 mL) was added to the orange reaction mixture and the solution was stirred for 20 min and then extracted with 3× diethyl ether and 3× EtOAc. The organic phases were combined and dried over Na2SO4 and evaporated to give a brown residue. Further purification was done on Biotage (340 g column, 3 runs, heptane/EtOAc, gradient 20-60% EtOAc) to give tert-butyl 2-(4-chlorobenzyl)-4-cyanopiperidine-1-carboxylate (5.54 g, 61%). 1H NMR (400 MHz, cdcl3) δ, 1.21-1.50 (m, 9H), 1.58-2.14 (m, 4H), 2.55-3.27 (m, 4H), 4.06-4.25 (m, 1H), 4.34-4.60 (m, 1H), 7.02-7.34 (m, 4H). MS m/z 235, 237 (M-C5H8O2+H)+
Reaction SMILES: [OH-].[Na+].[CH2:3]([Cl:6])[CH:4]=[CH2:5].[C:7](#[N:10])[CH:8]=[CH2:9].S(OOS([O-])(=O)=O)([O-])(=O)=[O:12].[K+].[K+]>O>[C:7](#[N:10])[CH:8]=[CH2:9].[CH2:3]([OH:12])[CH:4]=[CH2:5].[CH2:3]([Cl:6])[CH:4]=[CH2:5]
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C=CCCl
Solvent: C=CC#N
Product: C=CCO
Reaction time: 6.5 h

Procedure:
About 10 parts by weight of fine granular silica, 2.5 parts by weight of sodium hydroxide flakes and 2 parts by weight of water are mixed then heated at 90 degrees to 100 degrees C. until the water evaporates, thereby producing an activated silica. 30 parts by weight of allyl chloride, 3 parts by weight of acrylonitrile, 12 parts by weight of water and 0.2 parts by weight of potassium persulfate are mixed then agitated at a temperature just below the boiling temperature of the reactants at ambient pressure for 1 to 12 hours, thereby producing a white, solid poly (allyl chloride allyl alcohol acrylonitrile) copolymer.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:23])([CH3:22])[CH2:10][CH:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=3)[NH:12]2)=[CH:7][CH:6]=1)=[O:4].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:23])([CH3:22])[CH2:10][CH:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:16]=3)[NH:12]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc2c(c1)NC(c1cccc(Br)c1)CC2(C)C
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: COC(=O)c1ccc2c(c1)NC(c1cccc(N3CCOCC3)c1)CC2(C)C
Temperature: 25 °C
Yield: 79.7 %

Procedure:
A mixture solution of 2-(3-bromo-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid methyl ester (11.2 g, 30.0 mmol), morpholine (26.0 mL, 294.0 mmol), copper(I) iodide (3.4 g, 18.0 mmol), N,N-dimethylglycine hydrochloride (3.4 g, 24.0 mmol), and potassium carbonate (12.4 g, 90.0 mmol) in dimethyl sulfoxide (65 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature. The reaction mixture was extracted with ethyl acetate (200 mL×2), washed with saturated aqueous ammonium chloride solution (50 mL×3) and brine (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 30-50% ethyl acetate in petroleum ether) to afford 4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid methyl ester (9.1 g, 80%) as a white solid: MS (ESI) M+1=381.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]([CH3:25])([CH3:24])[N:5]1[C:11]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=2[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:8][CH2:7][C:6]1=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:28].N1C=CC=CC=1>C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:26])[C:4]([CH3:25])([CH3:24])[N:5]1[C:11]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=2[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:8][CH2:7][C:6]1=[S:28]
Reactant: COC(=O)C(C)(C)N1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(C)(C)N1C(=S)CN=C(c2ccccc2)c2cc(Cl)ccc21

Procedure:
A mixture of 0.01 mole of 7-chloro-α,α-dimethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-acetic acid methyl ester, 0.0105 mole of phosphorus pentasulfide and 100 ml. of pyridine is heated under reflux for about 24 hours. The mixture is evaporated and the residue thus obtained is dissolved in methylene chloride-water. The organic layer is separated, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and evaporated to remove the solvent. The residue thus obtained is chromatographed on silica gel and eluted to give 7-chloro-α,α-dimethyl-2,3-dihydro-2-thioxo-5-phenyl-1H-1,4-benzodiazepin-1-acetic acid methyl ester.
Reaction SMILES: [C@H]1(N[C:12]([C@@H:14]2[CH2:23]C3C(=CC(OS(C(F)(F)F)(=O)=O)=CC=3)[CH2:16][N:15]2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:13])C2C(=CC=CC=2)CCC1.[NH2:39][C@@H:40]([C:69]([CH3:72])([CH3:71])[CH3:70])[C:41]([N:43]1[C@H:52]([C:53]([NH:55][C@H:56]2[C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[CH2:59][CH2:58][CH2:57]2)=[O:54])[CH2:51][C:50]2[C:45](=[CH:46][C:47]([N+:66]([O-:68])=[O:67])=[CH:48][CH:49]=2)[CH2:44]1)=[O:42].C(OC(N(C)[C@@H](C)C(O)=O)=O)(C)(C)C>>[CH3:70][C:69]([CH3:72])([CH3:71])[C@H:40]([NH:39][C:12](=[O:13])[C@@H:14]([N:15]([CH3:16])[C:32](=[O:33])[O:34][C:35]([CH3:36])([CH3:38])[CH3:37])[CH3:23])[C:41]([N:43]1[C@H:52]([C:53](=[O:54])[NH:55][C@H:56]2[C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[CH2:59][CH2:58][CH2:57]2)[CH2:51][C:50]2[C:45](=[CH:46][C:47]([N+:66]([O-:68])=[O:67])=[CH:48][CH:49]=2)[CH2:44]1)=[O:42]
Reactant: CC(C)(C)[C@H](N)C(=O)N1Cc2cc([N+](=O)[O-])ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Reactant: CC(C)(C)OC(=O)N1Cc2cc(OS(=O)(=O)C(F)(F)F)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Agent: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Product: C[C@@H](C(=O)N[C@H](C(=O)N1Cc2cc([N+](=O)[O-])ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Yield: 97 %

Procedure:
Following a procedure analogous to that for the synthesis of Compound D, (S)-2-((S)-2-amino-3,3-dimethylbutanoyl)-7-nitro-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (2.17 g, 4.67 mmol) and (S)-2-((tert-butoxycarbonyl)(methyl)amino)propanoic acid (Advanced ChemTech, 0.95 g, 4.67 mmol) were converted to the title compound (2.93 g, 97%). MS (ESI+) m/z 650.5 (M+H)+.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]([CH2:6][CH2:7][CH:8]1[CH:17]2[N:12]([CH2:13][CH2:14][C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][C:16]=32)[CH2:11][CH2:10][CH2:9]1)=[O:5].[C:25](=O)([O-])[O-].[Na+].[Na+]>ClCCl>[ClH:1].[CH2:2]([O:3][C:4]([CH2:6][CH2:7][CH:8]1[CH:17]2[N:12]([CH2:13][CH2:14][C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][C:16]=32)[CH2:11][CH2:10][CH2:9]1)=[O:5])[CH3:25]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)CCC1CCCN2CCc3c([nH]c4ccccc34)C12
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CCC1CCCN2CCc3c([nH]c4ccccc34)C12
Reaction time: 2 h

Procedure:
0.35 g (1 mmole) of 1-(2'-methoxycarbonyl-ethyl)-1,2,3,4,6,7.12,12b-octahydro-indolo[2,3-a]quinolizine hydrochloride are partitioned between 10 ml of dichloromethane and 3 ml of 5% aqueous sodium carbonate solution, and the aqueous phase is extracted with 2×3 ml of dichloromethane. The organic phases are combined, dried over magnesium sulfate, filtered, and the filtrate is evaporated. The oily residue is dissolved in 15 ml of absolute ethanol, 50 mg of sodium ethoxide are added to the solution, and the mixture is boiled for 2 hours. Thereafter the mixture is cooled, the sodium ethoxide is decomposed with glacial acetic acid, and the solution is evaporated to dryness in vacuo. The residue is admixed with 10 ml of 5% aqueous sodium carbonate solution, and the mixture is extracted with 20 ml of dichloromethane. The organic phase is filtered, the filtrate is dried over magnesium sulfate, filtered again, and then evaporated in vacuo to dryness. The obtained 0.30 g of oily residue are dissolved in 2 ml of ethanol, the solution is acidified to pH 6 with ethanolic hydrochloric acid, the separated salt is filtered off, washed with ethanol and ether, and dried.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH2:10]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:10][C:9]([C:2]1[CH:3]=[C:4]([C:9]([CH3:10])([CH3:8])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:1]=1[OH:7])([CH3:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1ccccc1
Reactant: C=C(C)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(c1ccccc1)c1ccc(O)c(C(C)(C)c2ccccc2)c1
Temperature: 140 °C

Procedure:
This intermediate was made by the general procedure of U.S. Pat. No. 2,714,120 by reacting a mixture of 705.8 grams (7.5 moles) of phenol with 1772.7 grams (15 moles) of α-methylstyrene in the presence of 25.7 grams (0.135 moles) of p-toluenesulfonic acid monohydrate catalyst. This mixture was heated under nitrogen at 140° C. for 2.5 hours. The reaction mixture was cooled to 110° C. and 1125 ml of toluene was added. After washing the resulting solution at 80° C. with 750 ml of an aqueous solution of 37.5 grams of sodium carbonate and 75 grams of sodium chloride, the organic phase was washed thrice with 1000 ml of aqueous sodium chloride solution; then dried over anhydrous sodium sulfate; filtered and vacuum distilled. The above-named product was obtained as the main fraction boiling at 172°-175° C./0.15-0.18 mm Hg in a yield of 1229.8 grams (49.6% of theory). The product melted 63° -65° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](I)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:12]1[O:16][C@H:15]([C:17]([NH:19][CH2:20][CH3:21])=[O:18])[C@@H:14]([OH:22])[C@H:13]1[OH:23].[CH2:24]([CH:27]1[CH2:32][CH2:31][CH:30]([C:33]([O:35][CH3:36])=[O:34])[CH2:29][CH2:28]1)[C:25]#[CH:26]>C(#N)C.[Cu]I.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>[CH3:21][CH2:20][NH:19][C:17]([C@H:15]1[O:16][C@@H:12]([N:6]2[C:7]3[N:8]=[C:9]([C:26]#[C:25][CH2:24][CH:27]4[CH2:32][CH2:31][CH:30]([C:33]([O:35][CH3:36])=[O:34])[CH2:29][CH2:28]4)[N:10]=[C:2]([NH2:1])[C:3]=3[N:4]=[CH:5]2)[C@H:13]([OH:23])[C@@H:14]1[OH:22])=[O:18]
Reactant: C#CCC1CCC(C(=O)OC)CC1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(N)nc(I)nc32)[C@H](O)[C@@H]1O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(N)nc(C#CCC4CCC(C(=O)OC)CC4)nc32)[C@H](O)[C@@H]1O
Temperature: 70 °C
Reaction time: 24 h
Yield: 24 %

Procedure:
To a degassed solution of 25 mg (0.063 mmol) of [(2S,3S,4R,5R)-5-(6-amino-2-iodopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]-N-ethylcarboxamide (6.9), 16.9 mg (0.094 mmol) (5.5), and 0.75 mg CuI in 5 mL each of TEA and acetonitrile was added 15 mg of Pd(PPh3)4. The solution was stirred for 24 hours at 70° C. after which time the solution was filtered through celite and chromatographed on silica gel with MeOH—CHCl3 (5:95) to give DWH-146e (24%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=2[O:18][CH3:19])[CH2:5][CH2:4][CH2:3][CH2:2]1.CC1C=C(C2OC(C)=NN=2)C=CC=1C1C=CC(C(O)=O)=CC=1>>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[C:13]([CH:12]=[CH:11][C:10]=2[O:18][CH3:19])[NH2:15])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc([N+](=O)[O-])cc1OCCN1CCCC1
Agent: Cc1nnc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)o1
Product: COc1ccc(N)cc1OCCN1CCCC1

Procedure:
The title compound was prepared from 2-(2-pyrrolidin-1-ylethoxy)-4-nitroanisole (D30) using a similar procedure to Description 2 (96%).