Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]C(=O)C)[CH2:7][N:6]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:4].ClCCl.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([SH:10])[CH2:7][N:6]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](SC(C)=O)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H](S)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of (2S,4R)-4-acetylsulfanyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (12.5 g, 41 mmol; CAS Reg. No. 188111-18-4) in MeOH (200 ml) and dichloromethane (20 ml) was added potassium carbonate (5.7 g, 41.2 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 1 h. After the starting material was consumed the solvent was evaporated. The residue was dissolved in water and extracted with EtOAc (2×200 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated to get the crude title compound (9.5 g, 36.1 mmol; 88%) which was used in next step without further purification. MS (ESI): m/z=262.0 [M+H]+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[N:15]([C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[N:18]=2)[CH:14]=[CH:13][S:12]3)=[CH:5][C:4]=1[O:30][CH3:31].CCN(C(C)C)C(C)C.[CH:41]1([S:44](Cl)(=[O:46])=[O:45])[CH2:43][CH2:42]1>C(Cl)Cl>[CH:41]1([S:44]([N:27]2[CH2:26][CH2:25][CH:24]([NH:23][C:19]3[N:18]=[C:17]([C:16]4[N:15]5[C:11]([S:12][CH:13]=[CH:14]5)=[N:10][C:9]=4[C:6]4[CH:7]=[CH:8][C:3]([F:2])=[C:4]([O:30][CH3:31])[CH:5]=4)[CH:22]=[CH:21][N:20]=3)[CH2:29][CH2:28]2)(=[O:46])=[O:45])[CH2:43][CH2:42]1
Reactant: COc1cc(-c2nc3sccn3c2-c2ccnc(NC3CCNCC3)n2)ccc1F
Reactant: O=S(=O)(Cl)C1CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(-c2nc3sccn3c2-c2ccnc(NC3CCN(S(=O)(=O)C4CC4)CC3)n2)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
The 4-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-[piperidin-4-yl]pyrimidin-2-amine hydrochloride (0.25 g, 0.50 mmol) in methylene chloride (DCM) (12 ml) was cooled to 0° C. and was treated with Hunig's base (440 μl, 2.5 mmol). The mixture was kept at 0° C. for 30 minutes then the cyclopropyl-sulfonyl chloride (72 μl, 0.60 mmol) was added. The reaction mixture was stirred at room temperature for one hour. The mixture was diluted with methylene chloride (10 ml) and was washed water (2×10 ml) and a saturated aqueous sodium chloride solution (10 ml). The organic phase was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient (ethyl acetate/hexanes, 30-75%), affording 0.253 g (96%) of the title compound as a pale yellow solid. M.p.: 146-148° C. 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 8.72 (br. s, 1H), 8.13 (d, J=5.1 Hz, 1H), 7.45 (d, J=4.3 Hz, 1H), 7.35 (dd, J=8.6, 2.0 Hz, 1H), 7.26 (dd, J=11.3, 8.2 Hz, 1H), 7.25 (br. S, 1H), 7.15 (ddd, J=8.2, 4.7, 2.0 Hz, 1H), 6.41 (d, J=5.1 Hz, 1H), 3.95-3.86 (m, 1H), 3.83 (s, 3H), 3.68-3.61 (m, 2H), 3.06-2.96 (m, 2H), 2.60-2.52 (m, 1H), 2.08-1.96 (m, 2H), 1.66-1.54(m, 2H), 1.04-0.94 (m, 4H). LCMS: 529 [M+H]. Calc. for C24H25N6O3S2F.0.13 water.0.7 diethyl ether: C, 54.31; H, 5.25; N, 14.18. Found C, 54.32; H, 4.89; N, 14.19.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O.C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:8][CH2:9][CH2:10][C:11]2=[O:13]
Reactant: O=C(O)CCCc1ccccc1F
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1CCCc2c(F)cccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
A round bottom flask was charged with 0.15 g of 4-(2-fluorophenyl)butanoic acid, which was dissolved in 20 mL DCM and cooled to 0° C. Oxalyl chloride (0.15 mL) was added, followed by 1 drop of DMF. A drying tube was attached, and the solution was stirred at 0° C. for two hours. Aluminum chloride (0.121 g) was added and the solution was allowed to slowly warm to RT overnight. The mixture was poured onto ice water, and extracted three times with DCM. The combined organic layers were washed with 0.5 M NaOH and brine. The organic phase was dried, evaporated, and purified by column chromatography (eluting with 20% EtOAc/Hexanes), to give 0.07 g (53%) of 5-fluoro-3,4-dihydronaphthalen-1(2H)-one (32).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[O:11]([CH2:19][CH2:20][CH2:21][OH:22])[Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].C(N(CC)CC)C.Cl>C(Cl)Cl>[O:11]([CH2:19][CH2:20][CH:21]=[O:22])[Si:12]([C:15]([CH3:17])([CH3:18])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)OCCCO
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCC=O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
DMSO (24 mmol) is added to oxalyl chloride (11 mmol) in 40 mL of CH2Cl2 cooled to −78° C. After 15 minutes, alcohol 46 (10 mmol) is added. After an additional 15 minutes, triethylamine (50 mmol) is added. The mixture is allowed to warm to 0° C. and then poured into 0.1 M HCl (100 mL). The phases are separated, and the aqueous phase is extracted with ethyl acetate (2×100 mL). The organic phases are washed with water (100 mL), dried over anhydrous MgSO4, and concentrated in vacuo. The mixture is purified by flash chromatography to give the product as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:11][C:12](=O)[CH3:13])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.Cl>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:11][CH2:12][CH3:13])([CH3:9])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(=O)NC(C)(C)c1ccc(Cl)nc1
Agent: Cl
Solvent: C1CCOC1
Product: CCNC(C)(C)c1ccc(Cl)nc1
Reaction time: 1 h

Procedure:
N-(2-(6-chloropyridin-3-yl)propan-2-yl)acetamide (11.3 g, 53.1 mmol, Eq: 1.00) was dissolved in anhydrous THF (350 ml) and refluxed. BMS (2M in THF) (53.1 ml, 106 mmol, Eq: 2) was added dropwise to the solution and refluxed over night. Conc. HCl solution (15 ml) was gently added to the refluxed reaction mixture and stirred for 1 hr. The reaction mixture was concentrated in vacuo.
Reaction SMILES: [CH:1]1([C:6]([O:8]C)=O)[CH2:5][CH:4]=[CH:3][CH2:2]1.[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>>[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:1]1([CH2:6][OH:8])[CH2:2][CH:3]=[CH:4][CH2:5]1
Reactant: COC(=O)C1CC=CC1
Reactant: BrCCCCCCOC1CCCCO1
Product: OCC1(CCCCCCOC2CCCCO2)CC=CC1

Procedure:
The above procedure was repeated except that methyl cyclopent-3-ene carboxylate (prepared as described by A. H. Schmid and A. W. Wolkoff, J. Org. Chem. 32, 254 (1967)) was used with the 6-tetrahydropyranyloxyhexyl bromide of part D of this example and 1-(6-tetrahydropyranyloxyhexyl)-1-hydroxymethylcyclopent-3-ene was obtained as an oil (IR 3400, 3010 cm-1, nmr τ 4.4, 5.4, 6.35, 7.8, 8.5).
Reaction SMILES: C(O)(=O)C.[N+:5]([C:8]1[CH:9]=[C:10]([CH:33]=[CH:34][CH:35]=1)[C:11]([NH:13][C:14]1[CH:32]=[CH:31][CH:30]=[CH:29][C:15]=1[O:16][C:17]1[CH:18]=[C:19]([C:26]([OH:28])=[O:27])[C:20](=[CH:24][CH:25]=1)[C:21]([OH:23])=[O:22])=[O:12])([O-])=O>[Pd].CO.O>[NH2:5][C:8]1[CH:9]=[C:10]([CH:33]=[CH:34][CH:35]=1)[C:11]([NH:13][C:14]1[CH:32]=[CH:31][CH:30]=[CH:29][C:15]=1[O:16][C:17]1[CH:18]=[C:19]([C:26]([OH:28])=[O:27])[C:20](=[CH:24][CH:25]=1)[C:21]([OH:23])=[O:22])=[O:12]
Reactant: O=C(Nc1ccccc1Oc1ccc(C(=O)O)c(C(=O)O)c1)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: Nc1cccc(C(=O)Nc2ccccc2Oc2ccc(C(=O)O)c(C(=O)O)c2)c1
Reaction time: 20 h

Procedure:
100% acetic acid (250 μl) and palladium on activated charcoal (10% Pd, 40 mg) was added to a solution of 4-[2-(3-nitrobenzoylamino)phenoxy]phthalic acid (130 mg, 0.308 mmol) in methanol/water (10:1) (11 ml). The mixture was hydrogenated in a Parr apparatus at 276 kPa (40 psi) for 20 hours. The mixture was filtered and evaporated to dryness in vacuo to give 4-[2-(3-aminobenzoylamino)phenoxy]phthalic acid as an oil (yield: 114 mg (95%)). LC-MS: m/e 393 (MH+), 375 (MH+-H2O).
Reaction SMILES: [CH3:1][C:2]([NH:36][C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])([CH3:35])[CH2:3][C:4]([NH:6][C@@H:7]1[CH2:13][CH2:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[N:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[C:26]([C:31](O)=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:21][CH:20]=2)[C:8]1=[O:34])=[O:5].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>COCCOC.O.C(OCC)(=O)C>[CH2:40]([O:39][C:37]([NH:36][C:2]([CH3:35])([CH3:1])[CH2:3][C:4]([NH:6][C@@H:7]1[CH2:13][CH2:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[N:9]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH2:31][OH:32])=[CH:23][CH:24]=2)[C:8]1=[O:34])=[O:5])=[O:38])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3C(=O)O)cc2)C1=O)NC(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CO)cc2)C1=O)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution of 124 mg (0.20 mmol) of 4'-[[2,3,4,5-tetrahydro-3(R)-[[3-methyl-1-oxo-3-[(benzyloxycarbonyl)amino]butyl]amino]-2-oxo-1H-1-benzazepin-1-yl]methyl][1,1'-biphenyl]-2-carboxylic acid (Example 72, Step B) in 1.5 mL of dry 1,2-dimethoxyethane at 0° C. was added 0.046 mL (0.421 mmol) of N-methylmorpholine followed by 0.055 mL (0.42 mmol) of isobutyl chloroformate. The reaction mixture was stirred at 0° C. for 1 hour then filtered. Solids were rinsed with 1,2-dimethoxyethane (2×1 mL) and the filtrates combined. To the filtrate at 0° C. was added by syringe a solution of 30.3 mg (0.801 mmol) of sodium borohydride in 0.3 mL of water. The reaction mixture was stirred at 0° C. for 15 minutes then diluted with ethyl acetate (75 mL). The organic layer was washed with saturated aqueous ammonium chloride (25 mL) and brine (25 mL), then dried over magnesium sulfate, filtered and the solvent was removed under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (75:25) to afford 86 mg (71%) of the product as a white solid. 1H NMR (200 MHz,CDCl3): 1.35 (s,3H), 1.37 (s,3H), 2.80 (m,2H), 2.50 (m,4H), 4.50 (m,3H), 4.90 (d,15 Hz,1H), 5.03 (dd;10,12 Hz;2H), 5.18 (d,15 Hz,1H), 5.77 (s,1H), 6.70 (d,8 Hz,1H), 7.10-7.40 (m,16H), 7.53 (m,1H). FAB-MS: calculated for C37H39N3O5 605; found 607 (30%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]([CH:5]1[CH2:6][NH:7][CH2:8][CH2:9][N:10]1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:4]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1CNCCN1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-(4-chloro-phenyl)-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (0.4 g, 1.13 mmol) in dichloromethane (5.0 mL) cooled at 0° C. was treated with trifluoroacetic acid (20%) and warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and free based with 10% aqueous sodium bicarbonate. The combined organics were dried over sodium sulfate and concentrated. The product was used without any further purification. ESI-MS m/z: 254 (M+1), UV retention time: 1.01 min.
Reaction SMILES: Br.[NH2:2][C:3]1[N:7]2[C:8](SC)=[N:9][CH:10]=[C:11]([Cl:12])[C:6]2=[N:5][N:4]=1.[C:15](OCC)(=[O:18])C=C.C[O-].[Na+].C(O)(=O)C>CO>[NH2:2][C:3]1[N:7]=[C:6]2[N:5]([C:8]([O:18][CH3:15])=[N:9][CH:10]=[C:11]2[Cl:12])[N:4]=1
Reactant: CSc1ncc(Cl)c2nnc(N)n12
Reactant: C=CC(=O)OCC
Agent: Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ncc(Cl)c2nc(N)nn12
Temperature: 25 °C

Procedure:
A mixture of 15.0 g (51 mmol) of 3-amino-8-chloro-5-methylthio[1,2,4]triazolo[4,3-c]pyrimidine hydrobromide, 8.2 mL (76 mmol) of ethyl acrylate, and 150 mL of methanol was prepared and cooled in an ice bath. A solution of 17 mL (76 mmol) of 4.5 molar sodium methoxide in methanol was added to this slowly with cooling and stirring. When the addition was complete, the mixture was allowed to warm to ambient temperature and was stirred for 18 hours. It was then neutralized with 2.0 mL of acetic acid. The solids that formed were recovered by filtration, washed with diethyl ether, and dried to obtain 7.7 g (75 percent of theory) of the title compound as a tan powder melting above 250° C.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11](F)([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)=[O:27])=[CH:24][C:23]=4[O:38][CH3:39])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.NCC(F)([C:46]([F:49])([F:48])[F:47])C(O)=O>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([C:46]([F:49])([F:48])[F:47])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)=[O:27])=[CH:24][C:23]=4[O:38][CH3:39])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCC(F)(C(=O)O)C(F)(F)F
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(C(F)(F)F)C(=O)N2C

Procedure:
The title compound was synthesized using the analogous procedure to that described in connection with Compound 3 except that 2-(aminomethyl)-2,3,3,3-tetrafluoropropanoic acid was used as the starting material. The final product was purified on reversed phase HPLC as TFA salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46-1.76 (m, 10H) 1.83-2.09 (m, 4H) 2.19 (s, 3H) 2.80 (d, J=11.9 Hz, 2H) 3.32 (s, 3H) 3.69-3.81 (m, 1H) 3.89 (t, 1H) 3.94 (s, 3H) 4.15-4.35 (q, 1H) 4.72 (quin., J=8.1 Hz, 1H) 7.48 (dd, J=1.77 Hz, 1H) 7.50 (s, 1H) 8.00 (s, 1H) 8.10 (d, J=7.8 Hz, 1H) 8.26 (d, J=8.3 Hz, 1H) 8.32 (s, 1H). [M+H] calc'd for C28H35F4N7O3 594. found 594.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N:9]=O)=[C:4]([NH2:11])[N:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]#[N:21].C[O-].[Na+]>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]2[C:4](=[N:11][C:20]([NH2:21])=[C:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[Cl:12])[N:9]=2)[N:3]=1
Reactant: N#CCc1ccccc1Cl
Reactant: Nc1nc(N)c(N=O)c(N)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nc(N)c2nc(-c3ccccc3Cl)c(N)nc2n1

Procedure:
A stirred solution of 1.5 grams (0.01 0 mole) of 2,4,6-triamino-5-nitrosopyrimidine in 80 mL of N,N-dimethylformamide was heated to reflux, and 2.0 grams (0.013 mole) of 2-chlorophenylacetonitrile was added in one portion. Upon completion of addition, the reaction mixture was cooled, and 0.7 gram (0.013 mole) of sodium methoxide was added in one portion. The reaction mixture was again heated at reflux for 15 minutes. The reaction mixture was cooled in an ice-bath and then was filtered to collect a solid. The solid was slurried in diethyl ether and then was again collected by filtration, yielding, when dried, 2.5 grams of 2,4,7-triamino-6-(2-chlorophenyl)pteridine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][S:23](=[O:26])[CH2:22][CH2:21]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[N:7]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[O:26]=[S:23]1[CH2:24][CH2:25][N:20]([C:4]2[C:5]3[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)[C:6]=3[N:7]=[C:2]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[N:3]=2)[CH2:21][CH2:22]1
Reactant: O=S1CCN(c2nc(Cl)nc3c(NCc4cccnc4)ncnc23)CC1
Reactant: C1CNCCN1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(NCc4cccnc4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 118 from 2-chloro-4-(1-oxido-thiomorpholino)-8-(3-picolyl-amino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 227°-229° C.) and piperazine.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C@H:12]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:21]=2)[CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC(C)=O.O.CCOC(C)=O>[CH:29]1([O:28][C:22]2[CH:21]=[C:20]([C@@H:12]([C:9]3[CH:8]=[CH:7][C:6]([CH2:5][CH:4]=[O:3])=[CH:11][CH:10]=3)[CH2:13][C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)[CH:25]=[CH:24][C:23]=2[O:26][CH3:27])[CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CCOC(Cc1ccc([C@@H](Cc2ccncc2)c2ccc(OC)c(OC3CCCC3)c2)cc1)OCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc([C@H](Cc2ccncc2)c2ccc(CC=O)cc2)cc1OC1CCCC1
Temperature: 25 °C
Yield: 39.4 %

Procedure:
A solution of (R)-4-[1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl]-phenylacetaldehyde diethyl acetal from Step 4 (1.14 g, 2.33 mmol), pyridinium p-toluenesulfonate (0.761 g, 3.03 mmol) in acetone (30 mL) and water (1.3 mL) was heated to reflux for 20 h. It was then allowed to cool to room temperature, diluted with EtOAc, successively washed with 5% aqueous NaHCO3 (2×) and brine, dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica (EtOAc/hexane 3:2→7:3→4:1→1:0) to afford the title compound as a white foam (0.381 g, 39%).
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[CH3:26][C:27]1[C:32]([C:33]#[N:34])=[C:31]([SH:35])[N:30]=[C:29]([CH3:36])[CH:28]=1>>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:35][C:31]3[N:30]=[C:29]([CH3:36])[CH:28]=[C:27]([CH3:26])[C:32]=3[C:33]#[N:34])=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Reactant: Cc1cc(C)c(C#N)c(S)n1
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3nc(C)cc(C)c3C#N)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and 4,6-dimethyl-2-mercaptonicotinonitrile was used in place of 6-hydroxy-8-mercaptopurine monohydrate.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[NH2:8].[CH3:13][O:14][C:15]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:16]=1[CH:17]=[CH:18][C:19](O)=O>>[CH3:13][O:14][C:15]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:16]=1/[CH:17]=[CH:18]/[C:19]1[NH:1][C:2]2[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=2[N:8]=1
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Reactant: COc1ccc(C=CC(=O)O)c(OC)c1
Product: COc1ccc(/C=C/c2nc3c([nH]2)c(=O)n(C)c(=O)n3C)c(OC)c1
Yield: 11 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 1.0 g (5.88 mmol) of 5,6-diamino-1,3-dimethyluracil and 1.35 g (6.48 mmol) of 2,4-dimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dimethylformamide to give 221 mg (yield 11%) of Compound 90 as pale yellow grains.
Reaction SMILES: [CH3:1][CH:2]([CH3:4])[O-:3].[Al+3].[CH3:6][CH:7]([CH3:9])[O-].[CH3:10][CH:11]([CH3:13])[O-].[C:14]1([CH3:20])[CH:19]=[CH:18]C=C[CH:15]=1>>[CH3:6][C:7]1([CH3:9])[C:13]2[CH2:11][CH2:10][CH2:4][CH:2]([OH:3])[C:1]=2[C:14]([CH3:15])([CH3:20])[CH:19]1[CH3:18]
Reactant: Cc1ccccc1
Reactant: CC(C)[O-]
Agent: [Al+3]
Product: CC1C(C)(C)C2=C(C(O)CCC2)C1(C)C
Reaction time: 8 h

Procedure:
Into a 2-liter reaction vessel are placed 831 ml of toluene and 226.9 grams (1.11 moles) of aluminum isopropoxide. The mixture is heated to reflux and while refluxing, over a one hour period, tetrahydro pentamethylindane epoxide having the structure: ##STR63## is added to the reaction mass. The reaction mass is continued to be refluxed for a period of twelve hours while being monitored by GLC analysis. An additional 0.5 moles of aluminum isopropoxide is added (101.5 grams) at the end of the twelve hour period and the refluxing is continued for an additional eight hours. At the end of the twenty hour period, an additional 50.7 grams of aluminum triisopropylate is added and the reaction mass is continued to be refluxed for an additional twenty two hours (total reflux time 42 hours).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH2:21][CH2:22][CH2:23][OH:24])[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[O:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH2:21][CH2:22][CH2:23][O:24][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[O:33][C:34]4[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=4[N:36]=3)[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc(OCc3ccccc3)cc2)n1CCCO
Reactant: Oc1ccccc1-c1nc2ccccc2o1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(OCc3ccccc3)cc2)n1CCCOc1ccccc1-c1nc2ccccc2o1
Temperature: 80 °C
Reaction time: 12 h
Yield: 59.4 %

Procedure:
To a solution of 3-[2-(4-benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]propan-1-ol (1.00 g, 3.11 mmol), 2-(2-hydroxyphenyl)benzoxazole (986 mg, 4.67 mmol) and triphenylphosphine (1.22 g, 4.67 mmol) in toluene (2 ml) was added 1,1′-(azodicarbonyl)dipiperidine (1.18 g, 4.67 mmol) and the mixture was stirred at 80° C. for 12 hours. The reaction solution was poured into water and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate anhydride and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:1) to give the object compound as an oily substance. 950 mg (yield: 59.4%)
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][O:18][C:19](=[O:31])[C@H:20]([N:28]=[C:29]=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C1C=CN=CC=1>[CH3:17][O:18][C:19](=[O:31])[C@H:20]([NH:28][C:29]([O:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][CH:13]=1)=[O:30])[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: OCc1ccc(COc2ccccc2)cc1
Reactant: COC(=O)[C@@H](Cc1ccccc1)N=C=O
Agent: CN(C)c1ccncc1
Product: COC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccc(COc2ccccc2)cc1
Reaction time: 0.33 h
Yield: 95.4 %

Procedure:
(R)-Phenylalanine methyl ester hydrochloride (6.5 g, 30 mmol) was dissolved in methylene chloride and cooled to 0C. Phosgene (2M in toluene, 21.0 ml, 42.0 mmol) was added followed by pyridine (9.0 ml, 111 mmol). The mixture was allowed to warm to room temperature and was stirred for three hours. The mixture was then poured into dilute HCl. The layers were separated. The organic extracts were washed, dried, and concentrated to give about 5.8 g of a clear oil of (R)-2-isocyanato-3-phenyl-propionic acid methyl ester 5. 4-Phenoxymethylphenylmethanol 4 (0.857 g, 4.0 mmol), (R)-2-isocyanato-3-phenyl-propionic acid methyl ester 5 (1.026 g, 5.0 mmol) and 4-dimethylaminopyridine (DMAP) (10 mg) were combined, heated until molten, and stirred for 20 min. Upon cooling, the residue was purified by chromatography to give about 1.6 g of (R)-2-(4-phenoxymethyl-benzyloxycarbonylamino)-3-phenyl-propionic acid methyl ester 6.