Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C@@H:8]([NH:13][C:14](=[O:28])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@@H:23]3[CH2:27][CH2:26][CH2:25][O:24]3)=[CH:17][CH:16]=1)[CH2:7][CH2:6]2)=O.C1COCC1.[CH2:34]([NH:38][CH3:39])[CH:35]([CH3:37])[CH3:36].C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[CH2:34]([N:38]([CH2:1][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C@@H:8]([NH:13][C:14](=[O:28])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@@H:23]3[CH2:27][CH2:26][CH2:25][O:24]3)=[CH:17][CH:16]=1)[CH2:7][CH2:6]2)[CH3:39])[CH:35]([CH3:37])[CH3:36]
Reactant: CNCC(C)C
Reactant: O=Cc1ccc2c(c1)CC[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cc1)C2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CN(C)Cc1ccc2c(c1)CC[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cc1)C2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of N-((S)-6-formyl-1,2,3,4-tetrahydronaphthalen-2-yl)-4-[(S)-1-(tetrahydrofuran-2-yl)methoxy]benzamide (0.50 g), THF (5 ml), methanol (2 ml), isobutylmethylamine (0.23 g) and acetic acid (0.24 g) was added polymer-bound sodium cyanoborohydride (2.7 mmol), and the suspension was agitated at room temperature for 12 hours. The polymer was filtered off with suction and the filtrate was concentrated. The residue was purified by preparative HPLC. The product was thus obtained with the molecular weight of 450.63 (C28H38N2O3); MS (ESI): 451 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[F:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[F:28])[NH2:24].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:20][C:21]1[CH:22]=[C:23]([NH:24][C:16](=[O:18])[CH2:15][C:3]2[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)[N:4]=2)[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: Nc1ccc(F)c(F)c1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cn1c(CC(=O)Nc2ccc(F)c(F)c2)nc(N2CCOCC2)cc1=O
Yield: 54.4 %

Procedure:
The product is prepared according to the procedure described in example 5, using 250 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of example 68, 169 mg of 3,4-difluoroaniline, and 285 mg of N-[3-(dimethylamino)propyl]-N′ethylcarbodiimide hydrochloride in a mixture of 2 ml of pyridine and 2 ml of N,N-dimethylformamide. 180 mg of N-(3,4-difluorophenyl)-2-[1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [N:1](=[C:3]1[CH2:7][O:6][CH2:5][S:4]1)[OH:2].[C:8](Cl)(Cl)=[O:9].[CH3:12][N:13](C)[C:14]1C=CC=CC=1>CCOCC>[CH3:12][N:13]([CH3:14])[C:8]([O:2][N:1]=[C:3]1[CH2:7][O:6][CH2:5][S:4]1)=[O:9]
Reactant: ON=C1COCS1
Reactant: O=C(Cl)Cl
Reactant: CN(C)c1ccccc1
Solvent: CCOCC
Product: CN(C)C(=O)ON=C1COCS1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
A quantity of 6 grams of 4-oximino-1,3-oxathiolane dissolved in 100 ml of anhydrous ether was added over 30 minutes to a solution of 10 grams of phosgene in 100 ml of anhydrous ether maintained at -10°C. A quantity of 6 grams of N,N-dimethylaniline dissolved in 200 ml of anhydrous ether was then added dropwise to the cooled phosgene/oxime solution over a 30 minute period. The heterogeneous mixture was stirred at -10° for 2 hours, filtered in an inert atmosphere and the filtrate concentrated under a vacuum to about 250 ml. The concentrated solution was cooled to 10° in a stirring vessel, 12 ml of 40 percent aqueous dimethylamine was added dropwise, and the mixture stirred for 1 hour at 10°. A volume of 100 ml of water was added, the phases separated, and the organic phase washed with two 50 ml portions of saturated brine. The three aqueous solutions were extracted sequentially with a volume of 300 ml of ether. The combined ether solutions were dried over magnesium sulfate, filtered, and evaporated. Recrystallization of the crude 4-(dimethylcarbamoyloximino)-1,3-oxathiolane afforded pure product, mp 87.5°-88.0°.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C.CCOC(C)=O>[CH2:25]([NH:32][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)CCCCCCCCCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(CCCCCCCCCc1ccccc1)NCc1ccccc1
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To a solution of 10-phenyldecanoic acid (1.101 g, 4.43 mmol) in 20 mL of CH2Cl2 at room temperature was added oxalyl chloride (1.41 g, 11.08 mmol) and 1 drop of DMF, and the reaction mixture was stirred for 1 hour under nitrogen. The CH2Cl2 and excess oxalyl chloride were evaporated. The reaction was redissolved in CH2Cl2 and benzylamine (1.42 g, 13.3 mmol) and 2 mL of saturated aqueous NaHCO3 were added and the reaction stirred for 12 hours. The reaction was taken up in EtOAc and washed with 1N HCl×2, followed by saturated aqueous NaCl, and evaporated to give 1.462 g (98%) of an oil that was used without further purification. 1H NMR (CDCl3, 300 MHz) δ 1.30 (m, 10H), 1.55-1.72 (m, 4H), 2.20 (t, 2H), 2.59 (t, 2H), 4.45 (d, 2H), 5.68 (bs, 1H), 7.12-7.38 (m, 10H). MS (DCl--NH3) m/e (M+H)+ 338.
Reaction SMILES: [C:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:32]=[CH:31][C:29]([NH2:30])=[N:28][C:26]2=[O:27])[C@@H:22]([OH:33])[C@@H:21]1[OH:34])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].CN(C)C=O.[C:40]([O:44][C:45]([NH:47][CH2:48][C:49]([NH:51][CH2:52][C:53]([NH:55][C@H:56]([C:64](O)=[O:65])[CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:54])=[O:50])=[O:46])([CH3:43])([CH3:42])[CH3:41].C1(N=C=NC2CCCCC2)CCCCC1>CCOCC.O1CCOCC1>[C:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:32]=[CH:31][C:29]([NH:30][C:64](=[O:65])[C@H:56]([CH2:57][C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[NH:55][C:53](=[O:54])[CH2:52][NH:51][C:49](=[O:50])[CH2:48][NH:47][C:45]([O:44][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:46])=[N:28][C:26]2=[O:27])[C@@H:22]([OH:33])[C@@H:21]1[OH:34])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)OC[C@H]1O[C@@H](n2ccc(N)nc2=O)[C@@H](O)[C@@H]1O
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCC(=O)OC[C@H]1O[C@@H](n2ccc(NC(=O)[C@H](Cc3ccccc3)NC(=O)CNC(=O)CNC(=O)OC(C)(C)C)nc2=O)[C@@H](O)[C@@H]1O
Temperature: 5 °C
Reaction time: 96 h

Procedure:
A solution consisting of 4.82 g. (0.01 mole) 1-(5'-O-palmitoyl-β-D-arabinofuranosyl)cytosine and a solvent mixture consisting of equal parts dimethylformamide and dioxane was obtained by warming slightly. This solution was cooled to 5° C. and 3.8 g. (0.01 mole) N-[N-[N-(tertbutoxycarbonyl)glycyl]glycyl]-L-phenylalanine was added, followed by 2.47 g. (0.012 mole) dicyclohexylcarbodiimide. This reaction mixture was stirred continuously for 4 days while the temperature was maintained at 5° C. The reaction mixture was then filtered in order to remove the dicyclohexylurea that had formed. The solvents were removed from the filtrate by evaporation under reduced pressure. The residual oil thus obtained was dissolved in 25 ml. diethyl ether, and the ether solution was set aside in a refrigerator for about 16 hrs. Some solids that separated were removed by filtering, and the filtrate was concentrated to a glass by removing the ether by evaporation. The glassy residue was dissolved in 50 ml. of a solvent system consisting of 72 parts methyl ethyl ketone, 20 parts acetone, and 8 parts water, and the solution was poured onto a column of silica gel 45 mm. × 115 cm. amounting to 800 g. which had been equilibrated with this same solvent. The chromatogram was developed with about 100 ml. of the solvent mixture, and then 10 ml. fractions were collected. After combining fractions 75 through 105, and concentrating the solution by evaporation of the solvents under reduced pressure, the concentrate was lyophilized. There was thus obtained 4.0 g. of 1-(5'-O-palmitoyl-β-D-arabinofuranosyl)-N4 -[N-[N-[N-(tert-butoxycarbonyl)glycyl]glycyl]-L-phenylalanyl]cytosine having optical rotation [α]D25 = +46° (c 1.1 in methanol)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[C:9]#[C:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1.[N+:20](=[CH:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24])=[N-:21]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:9]2[C:22]([C:23](=[O:24])[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[N:20][NH:21][C:10]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:16])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1
Reactant: CCOC(=O)C#CC(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: [N-]=[N+]=CC(=O)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]nc(C(=O)c2ccccc2)c1C(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Yield: 74.3 %

Procedure:
A solution of ethyl 4-(4-chloro-2-nitrophenyl)-4-oxo-2-butynoate (prepared as described in Example 48(a)) (1.2 g, 4.11 mmol) and diazoacetophenone (1.2 g 8.22 mmol, prepared as described in Org. Syn. Coll. Vol. VI. pp. 386-388) in tetrahydrofiuran (THF) (21.6 mL) was stirred at room temperature for 16 hours. The reaction was concentrated by rotary evaporation and purified by flash chromatography eluting with hexanes:ethyl acetate (90:10, 80:20, 70:30) to give the title compound (1.3 g, 74.3%); Rf 0.38 (1:1 ethyl acetate:hexanes).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:20])=[C:4]([N:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[CH2:15][C:16]([NH:18][NH2:19])=[O:17])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C[Si]([N:25]=[C:26]=[O:27])(C)C>ClCCl.C(N(C(C)C)CC)(C)C>[C:26]([NH:19][NH:18][C:16](=[O:17])[CH2:15][CH:11]1[CH2:12][CH2:13][CH2:14][N:10]1[C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=1[CH3:20])(=[O:27])[NH2:25]
Reactant: C[Si](C)(C)N=C=O
Reactant: Cc1c(N2CCCC2CC(=O)NN)ccc(C#N)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(N2CCCC2CC(=O)NNC(N)=O)ccc(C#N)c1Cl

Procedure:
To a solution of 2-[1-(3-chloro-4-cyano-2-methylphenyl)pyrrolidin-2-yl]acetohydrazide (0.288 g, 1.030 mmol) in dichloromethane and diisopropylethylamine, add trimethylsilyl isocyanate (0.238 g, 2.060 mmol) and stir the reaction at 21° C. for 2 h. Partition the reaction is between ethyl acetate and brine. Dry the organic phase over magnesium sulphate, filter, and remove the solvent is under reduced pressure to yield the title compound. (0.303 g, 91%) mass spectrum (m/e): 322.1 (M+H); 1H NMR (300 MHz, CDCl3): δ 8.37 (s, 1H) 7.38 (d, 1H), 7.30 (s, 1H), 6.34 (d, 1H), 5.04 (s, 2H), 4.34 (t, 1H), 3.86 (m, 1H), 3.08 (m, 1H), 2.46 (m, 1H), 2.42 (s, 3H), 2.03 (s, 3H), 2.20-1.85 (m. 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C:13]2[C:8](=[C:9]([N+:15]([O-])=O)[C:10]([Cl:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:18])=[O:4].C(O)(=O)C.OS(O)(=O)=O>C(O)C.[Fe]>[CH3:1][O:2][C:3]([N:5]1[C:13]2[C:8](=[C:9]([NH2:15])[C:10]([Cl:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:18])=[O:4]
Reactant: COC(=O)n1c(C)cc2c([N+](=O)[O-])c(Cl)ccc21
Agent: [Fe]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)n1c(C)cc2c(N)c(Cl)ccc21
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
5-Chloro-2-methyl-4-nitro-indole-1-carboxylic acid methyl ester (2.1 g, 7.81 mmol) is dissolved in ethanol (40 ml) and glacial acetic acid (40 ml). Iron powder (1.74 g, 31.26 mmol, activated previously with H2SO4 conc and then washed with water) is added, and the reaction mixture is heated to 85° C. for 90 minutes. The reaction mixture is poured into water and stirred at RT for 30 minutes, after which a slightly brownish colored precipitate forms which is filtered off. After washing with water and drying, the title compound is obtained in pure form. 1H NMR (DMSO, 400 MHz, 120° C.) δ 2.51 (s, 3H), 4.05 (s, 3H), 5.0-5.2 (br s, 2H), 6.66 (s, 1H), 7.05 (d, J=9 Hz, 1H), 7.31 (d, J=9 Hz, 1H); ES-MS: 238 [M+H]+.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.Br[CH2:14][CH2:15][CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1.C1CCN2C(=NCCC2)CC1>C(O)(C)C>[N:17]1([CH2:16][CH2:15][CH2:14][S:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]3)[CH:21]=[N:20][CH:19]=[N:18]1
Reactant: O=C1CCc2cc(S)ccc2N1
Reactant: BrCCCn1cncn1
Solvent: CC(C)O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCc2cc(SCCCn3cncn3)ccc2N1

Procedure:
2.4 Grams (13.4 mM) of 6-mercapto-3,4-dihydrocarbostyril, 3,3 g (17.4 mM) of 1-(3-bromopropyl)-1,2,4-triazol, and 2.6 ml (17.4 mM) of DBU were added to 60 ml of isopropanol, and the whole mixture was refluxed by heating for 2 hours. After the reaction was completed, the reaction mixture was concentrated, the resulting residue was extracted with chloroform. The chloroform extract was washed with water, an aqueous solution saturated with sodium hydrogen carbonate, and water in this order, then dried with anhydrous sodium sulfate. The dried extract was concentrated by removing the solvent by evaporation, the residue was purified by means of a silica gel column chromatography (eluent: dichloromethane:methanol=20:1), and recrystallized from ethanol-n-hexane to yield 2.5 g of 6-[3-(1H-1,2,4-triazol-1-yl)propylthio]-3,4-dihydrocarbostyril. Colorless needle-like crystals. Melting point: 114.5°-115.5° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH:34]([CH3:36])[CH3:35])[C:3]([O:5][CH2:6][C@@H:7]1[C@@H:11]([OH:12])[CH2:10][C@H:9]([N:13]2[CH:18]=[C:17]3[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:24][CH:23]=4)[O:21][C:16]3=[N:15][C:14]2=[O:33])[O:8]1)=[O:4].[ClH:37].CC(O)C>>[ClH:37].[NH2:1][CH:2]([CH:34]([CH3:35])[CH3:36])[C:3]([O:5][CH2:6][C@@H:7]1[C@@H:11]([OH:12])[CH2:10][C@H:9]([N:13]2[CH:18]=[C:17]3[CH:19]=[C:20]([C:22]4[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:26][CH:27]=4)[O:21][C:16]3=[N:15][C:14]2=[O:33])[O:8]1)=[O:4]
Reactant: CCCCCc1ccc(-c2cc3cn([C@H]4C[C@H](O)[C@@H](COC(=O)[C@@H](N)C(C)C)O4)c(=O)nc3o2)cc1
Agent: Cl
Solvent: CC(C)O
Product: CCCCCc1ccc(-c2cc3cn([C@H]4C[C@H](O)[C@@H](COC(=O)C(N)C(C)C)O4)c(=O)nc3o2)cc1
Reaction time: 1 h

Procedure:
The above reaction mixture from Example 15 was cooled below 5° C. and was added with 20% of HCl IPA solution until pH 1˜4. The mixture was stirred for additional 1 h and was filtered. The filter cake was washed with 34.6 kg of dichloromethane. Desired crude product was obtained. The overall yield from Example 12 was 67% and the purity was 97%. The crude product was recrystallized with methanol/dichloromethane/MTBE to give the desired pure product.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18]([C:26]([F:29])([F:28])[F:27])=[N:19]3)[CH2:11][CH2:10][N:9]1[CH2:30][C:31]([OH:33])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:35]([O:38][NH2:39])[CH:36]=[CH2:37].C(N(CC)CC)C.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH2:35]([O:38][NH:39][C:31](=[O:33])[CH2:30][N:9]1[CH2:10][CH2:11][N:12]([C:14]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18]([C:26]([F:27])([F:28])[F:29])=[N:19]3)[CH2:13][C@@H:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:36]=[CH2:37]
Reactant: C=CCON
Reactant: COc1ccc(N2CCN(CC(=O)O)[C@@H](Cc3ccccc3)C2)c2ccc(C(F)(F)F)nc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=CCONC(=O)CN1CCN(c2ccc(OC)c3nc(C(F)(F)F)ccc23)C[C@@H]1Cc1ccccc1
Reaction time: 3 h
Yield: 68.4 %

Procedure:
A solution of (S)-2-(2-benzyl-4-(8-methoxy-2-(trifluoromethyl)quinolin-5-yl)piperazin-1-yl)acetic acid (115 mg, 0.25 mmol) in CH2Cl2 (2 mL) at 0-5° C. was treated with O-allylhydroxylamine hydrochloride (31 mg, 0.28 mmol), triethylamine (38 μL, 0.28 mmol), catalytic DMAP, and finally DCC (57 mg, 0.28 mmol). The reaction mixture was stirred for 3 h after which time the mixture was treated with EtOAc (5 mL), filtered and evaporated. The residue was purified by silica gel flash chromatography with 50% EtOAc/hexane, then 100% EtOAc, as eluant to afford the title compound as an oil (88 mg, 68%). LC/MS (Method A) 5.66 min, [M+1]+ 515.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][C:10]2=[O:16])=[CH:5][CH:4]=1.[CH3:17][CH2:18][CH2:19][C:20](Cl)=[O:21].COC1C=CC(C2CCC(OC(=O)CCC)=CC2=O)=CC=1.COC1C=CC(C2C(OC(=O)CCC)=CC(=O)CC2)=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1.C(N(CC)CC)C>[C:20]([C:11]1[C:12](=[O:15])[CH2:13][CH2:14][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:10]=1[OH:16])(=[O:21])[CH2:19][CH2:18][CH3:17]
Reactant: CCCC(=O)Cl
Reactant: COc1ccc(C2CCC(=O)CC2=O)cc1
Agent: CCCC(=O)OC1=CC(=O)C(c2ccc(OC)cc2)CC1
Agent: CCCC(=O)OC1=CC(=O)CCC1c1ccc(OC)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCC(=O)C1=C(O)C(c2ccc(OC)cc2)CCC1=O
Reaction time: 1 h
Yield: 86.8 %

Procedure:
Triethylamine (11.1 g) was added dropwise to a stirred solution of 4-(4-methoxyphenyl)cyclohexane-1,3-dione (21.8 g) and n-butyryl chloride (17.6 g) in methylene chloride (100 ml) at ambient temperature. After stirring for a further 1 hour, the reaction solution was washed with water, brine and dried over anhydrous magnesium sulphate. The methylene chloride was removed in vacuo to give a mixture of 4-(4-methoxyphenyl)-1-butyryloxycyclohex-1-en-3-one and 6-(4-methoxyphenyl)-1-butyryloxycyclohex-1-ene-3-one. Toluene (150 ml) was added followed by 4-(N,N-dimethylamino) pyridine (0.5 g) and the mixture refluxed for 8 hours. Evaporation of the toluene in vacuo gave a red oil. Purification on a silica gel column using 5% v/v diethyl ether-methylene chloride as eluant gave the title compound (25 g) as an orange oil.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([CH2:8][CH3:9])[C:6](=[O:10])[CH2:5][CH2:4][CH:3]1[C:11]([O:13][CH2:14][CH3:15])=[O:12].CO.[BH4-].[Na+]>C(O)(=O)C>[CH3:1][CH:2]1[CH:7]([CH2:8][CH3:9])[CH:6]([OH:10])[CH2:5][CH2:4][CH:3]1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C1CCC(=O)C(CC)C1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)C1CCC(O)C(CC)C1C
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of 22.5 g. of ethyl 2-methyl-3-ethyl-4-ketocyclohexanecarboxylate (all-cis form, m.p. 28°-32°) in 450 ml. of methanol is stirred and maintained at a temperature of 5°-7° C. while a total of 11.0 g. of sodium borohydride is added over a period of 40 minutes. The reaction mixture is stirred at 5° C. for an additional one hour after which a total of 40 ml. of acetic acid is added cautiously to neutralize the base. The methanol solution is evaporated under vacuum to a pasty residue which is shaken with ether and water. The ether phase is washed with aqueous sodium bicarbonate and is dried and evaporated to yield a colorless oil. Upon distillation of the oil, 21.5 g. of ethyl 2-methyl-3-ethyl-4-hydroxycyclohexanecarboxylate is obtained as a mobile oil having a boiling point of 88°-91° at 0.001 mm.
Reaction SMILES: [C:1]([CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][NH:5]1)([OH:3])=[O:2].[C:14](Cl)(=[O:23])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[OH-].[Na+]>[C:14]([N:5]1[CH:4]([C:1]([OH:3])=[O:2])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:23]
Reactant: O=C(O)C1Cc2ccccc2CN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1Cc2ccccc2CN1C(=O)OCc1ccccc1

Procedure:
188 g (1.05 moles) of 3-carboxy-1,2,3,4-tetrahydroisoquinoline are added to 1,050 ml of 1N NaOH at 0°, and 160 ml of benzyl chlorocarbonate and a further 1,050 ml of 1N NaOH are then simultaneously added dropwise at this temperature, whilst stirring. The mixture is then stirred for 2 hours at room temperature and extracted three times with ether, and the alkaline/aqueous phase is acidified to pH 1 with concentrated HCl. The oil which separates out is extracted with ethyl acetate. The ethyl acetate solution is washed with water until the water phase has a pH of 3.0. After the ethyl acetate solution has been dried over sodium sulfate, the product crystallizes from this solution after concentration and trituration. 1.5 liters of diisopropyl ether are added to the suspension of crystals, and the latter is stirred for one hour at room temperature, and filtered under suction. The product is dried over phosphorus pentoxide in a high vacuum. Yield: 256.7 g Melting point 138°-39° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:18](Br)[CH2:19][CH2:20][CH3:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:15][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1
Reactant: CCCCBr
Reactant: OC(Cn1cncn1)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Product: CCCCOC(Cn1cncn1)c1ccc(Cl)cc1

Procedure:
Following the procedure of Example 9, Step 2, 1-p-chlorophenyl-2-(1,2,4-triazol-1-yl)-ethanol (2.23 g), sodium hydride (440 mg; 50%) and n-butyl bromide (1.37 g) were reacted to give the title compound as an oil.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:27]([OH:29])=O)=[C:21]5[C:25]=4[O:24][CH:23]([CH3:26])[CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:30])[C:8](=[O:31])[C@H:7]2[CH2:32][CH3:33])[CH2:5][CH2:4][CH2:3][CH2:2]1.F[B-](F)(F)F.[N:39]1(OC(N(C)C)=[N+](C)C)[C:43]2[CH:44]=[CH:45]C=[CH:47][C:42]=2N=N1.[CH:56]([N:59](C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:27]([NH:39][CH:43]5[CH2:42][CH2:47][N:59]([CH3:56])[CH2:45][CH2:44]5)=[O:29])=[C:21]5[C:25]=4[O:24][CH:23]([CH3:26])[CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:30])[C:8](=[O:31])[C@H:7]2[CH2:32][CH3:33])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OC(C)C4)nc2N1C1CCCC1
Reactant: CCN(C(C)C)C(C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)NC4CCN(C)CC4)c4c3OC(C)C4)nc2N1C1CCCC1
Reaction time: 2 h
Yield: 36.5 %

Procedure:
7-[[(7R)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2-methyl-2,3-dihydrobenzofuran-4-carboxylic acid 30d (70 mg, 0.20 mmol), 1-methyl-piperidyl-4-yl-amine (23 mg, 0.20 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium tetrafluoroborate (64 mg, 0.20 mmol) and diisopropylethylamine (65 mg, 0.50 mmol) were dissolved in 30 mL of dichloromethane. The reaction solution was stirred for 2 hours. The resulting solution was added with 20 mL of saturated sodium bicarbonate solution and extracted with dichloromethane (50 mL×3). The combined organic phase was washed with water (30 mL) and saturated sodium chloride solution (30 mL) successively, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2-methyl-N-(1-methyl-4-piperidyl)-2,3-dihydrobenzofuran-4-carboxamide 30 (40 mg, yield: 36.0%) as a white solid.