Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:13]3[CH:12]([CH2:14][CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19])[CH2:11][CH2:10][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1.CCCCCC.C(O)C.C(NCC)C>>[CH3:1][C:2]1[O:3][C:4]2[C:13]3[C@H:12]([CH2:14][CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19])[CH2:11][CH2:10][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CCC(=O)NCCC1CCc2ccc3nc(C)oc3c21
Solvent: CCCCCC
Solvent: CCO
Solvent: CCNCC
Product: CCC(=O)NCC[C@@H]1CCc2ccc3nc(C)oc3c21
Yield: 47.8 %

Procedure:
Racemic N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]propionamide (96 mg, 0.353 mmol) was fractionated by high performance liquid chromatography (instrument: Prep LC 2000 (manufactured by Nihon Waters K.K.), column: CHIRALPAK AS (50 mmID×500 mL, manufactured by Daicel Chemical Industries, Ltd.), mobile phase: hexane/ethanol/diethylamine=94/6/0.1, flow rate: 60 mL/min, column temperature: 30° C., sample concentration: 1.61 mg/mL, injection weight: 48 mg). A fraction containing an optically active compound having a shorter retention time under the above-mentioned high performance liquid chromatography conditions was concentrated. The concentrate was re-dissolved in ethanol, and concentrated to dryness. Hexane was added again, and the mixture was concentrated to dryness to give the title compound (46 mg, 99.9% ee). Enantiomer excess (ee) was measured by high performance liquid chromatography (column: CHIRALPAK AS (4.6 mmID×250 mL, manufactured by Daicel Chemical Industries, Ltd.), mobile phase: hexane/ethanol/diethylamine=95/5/0.1, flow rate: 0.5 mL/min, column temperature: 30° C., sample concentration: 0.62 mg/mL (hexane/ethanol), injection volume: 10 μL).
Reaction SMILES: C[N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[N:3]1.[F:31][C:32]([F:37])([F:36])[CH2:33]NN>>[N:10]1[CH:9]=[CH:8][C:7]([C:5]2[CH:6]=[N:2][N:3]([CH2:33][C:32]([F:37])([F:36])[F:31])[C:4]=2[C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[CH:12][CH:11]=1
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Reactant: NNCC(F)(F)F
Product: FC(F)(F)Cn1ncc(-c2ccncc2)c1-c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
Following the procedure for the preparation of 2-[4-(1-Methyl-4-pyridin4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting (2,2,2-trifluoro-ethyl)-hydrazine provided the title compound. MS: (M+H m/z=461.2).
Reaction SMILES: O[C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[O:21][CH3:22])[CH2:3]1.[Cl:23]N1C(=O)CCC1=O>>[Cl:23][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[O:21][CH3:22])[CH2:3]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Product: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](Cl)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Following the general procedure of Example 28 and making non-critical variations 3α-hydroxy-17β-methoxy-5α-androstane (Example 27, 0.47 g.) is reacted with N-chlorosuccinimide for 2 hours. The mixture is extracted with SSB, concentrated, and chromatographed on silica gel eluting with ethyl acetate-hexane (5:95) to obtain the title compound, upon recrystallization from methanol, NMR (CDCl3) 0.74, 0.84, 3.16, 3.33 and 3.75 δ; MS (m/e) 324, 309, 292, 277 and 251.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:36][CH2:35][C:11]2([C:15](=[O:16])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:28][CH2:27][CH:26](OS(C)(=O)=O)[CH2:25][CH2:24]4)=[CH:19][C:18]=3[F:34])[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:40][CH2:39][CH2:38]1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:15](=[O:16])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:28][CH2:27][CH:26]([N:37]5[CH2:40][CH2:39][CH2:38]5)[CH2:25][CH2:24]4)=[CH:19][C:18]=3[F:34])[CH2:13][CH2:12]2)[CH2:35][CH2:36]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(c1ccc(C3CCC(OS(C)(=O)=O)CC3)cc1F)C2=O
Reactant: C1CNC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(c1ccc(C3CCC(N4CCC4)CC3)cc1F)C2=O

Procedure:
The title compound was synthesized in the same manner as Example 13 by condensing 2-[2-fluoro-4-(4-methanesulfonyloxy-cyclohexyl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (Intermediate 28) (150 mg, 0.3 mmol, 1 equiv.) with azetidine (67.8 mg, 1.19 mmol) to obtain 55 mg (85% yield) of the compound.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([O:15][CH:16]([CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1)[CH2:17][CH2:18][CH2:19][OH:20])(=[O:14])[CH3:13].O>N1C=CC=CC=1.CCOCC>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:20][CH2:19][CH2:18][CH2:17][CH:16]([O:15][C:12](=[O:14])[CH3:13])[CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)OC(CCCO)COc1cccc(C(F)(F)F)c1
Solvent: O
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)OC(CCCOS(=O)(=O)c1ccc(C)cc1)COc1cccc(C(F)(F)F)c1
Reaction time: 1.17 h
Yield: 94 %

Procedure:
A solution of p-toluenesulfonyl chloride (65.2 g., 0.342 mole) in pyridine (130 ml.) is cooled in a cold water (10°-15°) bath while 4-acetoxy-5-(3-trifluoromethylphenoxy)-1-pentanol (90.7 g., 0.297 mole) is added dropwise with stirring during 70 minutes. The mixture is then stirred 2 hours in the same cold water bath. It is poured into 400 ml. of water. The oily product is taken up in ether, washed with water, 2N hydrochloric acid and dilute sodium bicarbonate solution and dried over magnesium sulfate. The solvent is evaporated in vacuo to leave 125 g. (94%) of the crude title compound as a nearly colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][C:3]=1[C:15]([O:17]C)=O.C(N(CC)CC)C.[CH2:26]([N:33]=[C:34]=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.ClCCl>C1(C)C=CC=CC=1>[CH2:26]([N:33]1[C:15](=[O:17])[C:3]2[CH2:4][N:5]([CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:6][CH2:7][C:2]=2[NH:1][C:34]1=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)C1=C(N)CCN(Cc2ccccc2)C1
Reactant: O=C=NCc1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1[nH]c2c(c(=O)n1Cc1ccccc1)CN(Cc1ccccc1)CC2
Temperature: 80 °C
Yield: 34.8 %

Procedure:
A mixture of 165 g of methyl 4-amino-1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylate, 68 g of triethylamine and 100 g of benzyl isocyanate in 700 ml of toluene was heated at the reflux temperature for 8 h, with stirring. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in 300 ml of ethanol, 58 g of sodium ethylate in 400 ml of ethanol were added and the mixture was heated at 80° C. for 1.5 h, with stirring. After this mixture had been concentrated under reduced pressure, the residue was worked up by extraction with dichloromethane and water and the combined and dried dichloromethane extracts were concentrated under reduced pressure. The combined aqueous phases were adjusted to pH 7 with conc. hydrochloric acid. After drying, the precipitate formed was combined with the concentrated dichloromethane extracts and the mixture was purified by recrystallization from ethanol to give 81 g of 3,6-dibenzyl-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione. 10 g of this base were dissolved in dichloromethane and the hydrochloride was precipitated by the addition of a solution of hydrochloric acid in ether. Recrystallization from ethanol/water (volume ratio 1:1) gave 10.1 g of 3,6-dibenzyl-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione hydrochloride.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[O:6][C:7]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:8]=2[C:9]=1[CH2:10][C:11](O)=[O:12])=[O:4].C1C=CC2N(O)N=NC=2C=1.[CH2:32]([NH:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[CH3:33].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH:35]1([N:34]([CH2:32][CH3:33])[C:11](=[O:12])[CH2:10][C:9]2[C:8]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:7]=3[O:6][C:5]=2[C:3](=[O:4])[C:2]([CH3:1])([CH3:20])[CH3:21])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CCNC1CCCCC1
Reactant: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(=O)O)c2c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C(=O)Cc1c(C(=O)C(C)(C)C)oc2ccc(OC)cc12)C1CCCCC1
Temperature: 40 °C

Procedure:
Dissolve a mixture of 17 mg [2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid from the Step B Example 1 and 18.5 mg HOBt in 1 mL dry DMF. Add 13.2 μL N-ethylcyclohexylamine followed by 23.0 mg EDC and 35 μL DIEA. This solution was heated at 40° C. for 2 hours. It was purified directly on RP-HPLC using 65-100% MeCN gradient. The fractions containing pure product were pooled and lyophilized to give the title compound. LC-MS: 4.34 min. (m/Z=400.2, 422.1, 316.1).
Reaction SMILES: [C:1]([CH:5]1[CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:8]=2[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].OO.[Mn]([O-])(=O)(=O)=[O:28].[K+]>CO.O>[C:1]([CH:5]1[CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:18][CH2:19][N+:20]3([O-:28])[CH2:21][CH2:22][CH2:23][CH2:24]3)[C:8]=2[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(C)(C)C1CCc2c(c3ccccc3n2CCN2CCCC2)C1
Agent: OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)C1CCc2c(c3ccccc3n2CC[N+]2([O-])CCCC2)C1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
The product of Example 1 as free base (22.25g) in methanol (300 ml) was cooled to 0° (ice/water bath). Aqueous 30% w/v hydrogen peroxide (31.4g) was added dropwise over about 15 minutes, with cooling and stirring. The mixture was kept at ambient temperature for 3 days, and the excess hydrogen peroxide was then decomposed with a trace of potassium permanganate. The mixture was evaporated to dryness and the residue was dissolved in hot isopropanol (40 ml). Water (500 ml) was added with stirring and the mixture was refrigerated overnight, yielding a precipitate which was dissolved in hot water, filtered, and cooled, yielding a precipitate of 14.5g of 1-[2-(3-tert-butyl-1,2,3,4-tetrahydrocarbazole-9-yl) ethyl]pyrrolidine-N-oxide quarter-hydrate, m.p. 163-5°C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][C:9]#[N:10])=[CH:6][CH:5]=1.CS(O[CH2:18][CH2:19][C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)(=O)=O.Cl>CCCCCC.CN(C=O)C>[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([CH:8]([CH2:18][CH2:19][C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[C:9]#[N:10])=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)OCCc1cccs1
Reactant: N#CCc1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: N#CC(CCc1cccs1)c1ccc(Cl)cc1
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
To a flask under a nitrogen atmosphere was added, with stirring, 3.3 g. (0.0825 mole) of 60% sodium hydride, washed twice with hexane to remove the original mineral oil, in 75 ml. of a dry 2 to 1 mixture of DMF and toluene. To this slurry at room temperature was added 11.30 g. (0.075 mole) of 4-chlorobenzyl cyanide in 40 ml. of DMF. After 1.5 hours, the mixture was cooled to 10° C. and 13.7 g. (0.0782 mole) of 2-(2-thienyl)ethyl methanesulfonate in 25 ml. of DMF was added dropwise. The reaction was stirred at room temperature for 13 hours. Then aqueous 10% hydrochloric acid, 20 ml., was added followed by 150 ml. of diethyl ether which was washed three times with 50 ml. portions of water. After drying the ether and concentrating, the product was distilled at 130°-150° C. at 1-2 mm of Hg yielding 2-(4-chlorophenyl)-4-(2-thienyl)butyronitrile as an oil.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:9]=[C:8]2[CH:10]=[CH:11][N:12]([CH3:13])[C:7]2=[CH:6][C:5]=1[N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)[CH3:3].[Cl:19][C:20]1[C:21]([NH2:28])=[N:22][C:23]([NH2:27])=[N:24][C:25]=1Cl.CCN(CC)CC>C(#N)C.O>[NH2:27][C:23]1[N:24]=[C:25]([NH:1][CH:2]([C:4]2[N:9]=[C:8]3[CH:10]=[CH:11][N:12]([CH3:13])[C:7]3=[CH:6][C:5]=2[N:14]2[CH2:17][CH:16]([OH:18])[CH2:15]2)[CH3:3])[C:20]([Cl:19])=[C:21]([NH2:28])[N:22]=1
Reactant: CC(N)c1nc2ccn(C)c2cc1N1CC(O)C1
Reactant: Nc1nc(N)c(Cl)c(Cl)n1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(Nc1nc(N)nc(N)c1Cl)c1nc2ccn(C)c2cc1N1CC(O)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 8.5 %

Procedure:
To a 10 mL vial were added 1-(5-(1-aminoethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)azetidin-3-ol (75 mg, 0.304 mmol), 5,6-dichloropyrimidine-2,4-diamine (65.4 mg, 0.365 mmol) and Et3N (0.085 mL, 0.61 mmol) in acetonitrile (2 mL) and water (0.5 mL). The resulting brown solution was heated to 90° C. and stirred overnight. The crude product was purified by preparative HPLC eluting with 20-40% ACN in water (with 0.05% ammonium bicarbonate). The fractions containing the desired product were combined and lyophilized to give the title compound as an off-white solid (10 mg, 8.5%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03-1.14 (m, 3 H), 1.28-1.37 (m, 3 H), 3.48-3.56 (m, 1 H), 3.65-3.74 (m, 1 H), 3.74-3.83 (m, 3 H), 4.02-4.15 (m, 1 H), 4.23-4.33 (m, 1 H), 4.51-4.61 (m, 1 H), 5.33-5.48 (m, 1 H), 5.56-5.63 (m, 1 H), 5.64-5.73 (m, 2 H), 5.86-6.00 (m, 2H), 6.40-6.52 (m, 2 H), 7.07-7.16 (m, 1 H), 7.35-7.46 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C17H21ClN8O, 389; found 389.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([C:9]([F:13])=[CH:10][C:11]=1[Cl:12])[NH2:8])[CH:2]=[CH2:3].[C:14]1(=O)[O:19][C:17](=[O:18])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([N:8]2[C:17](=[O:18])[C:16]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]3[C:14]2=[O:19])[C:9]([F:13])=[CH:10][C:11]=1[Cl:12])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(N)c(F)cc1Cl
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CCOc1cc(N2C(=O)c3ccccc3C2=O)c(F)cc1Cl

Procedure:
A mixture of 20.2 g of 19A and 14.8 g of phthalic anhydride in 300 mL of toluene was treated with 1.01 g of triethylamine and heated to reflux for 16 hours with a Dean-stark trap to effect azeotropic removal of water. The toluene was removed in vacuo, The residue was dissolved in 800 mL of methylene chloride, and treated with 35 g charcoal. After filtration through celite and concentration of solvent in vacuo, the residue was recrystallized from ethanol to afford N-[3-(allyloxy)-4-chloro-6-fluorophenyl]-phthalimide (41A) as tan crystals, m.p.: 148°-150° C.
Reaction SMILES: CC[N:3](C1C=CC=CC=1)CC.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[C:21]([OH:23])=O.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C1COCC1>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[C:21]([NH2:3])=[O:23]
Reactant: CCN(CC)c1ccccc1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: NC(=O)c1cc2ccccc2[nH]1
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 327 %

Procedure:
Diethylaniline (0.33 μL, 2.1 μmol, 1.1 equiv) was added in one portion to a stirred solution of the amine (1.0 mg, 1.9 μmol, 1 equiv) in THF (0.15 mL) at 0° C. under an argon atmosphere and the solution was stirred for 5 min. Indole-2-carboxylic acid (0.40 mg, 2.5 μmol, 1.3 equiv), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.48 mg, 2.5 μmol, 1.3 equiv) and 1-hydroxybenzotriazole (0.31 mg, 2.3 μmol, 1.2 equiv) were then added separately, each in one portion, to the above solution at 0° C. The reaction mixture was warmed to 23° C. over 15 h 30 min, then was quenched with saturated aqueous ammonium chloride solution (3 mL). The mixture was diluted with ethyl acetate (10 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (10 mL) and the combined organic layer was dried over sodium sulfate. Concentration in vacuo left a white solid, which was purified by flash column chromatography (60% ethyl acetate-hexanes) to give the indole-2-carboxylic acid amide derivative (1.1 mg, 87%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1.[C:35](=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:35])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 89.2 %

Procedure:
A mixture of 0.60 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine [present compound 7-7], 0.13 g of sodium carbonate and 7.0 ml of ethanol was heated under reflux for 2 hours. It was cooled to room temperature, then, the solvent was distilled off under reduced pressure, and the resulted residue was subjected to silica gel chromatography to obtain 0.55 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(ethoxycarbonyl)methoxypyridine [present compound 7-8].
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.[OH2:12].O1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>>[O:16]([C:15]1[CH:14]=[C:5]([CH:6]([OH:12])[C:1]#[CH:11])[CH:4]=[CH:3][CH:2]=1)[C:17]1[CH:18]=[CH:3][CH:2]=[CH:1][CH:6]=1
Reactant: C1COCCO1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O
Product: C#CC(O)c1cccc(Oc2ccccc2)c1

Procedure:
A mixture of 10.4 g (1R, 5S) of 6,6-dimethyl-4(R)-[(S)-ethynyl-(3'-phenoxy-phenyl)-methoxy]-3-oxabicyclo-(3,1,0)-hexan-2-one, 1 g of p-toluene sulfonic acid, 80 ml of water and 80 ml of dioxane was refluxed for 2 hours and was evaporated to dryness under reduced pressure. The residue was added to water and the mixture was stirred and was extracted with isopropyl ether. The organic phase was subjected to the usual treatment and was evaporated to dryness under reduced pressure. The 6 g of residue was chromatographed over silica gel and was eluted with a 7-3 benzeneethyl acetate mixture to obtain 5.1 g of (S) 1-(3-phenoxyphenyl)-prop-2-yn-1-ol with a specific rotation of [α]D20 =+10.5° (c=0.63% in benzene).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[CH:4][C:3]=1[NH:10][C:11](=[O:24])[C@@H:12]([OH:23])[CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].[C:25](Cl)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C.O>CN(C)C=O>[OH:23][C@H:12]([C:11]([NH:10][C:3]1[CH:4]=[N:5][N:6]([CH2:7][CH2:8][OH:9])[C:2]=1[NH:1][C:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:24])[CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCC[C@H](O)C(=O)Nc1cnn(CCO)c1N
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)NCC[C@H](O)C(=O)Nc1cnn(CCO)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
To a solution of tert-butyl ((3S)-4-{[5-amino-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}-3-hydroxy-4-oxobutyl)carbamate (2.86 g) in N,N-dimethylformamide (30 ml) were added trityl chloride (3.48 g) and triethylamine (3.48 ml), and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the whole mixture was extracted with ethyl acetate. The extract was washed with water and brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure gave crude crystals, which were washed with ethyl acetate-diisopropyl ether (2:1) and collected by filtration to give tert-butyl ((3S)-3-hydroxy-4-{[1-(2-hydroxyethyl)-5-(tritylamino)-1H-pyrazol-4-yl]amino}-4-oxobutyl)carbamate (3.5 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH3:13]O>>[CH3:13][O:11][C:10](=[O:12])[CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=1
Reactant: CO
Reactant: Nc1cccc(CCC(=O)O)c1
Product: COC(=O)CCc1cccc(N)c1

Procedure:
3-(3-Amino-phenyl)-propionic acid (495 mg, 3 mmol) was esterified with MeOH using Method A, except that the residue was partitioned between EtOAc (10 ml) and saturated aqueous NaHCO3 (10 ml). The organic layer was dried (MgSO4), filtered and evaporated in vacuo to give the title compound.
Reaction SMILES: [CH2:1]([Mg]Br)C.C[C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[O:8][CH2:9][C:10]#[CH:11].Br[CH2:17][C:18]#[C:19][CH2:20][C:21]#[CH:22].S(=O)(=O)(O)O>CCOCC.O1CCCC1>[CH3:1][C:13]1[CH:12]=[C:7]([CH:6]=[CH:15][CH:14]=1)[O:8][CH2:9][C:10]#[C:11][CH2:17][C:18]#[C:19][CH2:20][C:21]#[CH:22]
Reactant: C#CCOc1ccccc1C
Reactant: CC[Mg]Br
Reactant: C#CCC#CCBr
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CCC#CCC#CCOc1cccc(C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
14.55 ml (6.79 g, 50.9 mmol) of a 3.5N solution of ethylmagnesium bromide in ether was added dropwise, under argon to a cold (0°-5° C.) solution of 7.82 g (53 mmol) of 3-(methylphenoxy)-1-propyne (C.A. 82, 155636 d) in 150 ml of anhydrous tetrahydrofuran at such a rate to maintain the temperature at 0° C.Thereafter, the reaction mixture was stirred for 1 hour further at 0°-5° C. Then, 246 mg of cuprous cyanide was added. After stirring 20 minutes more, a solution of 4 g (25.4 mmol) of 1-bromo-2,5-hexadiyne in 25 ml of anhydrous tetrahydrofuran was added dropwise, maintaining the temperature between 0°-5° C. The mixture was stirred at room temperature for 3 additional hours, and pouredinto 200 ml of 1N sulfuric acid and ice. After extraction with ether (3×100 ml) the combined organic extracts were concentrated in vacuo to a small volume, and washed several times with EDTA, to remove the copper salts, and then with water, dried over sodium sulfate and evaporated. The crude material was purified by column chromatography on 250 g of silica gel, using hexane as eluant, to yield 9-(m-methylphenoxy)-1,4,7-nonatriyne, as an oil. The product was stored indry ice.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[C:7]1(=[O:17])[O:12][C:10](=O)[CH:9]2[CH2:13][CH2:14][CH2:15][CH2:16][CH:8]12>C(O)C>[C:10]([O:6][CH:3]([CH2:4][O:5][C:7](=[O:17])[CH:8]=[CH2:16])[CH2:2][N:1]1[C:7](=[O:17])[CH:8]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:9]2[C:10]1=[O:12])(=[O:12])[CH:9]=[CH2:13]
Reactant: NCC(O)CO
Reactant: O=C1OC(=O)C2CCCCC12
Solvent: CCO
Product: C=CC(=O)OCC(CN1C(=O)C2CCCCC2C1=O)OC(=O)C=C
Yield: 109.7 %

Procedure:
A 500-ml, two necked flask was equipped a magnetic stirring bar, heating mantle and condenser. The flask was charged with 46 g of 3-amino-1,2-propanediol (0.50 mol.) and 300 ml of ethanol. Next, 77 g of hexahydrophthalic anhydride (0.50 mol.) was slowly added to the flask after which the reaction was refluxed for 12 hours. The imide formation was confirmed by IR. The ethanol was removed by a rotoevaporator to yield 92 g (81%) of the N-[2,3-di(hydroxy)propyl]hexahydrophthalimide.