Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C1C=CC=CC=1.[C:10](Cl)(=[O:19])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH2:21][C:22]1[CH:23]=[C:24]([CH:35]=[CH:36][N:37]=1)[C:25]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>>[CH2:28]([NH:27][C:25](=[O:26])[C:24]1[CH:35]=[CH:36][N:37]=[C:22]([NH:21][C:10](=[O:19])[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:23]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Nc1cc(C(=O)NCc2ccccc2)ccn1
Reactant: O=C(Cl)CCc1ccccc1
Solvent: O=C(Cl)c1ccccc1
Product: O=C(CCc1ccccc1)Nc1cc(C(=O)NCc2ccccc2)ccn1
Yield: 42 %

Procedure:
Following the procedure as describe in preparation of Example 5, making variations as required to replace benzoyl chloride with hydrocinnamoyl chloride, to react with 2-amino-N-benzylisonicotinamide, N-benzyl-2-(3-phenylpropanamido)-isonicotinamide was obtained in 42% yield: mp 177-179° C.; 1H NMR (300 MHz, CDCl3) δ 10.63 (s, 1H), 9.26 (s, 1H), 8.46-8.36 (m, 2H), 7.54-7.14 (m, 11H), 4.43 (s, 2H), 2.86-2.68 (m, 4H); MS (ES+) m/z 360.6 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9](=[O:10])[O:8][CH2:7]2)([O-])=O>CO.O1CCCC1.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9](=[O:10])[O:8][CH2:7]2
Reactant: O=C1OCc2cc([N+](=O)[O-])c(Oc3ccccc3)cc21
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cc2c(cc1Oc1ccccc1)C(=O)OC2
Yield: 67.5 %

Procedure:
950 mg of 5-nitro-6-phenoxyphthalide in 120 ml of methanol and 30 ml of tetrahydrofuran is hydrogenated in the presence of 2 g of Raney nickel within 3 hours at 20 bar, filtered, and concentrated. From methanol, 570 mg of 5-amino-6-phenoxyphthalide is obtained, mp 205°-206.5° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][C:10]2[S:19][C:18]3[N:17]4[C:20]([CH3:23])=[N:21][N:22]=[C:16]4[CH2:15][N:14]=[C:13]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:30])[C:12]=3[CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[N:1]1([CH2:7][CH2:8][CH2:9][C:10]2[S:19][C:18]3[N:17]4[C:20]([CH3:23])=[N:21][N:22]=[C:16]4[CH2:15][NH:14][CH:13]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:30])[C:12]=3[CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Cc1nnc2n1-c1sc(CCCN3CCOCC3)cc1C(c1ccccc1Cl)=NC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nnc2n1-c1sc(CCCN3CCOCC3)cc1C(c1ccccc1Cl)NC2
Reaction time: 0.5 h
Yield: 13.3 %

Procedure:
1.2 g (0.0027 mol) of 2-[3-(N-Morpholinyl)-n-propyl]- 4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepine in 20 ml of anhydrous THF are added dropwise to a prepared suspension of 0.1 g (0.0027 mol) of lithium aluminium hydride in 20 ml of anhydrous THF at ambient temperature and the mixture is refluxed for one hour. 0.1 ml of water, 0.1 ml of 15% sodium hydroxide solution and 0.3 ml of water are added to the reaction mixture which is then stirred for 30 minutes and the precipitate obtained is suction filtered. The filtrate is concentrated by evaporation, taken up in methylene chloride, washed and dried and the solvent is removed. The residue is chromatographed on silica gel using methylene chloride/methanol 95:5 as eluant. 0.16 g (yield 13%) of the desired compound are obtained, m.p. 135°-138° C.
Reaction SMILES: CC(C)(C)C([NH:5][C:6]1[CH:7]=[N:8][C:9]([N:19]2[CH2:24][CH2:23][S:22][CH2:21][CH2:20]2)=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])=O>Cl>[N:19]1([C:9]2[N:8]=[CH:7][C:6]([NH2:5])=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[CH:10]=2)[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1
Reactant: Cc1ccccc1-c1cc(N2CCSCC2)ncc1NC(=O)C(C)(C)C
Agent: Cl
Product: Cc1ccccc1-c1cc(N2CCSCC2)ncc1N
Temperature: 110 °C
Yield: 95.3 %

Procedure:
A suspension of 3.45 g (9.3 mmol) 2,2-dimethyl-N-(6-thiomorpholin-4-yl-4-o-tolyl-pyridin-3-yl)-propionamide in 95 ml 3 N hydrochloric acid solution was heated under argon at 110° C. overnight. The reaction mixture was cooled to room temperature, washed with two 100-ml portions of diethyl ether and filtered over celite. The filtrate was diluted with 20 ml water and was adjusted to pH 11 by addition of 28% sodium hydroxide solution under ice cooling. The product was extracted with three 100-ml portions of dichloromethane. The combined organic layers were washed with 50 ml brine, dried (sodium sulfate) and evaporated to give 2.53 g (95%) of the title compound as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[N:15][N:16]([CH3:19])[C:17]=1[CH3:18]>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[CH:14]=[N:15][N:16]([CH3:19])[C:17]=2[CH3:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: Cc1c(N)cnn1C
Solvent: c1ccncc1
Product: Cc1c(NS(=O)(=O)c2ccc(Br)cc2)cnn1C
Yield: 71 %

Procedure:
Prepared from 4-bromobenzenesulfonyl chloride (0.396 g, 1.55 mmol) and 4-amino-1,5-dimethyl-1H-pyrazole (0.172 g, 1.55 mmol) in pyridine (3 ml) according to the method of intermediate 1, to give the title compound as a yellow solid (0.362 g, 1.10 mmol, 71%). 5H (D-6 DMSO, 300K) 9.43 (1H, s), 7.80 (2H, d J 8.7 Hz), 7.58 (2H, d J 8.7 Hz), 3.63 (3H, s), 1.89 (3H, s). m/z (ES+, 70V) 332.0 (MH+).
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:63])[CH2:20][O:21][CH2:22][C:23](=[O:62])[NH:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([NH:51][C:52]([CH:54]2[CH2:59][CH2:58][C:57]([F:61])([F:60])[CH2:56][CH2:55]2)=[O:53])[CH2:32][CH2:33][N:34]2[CH:39]3[CH2:40][CH2:41][CH:35]2[CH2:36][CH:37]([N:42]2[C:46]([CH3:47])=[N:45][N:44]=[C:43]2[CH:48]([CH3:50])[CH3:49])[CH2:38]3)=[CH:27][CH:26]=1)C1C=CC=CC=1>CO.[Pd]>[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([CH2:20][O:21][CH2:22][C:23]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([NH:51][C:52]([CH:54]2[CH2:55][CH2:56][C:57]([F:61])([F:60])[CH2:58][CH2:59]2)=[O:53])[CH2:32][CH2:33][N:34]2[CH:39]3[CH2:40][CH2:41][CH:35]2[CH2:36][CH:37]([N:42]2[C:46]([CH3:47])=[N:45][N:44]=[C:43]2[CH:48]([CH3:50])[CH3:49])[CH2:38]3)=[CH:27][CH:26]=1)=[O:62])=[O:63]
Reactant: Cc1nnc(C(C)C)n1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)c1ccc(NC(=O)COCC(=O)NCCCCCCCNC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: Cc1nnc(C(C)C)n1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)c1ccc(NC(=O)COCC(=O)NCCCCCCCN)cc1
Yield: 51 %

Procedure:
A solution of 27 (260 mg, 0.291 mmol) in methanol (15 mL) was hydrogenated in the presence of 5% Pd/C (26 mg) under a H2 atmosphere (60 psi) at room temperature for 48 h. The mixture was filtered, and the filtrate was concentrated to give 28 as white foaming (113 mg, 51% yield). 1H NMR (400 MHz, CDCl3): δ 8.80 (s, 1H), 7.58 (d, J=8.48 Hz, 2H), 7.25 (d, J=8.48 Hz, 2H), 6.61 (d, J=7.48 Hz, 1H), 6.47 (m, 1H), 5.10 (q, J=7.00 Hz, 1H), 4.30 (m, 1H), 4.17 (s, 2H), 4.12 (s, 2H), 3.40-0 (m, 4H), 2.98 (seq, J=6.90 Hz, 1H), 2.68 (t, J=6.84 Hz, 2H), 2.48 (s, 3H), 2.43 (t, J=6.62 Hz, 2H), 2.26-2.12 (m, 5H), 2.08-3 (m, 16H), 1.44 (qu, J=6.72 Hz, 2H), 1.383 (d, J=6.76 Hz, 3H), 1.382 (d, J=6.80 Hz, 3H); 1.34-0 (m, 6H); 1H NMR (400 MHz, CD3OD): δ7.60 (d, J=8.52 Hz, 2H), 7.33 (d, J=8.56 Hz, 2H), 5.03 (t, J=7.34 Hz, 1H), 4.39 (m, 1H), 4.20 (s, 2H), 4.12 (s, 2H), 3.41 (m, 2H), 3.30-3.21 (m, 3H), 2.69 (t, J=7.32 Hz, 2H), 2.50 (s, 3H), 2.46-2.41 (m, 2H), 2.40-2.30 (m, 1H), 2.30-2.05 (m, 2H), 2.05-2.03 (m, 4H), 2.02-1.96 (m, 2H), 1.89-1.65 (m, 10H), 1.60-1.45 (m, 4H), 1.36-4 (m, 12H); 13C NMR (100 MHz, CDCl3): δ 176.59, 171.68, 170.07, 161.41, 152.60, 140.39, 138.07, 128.21, 123.91 (J13C-19F 239 Hz), 121.88, 71.95, 71.75, 60.69, 60.19, 52.41, 43.69, 42.03, 40.07, 36.77, 36.16, 33.90 (J13C-19F 24 Hz), 33.87 (J 13C-19F 24 Hz), 32.28, 30.38, 30.11, 27.86, 27.78, 27.20 (1 13C-19F 9 Hz), 27.05 (J13C-19F 9 Hz), 26.76, 22.07, 12.45. mp 100-102° C. IR v (Diamond, cm−1): 3256, 1651, 1538, 1515, 1261, 1103, 743. MS (ESI) found 757.9 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.C[O:27][C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][N:31]=1)=[O:29]>>[CH3:18][C:14]1[CH:13]=[C:12]([C:10](=[O:11])[CH2:9][CH:8]([C:4]2[CH:3]=[C:2]([C:33]3[CH:34]=[CH:35][C:30]([C:28]([OH:27])=[O:29])=[N:31][CH:32]=3)[CH:7]=[CH:6][CH:5]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH:17]=[CH:16][N:15]=1
Reactant: Cc1cc(C(=O)CC(c2cccc(Br)c2)c2ccccc2C)ccn1
Reactant: COC(=O)c1ccc(B(O)O)cn1
Product: Cc1cc(C(=O)CC(c2cccc(-c3ccc(C(=O)O)nc3)c2)c2ccccc2C)ccn1

Procedure:
In analogy to example 74, step 6, from 3-(3-bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one (example 98, step 5) and 2-(methylcarboxy)pyridine-5-boronic acid (4 h at 80° C., 40 h at rt) was prepared the title compound as an off-white semisolid, MS (ESI−): m/z=435.2 ([M−H]−, 1Br).
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[C:25]([O:27][CH3:28])=[O:26])[C:19](O)=[O:20].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.O>CN(C=O)C>[I:15][C:16]1[CH:17]=[C:18]([C:19](=[O:20])[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:22]=[CH:23][C:24]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: Nc1ccccc1Oc1ccccc1
Reactant: COC(=O)c1ccc(C(=O)O)cc1I
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(C(=O)Nc2ccccc2Oc2ccccc2)cc1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To a stirring solution of 2-phenoxyaniline 99 (0.813 g, 4.39 mmol) and 3-iodo-4-(methoxycarbonyl)benzoic acid 100 (1.28 g, 4.18 mmol) in DMF (15 mL) was added BOP (1.942 g, 4.39 mmol) and TEA (1.166 mL, 8.36 mmol), the reaction mixture was stirred at room temperature for 1 h then poured into water. The desired product was extracted with ethyl acetate and the combined organic layers were washed with water, brine, dried over Na2SO4, filtered and solvent evaporated to provide methyl 2-iodo-4-(2-phenoxyphenylcarbamoyl)benzoate 101 (1.382 g, 70% yield) as a red foam after purification by flash chromatography (0 to 40% ethyl acetate in hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([NH2:21])[CH:15]=1>CS(C)=O.CCOC(C)=O>[CH3:11][O:12][C:13]([C:14]1[CH:19]=[CH:18][C:17]2[N:20]=[C:4]([C:3]3[C:2]([Cl:1])=[CH:9][CH:8]=[CH:7][C:6]=3[Cl:10])[NH:21][C:16]=2[CH:15]=1)=[O:22]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: COC(=O)c1ccc(N)c(N)c1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Reaction time: 17 h

Procedure:
Slowly add a solution of FeCl3 (1.46 g, 9.02 mmol) in DMSO (10 mL) to a stirring solution of 2,6-dichloro-benzaldehyde (5.27 g, 30.1 mmol) and 3,4-diamino-benzoic acid methyl ester (5.00 g, 30.1 mmol) in DMSO (90 mL). Allow the reaction to stir open to the air for 17 hr. Add additional FeCl3 (0.73 g, 4.51 mmol). Stir for an additional 24 hr. Dilute with EtOAc (600 mL) and extract with water (3×50 mL). Dry the organic phase over Na2SO4 and evaporate the solvent. Triturate the residue with DCM to afford the desired product as a light tan solid: 1H NMR (400 MHz, MeOD) δ ppm 3.96 (s, 3H) 7.55-7.63 (m, 3H) 7.71 (d, J=8.21 Hz, 1H) 8.04 (dd, J=8.53, 1.58 Hz, 1H) 8.37 (br. s., 1H); (M+H)+ 320.9.
Reaction SMILES: COC(=O)C(C1C=CC(S)=C(OC)C=1)(C)C.[CH3:17][O:18][C:19](=[O:36])[CH2:20][N:21]1[C:30]2[C:25](=[CH:26][C:27]([S:31](Cl)(=O)=O)=[CH:28][CH:29]=2)[CH2:24][CH2:23][C:22]1=[O:35].COC(=O)CN1C2C(=CC(SCC3C=CC(OCC4C=CC(C(F)(F)F)=CC=4)=CC=3)=CC=2)CCC1=O>>[CH3:17][O:18][C:19](=[O:36])[CH2:20][N:21]1[C:30]2[C:25](=[CH:26][C:27]([SH:31])=[CH:28][CH:29]=2)[CH2:24][CH2:23][C:22]1=[O:35]
Reactant: COC(=O)CN1C(=O)CCc2cc(S(=O)(=O)Cl)ccc21
Agent: COC(=O)C(C)(C)c1ccc(S)c(OC)c1
Agent: COC(=O)CN1C(=O)CCc2cc(SCc3ccc(OCc4ccc(C(F)(F)F)cc4)cc3)ccc21
Product: COC(=O)CN1C(=O)CCc2cc(S)ccc21

Procedure:
Compound 49C was prepared analogously to compound 21C using the product prepared from compound 49B. Yield was quantitative. MS m/z 252 (M+1). Step 4. Preparation of {2-Oxo-6-[4-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-3,4-dihydro-2H-quinolin-1-yl-acetic acid methyl ester (Compound 49D).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:17][C:18]1([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.O>CS(C)=O>[CH3:17][C:18]1([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:20][CH2:19]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: COC(=O)CC1(C)CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)CC1(C)CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 60 °C
Yield: 67.2 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (2.97 g, 18.77 mmol) in DMSO (30 mL) was added sodium carbonate (6.4 g, 60.38 mmol) followed by methyl (4-methylpiperidin-4-yl)acetate (3.21 g, 18.77 mmol) (prepared according to the procedures described by Janet Ralbovsky, Joseph Lisko and Wei He, Synthetic Communications, 2005, 35 (12), 1613-1625 and Gerhard Hund, and Woldemar Schneider, Chem Ber 1980,113 (2), 401-7). The reaction mixture was heated to 60° C. for 1.5 hours, then allowed to cool and water (100 mL) was added. The suspension filtered, and dried to leave a yellow solid (3.70 g, 12.62 mmol, 67%). 1H NMR δ 1.08 (s, 3H), 1.45-1.48 (m, 2H), 1.55-1.61 (m, 2H), 2.38 (s, 2H), 3.59 (s, 3H), 3.64-3.70 (m, 2H), 3.85-3.91 (m, 2H), 6.95 (d, 1H), 8.19 (d, 1H), 8.95 (s, 1H); MS m/e MH+ 294.
Reaction SMILES: [C:1]([CH:4]([N:6]1[CH2:11][CH2:10][CH:9]=[C:8]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)[CH2:7]1)[CH3:5])([OH:3])=[O:2].[CH2:17](I)[CH3:18]>>[CH2:17]([N:14]1[N:15]=[N:16][C:12]([C:8]2[CH2:7][N:6]([CH:4]([C:1]([OH:3])=[O:2])[CH3:5])[CH2:11][CH2:10][CH:9]=2)=[N:13]1)[CH3:18]
Reactant: CC(C(=O)O)N1CCC=C(c2nnn[nH]2)C1
Reactant: CCI
Product: CCn1nnc(C2=CCCN(C(C)C(=O)O)C2)n1

Procedure:
The title compound was prepared by treating 5 (5.97 g, 0.027 mol) with ethyl iodide instead of methyl iodide as described in Example 5. Yield: 4.14 g (0.0164 mol, 61%) as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([Mg]Br)[CH3:20]>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]([OH:18])[CH2:19][CH3:20])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[Mg]Br
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: C1CCOC1
Product: CCC(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 1 h
Yield: 61.6 %

Procedure:
To a solution of 4-formylpiperidine-1-carboxylic acid benzyl ester (1.0 g, 4.04 mmol) in THF (15 mL) at 0° C. was added ethylmagnesium bromide (1.0M in THF, 8.1 mL, 8.08 mmol) and the mixture was stirred at 0° for 1 h. The reaction mixture was then quenched with water and extracted with EtOAc. The organic phase was washed with brine, dried (MgSO4) and then concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-100% EtOAc in hexane) affording 4-(1-Hydroxypropyl)piperidine-1-carboxylic acid benzyl ester (690 mg, 62%). 1H NMR (CDCl3, 400 MHz): δ 7.38-7.27 (5H, m), 5.13 (2H, bs), 4.25 (2H, s), 3.36-3.29 (1H, m), 2.83-2.66 (2H, m), 1.85-1.77 (1H, bd, J=13.16 Hz), 1.64-1.19 (7H, m), 0.97 (3H, t, J=7.41 Hz).
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])[CH:5]=1.[OH-].[Na+]>CO>[CH2:12]([N:11]([CH2:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:18])=[O:2])[CH2:15][CH2:16][CH3:17])[CH2:13][CH3:14]
Reactant: CCCN(CCC)Cc1cccc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCN(CCC)Cc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
The compound (858 mg) obtained in Example 18-1 was dissolved in methanol (18 ml) and added with a 1 mol/l sodium hydroxide aqueous solution (9.0 ml) and the whole was stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in a 1 mol/l hydrochloric acid. After addition of chloroform, the resultant was added with sodium chloride to make the aqueous layer to be a saturated saline solution. The whole was subjected to extraction with chloroform and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was dried under vacuum, thereby obtaining the subject compound (781 mg) as a white solid.
Reaction SMILES: [CH3:1][CH:2]([OH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.ON1C(=O)C2=CC=CC=C2C1=O.C=CC.O=O.C1OC1C>C([O-])(=O)C.[Co+2].C([O-])(=O)C.C(#N)C1C=CC=CC=1>[C:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:9])[CH3:1]
Reactant: CC(O)c1ccccc1
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: CC1CO1
Solvent: N#Cc1ccccc1
Solvent: C=CC
Product: CC(=O)c1ccccc1
Yield: 98 %

Procedure:
To a mixture of 1 mole of α-phenethyl alcohol, 0.1 mole of N-hydroxyphthalimide, 1 mmol of cobalt (II) acetate and 1 l of benzonitrile was added 1.5 moles of propylene, and the resultant mixture was stirred at 80° C. under oxygen atmosphere (oxygen: 1 atm) for 6 hours. Gas chromatographic analysis of products in a reaction mixture revealed that 0.92 mole of propylene oxide was formed, and that acetophenone (yield 98%: on α-phenethyl alcohol basis) was produced. The conversion rate from (x-phenethyl alcohol was 99%.
Reaction SMILES: CO[C:3](=[O:26])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1.[NH:27]([CH2:31][CH2:32][OH:33])[CH2:28][CH2:29][OH:30]>CO.O1CCCC1>[OH:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][OH:33])[C:3](=[O:26])[C:4](=[O:25])[C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:9][CH:10]=1
Reactant: OCCNCCO
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: O=C(C(=O)N(CCO)CCO)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Yield: 30.6 %

Procedure:
A solution of 4-[[2-(2-naphthalenyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.5 g) in methanol (40 mL) and tetrahydrofuran (10 mL) was treated with diethanolamine (0. 162 g) and the mixture was refluxed for 18 hours. The solvents were removed by evaporation and the residue was crystallized from acetone to give 0.185 g of N,N-bis(2-hydroxyethyl)-4-[[2-(2-naphthalenyloxy)ethyl]oxy]-alpha-oxobenzeneacetamide as a colorless solid, mp 128°-133° C.
Reaction SMILES: [Br:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].F[B-](F)(F)F.[O:19]=[N+:20]=[O:21]>C(#N)C>[Br:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[C:6]([N+:20]([O-:21])=[O:19])[C:3]=1[C:4]#[N:5]
Reactant: O=[N+]=O
Reactant: COc1ccc(C#N)c(Br)c1OC
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: COc1cc([N+](=O)[O-])c(C#N)c(Br)c1OC
Reaction time: 4 h
Yield: 85.3 %

Procedure:
To a stirred solution of 2-bromo-3,4-dimethoxybenzonitrile (prepared according to step (b), 5.77 g, 23.8 mmol) in acetonitrile (58 ml) at 0° C. was added nitronium tetrafluoroborate (5.67 g, 42.9 mmol) portionwise ensuring that the temperature did not rise above 10° C. After stirring for 4 hours in the range 0° C. to 10° C., the reaction was cautiously quenched into 10% aqueous NaHCO3 (66 ml). The resulting suspension was filtered and the solid dried in vacuo overnight to give 5.83 g of the subtitle product (85%).
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]2[CH:7]=[N:8][C:9]([N:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)=[N:10][CH:11]=2)[CH2:3][CH2:2]1.[ClH:25].O1CCOCC1>O1CCOCC1>[ClH:25].[CH:1]1([C:4]#[C:5][C:6]2[CH:7]=[N:8][C:9]([N:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)=[N:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C#CC3CC3)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C(#CC1CC1)c1cnc(N2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-(5-(cyclopropylethynyl)pyrimidin-2-yl)piperazine-1-carboxylate (150 mg, 0.46 mmol) in dioxane (3 mL) was added 4 M HCl-dioxane (3 mL), and the reaction mixture was stirred room temperature for 1 hour. LCMS showed the reaction was completed. The reaction mixture was concentrated to afford 5-(cyclopropylethynyl)-2-(piperazin-1-yl)pyrimidine HCl salt as a white solid (100 mg, crude), which was directly used in the next step without further purification. MS (ES+) C13H16N4 requires: 228, found: 229 [M+H]+.
Reaction SMILES: CO/[CH:3]=[CH:4]/[C:5](=[O:7])[CH3:6].[C:8]([SH:12])([CH3:11])([CH3:10])[CH3:9].FC(F)(F)C(O)=O.C(OCC)C>C(Cl)(Cl)(Cl)Cl>[C:8]([S:12]/[CH:3]=[CH:4]/[C:5](=[O:7])[CH3:6])([CH3:11])([CH3:10])[CH3:9]
Reactant: CO/C=C/C(C)=O
Reactant: CC(C)(C)S
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)/C=C/SC(C)(C)C
Temperature: 95 °C
Yield: 89.6 %

Procedure:
To a solution of (E)-4-methoxy-3-buten-2-one (purity: 90%, 7.92 ml, 69.9 mmol) and tert-butylmercaptan (5.54 ml, 48.9 mmol) in carbon tetrachloride (70 ml) was added, under ice cooling, trifluoroacetic acid (7.54 ml, 97.9 mmol), followed by heating, under reflux, on an oil bath at 95° C. for 4 hours. After ice cooling, ethyl ether was added 5 thereto, followed by washing with water (twice), an aqueous saturated sodium hydrogen carbonate solution, water and saturated brine. After drying with anhydrous magnesium sulfate, the resultant product was concentrated under a reduced pressure and the residue was treated with the column chromatography (420 g, n-hexane:ethyl acetate=1:0-6:1) to thereby obtain the titled compound in the form of a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[NH2:10][CH:11]1[CH:18]2[CH2:19][C:14]3([C:21]([NH2:23])=[O:22])[CH2:15][CH:16]([CH2:20][CH:12]1[CH2:13]3)[CH2:17]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[Br:1][C:2]1[O:6][C:5]([C:7]([NH:10][CH:11]2[CH:12]3[CH2:20][CH:16]4[CH2:15][C:14]([C:21](=[O:22])[NH2:23])([CH2:19][CH:18]2[CH2:17]4)[CH2:13]3)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)o1
Reactant: NC(=O)C12CC3CC(C1)C(N)C(C3)C2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)C12CC3CC(C1)C(NC(=O)c1ccc(Br)o1)C(C3)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution prepared by dissolving 100 mg of 5-bromofuran-2-carboxylic acid, 145 mg of (E) type 4-aminoadamantane-1-carboxylic acid amide (prepared from Preparation Example 1), and 202 mg of TBTU in MC was added dropwise 0.2 mL of DIEA and then stirred at room temperature for 4 hours. The reaction solution was washed with a 1N solution of HCl and a 1N solution of NaOH, respectively, and then washed again with brine. The resulting organic solution was dried over MgSO4 and after filtration, was distilled under a reduced pressure. The compound thus obtained was purified via recrystallization by using MeOH and ether to produce 150 mg of a white solid product.