Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH:28]3[CH2:33][CH2:32][N:31]([CH:34]([CH3:38])[CH2:35][CH2:36][NH2:37])[CH2:30][CH2:29]3)[CH2:18][C:19]3[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[CH:21][C:20]=3[F:27])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.[CH3:40][C:41]1[CH:49]=[CH:48][CH:47]=[C:46]([CH3:50])[C:42]=1[C:43](O)=[O:44]>>[C:25]([C:23]1[CH:22]=[CH:21][C:20]([F:27])=[C:19]([CH:24]=1)[CH2:18][N:17]([CH:28]1[CH2:33][CH2:32][N:31]([CH:34]([CH3:38])[CH2:35][CH2:36][NH:37][C:43](=[O:44])[C:42]2[C:46]([CH3:50])=[CH:47][CH:48]=[CH:49][C:41]=2[CH3:40])[CH2:30][CH2:29]1)[C:14]1[CH:15]=[CH:16][C:11]([O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:39])=[CH:5][CH:6]=2)=[CH:12][CH:13]=1)#[N:26]
Reactant: Cc1cccc(C)c1C(=O)O
Reactant: COC(=O)c1ccc(Oc2ccc(N(Cc3cc(C#N)ccc3F)C3CCN(C(C)CCN)CC3)cc2)cc1
Product: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cc(C#N)ccc2F)c2ccc(Oc3ccc(C(=O)O)cc3)cc2)CC1

Procedure:
Using general procedure E with 4-{4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(5-cyano-2-fluoro-benzyl)-amino]-phenoxy}-benzoic acid methyl ester (see EXAMPLE 228) (90 mg, 0.17 mmol) and 2,6-dimethylbenzoic acid (29 mg, 0.19 mmol) followed by general procedure K with the resulting ester afforded COMPOUND 229 as a white solid (58 mg, 53% over 2 steps). 1H NMR (CDCl3) δ 1.06-1.16 (m, 3H), 1.53-1.69 (m, 1H), 1.78-2.04 (m, 3H), 2.28 (s, 6H), 2.32-2.45 (m, 1H), 2.63-2.75 (m, 1H), 2.92-3.18 (m, 3H), 3.29-3.45 (m, 2H), 3.57-3.82 (m, 3H), 4.11 (s, 2H), 6.58-6.65 (m, 2H), 6.82-7.03 (m, 7H), 7.12-7.21 (m, 1H), 7.50-7.85 (m, 2H), 7.79-8.01 (m, 3H). 13C NMR (CDCl3) δ 11.81, 18.19, 26.45, 27.05, 30.35, 36.88, 42.30, 43.32, 49.61, 55.06, 57.96, 107.47, 114.99, 115.37, 115.81, 117.29, 120.17, 125.91, 126.28, 127.40, 128.17 (d, J=15 Hz), 130.59, 131.94, 132.92, 136.93, 143.59, 147.04, 160.57, 161.58 (d, J=256 Hz), 169.66, 170.16. ES-MS m/z 649 (M+H). Anal. Calcd. for C39H41N4O4F.0.9CH2Cl2: C, 66.08; H, 5.95; N, 7.73; F, 2.62. Found: C, 66.11; H, 6.08; N, 7.64; F, 2.48.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[C:13]([CH3:35])[CH:14]2[Si:20]([CH:23]1[C:31]2[C:26](=[C:27](Br)[C:28]([CH3:32])=[CH:29][CH:30]=2)[CH:25]=[C:24]1[CH3:34])([CH3:22])[CH3:21]>C1COCC1.[Cl-].[Cl-].[Zn+2].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:1]1([C:10]2[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]3[C:11]=2[CH:12]=[C:13]([CH3:35])[CH:14]3[Si:20]([CH:23]2[C:31]3[C:26](=[C:27]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:28]([CH3:32])=[CH:29][CH:30]=3)[CH:25]=[C:24]2[CH3:34])([CH3:22])[CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CC1=Cc2c(ccc(C)c2Br)C1[Si](C)(C)C1C(C)=Cc2c1ccc(C)c2Br
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CC1=Cc2c(ccc(C)c2-c2ccccc2)C1[Si](C)(C)C1C(C)=Cc2c1ccc(C)c2-c1ccccc1
Reaction time: 1 h

Procedure:
In an argon atmosphere, to a solution of 15 mL of THF with 29.0 ml of 0.5 M ZnCl2 (14.5 mmol) in THF, 13.0 ml of 1.0 M phenylmagnesium bromide (13.0 mmol) in THF was added at ambient temperature. This mixture was stirred for 1 hour, and, then, 10.0 ml of 0.02 M Pd(PtBu3)2 (0.20 mmol, 4 mol. %) in THF and 2.51 g (5.0 mmol) of 2 were added. The resulting mixture was stirred for 5 hours at reflux. The product was isolated by flash chromatography on Silica Gel 60 (40-63 μm, d 30 mm, l 100 mm; eluent: hexanes). Yield 2.36 g (95%) of white solid of ca. 1 to 1 mixture of rac- and meso-compounds.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)[N:4]=1)#[N:2].[CH2:19]([NH2:21])[CH3:20]>O1CCCC1>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([NH:21][CH2:19][CH3:20])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)[N:4]=1)#[N:2]
Reactant: CCN
Reactant: N#Cc1nc(Cl)c(-c2cccc(Br)c2)nc1C#N
Solvent: C1CCOC1
Product: CCNc1nc(C#N)c(C#N)nc1-c1cccc(Br)c1
Temperature: 0 °C
Yield: 80 %

Procedure:
2,3-Dicyano-5-chloro-6-(m-bromophenyl)pyrazine (1.15 g; 0.0036 mole) was dissolved in 20 ml of tetrahydrofuran. The solution was cooled to 0° C., and 0.50 g of a 70% aqueous solution of ethylamine was added. The mixture was worked up in the same way as in Example 13, and recrystallized from ethanol to afford 0.95 g (yield 80%) of 2,3-dicyano-5-ethylamino-6-(m-bromophenyl)pyrazine.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:11]=[C:12]([C:13]([OH:15])=O)[C:7]=2[CH:6]=[N:5]1)[CH3:3].Cl.[NH:23]1[C:27]([C:28]2[CH:29]=[C:30]3[C:40](=[CH:41][CH:42]=2)[O:39][C:33]2([CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:32][C:31]3=[O:43])=[N:26][N:25]=[N:24]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl>O.CN(C=O)C>[CH3:3][CH:2]([N:4]1[C:8]2=[N:9][C:10]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:11][C:12]([C:13]([N:36]3[CH2:37][CH2:38][C:33]4([CH2:32][C:31](=[O:43])[C:30]5[C:40](=[CH:41][CH:42]=[C:28]([C:27]6[NH:26][N:25]=[N:24][N:23]=6)[CH:29]=5)[O:39]4)[CH2:34][CH2:35]3)=[O:15])=[C:7]2[CH:6]=[N:5]1)[CH3:1]
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3nnn[nH]3)cc21
Reactant: CC(C)n1ncc2c(C(=O)O)cc(-c3ccccc3)nc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1ncc2c(C(=O)N3CCC4(CC3)CC(=O)c3cc(-c5nnn[nH]5)ccc3O4)cc(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TEA (0.2 mL) was added to a DMF suspension (2 mL) of 1-(1-methylethyl)-6-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid, 6-(tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride, EDCI and HOBT.H2O, heated at 80° C. and stirred for 2 hours. This was cooled to room temperature, iced water was added thereto, and its pH was adjusted to 2.5 with 1 N HCl solution added thereto. The resulting crystal was taken out through filtration, washed with water, washed with Et2O, and dried in vacuum at 70° C. to obtain the title compound as a pale brown powder. 1H-NMR (400 MHz, DMSO-d6) δ: 8.34 (1H, d, J=2.2 Hz), 8.26-8.21 (2H, m), 8.19 (1H, s), 8.19 (1H, dd, J=8.4, 2.6 Hz), 7.82 (1H, s), 7.58-7.47 (3H, m), 7.20 (1H, d, J=8.4 Hz), 5.33 (1H, sept, J=6.8 Hz), 4.45-4.30 (1H, m), 3.70-3.00 (3H, m), 2.95 (2H, s), 2.20-1.70 (4H, m), 1.55 (6H, d, J=6.8 Hz). MS [M+H]+=549.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([O:9]C)=[O:8].[OH-].[Na+].O.Cl>C(O)C>[CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1occc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccoc1C(=O)O

Procedure:
3-Methyl-2-furancarboxylic acid (41 g, m.p. 136°-138° C.) was prepared by refluxing methyl 3-methyl-2-furancarboxylate 54g, (Organic Synthesis, Coll. Vol. IV, p. 649), sodium hydroxide (20 g), water (100 ml) and ethanol (100 ml), then cooling and acidifying with concentrated hydrochloric acid.
Reaction SMILES: [H-].C(O[Al](OCC)OCC)C.[Li+].[Li].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2([C:28]#[N:29])[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)=[C:17](F)[CH:16]=1.[OH-].[Na+]>C(COC)OC.O.C(O)C>[Cl:14][C:15]1[CH:20]=[C:19]2[NH:29][CH2:28][C:21]3([CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[C:18]2=[CH:17][CH:16]=1
Reactant: CN1CCC(C#N)(c2ccc(Cl)cc2F)CC1
Agent: CCO[Al](OCC)OCC
Agent: [H-]
Agent: [Li+]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: CN1CCC2(CC1)CNc1cc(Cl)ccc12

Procedure:
To a refluxing suspension of lithium triethoxyaluminum hydride (prepared by dropping 12 ml of absolute ethyl alcohol carefully into a cooled slurry of 4.9 g of lithium aluminumhydride in 150 ml of glyme) is added over a 30 minute span a mixture of 8.1 g of 4-(4-chloro-2-fluorophenyl)-4-cyano-1-methylpiperidine in 80 ml of glyme. After total addition, stirring is continued at reflux for 72 hours. Thereafter, the mixture is permitted to cool before successively adding 5 ml of water, 5 ml of a 15% aqueous sodium hydroxide solution and 15 ml of water effecting a precipitate. The precipitate is collected by filtration followed by repeated washings with warm methylene chloride. The filtrate, combined with the washings, is successively washed with water, dried and evaporated to dryness leaving a white crystalline solid. The solid is recrystallized from an acetone-pentane mixture to provide fine needles, mp 172°-173° C. of 6-chloro-1'-methylspiro[indoline-3,4'-piperidine].
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@@H:9]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:11][S:12]2)=[CH:7][C:6]=1[CH3:23])=[O:4].C(=O)([O-])[O-].[K+].[K+]>>[C:19]([O:18][C:16]([NH:15][C@@H:9]1[C:8]2[C:13](=[CH:14][C:5]([C:3]([OH:4])=[O:2])=[C:6]([CH3:23])[CH:7]=2)[S:12][CH2:11][CH2:10]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: COC(=O)c1cc2c(cc1C)[C@@H](NC(=O)OC(C)(C)C)CCS2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc2c(cc1C(=O)O)SCC[C@@H]2NC(=O)OC(C)(C)C
Yield: 77.9 %

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 6 using (S)-4-(tert-butoxycarbonylamino)-6-methylthiochromane-7-carboxylic acid methyl ester (8.10 g) and potassium carbonate (9.94 g), the objective (S)-4-(tert-butoxycarbonylamino)-6-methylthiochromane-7-carboxylic acid (6.05 g) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:14][C:13]=2[CH:12]=[C:11]([O:30][CH3:31])[CH:10]=1.[CH3:32][NH2:33]>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH:33][CH3:32])[CH2:14][C:13]=2[CH:12]=[C:11]([O:30][CH3:31])[CH:10]=1
Reactant: COc1cc2c(c(-c3cccc(C)c3C)c1)OC(COS(=O)(=O)c1ccc(C)cc1)C2
Reactant: CN
Product: CNCC1Cc2cc(OC)cc(-c3cccc(C)c3C)c2O1

Procedure:
The title compound was prepared (0.064 g, 64%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2,3-dimethylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.132 g, 0.30 mmol) and methylamine (0.093 g, 3.0 mmol). mp 177-179° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.O.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](O)(=[O:20])=[O:19])=[CH:14][CH:13]=1.CS(OCCCCOS(C)(=O)=O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[Br:1][C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([S:18]([C:15]2[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=2)(=[O:20])=[O:19])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Brc1cccc2c1OCC2
Agent: CS(=O)(=O)OCCCCOS(C)(=O)=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: Cc1ccc(S(=O)(=O)c2cc(Br)c3c(c2)CCO3)cc1
Yield: 113.2 %

Procedure:
7-Bromo-1,2-dihydrobenzofuran (64 mg, 0.3 mmol; Intermediate 77) and para-toluenesulfonic acid monohydrate (62 mg, 0.3 mmol) were mixed and then a 1:10 mixture (by weight) of methanesulfonic and phosphorous pentoxide (1 mL) was added. The resultant mixture was stirred over night at room temperature and was then poured onto ice/water. The obtained crystalline material was filtered and dried to give 120 mg of the title product. 1H NMR (400 MHz, CDCl3) δ 2.40 (s, 3H), 3.33 (t, 2H), 4.73 (t, 2H), 7.29 (d, 2H), 7.65 (d, 1H), 7.79 (d, 2H), 7.89 (d, 1H); GC-MS (EI+) for C15H13BrSO3 m/z 354 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.[OH-].[Na+].[CH2:12]([O:19][C:20](Cl)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>O>[CH2:12]([O:19][C:20]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
To the solution of piperidine-4-carboxylic acid (1.3 g, 10 mmol) of water (20 ml) was added sodium hydroxide (1.6 g, 40 mmol). Then benzyloxycarbonyl chloride (2.02 g, 12 mmol) was added dropwise at 0° C. The mixture was stirred at 0° C. for 2 h. The resulting mixture was treated with 5N hydrochloric acid to pH=6 and extracted with ethyl acetate, the solvent was removed under reduced pressure and dried in vacuum. 2.2 g of crude 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid was obtained. To a stirred solution of crude 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid (1.05 g, 4 mmol) in anhydrous dichloromethane (10 mL) was added dropwise thionyl chloride (0.573 g, 4.81 mmol) at 0° C. After the addition, the solution was stirred at room temperature overnight. Solvent was removed in vacuum to give crude benzyl-4-(chlorocarbonyl)piperidine-1-carboxylate. To a stirred solution of ethyl 3-amino-2-hydroxybenzoate (0.501 g, 3.0 mmol) and triethylamine (0.455 g, 4.5 mmol) in anhydrous dichloromethane (20 mL) was added dropwise a solution of crude benzyl-4-(chlorocarbonyl)piperidine-1-carboxylate (1.014 g, 3.6 mmol) in anhydrous dichloromethane (5 mL) at 0° C. After the addition, the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane, washed with water (30 mL×3), brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=30:1 to 5:1) to give benzyl-4-(2-hydroxy-3-(methoxycarbonyl)phenylcarbamoyl)piperidine-1-carboxylate (0.25 g, yield 20%; LC-MS (ESI) m/z: 413 (M+1)+) and 1-benzyl 4-(2-(1-(benzyloxycarbonyl)piperidine-4-carboxamido)-6-(methoxycarbonyl)phenyl)piperidine-1,4-dicarboxylate (1.0 g, yield 51%; LC-MS (ESI) m/z: 658 (M+1)+).
Reaction SMILES: [CH:1]1([CH2:8][CH2:9][C:10]#[N:11])[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].ClC1C=CC=C(C(OO)=[O:20])C=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([OH:29])=[O:28]>CCCCCC>[C:10]([CH2:9][CH2:8][CH:1]1[O:20][C:2](=[O:7])[CH2:3][CH2:4][CH2:5][CH2:6]1)#[N:11].[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([OH:29])=[O:28]
Reactant: N#CCCC1CCCCC1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C(O)c1cccc(Cl)c1
Solvent: CCCCCC
Product: N#CCCC1CCCCC(=O)O1
Temperature: 55 °C

Procedure:
A reactor is loaded with 151 g of 3-(2-cyclohexanonyl)propionitrile in 500 ml of n-hexane and 260 g of m-chloroperbenzoic acid (70% titer) dissolved at 50° C. in 2000 ml of n-hexane in 30 minutes. The solution is heated to 55° C. for 15 hours. Cooling of the solution separates, in crystalline form, part of the m-chlorobenzoic acid which is scarcely soluble in the system, together with a heavy liquid phase which is formed by 7-cyanoethyl-2-oxepanone and by m-chlorobenzoic acid. 71.5 g of 7-cyanoethyl-2-oxepanone, impure with m-chlorobenzoic acid, are recovered from the lower phase. 24 g of 7-cyanoethyl-2-oxepanone are recovered from the upper phase by concentration and several crystallizations. Conversion over the initial ketone is 85%. Yield on the converted amount is 57%.
Reaction SMILES: [OH-].[Na+].[CH2:3]([SH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][NH:16][N:15](Cl)[CH:14]=1.[Cl-].[NH4+]>CS(C)=O>[CH2:3]([S:10][N:15]1[CH:14]=[C:13]([O:12][CH3:11])[CH:18]=[CH:17][NH:16]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC1=CN(Cl)NC=C1
Reactant: SCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC1=CN(SCc2ccccc2)NC=C1
Reaction time: 0.17 h
Yield: 39.5 %

Procedure:
In dimethyl sulfoxide (30 ml) was suspended 843 mg (21 mmol, 55% in oil) of sodium hydroxide, and 2.0 ml (16.7 mol) of benzylmercaptan was added thereto under ice-cooling, followed by stirring for 10 minutes. To the reaction mixture was added 2.5 g (17.6 mmol) of 4-methoxy-2-chloropyridazine, followed by stirring at room temperature overnight. To the reaction mixture was added an aqueous saturated ammonium chloride, followed by extracting with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. Then, the residue was purified by silica gel chromatography, to give 1.63 g of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pt]=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)=[CH:19][CH:20]=1
Reactant: O=C(O)Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Agent: O=[Pt]
Solvent: CCO
Product: Nc1ccc(Oc2ccc(CC(=O)O)cc2)cc1
Reaction time: 2 h
Yield: 40.3 %

Procedure:
To a solution of 13.65 g of [p-(p-nitrophenoxy)phenyl]acetic acid in 100 ml of ethanol is added 130 mg of platinum oxide. The mixture is shaken under 45 lb hydrogen pressure in a Parr shaker. After 2 hours, a thick white solid precipitates. The mixture is filtered, and 200 mg of fresh platinum oxide is added to the filtrate which is subjected to the reducing conditions. After an additional hour, the mixture is filtered and washed with cold ethanol. The combined solids are dissolved in hot methanol and filtered. Water is added to the filtrate to afford 4.9 g of a brown solid. A portion is recrystallized from methanol to yield the product as cream colored crystals, mp 172° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[C:9][Si](C)(C)C)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[CH:9])[CH:7]=1
Reactant: C[Si](C)(C)C#Cc1cncc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cncc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
3-Chloro-5-[(trimethylsilyl)ethynyl]pyridine (1.4 g, 6.7 mmol) was dissolved in methanol (15 ml) and cooled to 0° C., to the resulting solution was added potassium carbonate (93 mg, 0.67 mmol). The ice bath was removed and the reaction mixture was stirred at ambient temperature for 0.5 h at which time thin layer chromatography (TLC) and GC/MS analysis indicated that the reaction was complete. The solvent was removed in vacuo and the residue was dissolved in diethyl ether (50 mL), washed with water (100 mL), brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford 3-chloro-5-ethynylpyridine (822 mg, 90% yield) which was pure by GC/MS analysis. MS (EI ionization) 137 (35Cl M+), 139 (37Cl M+). This material was carried on to the next step without further purification.
Reaction SMILES: [ClH:1].C(OCC)(=O)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][C:17]([CH3:29])([CH3:28])[NH:16]2)=[CH:11][CH:10]=1>>[ClH:8].[ClH:1].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[CH2:20][NH:19][CH2:18][C:17]([CH3:29])([CH3:28])[NH:16]2)=[CH:13][CH:14]=1
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)CC(c2ccc(Cl)cc2)N1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC1(C)CNCC(c2ccc(Cl)cc2)N1
Reaction time: 12 h
Yield: 95 %

Procedure:
4 M Hydrogen chloride in ethyl acetate (5.0 mL, 20.0 mmol) was added to a solution of 2-(4-chlorophenyl)-4-t-butoxycarbonyl-6,6-dimethyl-piperazine (1.69 g, 5.2 mmol). After 12 h, removing the solvent, filtrating and washing the precipitate with ethyl acetate gave 2-(4-chlorophenyl)-6,6-dimethyl-piperazine dihydrochloride (1.43 g, 95%). 1H NMR (300 MHz, DMSO-d6), δ 1.40 (3H, s), 1.58(3H, s), 3.24-3.99(4H, m), 4.73(1H, m), 7.69(2H, d, J=8.4 Hz), 7.79(2H, m), 9.99-10.12(2H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[CH:20][C:12]([CH:13]=[CH:14][C:15](OCC)=[O:16])=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:1]([O:8][C:9]1[CH:21]=[CH:20][C:12]([CH2:13][CH2:14][CH2:15][OH:16])=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=Cc1ccc(OCc2ccccc2)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1cc(CCCO)ccc1OCc1ccccc1
Yield: 56 %

Procedure:
In substantially the same manner as in Reference Example 82, ethyl 4-benzyloxy-3-methoxycinnamate was subjected to reduction with lithium aluminum hydride to obtain 3-(4-benzyloxy-3-methoxyphenyl)propanol. The yield was 56%. Recrystallization from ethyl acetate-hexane gave colorless prisms, 57-58° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.[C:14]([NH:21][C@H:22]([C:38]([OH:40])=O)[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:26][CH:25]=1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>>[C:14]([NH:21][C@H:22]([C:38]([N:2]([CH3:1])[CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)=[O:40])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:26][CH:25]=1)([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15]
Reactant: CNCc1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Product: CN(Cc1cccc2ccccc12)C(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C

Procedure:
In substantially the same manner as Working Example 2, N-methyl-1-naphthalenemethylamine (877 μl) was condensed with Boc-(O-benzyl)-L-tyrosine (2.00 g) to give N-[Boc-(O-benzyl)-L-tyrosyl]-N-methyl-1-naphthalenemethylamine (2.60 g) as a white powdery product (yield 92%). The Boc group of the product was deprotected by using TFA, and 2.02 g of thus-obtained compound was condensed, in substantially the same manner as Working Example 2, with Compound 1 (1.40 g) to give N-[N-[(2S,3S)-N-Z-3-ethoxycarbonylaziridine-2-carbonyl]-(O-benzyl)-L-tyrosyl]-N-methyl-1-naphthalenemethylamine (1.73 g) as a white powdery product (yield 52%). This compound was subjected to catalytic reduciton to thereby deprotect the Z group and benzyl group in substantially the same manner as Working Example 3 to give the above-titled compound (compound 133; 580 mg) as white crystals (yield 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:28])[C:9]=1[NH:10][C:11]1[C:20]2[CH:21]=[CH:22][N:23]=[C:24]([O:25][CH2:26][CH3:27])[C:19]=2[C:18]2[C:13](=[CH:14][CH:15]=[N:16][CH:17]=2)[N:12]=1)[C:5]#[N:6].C(N(CC)CC)C.[Cl-].[OH:37][NH3+:38]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[N:38][OH:37])[NH2:6])[CH:7]=[C:8]([Cl:28])[C:9]=1[NH:10][C:11]1[C:20]2[CH:21]=[CH:22][N:23]=[C:24]([O:25][CH2:26][CH3:27])[C:19]=2[C:18]2[C:13](=[CH:14][CH:15]=[N:16][CH:17]=2)[N:12]=1
Reactant: CCOc1nccc2c(Nc3c(Cl)cc(C#N)cc3Cl)nc3ccncc3c12
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOc1nccc2c(Nc3c(Cl)cc(C(N)=NO)cc3Cl)nc3ccncc3c12
Temperature: 80 °C

Procedure:
To a solution of 3,5-dichloro-4-[(10-ethoxypyrido[4,3-c]-1,6-naphthyridin-6-yl)amino]benzonitrile (Example 160, Step 1) (200 mg, 0.49 mmol) in ethanol (6 mL) was added triethylamine (0.285 mL, 2.04 mmol) and hydroxyammonium chloride (105 mg, 1.51 mmol). The reaction mixture was heated to 80° C. for 3 h in a sealed tube. After cooling to room temperature, the solid was filtered, washed with ethanol and water and dried under vacuum to afford the title compound.
Reaction SMILES: C([C:3]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)#N.[N-:24]=[N+:25]=[N-:26].[Na+]>CS(C)=O>[C:5]1([C:4]2[NH:26][N:25]=[N:24][C:3]=2[N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCN(C(C#N)=Cc2ccccc2)CC1
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2nn[nH]c2-c2ccccc2)CC1
Temperature: 110 °C

Procedure:
To a stirred solution of tert-butyl 4-(1-cyano-2-phenylvinyl)piperazine-1-carboxylate (100 mg) taken in dry DMSO (2 ml) added sodium azide (0.2 g) and heated to 110° C. overnight. The reaction mixture was carefully quenched with water (10 ml) and the reaction mixture was extracted with dichloromethane (3×10 ml). The combined organic layer was washed with brine (10 ml), dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using MeOH: CH2Cl2 (1:9) as an eluent to afford tert-butyl 4-(5-phenyl-1H-1,2,3-triazol-4-yl)piperazine-1-carboxylate as white solid.