Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]([CH3:28])([CH3:27])/[CH:5]=[CH:6]/[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]([C@H:17]([N:19]([CH3:26])[S@@](C(C)(C)C)=O)[CH3:18])=[N:14]2)=[CH:9][CH:8]=1.[ClH:30]>CO.O1CCOCC1>[ClH:30].[CH3:1][O:2][C:3](=[O:29])[C:4]([CH3:28])([CH3:27])/[CH:5]=[CH:6]/[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]([C@H:17]([NH:19][CH3:26])[CH3:18])=[N:14]2)=[CH:9][CH:8]=1
Reactant: COC(=O)C(C)(C)/C=C/c1ccc2ccc([C@@H](C)N(C)[S@](=O)C(C)(C)C)nc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CN[C@H](C)c1ccc2ccc(/C=C/C(C)(C)C(=O)OC)cc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (E)-2,2-dimethyl-4-(2-{(R)-1-[methyl-((R)-2-methyl-propane-2-sulfinyl)-amino]-ethyl}-quinolin-7-yl)-but-3-enoic acid methyl ester (77 mg, 0.19 mmol) in methanol (10 mL) was treated with hydrochloric acid in 1,4-dioxane (4 M, 5 mL). After stirring at room temperature for 2 h, the volatiles were removed in vacuo. The residual solvent was removed by azeotroping with toluene (3×10 mL) to give crude (E)-2,2-dimethyl-4-[2-((R)-1-methylamino-ethyl)-quinolin-7-yl]-but-3-enoic acid methyl ester hydrochloride.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:6][CH:5]=[CH:4][N:3]=1.C([N:25]1[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]1)(OC(C)(C)C)=O>>[NH:25]1[CH2:30][CH2:29][CH:28]([O:31][C:2]2[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1nccnc1OCCOc1ccccc1
Product: c1ccc(OCCOc2nccnc2OC2CCNCC2)cc1
Yield: 35.5 %

Procedure:
The title compound was prepared according to the procedure described in Example 49 starting from 2-chloro-3-(2-phenoxyethoxy)pyrazine (250 mg, 1.00 mmol; from Example 1, Step 1) and N-Boc-4-hydroxypiperidine (234 mg, 1.16 mmol) to give 112 mg (35%) of the title product. HRMS m/z calcd for C17H23N3O3(M)* 315.1583, found 315.1570.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([CH2:16][CH2:17][C:18]([N:20]2[CH2:25][CH2:24][CH:23]([C:26]([OH:28])=O)[CH2:22][CH2:21]2)=[O:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.FC(F)(F)C(O)=O.[NH2:57][CH2:58][C:59]([N:61]1[CH2:66][CH2:65][N:64]([C:67](=[O:78])[C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][C:69]=2[C:74]([F:77])([F:76])[F:75])[CH2:63][CH2:62]1)=[O:60]>CN(C=O)C.O>[O:60]=[C:59]([N:61]1[CH2:62][CH2:63][N:64]([C:67](=[O:78])[C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][C:69]=2[C:74]([F:77])([F:76])[F:75])[CH2:65][CH2:66]1)[CH2:58][NH:57][C:26]([CH:23]1[CH2:22][CH2:21][N:20]([C:18](=[O:19])[CH2:17][CH2:16][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:25][CH2:24]1)=[O:28]
Reactant: O=C(O)C1CCN(C(=O)CCc2ccccc2)CC1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)C1CCN(C(=O)CCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 27.8 %

Procedure:
DIPEA (72.27 mg, 0.09 mL, 0.55 mmol) was added to a stirred solution of 1-(3-phenyl-propionyl)-piperidine-4-carboxylic acid (58.38 mg, 0.22 mmol) in DMF (1 mL). HOBT (30.2 mg, 0.22 mmol) and EDCI (42.76 mg, 0.22 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone trifluoroacetic acid salt (80 mg, 0.18 mmol) was added and the resulting mixture was stirred at room temperature for 16 hrs. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 28 mg (26.89% yield) of 1-(3-phenyl-propionyl)-piperidine-4-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide, LCMS Purity: 92.41%. 1H NMR (CDCl3): δ 7.8-7.7 (d, 1H), 7.68-7.52 (m, 2H), 7.38-7.28 (m, 2H), 7.26-7.14 (m, 3H), 6.62-6.48 (s, 1H), 4.7-4.55 (d, 1H), 4.2-3.4 (m, 9H), 3.4-3.1 (d, 3H), 3.05-2.85 (t, 3H), 2.7-2.5 (t, 3H), 2.5-2.3 (t, 2H), 1.9-1.3 (t, 2H), 0.9 (d, 1H).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH:4]=[N:3][CH:2]=1.[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[O:24])=[C:21]([CH3:32])[NH:20][C:19]=1[CH:33]=O>>[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)=[O:24])=[C:21]([CH3:32])[NH:20][C:19]=1[CH:33]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:5]2[CH:6]=[N:1][CH:2]=[N:3][CH:4]=2)[NH:11][C:10]1=[O:16]
Reactant: O=C1Cc2c(cccc2-c2cncnc2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cncnc4)c32)c(C)c1C(=O)N1CCN(C)CC1

Procedure:
4-Pyrimidin-5-yl-1,3-dihydroindol-2-one (53 mg, 0.25 mmol) was condensed with 3, 5-dimethyl-4-(4-methylpiperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (69 mg, 0.275 mmol) to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([O:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])(=[O:21])=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[CH:5][CH:4]=1)#[N:2].Cl.C(=O)([O-])[O-].[NH4+:34].[NH4+]>C(Cl)Cl.C(O)C>[ClH:28].[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([O:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])(=[O:21])=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[CH:5][CH:4]=1)(=[NH:34])[NH2:2]
Reactant: [NH4+]
Reactant: Cc1cc(OCc2ccc(C#N)cc2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(OCc2ccc(C(=N)N)cc2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 147.6 %

Procedure:
To a solution of 2-chlorobenzenesulfonic acid 3-[(4-cyanophenyl)methoxy]-5-methylphenyl ester (414 mg, 1.0 mmol), as prepared in the preceding step, in methylene chloride (10 mL) was added 37% HCl in ethanol (20 mL) at 0° C. The mixture was stirred at room temperature for 2 days. The solvent was evaporated and the residue was co-evaporated with methylene chloride several times. The residue was then dissolved in ethanol (20 mL) and ammonium carbonate (385 mg, 4.0 mmol) was added at 0° C. The mixture was stirred at room temperature overnight. The reaction mixture was partitioned between methylene chloride and 10% K2CO3 (50 mL). The organic phase was washed with 50 mL of 10% K2CO3 and dried over K2CO3. The solvent was removed in vacuo. The residue was diluted with CH2Cl2, treated with HCl in methanol (30 mL), and concentrated. The residue was then purified by crystallization (methanol and ethyl acetate) to give the title compound as a white solid (345 mg, 74%). 1H-NMR (300 MHz, DMSO-d6) δ 2.21 (s, 3H), 5.16 (s, 2H), 6.53 (t, 2H, J=9.3 Hz)), 6.86 (s, 1H), 7.55-7.62 (m, 3H), 7.82-7.89 (m, 4 H), 7.93 (d, 1H, J=4.0 Hz), 9.24 (br s, 2H) and 9.44 (br s, 2H). Mass spectrum (MALDI-TOF, sinapinic acid matrix) calcd. for C21H19N2ClO4S: 431.1 (M+H). Found: 43 1.1.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.C(N(CC)CC)C.Cl[C:22]1[N:27]([CH3:28])[C:26](=[O:29])[C:25]([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[C:24]([C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)[N:23]=1>ClCCl>[OH:13][CH:3]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[CH2:2][NH:1][C:22]1[N:27]([CH3:28])[C:26](=[O:29])[C:25]([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[C:24]([C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)[N:23]=1
Reactant: Cn1c(Cl)nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c1=O
Reactant: COc1ccc(CC(O)CN)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CC(O)CNc2nc(-c3ccncc3)c(-c3ccc4ccccc4c3)c(=O)n2C)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirring solution of 1-amino-3-(4-methoxy-phenyl)-propan-2-ol (1.1 g, 6.1 mmol) and triethylamine in 25 mL dichloromethane was added 2-chloro-3-methyl-5-naphthalen-2-yl-6-pyridin-4-yl-3H-pyrimidin-4-one. The solution was stirred at room temperature for 72 h. The organic layer was washed twice with 5% sodium bicarbonate, once with brine, then dried over magnesium sulfate. The product was purified on 90 g of silica eluting with 1 to 5% methanol/dichloromethane to give a yellow foam. M+1=493.2.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][C:8]([OH:10])=O)=[C:5]([CH3:11])[O:4][N:3]=1.CN(C=O)C.C(Cl)(C(Cl)=O)=O.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][N:33]([CH:36]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:37]([N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])=[O:38])[CH2:32][CH2:31]2)=[C:26]([F:50])[CH:25]=1>ClCCCl>[CH3:1][C:2]1[C:6]([CH2:7][C:8]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][N:33]([CH:36]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[C:37]([N:39]([CH2:40][CH3:41])[CH2:42][CH3:43])=[O:38])[CH2:32][CH2:31]3)=[C:26]([F:50])[CH:25]=2)=[O:10])=[C:5]([CH3:11])[O:4][N:3]=1
Reactant: Cc1noc(C)c1CC(=O)O
Reactant: CCN(CC)C(=O)C(c1ccccc1)N1CCN(c2ccc(N)cc2F)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)C(c1ccccc1)N1CCN(c2ccc(NC(=O)Cc3c(C)noc3C)cc2F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
A mixture of (3,5-dimethyl-isoxazol-4-yl)-acetic acid (1.0 mmol) and DMF (0.050 mL) in DCE (10 mL) was treated with (COCl)2 (10 mmol) dropwise, and was stirred at rt for 1 h. The mixture was concentrated and dried under vacuum. The residue was diluted with DCE (10 mL) and 2-[4-(4-amino-2-fluoro-phenyl)-piperazin-1-yl]-N,N-diethyl-2-phenyl-acetamide (0.30 mmol) and TEA (2.0 mmol) were added. The mixture was stirred at rt for 16 h, then was washed with H2O (10 mL). The organic layer was concentrated, and the residue was purified by PTLC to provide the title compound (78 mg, 45%). MS (ESI): mass calcd. for C29H36FN5O3, 521.28. m/z found, 522.4 [M+H]+. 1H NMR (CDCl3): 7.59-7.25 (m, 6H), 7.09-6.98 (m, 1H), 6.68-6.57 (m, 1H), 4.21 (s, 1H), 3.50-3.36 (m, 4H), 3.35-3.15 (m, 2H), 3.13-3.00 (m, 4H), 2.73-2.60 (m, 4H), 2.37 (s, 3H), 2.23 (s, 3H), 1.16-1.06 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][CH3:20].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:18][CH2:19][CH3:20])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1ccc(Br)cc1C=O
Temperature: 90 °C
Reaction time: 3 h

Procedure:
In DMF (160 ml) was dissolved 5-bromosalicylaldehyde (20 g). To the mixture was added at room temperature potassium carbonate (17.9 g) and then was added 1-bromopropane (10.8 ml), and the mixture was stirred at 90° C. for 3 hours and cooled to room temperature. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=6/1) to give 5-bromo-2-propoxybenzaldehyde (21.9 g).
Reaction SMILES: [NH2:1][C:2]([O:4][CH2:5][C@H:6]1[O:10][CH2:9][C@@H:8]([S:11]C(=O)C)[CH2:7]1)=[O:3].C[O-].[Na+].CO.Cl.C(O)(C)C>O1CCCC1>[C:2]([O:4][CH2:5][C@H:6]1[CH2:7][C@@H:8]([SH:11])[CH2:9][O:10]1)(=[O:3])[NH2:1]
Reactant: CC(=O)S[C@@H]1CO[C@H](COC(N)=O)C1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(C)O
Solvent: C1CCOC1
Product: NC(=O)OC[C@H]1C[C@@H](S)CO1
Reaction time: 0.33 h

Procedure:
Under anhydrous conditions, 0.109 g of product from Example 10 dissolved in 1.75 ml of tetrahydrofuran, cooled in an ice bath, is treated, via syringe, with 120 microliter of sodium methoxide/methanol (25 wt % in methanol). The progress of the reaction is monitored by thin layer chromatography. After 20 minutes, 280 microliter of 1.86N hydrochloric acid/isopropyl alcohol is added and the reaction is stirred for 5 minutes. The reaction is concentrated in vacuo to give the desired product as a white solid which is used as is in the following reaction.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[O:5][C:6]2[CH:12]=[C:11]([C:13](=[O:25])[NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([O:23]C)=[O:22])=[CH:17][N:16]=3)[CH:10]=[C:9]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C:7]=2[CH:8]=1.CO.C1COCC1>O>[CH3:3][C:4]1[O:5][C:6]2[CH:12]=[C:11]([C:13](=[O:25])[NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][N:16]=3)[CH:10]=[C:9]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C:7]=2[CH:8]=1
Reactant: COC(=O)c1ccc(NC(=O)c2cc(OCC(C)C)c3cc(C)oc3c2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2c(OCC(C)C)cc(C(=O)Nc3ccc(C(=O)O)cn3)cc2o1
Temperature: 25 °C

Procedure:
Sodium hydroxide solution (0.94 ml of 1M, 0.94 mM) was added to a solution of 2-methyl-4-isobutoxy-6-[N-(5-methoxycarbonylpyridin-2-yl)carbamoyl]benzofuran (Method 1; 120 mg, 0.314 mM) in a methanol/THF mixture (1 ml+4 ml), and the resulting solution stirred at ambient temperature. After 4 hrs the reaction mixture was diluted with water (5 ml) and concentrated to half volume in vacuo. The resulting mixture was acidified to pH6 with 1M HCl. The resulting solid precipitate was filtered, washed with water, and dried to give a pale cream solid. This was chromatographed (10 g Bondelut), eluting with DCM containing methanol (0-10% gradient) to give the title compound as a colourless solid. NMR: 1.03 (d, 6H), 2.09 (sept, 1H), 2.45 (s, 3H), 3.97 (d, 2H), 6.66 (s, 1H), 7.44 (s, 1H), 7.85 (s, 1H), 8.31 (t, 2H), 8.87 (s, 1H), 11.10 (bs, 1H); m/z 367 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([O:6][CH2:7][C:8]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([CH2:18][CH3:19])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)(=[O:5])[CH3:4].[C:28]1([CH2:34][CH2:35][CH2:36][CH2:37]I)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C)C=O>[C:3]([O:6][CH2:7][C:8]([NH:20][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])([CH2:18][CH3:19])[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:37][CH2:36][CH2:35][CH2:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:15][CH:16]=1)(=[O:5])[CH3:4]
Reactant: CCC(CCc1ccc(O)cc1)(COC(C)=O)NC(=O)OC(C)(C)C
Reactant: ICCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CCc1ccc(OCCCCc2ccccc2)cc1)(COC(C)=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
To a suspension of sodium hydride (0.65 g) in dimethylformamide (16 ml) was added a solution of 2-tert-butoxycarbonylamino-2-ethyl-4-(4-hydroxyphenyl)butyl acetate (6.0 g) in dimethylformamide (50 ml) at 0° C. and the mixture was stirred at room temperature for an hour. 4-Phenyl-butyl iodide (90 g) was added to the solution at 0° C. and the mixture was allowed to stand at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and a saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure and the residue obtained was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=1:1) to give the subject compound (3.6 g).
Reaction SMILES: [NH2:1][CH:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:13]([NH:23][C@H:24]([C:29]([OH:31])=[O:30])[CH2:25][C:26]([OH:28])=[O:27])([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].S(=O)(=O)(O)O.[OH-].[Na+].N[C@@H](C(O)=O)CC1C=CC=CC=1>O>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:13]([NH:23][C@H:24]([C:29]([OH:31])=[O:30])[CH2:25][C:26]([OH:28])=[O:27])([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: NC(Cc1ccccc1)C(=O)O
Agent: N[C@H](Cc1ccccc1)C(=O)O
Agent: O=C(O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 50 °C

Procedure:
Eight grams of DL-phenylalanine, 10 g of N-carbobenzoxy-L-aspartic acid and 2.4 g of sulfuric acid were dissolved in 90 ml of water. A 10% aqueous solution (9.7 ml) of caustic soda was added to the resulting solution over six hours while it was continuously stirred at 50° C. As a result, half of the sulfuric acid was neutralized, and the molar amount of the remaining sulfuric acid was a quarter of the amount of DL-phenylalanine. (It will be noted that in the other examples also, the amount of sulfuric acid was adjusted to be one mol per 2 mols of the finally present D-phenylalanine.) The resulting crystal was separated, washed with 10 ml of water and dried to give 8.2 g of L-phenylalanine/N-carbobenzoxy-L-aspartic acid salt. An analysis revealed that the optical purity of the L-phenylalanine contained in this salt was 98%. The molar ratio of L-phenylalanine to N-carbobenzoxy-L-aspartic acid contained in this salt was 1:1.5. An X-ray diffraction pattern of this salt in powder form had peaks at 2θ=4, 16.2, 17.4, 17.6, 18.6, 19.1, 24.6 and 28.8 (degrees).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:10])[CH:3]=1.Cl.N1C=CC=CC=1.[CH3:27][NH:28][C:29]([N:31]1[C:39]2[C:34](=[CH:35][C:36]([NH2:40])=[CH:37][CH:38]=2)[CH:33]=[CH:32]1)=[O:30].C(OCC)(=O)C>C(OC(O)C)C.CO>[CH3:27][NH:28][C:29]([N:31]1[C:39]2[C:34](=[CH:35][C:36]([NH:40][C:2]3[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:10])[CH:3]=3)=[CH:37][CH:38]=2)[CH:33]=[CH:32]1)=[O:30]
Reactant: CCN(CC)CCCNC(=O)Nc1cc(Cl)ccn1
Reactant: CNC(=O)n1ccc2cc(N)ccc21
Agent: CCOC(C)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: c1ccncc1
Product: CCN(CC)CCCNC(=O)Nc1cc(Nc2ccc3c(ccn3C(=O)NC)c2)ccn1
Temperature: 130 °C
Reaction time: 2 h
Yield: 16.4 %

Procedure:
1-(4-Chloropyridin-2-yl)-3-(3-diethylaminopropyl)urea (30 mg, 0.11 mmol) was dissolved in ethoxyethanol (1.1 ml); pyridine hydrochloride (24 mg, 0.22 mmol) and 5-aminoindole-1-carboxylic acid methylamide (22 mg, 0.12 mmol, Production example 218-2) was added thereto; and the reaction mixture was stirred at 130° C. for 2 hours. After cooled down to room temperature, the reaction mixture was partitioned between a saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate; and the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia NH, hexane:ethyl acetate=1:3, ethyl acetate, ethyl acetate:methanol=93:7 in this order) to yield the title compound (8 mg, 0.018 mmol, 17%) as pale yellow powder.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[N:12]=[CH:13][N:14](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:36][C:37]1[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=1[C:39]#[N:40].C(NCC)C>C(#N)C>[Si:1]([O:8][CH2:9][CH2:10][C:11]1[N:12]([CH2:36][C:37]2[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=2[C:39]#[N:40])[CH:13]=[N:14][CH:15]=1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: N#Cc1ccccc1CBr
Reactant: CC(C)(C)[Si](C)(C)OCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CC#N
Solvent: CCNCC
Product: CC(C)(C)[Si](C)(C)OCCc1cncn1Cc1ccccc1C#N
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of 4-[2-(tert-butyldimethylsilanyloxy)-ethyl]-1-trityl-1H-imidazole (2.10 g, 4.48 mmol) in acetonitrile (20 mL) is added 2-bromomethylbenzonitrile (0.967 g, 4.93 mmol). The reaction mixture is stirred at 60° C. for 16 h. It is then cooled to room temperature and diethylamine (5 mL, 44.8 mmol) is added. The reaction mixture is stirred at 60° C. for 30 min. It is then cooled to room temperature and the solvents are removed in vacuo. Methanol (25 mL) is added and stirring is continued for 1 h at room temperature. Methanol is removed by concentration in vacuo. The residue is dissolved in ethyl acetate and washed with water twice. The combined organic phase is dried over Na2SO4 and concentrated in vacuo. The residue is purified by silica gel chromatography (dichloromethane-methanol, 19:1) to give 2-{5-[2-(tert-butyldimethylsilanyloxy)-ethyl]-imidazol-1-ylmethyl}-benzonitrile; MS (ESI) m/z 342 (M+H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH2:7][NH:8][CH2:9][CH:10]([OH:32])[CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:20]([O:23]CC2C=CC=CC=2)=[C:19]2[C:14]=1[CH2:15][CH2:16][C:17](=[O:31])[NH:18]2.C(O)C.[ClH:41].[H][H]>CO.[C].[Pd]>[ClH:41].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH2:7][NH:8][CH2:9][CH:10]([OH:32])[CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]2[C:14]=1[CH2:15][CH2:16][C:17](=[O:31])[NH:18]2
Reactant: [H][H]
Reactant: COc1ccc(CCNCC(O)COc2ccc(OCc3ccccc3)c3c2CCC(=O)N3)cc1OC
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: COc1ccc(CCNCC(O)COc2ccc(O)c3c2CCC(=O)N3)cc1OC
Temperature: 25 °C

Procedure:
2.0 g of 5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-8-benzyloxy-3,4-dihydrocarbostyril was suspended in 50 ml of methanol, and an ethanol solution containing hydrogen chloride was added to the suspension until the mixture showed acidity. After the mixture became homogenous, 0.7 g of 10% palladium carbon was added thereto followed by stirring at room temperature and at atmospheric pressure thereby absorbing hydrogen. The reaction completed when the absorption of hydrogen ceased. The catalyst was removed by filtration, and the methanol evaporated. A small amount of ethanol was added to the residue to crystallize the product. Recrystallization from ethanol gave 1.5 g of 5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-8-hydroxy-3,4-dihydrocarbostyril hydrochloride as colorless powdery crystals having a melting point of 171°-173° C.
Reaction SMILES: CS(O)(=O)=O.CS(O)(=O)=O.[NH2:11][C:12]1[C:19](=[O:20])[N:15]2[CH2:16][CH2:17][CH2:18][N:14]2[C:13]=1[NH2:21].[NH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:33][CH3:34])=[C:27]([NH:29][CH2:30][CH2:31][OH:32])[CH:28]=1.N.OO>O.C(O)C>[NH2:21][C:13]1[N:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19](=[O:20])[C:12]=1[N:11]=[C:24]1[C:23]([NH2:22])=[CH:28][C:27](=[N:29][CH2:30][CH2:31][OH:32])[C:26]([O:33][CH3:34])=[CH:25]1
Reactant: Nc1c(N)n2n(c1=O)CCC2
Reactant: COc1ccc(N)cc1NCCO
Agent: COC1=C/C(=N/c2c(N)n3n(c2=O)CCC3)C(N)=C/C1=N\CCO
Agent: CS(=O)(=O)O
Agent: N
Solvent: CCO
Solvent: O
Product: COC1=CC(=Nc2c(N)n3n(c2=O)CCC3)C(N)=CC1=NCCO

Procedure:
0.05 mmol of 2,3-diamino-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-1-one dimethane sulfonate was dissolved in a mixture of water and ethanol (7.5 ml/1.5 ml). This solution was admixed with 0.05 mmol of 2-[(5-amino-2-methoxyphenyl)amino]ethanol, then with 1.8 ml of concentrated aqueous ammonia, then with 9 ml of hydrogen peroxide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][CH:11]([CH2:13][CH2:14][OH:15])[CH2:10][O:9]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:49][C:50]([Cl:63])=[CH:51][CH2:52][O:53][C:54]1[CH:59]=[C:58]([Cl:60])[C:57](O)=[C:56]([Cl:62])[CH:55]=1>O1CCCC1>[Cl:60][C:58]1[CH:59]=[C:54]([O:53][CH2:52][CH:51]=[C:50]([Cl:63])[Cl:49])[CH:55]=[C:56]([Cl:62])[C:57]=1[O:15][CH2:14][CH2:13][CH:11]1[CH2:10][O:9][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[O:12]1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: OCCC1COC(c2ccc(Cl)cc2)O1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCC2COC(c3ccc(Cl)cc3)O2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.7 %

Procedure:
To a mixture of 0.4 g of 2-[2-(4-chlorophenyl)-1,3-dioxolan-4-yl]ethanol, 0.46 g of triphenylphosphine and 6 ml of tetrahydrofuran was added dropwise 0.35 ml of diisopropyl azodicarboxylate, while stirring at room temperature. After further stirring for 15 minutes, a solution of 0.5 g of 4-(3,3-dichloro-2-propenyloxy)-2,6-dichlorophenol in 2 ml of tetrahydrofuran was added. After stirring continued at room temperature for 3 hours, the reaction mixture was concentrated, and the residue was subjected to silica gel chromatography, which afforded 0.3 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-[2-[2-(4-chlorophenyl)-1,3-dioxolan-4-yl]ethoxy]benzene (35% yield), m.p. 84.1° C.