Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:21]=[CH:20][C:7]([C:8]([NH:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].O=[C:23]([CH2:30][CH2:31][CH3:32])[CH2:24][C:25]([O:27]CC)=[O:26].[O-]CC.[Na+].O>C(O)C>[C:14]1([CH2:13][CH2:12][CH2:11][NH:10][C:8]([C:7]2[CH:20]=[CH:21][C:4]([N:1]3[C:23]([CH2:30][CH2:31][CH3:32])=[C:24]([C:25]([OH:27])=[O:26])[N:3]=[N:2]3)=[CH:5][CH:6]=2)=[O:9])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: [N-]=[N+]=Nc1ccc(C(=O)NCCCc2ccccc2)cc1
Reactant: CCCC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCc1c(C(=O)O)nnn1-c1ccc(C(=O)NCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.7 %

Procedure:
The pale-yellow solid of 4-azido-N-(3-phenylpropyl)benzamide obtained in Example 60a) and ethyl 3-oxohexanoate (1.08 ml, 6.43 mmol, 1.25 eq.) were dissolved in ethanol (20 ml), sodium ethoxide (486 mg, 6.43 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 10 min, and then at 60° C. for 13 hr. Water (20 ml) was added to the reaction mixture, ethanol was evaporated, and the residue was diluted with 2% aqueous sodium carbonate solution (20 ml) and washed with ethyl acetate-hexane (2:1, 50 ml). The organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml). The aqueous layers were combined, washed with ethyl acetate-hexane (1:1, 30 ml), acidified with 6N hydrochloric acid and stood still at 0° C. The precipitate was collected by filtration, washed with ice-cold water and dried to give the title compound as a grayish white powder (1.99 g, 5.07 mmol, 98.7%)
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]=1[C:20]#[N:21].[CH:22]([CH:24]([CH:30]=O)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=O>CCO.CC(O)=O>[C:20]([C:3]1[C:4]([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)=[N:5][N:6]2[CH:30]=[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:22]=[N:1][C:2]=12)#[N:21]
Reactant: CCOC(=O)C(C=O)C=O
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cnc2c(C#N)c(-c3ccc(Oc4ccccc4)cc3)nn2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
To a solution of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile (276 mg, 1.0 mmol) in EtOH (10 mL) was added ethyl 2-formyl-3-oxopropanoate (144 mg, 1.0 mmol) and HOAc (5 drops). After stirring at RT for 16 hr, the mixture was filtered. The cake was washed with H2O (10 mL×2) and dried to afford 250 mg (65%) of ethyl 3-cyano-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-6-carboxylate as a yellow solid. MS (ESI) m/e [M+1]+ 384.9.
Reaction SMILES: [CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[H-].[Na+].[CH2:20](Br)[CH:21]=[CH2:22]>CN(C)C=O.[Cl-].[Na+]>[CH2:22]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:21]=[CH2:20]
Reactant: C=CCBr
Reactant: CCCCCCCCCCCCCCCCO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOCCCCCCCCCCCCCCCC
Temperature: 50 °C
Yield: 49.6 %

Procedure:
n-Hexadecanol (24.2 g, 0.1 mol) was added to a suspension of sodium hydride (9.6 g of a 50% dispersion in mineral oil, 0.2 mol) in dimethylformamide (200 ml) and heated to 50° C. for 30 minutes. Allyl bromide, (24.2 g, 0.2 mol) was then added and the mixture heated to 90° C. for 5 hours. The reaction was cooled, diluted with a solution of saturated sodium chloride (300 ml), and extracted with ether (2×300 ml). The combined ether extracts were washed with a saturated solution of sodium chloride (200 ml), filtered, dried over magnesium sulfate, treated with activated charcoal, filtered, and evaporated under reduced pressure to an oil. The resulting oil was purified by absorbing it on silica gel, placing the silica gel in a sintered glass filter, and eluting the product off with hexane (7×200 ml) followed by toluene (4×200 ml). Concentration yielded the pure ether (14 g, 50% yield): NMR (CDCl3) 3.40 (t, 2, --CH2 --O--CH2CH=CH2), 3.92 (d, 2, --O--CH2CH=CH2), 4.95-5.38 (m, 2, =CH2) and 5.58-6.20 (m, 1, --CH=CH2).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9]([C:11]2[C:12]([CH3:23])=[C:13]3[C:18](=[C:19]([CH3:21])[CH:20]=2)S[CH:16]=[CH:15][C:14]3=[O:22])=[O:10])[CH:5]=[N:4]1)[CH3:2].C(OO)(=O)C.C(O)(=O)C.[S:33]([O-:36])([O-])=[O:34].[Na+].[Na+].C(OO)(=O)C>C(Cl)(Cl)Cl.O>[CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9]([C:11]2[C:12]([CH3:23])=[C:13]3[C:18](=[C:19]([CH3:21])[CH:20]=2)[S:33](=[O:36])(=[O:34])[CH:16]=[CH:15][C:14]3=[O:22])=[O:10])[CH:5]=[N:4]1)[CH3:2]
Reactant: O=S([O-])[O-]
Reactant: CCn1ncc(C(=O)c2cc(C)c3sccc(=O)c3c2C)c1O
Agent: CC(=O)OO
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: CCn1ncc(C(=O)c2cc(C)c3c(c2C)C(=O)C=CS3(=O)=O)c1O
Temperature: 25 °C
Reaction time: 17 h
Yield: 77 %

Procedure:
0.39 Gram (1.2 mmol) of 6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonyl-5,8-dimethylthiochrom-2-en-4-one was dissolved in 4 ml of chloroform, and 0.62 g (2.6 mmol) of a 32 wt % peracetic acid/acetic acid solution was added. The mixture was allowed to react at room temperature for 5 hours, and then allowed to react at 50° C. for 2 hours and further stirred at room temperature for 17 hours. After the reaction, the reaction mixture was diluted with water, and a 1 wt % sodium sulfite aqueous solution was added to decompose excess peracetic acid. An organic substance was extracted with ethyl acetate, washed with a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 0.33 g (yield 77%) of the titled compound. Table 24 shows the physical property data of the titled compound.
Reaction SMILES: [CH:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.F[C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[S:20]([CH3:23])(=[O:22])=[O:21].C(N(C(C)C)CC)(C)C>CC#N>[F:19][C:17]1[CH:18]=[CH:13][C:14]([S:20]([CH3:23])(=[O:22])=[O:21])=[C:15]([NH:11][CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)[CH:16]=1
Reactant: NC1CCCc2ccccc21
Reactant: CS(=O)(=O)c1ccc(F)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(F)cc1NC1CCCc2ccccc21
Yield: 114.7 %

Procedure:
A solution of 1,2,3,4-tetrahydronaphthalen-1-amine (0.82 mL, 5.73 mmol), 2,4-difluoro-1-(methylsulfonyl)benzene (1.1 g, 5.73 mmol) and diisopropylethylamine (2.0 mL, 11.46 mmol) in CH3CN (15 mL) was stirred at 60° C. for 48 h. The solvent was concentrated in vacuo, the residue was taken up in dichloromethane and washed with water and brine, dried, and concentrated under reduced pressure to yield 2.1 g of a yellow oil. The residue was purified by PTLC (20% ethyl acetate in hexanes) to give 720 mg (39%) of the desired aniline: 1H NMR (400 MHz, CDCl3) δ 7.78 (dd, 1H), 7.28-7.13 (m, 3H), 6.60 (dd, 1H), 6.51-6.45 (m, 2H), 4.62 (dd, 1H), 2.96 (s, 3H), 2.91-2.74 (m, 2H), 2.05-1.98 (m, 2H), 1.91-1.85 (m, 2H). MS (ESI) m/z: Calculated: 319.39; Observed: 661.0 (2M++23).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[S:10]1[C:14]([C:15]([Cl:17])=[O:16])=[CH:13][C:12]2[CH:18]=[CH:19][CH:20]=[CH:21][C:11]1=2.[NH2:22][C:23]1[N:32]=[C:31]([NH:33][C@H:34]2[CH2:39][CH2:38][CH2:37][CH2:36][C@H:35]2[NH:40][C:41]([NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])=[N:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH3:58])[CH:29]=2)[N:24]=1.O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[ClH:17].[ClH:17].[C:54]([O:53][C:51]([NH:50][C:41]([NH:40][C@@H:35]1[CH2:36][CH2:37][CH2:38][CH2:39][C@@H:34]1[NH:33][C:31]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH3:58])[CH:29]=2)[N:24]=[C:23]([NH:22][C:15]([C:14]2[S:10][C:11]3[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=3[CH:13]=2)=[O:16])[N:32]=1)=[N:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:52])([CH3:55])([CH3:56])[CH3:57]
Reactant: Cc1ccc2nc(N)nc(N[C@H]3CCCC[C@H]3NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2c1
Reactant: O=C(Cl)c1cc2ccccc2s1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc2nc(NC(=O)c3cc4ccccc4s3)nc(N[C@H]3CCCC[C@H]3NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2c1
Product: Cl
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To a 604 mg of N,N-diisopropylethylamine in 4 ml of methylene chloride, 10 mg of 4-dimethylaminopyridine and 613 mg of benzo[b]thiophene-2-carbonylchloride were added, and the mixture was stirred for 60 minutes. To the mixture was added dropwise a solution of 800 mg of N-{(1R,2S)-2-[(2-amino-6-methylquinazolin-4-yl)amino]cyclohexyl}-N′,N″-bis(tert-butoxycarbonyl)guanidine obtained in Reference Example 1 in 5 ml of methylene chloride, followed by stirring at room temperature for 15 hours. The reaction solution was mixed with water, extracted with methylene chloride and then dried. The solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform:methanol=30:1) to obtain 890 mg of the desirable compound.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Cl:6][C:7]1[C:8]([OH:15])=[N:9][C:10]([Cl:14])=[C:11]([Cl:13])[CH:12]=1.N1C=CC=CC=1>C(Cl)Cl>[C:2](=[O:3])([O:15][C:8]1[C:7]([Cl:6])=[CH:12][C:11]([Cl:13])=[C:10]([Cl:14])[N:9]=1)[O:4][CH3:5]
Reactant: COC(=O)Cl
Reactant: Oc1nc(Cl)c(Cl)cc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Oc1nc(Cl)c(Cl)cc1Cl

Procedure:
Methyl 3,5,6-trichloro-2-pyridyl carbonate was prepared by reacting methyl chloroformate with 3,5,6-trichloro-2-pyridinol at 0° C.-5° C. in the presence of an equivalent of pyridine as acid acceptor and using methylene chloride as the reaction solvent.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:18])[C:15]([OH:17])=O)[CH:5]=[CH:6][C:7]=1[CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11].[CH:19]1([C:22]2[N:27]=[C:26]([C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)[C:25]([CH2:35][NH2:36])=[CH:24][CH:23]=2)[CH2:21][CH2:20]1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>O1CCOCC1.C(OC(=O)C)C>[CH:19]1([C:22]2[N:27]=[C:26]([C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)[C:25]([CH2:35][NH:36][C:15](=[O:17])[CH:14]([C:4]3[CH:5]=[CH:6][C:7]([CH2:8][NH:9][S:10]([CH3:13])(=[O:11])=[O:12])=[C:2]([F:1])[CH:3]=3)[CH3:18])=[CH:24][CH:23]=2)[CH2:21][CH2:20]1
Reactant: Cc1cccc(-c2nc(C3CC3)ccc2CN)c1
Reactant: CC(C(=O)O)c1ccc(CNS(C)(=O)=O)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1cccc(-c2nc(C3CC3)ccc2CNC(=O)C(C)c2ccc(CNS(C)(=O)=O)c(F)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 51.8 %

Procedure:
To a stirred solution of 2-(3-fluoro-4-(methylsulfonamidomethyl)phenyl)propanoic acid (41 mg, 0.148 mmol) and (6-cyclopropyl-2-m-tolylpyridin-3-yl)methanamine (35 mg, 0.148 mmol) in dioxane were added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (43 mg, 0.222 mmol), 1-hydroxybenzotriazole (30 mg, 0.222 mmol) and triethylamine (0.05 mL, 0.37 mmol). The reaction mixture was stirred for 15 h at room temperature. The residue dissolved in ethylacetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. N-((6-cyclopropyl-2-m-tolylpyridin-3-yl)methyl)-2-(3-fluoro-4-(methylsulfonamidomethyl)phenyl)propanamide (example 20) (38 mg) was obtained as 52% yield.
Reaction SMILES: [O:1]([CH2:8][CH:9]1[CH2:13][O:12][C:11](=O)[O:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[C:11](=[O:12])=[O:10].[CH2:8]([O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:9]1[O:12][CH2:13]1
Reactant: O=C1OCC(COc2ccccc2)O1
Solvent: CO
Product: O=C=O
Product: c1ccc(OCC2CO2)cc1

Procedure:
The extracts from the sample piece of the thermal insulating foamed material into methanol were analyzed by liquid chromatography. The measurement showed 0.025 mole of 4-(phenoxymethyl)-1,3-dioxolan-2-on, a cyclic carbonate produced by addition reaction of carbon dioxide to phenyl glycidyl ether, per 100 g of the thermal insulating foamed material. Only one gram of water was used as the reactive blowing agent to 100 g of polyol. This resulted in a small amount of carbon dioxide evolved through the reaction of water with the polyisocyanate and there a small amount of the carbonate produced.
Reaction SMILES: [N:1]1([C:7]2[O:8][C:9]([C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[CH2:25][NH:24][CH2:23][CH2:22]4)=[O:17])=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].I[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38]>CC#N.CCOC(C)=O>[N:1]1([C:7]2[O:8][C:9]([C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[CH2:25][N:24]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:23][CH2:22]4)=[O:17])=[C:10]([C:12]([F:14])([F:13])[F:15])[N:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(Nc1ccc2c(c1)CCNC2)c1oc(N2CCCCC2)nc1C(F)(F)F
Reactant: CCOC(=O)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)CN1CCc2cc(NC(=O)c3oc(N4CCCCC4)nc3C(F)(F)F)ccc2C1
Temperature: 25 °C
Reaction time: 19 h
Yield: 54 %

Procedure:
To a suspension of compound 154 (0.098 g, 0.25 mmol) and K2CO3 (0.5 g) in CH3CN (5 mL) was added ethyl iodoacetate (0.036 mL). After 19 h of stirring at RT, the reaction mixture was diluted in EtOAc (50 mL) and filtered. The fitrate was washed with sat NaHCO3 (2×50 mL), dried over Na2SO4, filtered, and concentrated. The crude materials were purified by prep-TLC using 25% CH3CN in CH2Cl2 as eluents to yield compound 155 as a white solid (0.064 g, 54% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 7.47 (d, 1H, J=2.2 Hz), 7.41 (dd, 1H, J=8.0, 2.2 Hz), 7.02 (d, 1H, J=8.4 Hz), 4.11 (q, 2H, J=7.3 Hz), 3.66 (s, 2H), 3.61 (m, 4H), 3.41 (s, 2H), 2.80 (s, 4H), 1.61 (m, 6H), 1.21 (t, 3H, J=7.3 Hz); LCMS (ESI) Rt=3.21 min, [M+1]+ 481.3.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:42])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36](N(OC)C)=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][CH:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[CH3:43][Mg]Br.C(OCC)(=O)C.[Cl-].[NH4+]>O1CCCC1>[OH:37][CH:36]([CH3:43])[CH2:35][O:34][C@H:31]1[CH2:32][CH2:33][C@H:28]([N:18]2[C:17](=[O:42])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[CH:26][CH:27]=[C:19]23)[CH2:29][CH2:30]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)N(C)OC)CC2)c2ccnn12
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)O)CC2)c2ccnn12
Reaction time: 1 h

Procedure:
To a solution of 2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide (0.65 g) in tetrahydrofuran (6 mL) was added dropwise methylmagnesium bromide (1 M tetrahydrofuran solution, 2.3 mL) at 0° C., and the mixture was stirred for 1 hr. Ethyl acetate and then saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in ethanol (6 mL), and sodium borohydride (0.044 g) was added at 0° C. After stirring at 0° C. for 1 hr, ethyl acetate and then saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.57 g, 95%).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][C@H:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:11]1)=[O:7])(C)(C)C.[C:20]1([CH2:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[NH2:30][C:31]1[C:39]([Cl:40])=[CH:38][C:34](C(O)=O)=[C:33]([O:41][CH3:42])[CH:32]=1>>[NH2:30][C:31]1[C:39]([Cl:40])=[CH:38][C:34]([C:6]([NH:8][CH2:9][C@H:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:27](=[O:28])[CH2:26][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:11]2)=[O:7])=[C:33]([O:41][CH3:42])[CH:32]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CCN(CCCCN)C1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Product: COc1cc(N)c(Cl)cc1C(=O)NC[C@H]1CCN(CCCCNC(=O)Cc2ccccc2)C1

Procedure:
4-((3R)-3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)butylamine (1.00 g) as starting compound was reacted and treated in the same manner as in Example 1 using phenylacetyl chloride (0.50 ml) and 4-amino-5-chloro-2-methoxybenzoic acid (0.54 g) to give 4-amino-5-chloro-2-methoxy-N-((3R)-1-(4-phenylacetylaminobutyl)pyrrolidin-3-ylmethyl)benzamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C@H:8]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14](Br)=[C:13]([CH3:18])[N:12]([CH2:19][C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])[C:11]1=[O:28])([CH3:4])([CH3:3])[CH3:2].[NH:36]1[CH2:41][CH2:40][NH:39][CH2:38][C:37]1=[O:42]>C(#N)C>[C:1]([O:5][C:6](=[O:35])[NH:7][C@H:8]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:39]2[CH2:40][CH2:41][NH:36][C:37](=[O:42])[CH2:38]2)=[C:13]([CH3:18])[N:12]([CH2:19][C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])[C:11]1=[O:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(Br)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)c(=O)n1Cc1c(F)cccc1F
Reactant: O=C1CNCCN1
Solvent: CC#N
Product: Cc1c(N2CCNC(=O)C2)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)c(=O)n1Cc1c(F)cccc1F
Temperature: 140 °C
Reaction time: 3 h
Yield: 57.9 %

Procedure:
{(R)-2-[5-bromo-3-(2,6-difluoro-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid tert-butyl ester (100 mg, 0.182 mmol) and piperazine-2-one (187 mg, 1.82 mmol) were placed into a microwave flask along the wall of which 1 mL of acetonitrile was then added. The solution was stirred at 140° C. for 3 hrs while being irradiated with microwaves. After concentration in a vacuum, the concentrate was purified by column chromatography eluting with a dichloromethane/methanol (35/1) eluent to afford 60 mg of the compound as a yellowish solid (yield 58%). 1H NMR (300 MHz, CDCl3) δ 1.36 (9H, s), 2.43 (3H, s), 2.86 (1H, m), 3.27 (2H, m), 3.50 (1H, m), 3.74 (1H, m), 4.07 (2H, m), 4.27 (1H, m), 5.04 (1H, m), 5.29 (2H, dd), 5.68 (1H, m), 6.30 (1H, m), 6.90 (2H, t), 7.22-7.37 (6H, m)
Reaction SMILES: CO[C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:6][CH:5]=1.[Mg+2].[Br-].[Br-].O(CC)CC.[CH:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([CH3:28])[CH3:27]>C1COCC1>[NH3:6].[CH:26]([N:29]1[CH2:34][CH2:33][N:32]([C:3]([C:4]2[CH:5]=[N:6][C:7]([CH2:10][N:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)=[CH:8][CH:9]=2)=[O:17])[CH2:31][CH2:30]1)([CH3:28])[CH3:27]
Reactant: CC(C)N1CCNCC1
Reactant: COC(=O)c1ccc(CN2CCCCC2)nc1
Agent: [Br-]
Agent: [Mg+2]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)N1CCN(C(=O)c2ccc(CN3CCCCC3)nc2)CC1
Product: N
Temperature: 25 °C
Yield: 3 %
Yield: 140.4 %

Procedure:
A solution of 6-piperidin-1-ylmethyl-nicotinic acid methyl ester (0.300 g, 1.28 mmol), and MgBr2.OEt2 (0.900 g, 3.84 mmol) in THF (15 mL) was stirred for 15 min. A solution of 1-isopropyl-piperazine (0.325 g, 2.56 mmol) in THF (2 mL) was then added to the reaction drop-wise and the mixture was heated at reflux for 48 h. The reaction mixture was cooled to rt, concentrated, treated with 1 N aq. NaHCO3 (50 mL), and extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried (Na2SO4), and concentrated. Chromatography of the residue (SiO2; 3-6% 2 M NH3 in MeOH/DCM) gave the title compound as an oil (0.297 g, 70%). MS (ESI): exact mass calcd. for C19H30N4O, 330.2; m/z found, 331.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.55 (d, J=2.2, 1H), 7.87 (dd, J=7.8, 2.0, 1H), 7.62 (d, J=7.6, 1H), 3.78 (br s, 2H), 3.67 (s, 2H), 3.48 (br s, 2H), 2.77-2.73 (m, 1H), 2.65-2.48 (m, 8H), 1.65-1.59 (m, 4H), 1.49-1.48 (m, 2H), 1.09 (d, J=6.6, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:11])[C:7](=[CH:9][CH:10]=1)[OH:8])([O-:3])=[O:2].[C:12](Cl)(=[O:26])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[O:26]=[C:12]([O:11][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=[CH:9][C:7]=1[O:8][C:12](=[O:26])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Product: CCCCCCCCCCCCCC(=O)Oc1ccc([N+](=O)[O-])cc1OC(=O)CCCCCCCCCCCCC

Procedure:
Using this procedure, the reaction of 4-nitrocatechol with tetradecanoyl chloride gave 3,4-bis [(1-oxotetradecyl)oxy]nitrobenzene (mp 58°-60°, Anal. Calcd for C34H57NO6 : C, 70.72; H, 9.98; N, 2.43. Found: C, 70.91; H, 9.61; N, 2.41.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][NH:6][CH2:7][CH:8](O)[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1.S(=O)(=O)(O)O>FC(F)(F)C(O)=O>[CH3:18][O:17][C:11]1[CH:10]=[C:9]([CH:8]2[C:20]3[C:4](=[CH:3][C:2]([CH3:1])=[CH:22][CH:21]=3)[CH2:5][NH:6][CH2:7]2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: COc1ccc(C(O)CNCc2cccc(C)c2)cc1OC
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2CNCc3cc(C)ccc32)cc1OC
Yield: 51.4 %

Procedure:
1.8 g of α-[[(3-methylbenzyl)amino]methyl]-3,4-dimethoxybenzyl alcohol was dissolved in 13.5 ml of trifluoroacetic acid, and after adding thereto 0.41 ml of conc. sulfuric acid under ice cooling, the mixture was allowed to react for 40 minutes. The reaction solution was concentrated, and subjected to azeotropic distillation with chloroform 2 times, and after adding chloroform, the mixture was basified by addition of 28% aqueous ammonia. By a separating procedure, the chloroform layer was collected, washed with water once, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (chloroform-methanol-28% aqueous ammonia (15:1:0.1); a material of Rf being 0.46 [Kiesel gel 60F254 plate, chloroform-methanol-28% aqueous ammonia (15:1:0.1)] was collected, recrystallized from chloroform-n-hexane, and recrystallized from the same solvent system several times, giving 870 mg of 4- (3,4-dimethoxyphenyl)-7-methyl-1,2,3,4-tetrahydroisoquinoline, m.p. 129°-131° C.