Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH: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][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24].[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1.[Cl-]>N1C=CC=CC=1.C(Cl)Cl>[S:34]([O: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][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])([C:31]1[CH:32]=[CH:33][C:28]([CH3:27])=[CH:29][CH:30]=1)(=[O:36])=[O:35]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)CCCCCCCCCCCCCCCCCCCCCO
Agent: [Cl-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CCCCCCCCCCCCCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 1 h
Yield: 94.7 %

Procedure:
In a mixed solvent of 15 ml pyridine and 120 ml methylene chloride was dissolved methyl 22-hydroxydocosanoate (1.70 g, 4.59 mmoles) . P-toluenesulfonyl chloride (1.75 g, 9.18 mmoles) was gradually added to the obtained solution under ice-cooled condition, over a period of 1 hour, and the mixture was stirred for 14 hours in a refrigerator. Then, ptoluenesulfonyl chloride (1.75 g, 9.18 mmoles) was added to the reaction mixture, and reaction was effected for 24 hours. After the completion of reaction, the reaction mixture was treated in the same manner as in Reference Example 1, to give methyl 22-tosyloxydocosanoate (2.28 g, 75%) having the following properties.
Reaction SMILES: F[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([C:15]2[CH:16]=[CH:17][C:18]([O:27][CH3:28])=[C:19]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:20]=2)(=[O:14])=[O:13])=[CH:4][CH:3]=1.[OH-:29].[Na+].O.[CH3:32]O>>[CH3:28][O:27][C:18]1[CH:17]=[CH:16][C:15]([S:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([O:29][CH3:32])=[CH:3][CH:4]=2)(=[O:14])=[O:13])=[CH:20][C:19]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: CO
Reactant: [OH-]
Reactant: COc1ccc(S(=O)(=O)c2ccc(F)c3ccccc23)cc1N1CCNCC1
Agent: [Na+]
Solvent: O
Product: COc1ccc(S(=O)(=O)c2ccc(OC)c3ccccc23)cc1N1CCNCC1

Procedure:
To a solution of 1-[5-(4-fluoro-naphthalene-1-sulfonyl)2-methoxyphenyl] piperazine (0.050 g; 0.12 mmol) prepared in example 4 in methanol (2 mL) was added a solution of 6N NaOH (0.5 mL). After stirring at 80° C. for 30 min water was added (10 ml) and the mixture was extracted into ethyl acetate (20 mL). The organic phase was extracted into 2N aqueous HCl. The aqueous layer was adjusted with 6N NaOH solution to pH 14 and extracted with ethyl acetate. The organic phase was dried (Na2SO4) and concentrated in vacuo to give 1-[2-methoxy-5-(4-methoxy-naphthalene-1-sulfonyl)phenyl] piperazine (501) as a white solid (0.043 g; 88%). The hydrochloride salt was prepared from ethanol-hydrogen chloride, m. p. 240.243.0° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C@H:7]([C:11]([OH:13])=O)[CH:8]([CH3:10])[CH3:9])=[O:5])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=[N:24]C=2C=1.[S:28]1[C:32]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][N:40](N)[CH2:41][C@H:42]([OH:63])[C@@H:43]([NH:51][C:52](=[O:62])[C@H:53]([CH:59]([CH3:61])[CH3:60])[NH:54][C:55]([O:57][CH3:58])=[O:56])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:35][CH:34]=2)=[CH:31][N:30]=[CH:29]1>CN(C=O)C>[S:28]1[C:32]([C:33]2[CH:38]=[CH:37][C:36]([CH:39]([NH2:24])[N:40]([C:11](=[O:13])[C@H:7]([CH:8]([CH3:9])[CH3:10])[NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:41][C@H:42]([OH:63])[C@@H:43]([NH:51][C:52](=[O:62])[C@H:53]([CH:59]([CH3:61])[CH3:60])[NH:54][C:55]([O:57][CH3:58])=[O:56])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:35][CH:34]=2)=[CH:31][N:30]=[CH:29]1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2cncs2)cc1)C(C)C
Reactant: CCOC(=O)N[C@H](C(=O)O)C(C)C
Reactant: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCOC(=O)N[C@H](C(=O)N(C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)C)C(N)c1ccc(-c2cncs2)cc1)C(C)C

Procedure:
Analogously to Example 7, 213 mg (1.13 mmol) of N-ethoxycarbonyl-(L)-valine, 431 mg (2.25 mmol) of EDC and 304 mg (2.25 mmol) of HOBT in 18 ml of DMF and 627 μl (4.5 mmol) of TEA are reacted with 0.75 mmol of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-valyl)amino-6-phenyl-2-azahexane (Example 7b) to form the title compound: m.p: 243°-244° C; HPLC20-100 : tRet =14.0; FAB MS (M+H)+ =697.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])=[CH:6][CH:5]=[CH:4][C:3]=1[S:14]([NH:17][C@@H:18]([CH2:22][NH:23][C:24]([C:26]1[S:27][C:28]([Cl:31])=[CH:29][CH:30]=1)=[O:25])[C:19]([OH:21])=O)(=[O:16])=[O:15].[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[C:7]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])=[CH:6][CH:5]=[CH:4][C:3]=1[S:14]([NH:17][C@H:18]([C:19](=[O:21])[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[CH2:22][NH:23][C:24]([C:26]1[S:27][C:28]([Cl:31])=[CH:29][CH:30]=1)=[O:25])(=[O:16])=[O:15]
Reactant: C1CNCCN1
Reactant: O=C(NC[C@H](NS(=O)(=O)c1cccc(N2CCCC2=O)c1Cl)C(=O)O)c1ccc(Cl)s1
Product: O=C(NC[C@H](NS(=O)(=O)c1cccc(N2CCCC2=O)c1Cl)C(=O)N1CCNCC1)c1ccc(Cl)s1

Procedure:
Intermediate 47 (150 mg, 0.3 mmol) and piperazine (25.5 mg, 0.3 mmol) were coupled in close analogy to the procedure described in 3.5). The mixture was purified by prep.
Reaction SMILES: [C:1]([CH2:3][N:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])#[N:2].[C:22](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>C(#N)C>[CH3:22][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:5]=1[N:4]([CH2:3][C:1]#[N:2])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(N(CC#N)c2ccccc2)c(C(=O)O)c1
Agent: [K+]
Solvent: CC#N
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1cc(OC)ccc1N(CC#N)c1ccccc1
Yield: 68.8 %

Procedure:
A mixture of 7.1 g (0.025 mole) of 2-[(cyanomethyl)phenylamino]-5-methoxybenzoic acid [P. C. Unangst and M. E. Carethers, J. Heterocyclic Chem., 21, 709 (1974)], 4.0 g (0.029 mole) of anhydrous potassium carbonate, and 3.0 ml (4.0 g; 0.032 mole) of dimethyl sulfate in 200 ml of acetonitrile was stirred at reflux for 24 hours. The mixture was cooled and filtered, and the filter cake was washed several times with fresh acetonitrile. The combined filtrates were evaporated to an oil, which crystallized upon standing at room temperature. Recrystallization from aqueous methanol yielded 5.1 g (68% yield) of the ester product. A sample recrystallized again as above was analytically pure, mp 107°-109° C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][NH:13][CH2:14][C:15]#[CH:16]>ClCCl.C(N(CC)CC)C>[CH3:12][N:13]([CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH2:14][C:15]#[CH:16]
Reactant: C#CCNC
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCN(C)Cc1ccc([N+](=O)[O-])cc1
Reaction time: 8 h
Yield: 80 %

Procedure:
3.72 g (22.0 mmol) of p-nitrobenzyl chloride in 20 ml of dichloromethane is added, dropwise, at 0° C. to a solution of 1 g (1.45 mmol) of N-methylpropargylamine in 15 ml of dichloromethane and 3.1 ml of triethylamine. After stirring overnight, the reaction mixture is concentrated to dryness under vacuum, and the residue is diluted with dichloromethane and 40 ml of a saturated solution of NaCl. After stirring and decanting, the organic phase is separated and dried over magnesium sulphate, filtered and concentrated under vacuum. The expected product is obtained after chromatography on a silica column, eluent: (20% ethyl acetate in heptane), the pure fractions, after evaporation, produce a brown solid with a yield of 80%. Melting point: 47–49° C.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[CH2:22][C@@H:21]1[OH:34])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[CH2:45][O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.CCOCC>C(Cl)Cl>[CH2:47]([O:46][CH2:45][C@@:23]1([N:25]2[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[O:24][C@H:20]([CH2:19][O:18][Si:1]([C:14]([CH3:15])([CH3:17])[CH3:16])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:21]([OH:34])[CH2:22]1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: ClCOCc1ccccc1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cn([C@@]2(COCc3ccccc3)C[C@H](O)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Reaction time: 14 h
Yield: 88 %

Procedure:
To a stirred solution of 2 (117.0 g, 243.8 mmol) and Hunig's base (diisopropylethylamine, 63.0 g, 487.5 mmol) in CH2Cl2 (400 mL) at 23° C. was added a solution of benzyl chloromethyl ether (40.7 g, 260.0 mmol) over a 15 min. period. The resultant mixture was maintained at 23° C. and stirred for 14 h. Ether (1 L) was added to the mixture and the ethereal solution was washed with 10% aqueous HCl (2×100 mL) and H2O (200 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2 /AcOEt 40:1 then 10:1) to yield 128.9 g (88%) of 3 as a white solid. Rf (CH2Cl2 /AcOEt 10:1) 0.31. 1H-NMR (CDCl3): 1.10 (s, 9H, C-Me3), 1.65 (s, 3H, 5-Me), 2.16 (m, 1H, 2'-Hβ), 2.41 (m, 1H, 2'-Hβ), 2.53 (br s, 1H 3'-OH), 3.84 (d, 1H, J=8.8 Hz, 5'-CHH), 3.98 (d, 1H, J=8.8 Hz, 5'-CHH), 4.01 (s, 1H, 4'-H), 6.64 (br s, 1H, 3'-H), 4.70 (s, 2H, OCH2Ph), 5.50 (s, 2H, NCH2O), 6.41 (dd, 1H, J=8.0, 5.8 Hz, 1'-H), 7.20-7.50 (m, 13H, aromatic-H), 7.65-7.69 (m, 3H, 6-H and aromatic-H). 13C-NMR (CDCl3): 12.86 (-5-CH3) 19.45 (+, C-Me3), 27.09 (-, C-Me3), 41.16 (+, 2'-C), 64.25 (+, 5'-C), 70.70 (+, O--C--Ph), 71.97 (-, 4'-C), 72.29 (+, N--C--O), 85.51 (-, 3'-C), 87.20 (-, 1'-C), 110.47 (+, 5-C), 127.72, 128.08, 128.36 (-, aromatic-C), 130.25 (-, 6-C), 132.42, 133.00 (+, aromatic-C) 134.39, 135.37, 135.62 (-, aromatic-C), 137.95 (+, aromatic-C), 151.01 (+, 2-C), 163.68 (+, 4-C).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH3:11])[C:7]=2[CH:12]=1.[C:13](Cl)(=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[N+](C)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-]>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:13](=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:8]([CH3:11])[C:7]=2[CH:12]=1
Reactant: CCCCCCC(=O)Cl
Reactant: COc1ccc2occ(C)c2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C[N+](=O)[O-]
Product: CCCCCCC(=O)c1oc2ccc(OC)cc2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a mixture of 5-methoxy-3-methyl-1-benzofuran (1.87 g) synthesized in Example A104(2), heptanoyl chloride (2.14 mL) and nitromethane (20 mL) was added aluminum chloride (3.07 g), and the mixture was stirred overnight at room temperature. Water was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (7% ethyl acetate/hexane) to give the title object compound (2.34 g, 74%) as a pale-yellow solid.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:4]=1[O:5][C:6]1[CH:7]=[CH:8][C:9](N)=[C:10]([CH:16]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl.N([O-])=O.[Na+].[S:31](=[O:33])=[O:32]>O.[Cu](Cl)Cl.C(O)(=O)C.C1C=CC=CC=1>[Cl:2][C:3]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:4]=1[O:5][C:6]1[CH:7]=[CH:8][C:9]([S:31]([Cl:1])(=[O:33])=[O:32])=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:16]=1
Reactant: O=S=O
Reactant: CCOC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1N
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1S(=O)(=O)Cl
Reaction time: 8 h

Procedure:
Ethyl 5-(2-chloro-4-trifluoromethylphenoxy)-2-aminobenzoate hydrochloride (12 g) and conc. hydrochloric acid (6.6 ml) were added to acetic acid (85 ml), and the resultant mixture was cooled to less than 10° C. A solution of sodium nitrite (2.5 g) in water (6 ml) was dropwise added thereto. When the resulting mixture became completely transparent, benzene (20 ml), acetic acid (20 ml) saturated with sulfur dioxide and copper chloride (1.5 g) were added thereto. After stirring overnight, the reaction mixture was poured onto ice-water. The deposited oily substance was extracted with chloroform, washed with water and dried over anhydrous magnesium sulfate. The extract was concentrated and allowed to stand. The crystallized substance was recrystallized from hexane to give 9 g of 4-(2-chloro-4-trifluoromethylphenoxy)-2-ethoxycarbonylbenzenesulfonyl chloride. M.P., 96°-96.5° C.
Reaction SMILES: [Br:1][C:2]1[CH2:10][C:9](C)([N+:11]([O-:13])=[O:12])[C:8]2[NH:7][CH2:6][CH2:5][C:4]=2[CH:3]=1.[H-].[Na+].I[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[C:26](OCC)(=O)C>CN(C)C=O>[CH2:18]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[C:10]([CH3:26])[C:9]=2[N+:11]([O-:13])=[O:12])[CH2:5][CH2:6]1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCOC(C)=O
Reactant: CC1([N+](=O)[O-])CC(Br)=CC2=C1NCC2
Reactant: CCCCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCN1CCc2cc(Br)c(C)c([N+](=O)[O-])c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-Bromo-7-methyl-7-nitroindoline (3.6 g) was dissolved in N,N-dimethylformamide (36 ml), and sodium hydride (677 mg) was added, which was followed by stirring at room temperature for 0.5 hr. 1-Iodooctane (3.4 g) was added to the reaction mixture and the mixture was stirred at the same temperature for 24 hr. Ethyl acetate (200 ml) was added to the reaction mixture, and the mixture was washed with water and dried over anhydrous sodium sulfate. Ethyl acetate was evaporated under reduced pressure. The residue was purified by gel column chromatography (eluent: ethyl acetate/n-hexane=1/100-1/50) to give 4.0 g of oily 1-octyl-5-bromo-6-methyl-7-nitroindoline.
Reaction SMILES: [OH2:1].[NH2:2][CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5].[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][CH:17]=1.[ClH:26]>O1CCOCC1>[OH2:5].[OH2:1].[ClH:15].[ClH:26].[NH2:2][CH:3]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)=[CH:12][CH:13]=1)[C:4]([OH:6])=[O:5]
Reactant: Nc1ccc(CC(N)C(=O)O)cc1
Reactant: Clc1ccnc2ccccc12
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: NC(Cc1ccc(Nc2ccnc3ccccc23)cc1)C(=O)O
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 129.7 %

Procedure:
A mixture of 2-amino-3-(4-aminophenyl)-propionic acid hydrate (0.27 g, 1.5 mmol), 4-chloro-quinoline (0.245 g, 1.5 mmol) and conc. HCl (0.43 g) in dioxane (3 mL) is stirred at 120° C. temperature for 30 min in a tightly closed Pierce glass reaction vial. After cooling the liquid phase is separated and the solid residue is washed with acetonitrile (3×3 mL) and diethyl ether (5 mL) to give the title compound (0.405 g, 65%) as yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH2:11][C:12]([OH:14])=O.C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH2:11][C:12]([Cl:18])=[O:14]
Reactant: COc1cc(CC(=O)O)c(Br)cc1C
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(CC(=O)Cl)c(Br)cc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2-bromo-5-methoxy-4-methyl-phenyl)-acetic acid (149.4 mg) in dichloromethane (1.8 mL) was added oxalyl chloride (0.055 mL) followed by DMF (1 drop) uder argon. Mixture was stirred at rt for 3 h. Mixture was concentrated to dryness. Dichloroethane (ca. 10 mL) was added, and the mixture was back concentrated to dryness to obtain crude (2-bromo-5-methoxy-4-methyl-phenyl)-acetic acid chloride (151 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:24][C:25](Br)=[O:26].[NH2:28][C@@H:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][C@@H:30]1[OH:38]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:24][C:25]([NH:28][C@@H:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31][C@@H:30]2[OH:38])=[O:26])=[CH:21][CH:22]=1
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(Cl)cc1)NCC2
Reactant: O=C(Br)CBr
Product: COc1cc2c(cc1OC)C(Cc1ccc(Cl)cc1)N(CC(=O)N[C@@H]1c3ccccc3C[C@@H]1O)CC2

Procedure:
prepared by reaction of 1-(4-Chloro-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with (1R,2S)-1-amino-2-indanol
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:11][O:12][CH:13]([O:26][CH3:27])[C:14]1[C:23]([CH:24]=O)=[CH:22][C:21]2[CH2:20][CH2:19][CH2:18][NH:17][C:16]=2[N:15]=1.CCN(CC)CC.[BH4-].[Na+]>CC(N(C)C)=O.CO>[CH3:27][O:26][CH:13]([O:12][CH3:11])[C:14]1[C:23]([CH2:24][NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:22][C:21]2[CH2:20][CH2:19][CH2:18][NH:17][C:16]=2[N:15]=1
Reactant: CCOC(=O)CSCCN
Reactant: COC(OC)c1nc2c(cc1C=O)CCCN2
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)CSCCNCc1cc2c(nc1C(OC)OC)NCCC2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of ethyl 2-((2-aminoethyl)thio)acetate (intermediate 210, 675 mg, 2.87 mmol) in DMA (7.5 ml) and MeOH (7.5 ml) was added to a solution of 2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carbaldehyde (intermediate 41, 710 mg, 3.01 mmol) and Et3N (0.417 mL, 3.01 mmol) in MeOH (7.5 ml) and the reaction mixture was stirred at room temperature for 3 days. NaBH4 (142 mg, 3.75 mmol) was added portion wise and stirring was continued for 40 min at room temperature. Additional Et3N (500 μL, 3.61 mmol) was added and mixture was stirred for 4 h. Solvents were concentrated and the residue was partitioned between DCM and aqueous citric acid (5%). The aqueous layer was extracted with DCM (3×) and the combined organic layers were washed with aqueous citric acid (5%) (3×). The pH value of the combined water layers was adjusted to 9 using aqueous Na2CO3 and the water phase was back extracted with DCM (3×). The organic layers were combined, dried using Na2SO4, filtered and evaporated to yield the title compound as an orange oil. (UPLC-MS 3) tR 0.61 min; ESI-MS 384.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 7.16 (s, 1H), 6.40-6.36 (m, 1H), 5.08 (s, 1H), 4.12-4.05 (m, 2H), 3.61 (s, 2H), 3.36-3.21 (m, 10H), 2.71-2.61 (m, 6H), 1.80-1.72 (m, 2H), 1.19 (t, 3H
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:5]=[C:4]([NH:19][CH:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)[N:3]=1.[NH2:30][CH2:31][CH2:32][CH2:33][CH:34]([CH2:40][NH2:41])[CH2:35][CH2:36][CH2:37][CH2:38][NH2:39]>O>[CH3:28][C:22]1([CH3:29])[CH2:21][CH:20]([NH:19][C:4]2[N:5]=[C:6]([NH:8][CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]3)[N:7]=[C:2]([NH:30][CH2:31][CH2:32][CH2:33][CH:34]([CH2:40][NH:41][C:2]3[N:7]=[C:6]([NH:8][CH:9]4[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:17])([CH3:18])[CH2:10]4)[N:5]=[C:4]([NH:19][CH:20]4[CH2:25][C:24]([CH3:26])([CH3:27])[NH:23][C:22]([CH3:28])([CH3:29])[CH2:21]4)[N:3]=3)[CH2:35][CH2:36][CH2:37][CH2:38][NH:39][C:2]3[N:3]=[C:4]([NH:19][CH:20]4[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]4)[N:5]=[C:6]([NH:8][CH:9]4[CH2:10][C:11]([CH3:18])([CH3:17])[NH:12][C:13]([CH3:16])([CH3:15])[CH2:14]4)[N:7]=3)[N:3]=2)[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23]1
Reactant: NCCCCC(CN)CCCN
Reactant: CC1(C)CC(Nc2nc(Cl)nc(NC3CC(C)(C)NC(C)(C)C3)n2)CC(C)(C)N1
Solvent: O
Product: CC1(C)CC(Nc2nc(NCCCCC(CCCNc3nc(NC4CC(C)(C)NC(C)(C)C4)nc(NC4CC(C)(C)NC(C)(C)C4)n3)CNc3nc(NC4CC(C)(C)NC(C)(C)C4)nc(NC4CC(C)(C)NC(C)(C)C4)n3)nc(NC3CC(C)(C)NC(C)(C)C3)n2)CC(C)(C)N1

Procedure:
5.1 g of 2-chloro-4,6-bis[N-(2,2,6,6-tetramethyl-4-piperidyl)amino]-1,3,5-triazine [prepared as described in Preparation 9(b)] were reacted with 0.7 g of 1,8-diamino-4-aminomethyloctane, following the procedure described in Example 9. After completion of the reaction, the reaction mixture was poured into water and extracted with chloroform. The extract was dried over anhydrous potassium carbonate, and the solvent was distilled off. The residue was purified by column chromatography through silica gel, eluted with a 8:2:1 by volume mixture of ethyl acetate, ethanol and triethylamine, to give the desired Compound No. 1 in the form of crystals melting at 148°-158° C.
Reaction SMILES: [C:1]([NH:5][NH2:6])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.S([O-])([O-])(=O)=O.[Na+].[Na+].Cl[CH2:18][C:19](=O)[CH3:20]>CCCCC>[C:1]([N:5]=[N:6][C:19]([CH3:20])=[CH2:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)CCl
Reactant: CC(C)(C)NN
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCC
Product: C=C(C)N=NC(C)(C)C
Reaction time: 0.75 h

Procedure:
To a solution of 6.75 g. (0.077 m.) tert.-butylhydrazine in 50 ml. of methylene chloride containing 2 g. of anhydrous sodium sulfate, was added 3.0 g. (0.0326 m.) chloroacetone. The addition was carried out dropwise holding the reaction temperature below 10° C. with an ice bath. The reaction was stirred an additional 45 minutes and filtered. The filtrate was washed with cold water (10° C.), dried over anhydrous sodium sulfate, filtered and the methylene chloride evaporated off using a rotating evaporator and a 20° C. water bath. A yellow oil containing some solids suspended in it was obtained. The crude material was slurried in cold pentane and filtered. The pentane was then evaporated off from the filtrate on the rotating evaporator. The yield was 1.9 g. (47%) of a yellow oil. The infra-red spectrum was consistent with the structure of the proposed compound. 2-tert.-butylazopropene is a thermally unstable compound and evolves nitrogen at room temperature and is therefore a very low temperature blowing agent.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[H-].[Na+].[CH2:17]([N:24]1[CH2:28][CH:27](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:26][C:25]1=[O:40])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.[CH3:42]N(C=O)C>O>[CH2:17]([N:24]1[C:25](=[O:40])[CH2:26][CH:27]([CH2:42][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[C:2]2[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:28]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CC(=O)N(Cc3ccccc3)C2)cc1
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc2ccccc2n1CC1CC(=O)N(Cc2ccccc2)C1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A solution of 66.2 g of ethyl indole-2-carboxylate in 350 ml of DMF was added to a suspension of 12 g of sodium hydride (80% dispersion in mineral oil) in 80 ml of DMF. After stirring for 0.5 hour under a nitrogen atmosphere the solution obtained was treated with a solution of 115 g of 1-benzyl-4-(p-toluenesulphonyloxy)-2-pyrrolidinone in 500 ml of DMF. After completion of the addition the mixture was heated to 60° C. for 0.75 hour and then at 70° C. for 1 hour. The solution obtained was cooled in an ice bath and treated with water and 2M hydrochloric acid. After stirring for 15 minutes the precipitate formed was filtered off and dried to give 96.2 g of ethyl 1-[(1-benzyl-5-oxo-3-pyrrolidinyl)methyl]-2-indolecarboxylate of melting point 93°-94° C.