Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][Cl:35]>>[ClH:35].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][N:17]([CH2:34][C:33]4[CH:36]=[CH:37][CH:38]=[C:31]([O:30][CH3:29])[CH:32]=4)[C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COc1cccc(CCl)c1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2
Agent: Cl
Product: COc1cccc(CN2CN(c3ccccc3)C3(CCN(C4CCCCCCCCC4)CC3)C2=O)c1

Procedure:
The title compound, white solid, m. p. 175° C. and MS: m/e=490.4 (M+H+) was prepared in accordance with the general method of example 24 from 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one hydrochloride and 3-methoxybenzylchloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18](O)=[O:19])[N:9]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH3:34][NH:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>C(Cl)(Cl)Cl>[CH:36]1([N:35]([CH3:34])[C:18]([C:10]2[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:17]3[C:12]([CH:11]=2)=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:19])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: O=C(O)c1cc2ccccc2c(-c2ccccc2Cl)n1
Reactant: CNC1CCCCC1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C(=O)c1cc2ccccc2c(-c2ccccc2Cl)n1)C1CCCCC1
Yield: 64.8 %

Procedure:
Operations are carried out as for Example 7, starting from 2.83 g of 1-(2-chloro phenyl) isoquinoline 3-carboxylic acid, 1.15 g of triethylamine, 1.24 g of ethyl chloroformate and 1.46 g of N-methyl cyclohexylamine in 100 ml of chloroform. 2.45 g of N-cyclohexyl N-methyl 1-(2-chloro phenyl) isoquinoline 3-carboxamide melting at 131° C., are obtained.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]#[C:20][CH2:21][O:22][CH3:23])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:24](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:42][S:43]([C:46]1[CH:51]=[CH:50][C:49](B(O)O)=[CH:48][CH:47]=1)(=[O:45])=[O:44].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]#[C:20][CH2:21][O:22][CH3:23])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:24]([C:49]2[CH:50]=[CH:51][C:46]([S:43]([CH3:42])(=[O:45])=[O:44])=[CH:47][CH:48]=2)=[CH:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: COCC#Cc1cnc2c(c1)cc(C(=CC1CCCC1)OS(=O)(=O)c1ccc(C)cc1)n2S(=O)(=O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COCC#Cc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Yield: 45.5 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-[1-benzenesulfonyl-5-(3-methoxy-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2-cyclopentyl-vinyl ester (900 mg, 1.53 mmol), 4-(methanesulfonyl)phenylboronic acid (763 mg, 3.81 mmol) and dichlorobis(triphenylphosphine)palladium (II) (107 mg, 0.15 mmol) in dioxane (5 mL) was added an aqueous sodium carbonate solution (2 M, 1.9 mL). The mixture was subjected to microwave irradiation for 1 h at 100° C. The resulting mixture was diluted with ethyl acetate (150 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 33% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-(3-methoxy-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine (400 mg, 45.6%) as an orange oil: LC/MS m/e calcd for C31H30N2O5S2 [M+H]+ 575.72, observed 575.1.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C:11]1[CH:12]=[N:13][C:14]([N:17]2[CH2:22][CH:21]3[CH:19]([CH:20]3[N:23]([S:31]([C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH:35]=3)(=[O:33])=[O:32])[CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:18]2)=[N:15][CH:16]=1)=[O:10].C(O)(C(F)(F)F)=O.C(Cl)Cl>CO>[OH:7][NH:8][C:9]([C:11]1[CH:16]=[N:15][C:14]([N:17]2[CH2:22][CH:21]3[CH:19]([CH:20]3[N:23]([S:31]([C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH:35]=3)(=[O:33])=[O:32])[CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:18]2)=[N:13][CH:12]=1)=[O:10]
Reactant: O=C(NOC1CCCCO1)c1cnc(N2CC3C(C2)C3N(CCN2CCCC2)S(=O)(=O)c2ccc3ccccc3c2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: O=C(NO)c1cnc(N2CC3C(C2)C3N(CCN2CCCC2)S(=O)(=O)c2ccc3ccccc3c2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.2 %

Procedure:
To N-(tetrahydro-2H-pyran-2-yloxy) 2-{6-[(naphthalene-2-sulfonyl)-(2-pyrrolidin-1-ylethyl)amino]-3-azabicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide (0.234 g, 0.38 mmol) was added TFA:DCM:MeOH (6 ml, 1:1:1 mixture). The mixture was stirred for 3 h at r.t. and then concentrated in vacuo. The product was purified by reverse phase HPLC to yield the title compound (60 mg, 30%). LCMS Purity >98%, m/z 523.25 [M+H]+, 1H NMR (300 MHz, d6-DMSO) δ: 1.55-1.68 (4H, m), 1.78 (1H, m), 2.25-2.34 (2H, m), 2.35-2.45 (4H, m), 2.55-2.65 (2H, m), 3.25-3.42 (5H, m), 3.54-3.63 (2H, m), 3.73-3.85 (2H, m), 7.65-7.77 (2H, m), 7.86 (1H, d, J=8.5 Hz), 8.06 (1H, d, J=7.3 Hz), 8.17 (1H, d, J=7.3 Hz), 8.24 (1H, d, J=7.3 Hz), 8.55 (1H, s), 8.61 (2H, s), 9.00 (1H, br s), 11.05 (1H, br s).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl[CH2:11][CH:12]([OH:24])[CH2:13][N:14]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:15][CH:16]([OH:19])[CH2:17]Cl>C1(C)C(C)=CC=CC=1>[OH:24][CH:12]([CH2:13][N:14]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:15][CH:16]([OH:19])[CH2:17][NH:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:11][NH:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCN(CC(O)CCl)CC(O)CCl
Reactant: CCCCCCCCN
Solvent: Cc1ccccc1C
Product: CCCCCCCCNCC(O)CN(CCCC)CC(O)CNCCCCCCCC
Temperature: 70 °C
Yield: 83.3 %

Procedure:
A reactor was charged with 371 g (2.87 moles) of octylamine, and the contents were heated to 70° C. To the contents, a solution with 70 g (0.27 mole) of N,N-bis(3-chloro-2-hydroxypropyl)butylamine dissolved in 50 g of xylene was then added dropwise over 40 minutes. The resultant mixture was aged further for 4 hours. Thereafter, xylene was distilled off under reduced pressure, and unreacted octylamine was then distilled off at 70° C. and 0.5 mmHg. A mixture of 400 ml of xylene and 400 ml of 5% aqueous sodium hydroxide was added to the residue to subject it to extraction and washing. Thereafter, a xylene layer was taken out and concentrated, thereby obtaining 99.8 g (yield: 82%) of 11,15-dihydroxy-13-butyl-9,13,17-triazapentacosane represented by the following formula. ##STR11##
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH3:23])[CH:13]([OH:22])[C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)S(O[Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])(=O)=O.CC1C=CC=C(C)N=1.O>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH3:23])[CH:13]([O:22][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)C(C)(C)C(O)[C@H](C)NC(=O)OCc1ccccc1
Solvent: O
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)C(O[Si](C)(C)C(C)(C)C)[C@H](C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
A solution of ethyl(4S)-4-{[(benzyloxy)carbonyl]amino}-2,2-dimethyl-3-hydroxypentanoate (720 mg) in THF (20 mL) was cooled to 0° C., tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.589 mL) and 2,6-dimethylpyridine (0.390 mL) were added, and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/0→1/1) to give ethyl(4S)-4-{[(benzyloxy)carbonyl]amino}-3-(tert-butyldimethylsilyloxy)-2,2-dimethylpentanoate as a colorless oil (yield: 0.916 g, 94%).
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[Cl:6][C:7]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:8]=1[O:9][CH2:10][CH2:11][OH:12]>>[S:1]([O:12][CH2:11][CH2:10][O:9][C:8]1[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:7]=1[Cl:6])(=[O:4])(=[O:3])[NH2:2]
Reactant: OCCOc1ccc(Cl)cc1Cl
Reactant: NS(=O)(=O)Cl
Product: NS(=O)(=O)OCCOc1ccc(Cl)cc1Cl

Procedure:
The title compound was prepared by the procedures of Example 33 from sulfamoyl chloride and 2-(2,4-dichlorophenoxy)ethanol. The viscous oil obtained solidified and was recrystallized from isopropyl ether to give the solid title compound, mp 75°-77° C., in 35% yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[C:8]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([NH:22][CH2:23][CH:24]=[CH2:25])[CH:6]=1)[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[C:8]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:7]([NH:22][CH2:23][CH2:24][CH3:25])[CH:6]=1)[CH3:2]
Reactant: C=CCNc1cc(C(=O)OCC)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCNc1cc(C(=O)OCC)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
A solution of ethyl-3-allylamino-4-phenoxy-5-sulphamyl-benzoate (1.65 g) in ethanol (150 ml) was hydrogenated at room temperature and 1.1. atmospheres hydrogen pressure after the addition of a palladium-on-carbon catalyst (0.6 g catalyst containing 10% Pd). After the hydrogen uptake had become negligible, the catalyst was removed by filtration, and the filtrate was evaporated in vacuo. The residue was recrystallized twice from aqueous ethanol, resulting in ethyl-4-phenoxy-3-n-propylamino-5-sulphamyl-benzoate with a melting point of 150°-151° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([C:18]([F:21])([F:20])[F:19])[N:14](O)[C:13]=2[CH:12]=[C:11]([Br:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)Br.O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([C:18]([F:21])([F:19])[F:20])[NH:14][C:13]=2[CH:12]=[C:11]([Br:23])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: On1c(C(F)(F)F)nc2c(OCc3ccccc3)cc(Br)cc21
Agent: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: FC(F)(F)c1nc2c(OCc3ccccc3)cc(Br)cc2[nH]1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
To a suspension of 26.1 g (67.4 mmol) 4benzyloxy-6-bromo-2-trifluoromethyl-benzimidazol-1-ol in chloroform (260 ml) were cautiously added 19 ml (202 mmol) phosphorus tribromide and the reaction was refluxed for 4 h. After cooling to room temperature, the reaction mixture was poured into water (600 ml), neutralized with sodium bicarbonate solution and extracted with dichloromethane. The organic layers were dried over magnesium sulphate and concentrated in vacuo to afford 19.8 g (79%) of the title compound as a brown oil.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][CH:19]([O:22][CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+]>C(O)C>[CH:23]1([O:22][CH:19]2[CH2:20][CH2:21][N:16]([C:13]3[CH:14]=[CH:15][C:10]([N:7]4[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]4)=[CH:11][CH:12]=3)[CH2:17][CH2:18]2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CC(=O)N1CCN(c2ccc(N3CCC(OC4CCCCC4)CC3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1cc(N2CCC(OC3CCCCC3)CC2)ccc1N1CCNCC1
Yield: 97.1 %

Procedure:
A mixture of 1-acetyl-4-[4-(4-cyclohexyloxypiperidin-1-yl)phenyl]piperazine (0.37 g) and 10% sodium hydroxide (1.9 ml) in ethyl alcohol (7.4 ml) was refluxed for 10 hours. The reaction mixture was evaporated under reduced pressure. The residue was washed with water, and dried to give 1-[4-(4-cyclohexyloxypiperidin-1-yl)phenyl]piperazine (0.32 g).
Reaction SMILES: C[O:2][C:3](=[O:48])[C@@H:4]([NH:17][C:18](=[O:47])[CH2:19][NH:20][C:21]([C:23]1[CH:46]=[CH:45][C:26]2[N:27]([CH3:44])[C:28]([NH:30][C:31]3[S:32][C:33]4[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[CH:36][C:34]=4[N:35]=3)=[N:29][C:25]=2[CH:24]=1)=[O:22])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[OH-].[Na+]>CO.C1COCC1>[C:13]([O:12][C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]([NH:17][C:18](=[O:47])[CH2:19][NH:20][C:21]([C:23]1[CH:46]=[CH:45][C:26]2[N:27]([CH3:44])[C:28]([NH:30][C:31]3[S:32][C:33]4[CH:39]=[C:38]([C:40]([F:42])([F:41])[F:43])[CH:37]=[CH:36][C:34]=4[N:35]=3)=[N:29][C:25]=2[CH:24]=1)=[O:22])[C:3]([OH:48])=[O:2])=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(C(F)(F)F)cc3s1)n2C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)O)ccc21
Yield: 88.5 %

Procedure:
(S)-6-tert-Butoxycarbonylamino-2-(2-{[1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetylamino)-hexanoic acid (260 mg) was prepared by following General Procedure E starting from (S)-6-tert-butoxycarbonylamino-2-(2-{[1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetylamino)-hexanoic acid methyl ester (300 mg) and 2 N NaOH (2 mL) in MeOH:THF (1:1, 2 mL).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].C(OCC)(=O)C.[Cl:15][C:16]([Cl:23])([Cl:22])[CH2:17][O:18][C:19](Cl)=[O:20]>N1C=CC=CC=1>[Cl:15][C:16]([Cl:23])([Cl:22])[CH2:17][O:18][C:19]([O:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8])=[O:20]
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(OCC(Cl)(Cl)Cl)ON1C(=O)CCC1=O

Procedure:
Dissolve 5.75 gm. of N-hydroxysuccinimide in 200 ml. ethyl acetate and 4 gm. of pyridine; cool the resultant solution to 0° C. To this solution add 10.6 gm. 2,2,2-trichloroethylchloroformate dropwise over a period of 1.5 hours. Filter the resultant mixture and evaporate the filtrate to dryness. Wash the thereby formed needles with hexane to obtain N-(2,2,2-trichloroethoxycarbonyloxy) succinimide, mp. 98°-101° C; νmax (CHCl3) 1825, 1790, 1750, 1185, 826 cm.-1, δ(CDCl3) 2.85 (4H,s,--CO (CH2)2CO--) and 4.90 ppm. (2H,s,--COOCH2CCl3).
Reaction SMILES: CN1C2C=CC=CC=2NC2N=CC=CC=2C1=O.[CH3:18][N:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]([CH2:30][CH2:31][O:32]C2CCCCO2)[C:22]2[N:39]=[CH:40][CH:41]=[CH:42][C:21]=2[C:20]1=[O:43].ClCCOC1CCCCO1>>[OH:32][CH2:31][CH2:30][N:23]1[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N:19]([CH3:18])[C:20](=[O:43])[C:21]2[CH:42]=[CH:41][CH:40]=[N:39][C:22]1=2
Reactant: CN1C(=O)c2cccnc2N(CCOC2CCCCO2)c2ccccc21
Agent: CN1C(=O)c2cccnc2Nc2ccccc21
Agent: ClCCOC1CCCCO1
Product: CN1C(=O)c2cccnc2N(CCO)c2ccccc21

Procedure:
Using a procedure analogous to that described in Example 2, 22.52 g (0.1 mol) of 6,11-dihydro-6-methyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one were convened to 6,11-dihydro-6-methyl-11-[2-[(2-tetrahydropyranyl)oxy]ethyl]-5H-pyrido-[2,3-b][1,5]benzodiazepin-5-one by reaction with 21.8 g (0.132 mol) of 1-chloro-2-[(2-tetrahydropyranyl)-oxy]-ethane. The raw material thus obtained was dissolved in a mixture of 500 ml ethanol and 100 ml of concentrated aqueous hydrochloric acid. After having been refluxed for two hours, the reaction mixture was evaporated in vacuo. The residue was triturated with ethanol, the precipitated crystals were faltered off and the solvent was removed from the filtrate by distillation in vacuo. The residue was purified by column chromatography on silica gel (0.2-0.5 mm) using chloroform/ethylacetate/methanol 5/5/1 (v/v/v) as an eluent. Colorless crystals of m.p. 133°-134° C. (after recrystallization from xylene) were obtained in a yield of 9.0 g (33% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=[O:6].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:22](O)[CH2:23][OH:24].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:24][CH2:23][CH2:22][O:6]2)[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: OCCO
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Clc1cc(Cl)cc(C2OCCO2)c1

Procedure:
4.66 g of 3,5-dichlorobenzaldehyde is mixed with 0.23 g of paratoluenesulphonic acid, 3 ml of ethylene glycol and 40 ml of toluene. The reaction medium is heated under reflux for 2 hours, poured into a saturated solution of sodium bicarbonate and the aqueous phase is decanted. The organic phase is dried and evaporated under reduced pressure. 5.756 g of expected product is isolated in the form of an oil.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:42]=[CH:41][C:17]([CH2:18][N:19]4[CH:23]=[C:22]([CH2:24][CH:25](C(OCC)=O)[C:26]([O:28]CC)=[O:27])[C:21]([C:36]5[S:37][CH:38]=[CH:39][CH:40]=5)=[N:20]4)=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>C(O)C>[C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:42]=[CH:41][C:17]([CH2:18][N:19]4[CH:23]=[C:22]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C:21]([C:36]5[S:37][CH:38]=[CH:39][CH:40]=5)=[N:20]4)=[CH:16][CH:15]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(Cc1cn(Cc2ccc(OCc3coc(-c4ccccc4)n3)cc2)nc1-c1cccs1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCc1cn(Cc2ccc(OCc3coc(-c4ccccc4)n3)cc2)nc1-c1cccs1
Temperature: 110 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
A mixture of diethyl [1-[4-(2-phenyl-4-oxazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazol-4-yl]methylmalonate (1.75 g), 2N sodium hydroxide solution (10 ml), and ethanol (10 ml) was refluxed for 2 hour. After cooling, 1N hydrochloric acid (20 ml) was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless oily substance was dissolved in pyridine (30 ml), and stirred at 110° C. for 2 hours. After pyridine was removed under reduced pressure, ethyl acetate was added to the residue. The resulting solution was washed successively with dilute hydrochloric acid and saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[1-[4-(2-phenyl-4-oxazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazol-4-yl]propionic acid (1.24 g, yield: 85%). This was recrystallized from ethyl acetate-hexane. Melting point: 145˜146° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][O:28][CH2:29][CH3:30])=[O:24])[C:5]1=[O:31].C(N(C(C)C)CC)(C)C.Cl[C:42]([O:44][CH3:45])=[O:43]>CN(C=O)C>[CH2:29]([O:28][CH2:27][CH2:26][NH:25][C:23]([C:6]1[C:5](=[O:31])[N:4]([CH2:3][CH2:2][NH:1][C:42](=[O:43])[O:44][CH3:45])[C:13]2[C:8]([C:7]=1[OH:22])=[N:9][CH:10]=[C:11]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)[CH:12]=2)=[O:24])[CH3:30]
Reactant: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN)c1=O
Reactant: COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCNC(=O)OC)c1=O

Procedure:
A solution of 1-(2-aminoethyl)-N-[2-(ethyloxy)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.02 g, 0.047 mmol) and diisopropyl ethylamine (0.041 mL, 0.24 mmol) in DMF (5 mL) under nitrogen was treated with methyl chloroformate (0.0036 mL, 0.047 mmol) at ambient temperature. The reaction was concentrated in vacuo and the resulting residue treated with 1 N NaHSO4, filtered, then washed with 1 N NaHSO4 and Et2O before drying in vacuo to provide the title compound as an off-white solid: 1H NMR (300 MHz, DMSO-D6) δ ppm 1.1 (t, J=7.0 Hz, 3 H), 3.3 (m, 2 H), 3.4 (s, 3 H), 3.5 (m, 7 H), 4.1 (s, 2 H), 4.3 (t, J=6.0 Hz, 2 H), 7.1 (t, J=8.8 Hz, 2 H), 7.3 (m, 1 H), 7.4 (m, 2 H), 8.1 (s, 1 H), 8.5 (s, 1 H), 17.1 (s, 1 H); ES+ MS: 487 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7].[Br:10][CH2:11][CH2:12][CH2:13][C:14](Cl)=[O:15]>C1(C)C=CC=CC=1>[Br:10][CH2:11][CH2:12][CH2:13][C:14]([NH:7][C:6]1[CH:8]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:9])=[O:15]
Reactant: O=C(Cl)CCCBr
Reactant: Nc1cc(Br)ccc1F
Solvent: Cc1ccccc1
Product: O=C(CCCBr)Nc1cc(Br)ccc1F
Temperature: 100 °C

Procedure:
A solution of 5-bromo-2-fluoroaniline (10 g, 52 mmol) in toluene (150 ml) was treated with 4-bromobutyryl chloride (6.1 ml, 52 mmol) and then heated at 100° C. for 14 h. The reaction was cooled then washed with water, 10% sodium carbonate, 1N HCl and water, dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo. The resulting tan solid was triturated with 5% ether in isohexane and collected by filtration to afford 4-bromo-N-(5-bromo-2-fluorophenyl)butyramide. This solid was dissolved in anhydrous N,N-dimethylformamide (150 ml) then treated with sodium hydride (1.4 g of a 60% dispersion in oil) added in portions over 5 min. The resulting mixture was stirred at 60° C. for 60 min, cooled and treated with methanol (10 ml). The reaction was diluted with water (1500 ml) and extracted with ether (2×400 ml). The organics were combined, washed with water (×3), brine, dried over anhydrous magnesium sulphate, filtered and pre-adsorbed onto silica. Chromatography on silica gel, eluting with isohexane on a gradient of ethyl acetate (20-50%), gave 1-(5-bromo-2-fluorophenyl)pyrrolidin-2-one (9.1 g, 67%) as a straw-coloured solid: δH (400 MHz, CDCl3) 2.17-2.25 (2H, m), 2.55-2.59 (2H, m), 3.80-3.84 (2H, m), 7.20 (1H, dd, J 10.5 and 9), 7.33-7.37 (1H, m), 7.59 (1H, dd, J 7 and 2.5).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][CH2:11][CH:12]2[O:14][CH2:13]2)[CH2:4][C:3]1([CH3:16])[CH3:15].[NH:17]([CH2:21][CH2:22][OH:23])[CH2:18][CH2:19][OH:20]>O>[OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][CH2:11][CH:12]([OH:14])[CH2:13][N:17]([CH2:21][CH2:22][OH:23])[CH2:18][CH2:19][OH:20])[CH2:4][C:3]1([CH3:16])[CH3:15]
Reactant: CC1(C)CC(OCC2CO2)CC(C)(C)N1O
Reactant: OCCNCCO
Solvent: O
Product: CC1(C)CC(OCC(O)CN(CCO)CCO)CC(C)(C)N1O
Yield: 29.9 %

Procedure:
A solution of 2.28 g (0.01 mol) of 1-oxyl-2,2,6,6-tetramethyl-4-glycidyloxypiperidine and 1.05 g (0.01 mol) of diethanolamine in 25 mL of water is stirred at ambient temperature for 16 hours. The solution is then extracted with methylene chloride. The methylene chloride extract is dried over anhydrous magnesium sulfate, filter and concentrated. The crude reaction product is purified by column chromatography to afford 1.0 g of the title compound as a red oil.