Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([CH3:12])[OH:11])=[CH:4][CH:3]=1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>>[Si:13]([O:11][CH:10]([CH3:12])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(O)CCc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Product: CC(CCc1ccc(Br)cc1)O[Si](C)(C)C(C)(C)C
Yield: 73.1 %

Procedure:
3-(4-Bromophenyl)-1-methyl-1-propanol (2.186 g) and t-butyldimethylsilyl chloride (1.575 g) were treated in the same manner as in Example 163-1, to give 4-[3-(t-butyldimethylsilyloxy)-3-methylpropan-1-yl]-1-bromobenzene as a colorless oil (2.396 g). Subsequently, the resulting compound was treated with 7-(1-ethylpiperazin-4-yl)-5-bromofuro[2,3-c]pyridine (404 mg), in the same manner as in Example 167-2, to give the hydrochloride of the title compound as colorless crystals (recrystallized from ethanol/isopropyl ether) (390 mg, yield; 69%).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:25]([OH:27])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:28][C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[C:31]([CH3:36])[C:30]=1[S:37](Cl)(=[O:39])=[O:38]>>[CH3:28][C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[C:31]([CH3:36])[C:30]=1[S:37]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]([C:25]([OH:27])=[O:26])[NH:18][C:16]([O:15][CH2:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:17])(=[O:38])=[O:39]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Product: Cc1cc(C)c(S(=O)(=O)NCCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c(C)c1
Yield: 37 %

Procedure:
Nα-(9-fluorenylmethoxycarbonyl)-L-lysine was reacted with 2,4,6-trimethylbenzenesulfonyl chloride under the conditions used in example 2 giving 37% of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][C:3]=1[C:20](=[O:22])[CH3:21].I[CH2:24][CH2:25][CH3:26]>>[CH3:13][C:8]1([CH3:12])[CH:7]=[C:6]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:5]2[C:10](=[CH:11][C:2]([O:1][CH2:24][CH2:25][CH3:26])=[C:3]([C:20](=[O:22])[CH3:21])[CH:4]=2)[O:9]1
Reactant: CCCI
Reactant: CC(=O)c1cc2c(cc1O)OC(C)(C)C=C2c1ccccc1
Product: CCCOc1cc2c(cc1C(C)=O)C(c1ccccc1)=CC(C)(C)O2

Procedure:
Following General Procedure A, 1-(7-hydroxy-2,2-dimethyl-4-phenyl-2H-chromen-6-yl)-ethanone (Compound 61, 170 mg, 0.51 mmol) and 1-iodopropane (0.30 mL, 2.55 mmol) were reacted to produce the title compound as a colorless oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[N:6]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][C@H:26]([CH2:28]O)[O:25][C:24]4=[O:30])=[CH:19][C:18]=3[F:31])=[CH:13][N:12]=2)[CH:10]=[N:9][CH:8]=[N:7]1>>[N:6]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][C@H:26]([CH2:28][N:1]5[CH:5]=[CH:4][N:3]=[N:2]5)[O:25][C:24]4=[O:30])=[CH:19][C:18]=3[F:31])=[CH:13][N:12]=2)[CH:10]=[N:9][CH:8]=[N:7]1
Reactant: c1c[nH]nn1
Reactant: O=C1O[C@@H](CO)CN1c1ccc(-c2ccc(-n3cncn3)nc2)c(F)c1
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(-n3cncn3)nc2)c(F)c1

Procedure:
The same procedure as in Example 24 was conducted, except for adding 1,2,3-triazol and using the compound 17 as a starting material, to obtain the title compound.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([C:43]1[CH:48]=[C:47]([F:49])[CH:46]=[CH:45][C:44]=1[F:50])([S:33]([C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)(=[O:35])=[O:34])[CH3:32])(C(C)(C)C)(C)C>O1CCCC1.C(OCC)C>[Cl:42][C:39]1[CH:38]=[CH:37][C:36]([S:33]([C:31]([C:43]2[CH:48]=[C:47]([F:49])[CH:46]=[CH:45][C:44]=2[F:50])([CH3:32])[CH2:30][CH2:29][CH2:28][CH2:27][OH:26])(=[O:35])=[O:34])=[CH:41][CH:40]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCCC(C)(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(CCCCO)(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
After addition of tetrabutylammonium fluoride (a 1M tetrahydrofuran solution, 0.978 ml, 0.978 mmol) to a solution of 2-[5-(t-butyldimethylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]-1-methylpentyl]-1,4-difluorobenzene (164 mg, 0.326 mmol) in tetrahydrofuran (4 ml), the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with diethyl ether, washed successively with saturated ammonium chloride, water and brine, dried over MgSO4, and then concentrated. The residue thus obtained was purified by medium-pressure chromatography on a silica gel column (50% ethyl acetate-hexane), whereby the title compound (122 mg, 96%) was obtained as a colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11](/[CH:14]=[CH:15]/[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][CH:13]=2)=[CH:5][CH:4]=1.[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1>>[NH:24]1[CH:28]=[CH:27][N:26]=[C:25]1[CH2:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11](/[CH:14]=[CH:15]/[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: c1c[nH]cn1
Reactant: ClCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Product: C(=C/c1nc(COc2ccc(Cc3ncc[nH]3)cc2)co1)\c1ccccc1

Procedure:
In substantially the same manner as in Working Example 25, 4-(4-chloromethylphenoxymethyl)-2-[(E)-2-phenylethenyl]oxazole was allowed to react with imidazole to give 4-[4-(1-imidazolylmethyl)phenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 149-150° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:33])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:22]4[CH2:27][CH2:26][NH:25][CH:24]([C:28]5[O:29][CH:30]=[CH:31][CH:32]=5)[CH2:23]4)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])C.CS(O)(=O)=O.O>[OH-].[K+].C(O)C>[F:21][C:19]1[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH:24]([C:28]3[O:29][CH:30]=[CH:31][CH:32]=3)[CH2:23]2)=[CH:17][C:11]2=[N:12][C:13]3[N:14]([CH3:16])[CH:15]=[C:6]([C:4]([OH:5])=[O:3])[C:7](=[O:33])[C:8]=3[CH:9]=[C:10]2[CH:20]=1
Reactant: CCOC(=O)c1cn(C)c2nc3cc(N4CCNC(c5ccco5)C4)c(F)cc3cc2c1=O
Agent: CS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNC(c5ccco5)C4)cc3nc21
Temperature: 80 °C
Yield: 46.8 %

Procedure:
A suspension of (RS)-3-ethoxycarbonyl-7-fluoro-8-[3-(2-furyl)-1-piperazinyl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.3 g) in 0.5 N aqueous potassium hydroxide (12 cc) and ethanol (12 cc) is heated for 1 hour to a temperature in the region of 80° C. and then treated at the same temperature with an N aqueous solution (6 cc) of methanesulphonic acid. After cooling to approximately 20° C., the insoluble water is drained, washed with water (3×10 cc), ethanol (3×10 cc) and ethyl ether (3×10 cc) and recrystallized in a mixture of ethanol (13 cc) and dimethylformamide (27 cc). (RS)-7-Fluoro-8-[3-(2-furyl)-1-piperazinyl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (0.570 g) obtained in the form of a yellow solid, m.p. 258°-260° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][C:20]2[N:29]=[C:28]3[C:23]([C:24]([CH3:31])=[CH:25][C:26](=[O:30])[NH:27]3)=[CH:22][CH:21]=2)[CH2:11][CH2:10]1>C1COCC1.O.CCO.[Ni]>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[N:29]=[C:28]3[C:23]([C:24]([CH3:31])=[CH:25][C:26](=[O:30])[NH:27]3)=[CH:22][CH:21]=2)[CH2:11][CH2:10]1
Reactant: Cc1cc(=O)[nH]c2nc(C=CCCCN3CCN(c4cccc(Cl)c4Cl)CC3)ccc12
Agent: [Ni]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Cc1cc(=O)[nH]c2nc(CCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)ccc12
Reaction time: 5.5 h
Yield: 88.4 %

Procedure:
7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-4-methyl-1H-[1,8]naphthyridin-2-one (880 mg, 1.92 mmol) was dissolved in THF (50 mL) and added to a Parr bottle containing a suspension of Raney-Nickel (1.5 mL of a settled suspension in water) in EtOH (50 mL). The mixture was hydrogenated at 45 psi for 5.5 h. The reaction was not complete so additional Raney-Nickel (1 mL of a suspension in water) was added and the mixture was hydrogenated at 45 psi for 2.5 h. The reaction mixture was filtered through a bed of Celite and washed with EtOH. The filtrate was concentrated to give a white solid. Purification by column chromatography (10% MeOH/EtOAc) afforded the title compound as a white solid (780 mg, 88%). mp 195–196° C.; 1H NMR (CDCl3, 400 MHz): δ 9.16 (br s, 1H), 7.88 (d, 1H), 7.18–7.12 (m, 2H), 7.06 (d, 1H), 7.00–6.92 (m, 1H), 6.50 (s, 1H), 3.14–3.00 (m, 4H), 2.85 (t, 2H), 2.72–2.54 (m, 4H), 2.46 (d, 3H), 2.42 (t, 2H), 1.85–1.72 (m, 2H), 1.64–1.52 (m, 2H), 1.48–1.36 (m, 2H); MS ES: m/z=459.08, 461.03.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]1(=O)[O:11][C:9](=[O:10])[CH2:8][O:7][CH2:6]1>N1C=CC=CC=1>[OH:2][CH2:1][CH2:3][N:4]1[C:9](=[O:10])[CH2:8][O:7][CH2:6][C:5]1=[O:11]
Reactant: O=C1COCC(=O)O1
Reactant: NCCO
Solvent: c1ccncc1
Product: O=C1COCC(=O)N1CCO
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 12.6 %

Procedure:
Ethanolamine (2.44 g, 40 mmol) was added dropwise to a solution of diglycolic anhydride (2.32 g, 20 mmol) in pyridine (10 ml). The mixture was stirred for 5 minutes at ambient temperature and then heated at reflux for 2 hours. The volatiles were removed by evaporation and the residue was heated at 180° C. for 2 hours The reaction mixture was allowed to cool and was purified by column chromatography eluting with methylene chloride/methanol (9/1) to give 4-(2-hydroxyethyl)-3,5-dioxomorpholine (400 mg, 12.5%).
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][O:6][CH:5]([CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:4]=2[CH:3]=[CH:2]1.C1C(=O)N([I:26])C(=O)C1.CC(O)=O.C(N(CC)CC)C>C(Cl)(Cl)Cl>[I:26][C:2]1[S:1][C:9]2[CH2:8][CH2:7][O:6][CH:5]([CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)OC(=O)NCC1OCCc2sccc21
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC1OCCc2sc(I)cc21
Yield: 583.8 %

Procedure:
A solution of tert-butyl (6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methylcarbamate (2.9 g, 1.3 mmol, 1 eq), NIS (5.2 g, 2.2 mmol, 2 eq), and AcOH (3 mL) in CHCl3 (50 mL) was stirred at room temperature for 7 hr. The reaction mixture was neutralized with triethyl amine, concentrated, and diluted with water. The mixture was extracted with n-hexane. The organic phase was dried over Na2SO4, concentrated, and purified by column chromatography to give the desired product (3 g).
Reaction SMILES: [CH2:1]([O-:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Li+].C(O)CCCCCCC.C([Li])CCC.Br[C:26]1[C:31]([F:32])=[CH:30][C:29]([Br:33])=[CH:28][N:27]=1>CCCCCC.O1CCCC1>[Br:33][C:29]1[CH:30]=[C:31]([F:32])[C:26]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[N:27][CH:28]=1
Reactant: Fc1cc(Br)cnc1Br
Reactant: CCCCCCCC[O-]
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCCCCCCCO
Product: CCCCCCCCOc1ncc(Br)cc1F

Procedure:
Lithium octanolate (prepared in advance from 13.02 g (100.00 mmol) of 1-octanol and 69 ml (110.00 mmol) of a 1.6 molar n-butyllithium solution in n-hexane at 0° C. in 40 ml of tetrahydrofuran) and 25.49 g (100.00 mmol) of 2,5-dibromo-3-fluoropyridine are refluxed for 7 hours in 40 ml of tetrahydrofuran. The mixture is subsequently partitioned between aqueous sodium chloride solution and ether, and the ether phase is washed twice with aqueous sodium chloride solution, dried over sodium sulfate, filtered and freed from solvent. Chromatographic purification (silica gel/hexane: ethyl acetate 9:1) gives 18.19 g (59.80 mmol) of 5-bromo-3-fluoro-2-octyloxypyridine. ##STR23##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:34])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30](OC)=[CH:31][C:18]3=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:37]I.O>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([O:34][CH3:37])[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][CH:30]=[CH:31][C:18]3=4)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1ccccc1CO2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC1(c2ccc(Cl)cc2)CCN(CCC=C2c3ccccc3COc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-chlorophenyl)-1-[3-(6,11-dihydro-2-methoxydibenz[b,e]oxepin-11-ylidene)propyl]piperidin-4-ol (Example 2) (400 mg) in DMF (5 ml) were added sodium hydride (60% in oil, 50 mg), methyl iodide (0.07 ml) and the mixture was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane (1:1) to give the titled compound (100 mg).
Reaction SMILES: Br[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([NH:17][C:18](=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[CH:11]=2)=[O:8])=[CH:5][N:4]=1.[C:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)(=[O:31])[CH3:30]>>[C:29]([N:32]1[CH2:37][CH2:36][N:35]([CH2:2][C:3]2[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([NH:17][C:18](=[O:26])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:34][CH2:33]1)(=[O:31])[CH3:30]
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2cccc(Cl)c2)c1)c1ccc(CBr)nc1
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(Cc2ccc(C(=O)Nc3ccc(Cl)c(NC(=O)c4cccc(Cl)c4)c3)cn2)CC1

Procedure:
6-(bromomethyl)-N-(4-chloro-3-(3-chlorobenzamido)phenyl)nicotinamide (0.2 mmol) was used in general procedure 5 with 1-acetylpiperazine (0.4 mmol). The product was purified by RP-HPLC to give 6-((4-acetylpiperazin-1-yl)methyl)-N-(4-chloro-3-(3-chlorobenzamido)phenyl)nicotinamide. MS (Q1) 526.0 (M)+
Reaction SMILES: [CH2:1](I)[CH3:2].[OH:4][C:5]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]>>[CH2:1]([O:16][C:13]1[CH:14]=[CH:15][C:5]([OH:4])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2]
Reactant: CCOC(=O)c1cc(O)ccc1O
Reactant: CCI
Product: CCOC(=O)c1cc(OCC)ccc1O
Yield: 69.8 %

Procedure:
Using the general method of Example XXIII Part A, 31.2 g (0.20 mole) of ethyl iodide was reacted with 27.3 g (0.15 mole) of ethyl 2,5-dihydroxybenzoate to provide 22 g of white crystalline ethyl 5-ethoxy-2-hydroxybenzoate, m.p. 64°-66° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C1C(=O)N([Br:25])C(=O)C1.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][Br:25])=[CH:13][N:12]=2)[CH2:7][CH2:8][CH2:9][CH2:10]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(C)cn2)CCCC1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C1(c2ccc(CBr)cn2)CCCC1
Temperature: 0 °C

Procedure:
A mixture containing the product of Step 2, above (44) (1 equiv.), n-bromosuccinimide (1.1 equiv.), CCl4 and a catalytic amount of azobisisobutyronitrile was heated at reflux for 4 hours, cooled to 0° C. and filtered through celite. The residue was washed well with CCl4 and the filtrate was concentrated and chromatographed on silica gel to yield the title compound (45).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.C1COCC1.[CH2:17]([N:24]=[C:25]=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOCC>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH:9][C:25]([NH:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:26])=[O:7])=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccc(Cl)cc1
Reactant: O=C=NCc1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(NCc1ccccc1)NNC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred suspension of 4-chlorobenzoic acid, hydrazide (10.4932 g, 6.1508×10-2 mole) and dry THF (240 mL) was warmed with a heat gun until it was homogenous. To this stirred solution was added benzyl isocyanate (7.8 ml, 6.3×10-2 mole). After stirring overnight at room temperature, the reaction was diluted with ether. The precipitate was collected by filtration, washed with a little ether, and dried by suction Crystallization from ethanol afforded small colorless needles 15.69 g (84%), mp 244°-246° C.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][C:14]2[N:18]=[CH:17][O:16][N:15]=2)=[CH:8][CH:7]=1.[S-:19][C:20]#[N:21].[K+].C(=O)([O-])O.[Na+]>O.C(O)(=O)C.S(=O)(=O)(O)O>[S:19]([C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][C:14]2[N:18]=[CH:17][O:16][N:15]=2)=[CH:8][CH:7]=1)[C:20]#[N:21]
Reactant: Nc1ccc(SCc2ncon2)cc1
Reactant: N#C[S-]
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: N#CSc1ccc(SCc2ncon2)cc1

Procedure:
Sodium nitrite (1.38 g, 0.02 mol) in water (15 ml) was added dropwise to a solution of 3-(4-aminophenylthiomethyl)-1,2,4-oxadiazole, (4.14 g, 0.02 mol) in acetic acid (120 ml) and 2 N sulphuric acid (40 ml) at 0° with stirring. The pale yellow solution thus obtained was added over 30 min. to a stirred mixture of cuprous thiocyanate (6 g) and potassium thiocyanate (60 g) in water (100 ml) at 0°, and the mixture stirred overnight. The mixture was then neutralised with solid sodium hydrogen carbonate and extracted with chloroform to give a yellow solid which was recrystallised from propan-2-ol to give 3-(4-thiocyanatophenylthiomethyl)-1,2,4-oxadiazole, m.p. 78°.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[C:8]([C:12]([O:14]CC)=[O:13])=[CH:7][NH:6][C:5]=2[S:4][N:3]=1>[OH-].[Na+]>[CH3:1][C:2]1[C:10]2[C:9](=[O:11])[C:8]([C:12]([OH:14])=[O:13])=[CH:7][NH:6][C:5]=2[S:4][N:3]=1
Reactant: CCOC(=O)c1c[nH]c2snc(C)c2c1=O
Agent: [Na+]
Agent: [OH-]
Product: Cc1nsc2[nH]cc(C(=O)O)c(=O)c12
Yield: 94.5 %

Procedure:
Ethyl 3-methyl-4-oxo-4,7-dihydroisothiazolo[5,4-b]pyridine-5-carboxylate (18 g, 75.55 mmol) was suspended in 2 N NaOH (100 mL) and the mixture was heated at reflux for 3 h. After hydrolysis was complete, the reaction was filtered to yield a dark brown solid. The solid was washed with water (100 mL) and acetone (50 mL), then air dried to provide 3-methyl-4-oxo-4,7-dihydroisothiazolo[5,4-b]pyridine-5-carboxylic acid as a dark brown powder (15 g, 79% yield). LC/MS m/z 210.8 [M+H]+, retention time 0.67 min (RP-C18, 10-99% CH3CN/0.05% TFA over 3 min). 1H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H), 2.75 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([C:16]([C:18]2[N:22](COCC)[N:21]=[CH:20][CH:19]=2)=[CH2:17])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C(OC(C)C)(C)C>>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([C:16]([C:18]2[NH:22][N:21]=[CH:20][CH:19]=2)=[CH2:17])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: C=C(c1ccc(OCC(=O)OCC)c(Cl)c1Cl)c1ccnn1COCC
Solvent: CC(C)OC(C)C
Product: C=C(c1ccn[nH]1)c1ccc(OCC(=O)OCC)c(Cl)c1Cl
Yield: 86.2 %

Procedure:
1.10 g of ethyl {2,3-dichloro-4-[1-(1-ethoxymethyl-5-pyrazolyl)vinyl]phenoxy}acetate are treated in the same manner as described in Example 35 except that isopropyl ether is used as the crystallization solvent. 0.81 g of ethyl {2,3-dichloro-4-[1-(5-pyrazolyl)vinyl]phenoxy}acetate is obtained as crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:15]=[CH:14]3)=[N:8][CH:9]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:15]=[CH:14]3)=[N:8][CH:9]=1
Reactant: CCOC(=O)c1ccc2cc(Oc3ccc([N+](=O)[O-])cn3)ccc2c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc2cc(Oc3ccc(N)cn3)ccc2c1
Temperature: 50 °C
Reaction time: 7.5 h
Yield: 92.3 %

Procedure:
To a solution of ethyl 6-[(5-nitropyridin-2-yl)oxy]naphthalene-2-carboxylate (23.3 g) in EtOH (460 mL) was added Pd/C (0.367 g) under a H2 atmosphere. Then the reaction mixture was warmed to 50° C., and stirred for 7.5 hours. The reaction mixture was filtered off on celite, and the filtrate was concentrated under reduced pressure. The residual solid was dried under reduced pressure at 60° C. to afford ethyl 6-[(5-aminopyridin-2-yl)oxy]naphthalene-2-carboxylate as a pale brown powder (19.6 g).
Reaction SMILES: C([O:8][C:9](=[O:47])[CH2:10][CH2:11][NH:12][C:13](=[O:46])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21](=[O:45])[C@H:22]([CH2:31][CH2:32][CH2:33][NH:34]C(OCC2C=CC=CC=2)=O)[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:15]=1)C1C=CC=CC=1.C(O)C>[Pd].C(O)(=O)C>[C:9]([OH:47])(=[O:8])[CH3:10].[C:27]([O:26][C:24]([NH:23][C@H:22]([C:21]([NH:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[C:13]([NH:12][CH2:11][CH2:10][C:9]([OH:47])=[O:8])=[O:46])=[O:45])[CH2:31][CH2:32][CH2:33][NH2:34])=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)Nc1cccc(C(=O)NCCC(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](CCCN)C(=O)Nc1cccc(C(=O)NCCC(=O)O)c1
Yield: 178.5 %

Procedure:
500 mg of N-[m-[[N5 -(benzyloxycarbonyl)-N2 -t-butoxycarbonyl-L-ornithyl]amino]benzoyl]-β-alanine benzyl ester, 10 ml of ethanol, 0.05 ml of acetic acid and 125 mg of Pd/C are stirred under hydrogen for 3.5 hours. The reaction mixture is filtered and the filtrate is evaporated in a vacuum. There are obtained 333 mg of N-[m-[[(S)-N2 -(t-butoxycarbonyl)-L-ornithyl]amino]benzoyl]-β-alanine acetate (1:1), [α]D =-18.1° (MeOH, c=0.44%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][CH2:11][CH2:10][NH:9][CH2:8][C:7]=2[CH:13]=1.[C:14](Cl)(=[O:17])[CH:15]=[CH2:16]>C(N(CC)CC)C>[C:14]([N:9]1[CH2:8][C:7]2[CH:13]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[S:12][CH2:11][CH2:10]1)(=[O:17])[CH:15]=[CH2:16]
Reactant: C=CC(=O)Cl
Reactant: COc1ccc2c(c1)CNCCS2
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CCSc2ccc(OC)cc2C1
Yield: 83 %

Procedure:
7-Methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (10.0 g) (refer to preparation examples 1 to 6 as mentioned below), triethylamine (10.2 g) and acryloyl chloride (6.9 g) were reacted in the same manner as in Experimental Example 1 to give 4-acryloyl-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (10.6 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].[F:7][C:8]([F:31])([F:30])[O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:29])[C:18]2[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21](F)=[CH:20][C:19]=2[Cl:28])=[CH:12][CH:11]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:30][C:8]([F:7])([F:31])[O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:29])[C:18]2[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21]([NH:1][CH2:2][C:3]([OH:5])([CH3:6])[CH3:4])=[CH:20][C:19]=2[Cl:28])=[CH:12][CH:11]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: CC(C)(O)CN
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(O)CNc1cc(Cl)c(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of 1-amino-2-methyl-propan-2-ol (184 mg, 2.06 mmol), N-(4-trifluoromethoxy-phenyl)-2-chloro-4-fluoro-5-nitro-benzoic acid amide (650 mg, 1.7 mmol), Cs2CO3 (839 mg, 2.6 mmol) and 10 mL DMF is stirred for 1 h at 50° C., poured into ice water, concentrated and the resulting precipitate is collected by filtration, washed with water and dried.