Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18](=[O:35])[CH2:19][C:20]1[CH:25]=[CH:24][C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][CH:21]=1)[CH3:16]>>[CH2:15]([O:17][C:18](=[O:35])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[NH2:14])=[CH:4][CH:3]=2)=[CH:22][CH:21]=1)[CH3:16]
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3N)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=3)=[C:15]([C:26](OCC)=[O:27])[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH2:31]([CH2:33][NH2:34])[OH:32]>O>[CH2:1]([NH:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:16]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=3)=[C:15]([C:26]([NH:34][CH2:33][CH2:31][OH:32])=[O:27])[N:14]=[N:13]2)=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: NCCO
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)OCC)c2COc2cccc(C)c2)cc1
Solvent: O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NCCO)c2COc2cccc(C)c2)cc1
Temperature: 50 °C

Procedure:
A mixture of ethyl 1-{4-[(ethylamino)carbonyl]phenyl}-5-[(3-methylphenoxy)methyl]-1H-1,2,3-triazole-4-carboxylate (720 mg) obtained in Example 515a) and ethanolamine (2.5 ml) was heated at 50° C. for 14 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform, and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate to ethyl acetate/methanol=95/5) and recrystallized from ethyl acetate to give the title compound as a colorless powder (680 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([C:11](=O)[CH2:12]Br)=[N:8][CH:7]=1)=[O:5])C.[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH3:29])[C:21]([NH2:23])=[S:22])[CH3:16]>>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C:21]2[S:22][CH:12]=[C:11]([C:9]3[S:10][C:6]([C:4]([OH:3])=[O:5])=[CH:7][N:8]=3)[N:23]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH3:29])[CH3:16]
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Reactant: CCOC(=O)c1cnc(C(=O)CBr)s1
Product: CCOc1ccc(-c2nc(-c3ncc(C(=O)O)s3)cs2)cc1OCC

Procedure:
5-Ethoxycarbonyl-2-(α-bromoacetyl)thiazole and 3,4-diethoxythiobenzamide were subjected to the same reaction as in Example 1 and then to the same hydrolysis as in Example 147 to obtain 2-(3,4-diethoxyphenyl)-4-(5-carboxy-2-thiazolyl)thiazole. monoleate in this order. To the solution was added the distilled water for injection to obtain a desired final volume. The resulting solution was filtered through an appropriate filter paper and sterilized. 1 ml of the thus prepared solution was filled into each ampul to prepare an injection.
Reaction SMILES: Br[C@@:2]1([O:40][C@H:39]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[C@H:14]([O:15][CH:16]2[O:33][C@H:32]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[C@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]2[O:18][C:19](=[O:21])[CH3:20])[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:4]1[O:5][C:6](=[O:8])[CH3:7])O.CC1C=C(C)C=C(C)N=1.[Br:55][CH2:56][CH2:57][OH:58]>C(Cl)Cl.FC(F)(F)S([O-])(=O)=O.[Ag+]>[C:6]([O:5][C@@H:4]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:14]([O:15][C@H:16]2[O:33][C@H:32]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[C@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]2[O:18][C:19](=[O:21])[CH3:20])[C@@H:39]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[O:40][C@H:2]1[O:58][CH2:57][CH2:56][Br:55])(=[O:8])[CH3:7]
Reactant: OCCBr
Reactant: CC(=O)OC[C@H]1O[C@@](O)(Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC1O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@H](O[C@@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OCCBr)O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reaction time: 23 h
Yield: 76.2 %

Procedure:
A solution of the crude acetobromo sugar 49 (20.5 g; 29.3 mmol) in dry methylene chloride (100 ml) was added dropwise (ca 20 min) to a cold (-78°) solution of silver trifluoromethanesulfonate (nonpurified, commercial material; 10.3 g; 40 mmol), 2,4,6-tri-methylpyridine (3.6 g; 30 mmol) and 2-bromoethanol (17.5 g; 140 mmol) in methylene chloride (250 ml) under nitrogen. The reaction mixture was stirred in the dark for 23 h during which time it had reached room temperature. The yellowish-white precipitate, that had formed, was removed and the resulting colorless solution was washed consecutively with 1M hydrochloric acid, water, saturated sodium hydrogen carbonate solution and water. Drying (sodium sulfate), filtration and evaporation gave a residue which crystallized spontaneously. Recrystallization from ethyl acetate, followed by evaporation of the mother liquor and recrystallization from methanol, gave a total of 16.6 g (77%) of the title compound 15. Melting point and optical rotation are shown in Table 1 and the 13C- and 1H-NMR data are shown in Table 2 and 3 , respectively.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH:19]1[O:18][CH2:17][CH2:16][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.20 g, 1.0 mmol) (Aldrich Cat. No. 525057), 2-(2-bromoethoxy)tetrahydro-2H-pyran (170 μL, 1.1 mmol) (Aldrich Cat. No. 475394) and potassium carbonate (0.21 g, 1.5 mmol) in acetonitrile (2 mL) was stirred at r.t. overnight. After filtration the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product.
Reaction SMILES: [C:1]([C:3]1[CH:32]=[CH:31][C:6]([C:7]([NH:9][NH:10][C:11](=[O:30])[C@H:12]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([C:25]([F:28])([F:27])[F:26])[C:18]=2[CH3:29])[C@H:13]([OH:15])[CH3:14])=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH3:33][C:34]([Si:37](Cl)([CH3:39])[CH3:38])([CH3:36])[CH3:35].N1C=CN=C1>CN(C=O)C>[Si:37]([O:15][C@H:13]([CH3:14])[C@@H:12]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([C:25]([F:28])([F:27])[F:26])[C:18]=1[CH3:29])[C:11]([NH:10][NH:9][C:7](=[O:8])[C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:32][CH:31]=1)=[O:30])([C:34]([CH3:36])([CH3:35])[CH3:33])([CH3:39])[CH3:38]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)[C@@H](C)O)ccc(C#N)c1C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
The crude material 4-cyano-N′-((2R,3R)-2-(4-cyano-2-methyl-3-(trifluoromethyl)phenylamino)-3-hydroxybutanoyl)benzohydrazide (800 mg, 1.75 mmol) was added to DMF (40 mL), followed by addition of TBDMS-Cl (1.06 g, 7.00 mmol) and imidazole (954 mg, 14.01 mmol) at 0° C. The solution was allowed to stir at 0° C. for 30 min and then at room temperature for overnight. The reaction was quenched with the addition of 200 mL brine and extract with EtOAc. The resulting crude material was chromatographed to get the desired product (640 mg) 1H NMR (400 MHz, acetone-d6, δ in ppm): 9.62 (br s), 7.93 (d, J=9 Hz, 2H), 7.79 (d, J=9 Hz, 2H), 7.55 (d, J=9 Hz, 1H), 6.98 (d, J=9 Hz, 1H), 5.38 (d, J=9 Hz, 1H), 4.41 (m, 1H), 4.18 (m, 1H), 2.25 (m, 3H), 1.31 (d, J=6 Hz, 3H), 0.77 (s, 9H), 0.03 (s, 6H), 0.00 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:17]=O.CC([O-])=O.[Na+].Cl.[NH2:25][OH:26]>CO>[F:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:17]=[N:25][OH:26]
Reactant: NO
Reactant: O=Cc1ccc2c(ncn2C2CCCCO2)c1F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: ON=Cc1ccc2c(ncn2C2CCCCO2)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.1 %

Procedure:
To a solution of 148 (7.7 g, 0.031 mol) in dry MeOH (120 mL) was added NaOAc (3.31 g, 0.0372 moles) and hydroxylamine hydrochloride (2.57 g, 0.0372 mol). The reaction mixture was stirred at RT for 16 h. The solution was concentrated in vacuo, the residue taken up in water and extracted with DCM. The combined organic extracts were washed sequentially with water and brine, dried (Na2SO4), filtered and concentrated in vacuo to afford 5.8 g (71%) of 4-fluoro-1-(tetrahydro-pyran-2-yl)-1H-benzoimidazole-5-carbaldehyde oxime (150) as a white solid which was used without further purification.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([CH:7]=O)[C:4]([CH:9]=[O:10])=[CH:3][CH:2]=1.[C:11]([C:16]1[CH:21]=[CH:20][C:19]([N:22]=C=O)=[CH:18][CH:17]=1)([O:13][CH2:14][CH3:15])=[O:12]>C(Cl)(Cl)Cl>[O:10]=[C:9]1[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH2:7][N:22]1[C:19]1[CH:18]=[CH:17][C:16]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Reactant: O=Cc1ccccc1C=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(N2Cc3ccccc3C2=O)cc1
Temperature: 170 °C

Procedure:
A mixture of o-phthalicdicarboxaldehyde (17.54 g, 0.131 mol) and p-carbethoxyphenylisocyanate (25.0 g, 0.131 mol) is heated in an oil bath at 170° C. for 4.0 hours under nitrogen atmosphere. The hot melt is then slowly poured into CHCl3 (300 ml). The solution is then evaporated to dryness when a solid residue is obtained. The crude 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)benzoic acid, ethyl ester is triturated with isopropyl ether and then recrystallized from CH2Cl2 - isopropyl ether (1:1, 300 ml) to give white solid. Yield 5.07 g (13.8%); mp 182°-184° C.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([O:12][C@@H:13]1[O:39][C@H:38]([CH2:40][O:41][C:42](=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44])[C@@H:30]([O:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[C@H:22]([O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C@H:14]1[O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[N:6][NH:7]2)#[CH:2].I[C:49]1[CH:54]=[CH:53][C:52]([OH:55])=[C:51]([CH3:56])[CH:50]=1>C(N(CC)CC)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[OH:55][C:52]1[CH:53]=[CH:54][C:49]([C:2]#[C:1][C:3]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:4]=2[C:5]([O:12][C@@H:13]2[O:39][C@H:38]([CH2:40][O:41][C:42](=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44])[C@@H:30]([O:31][C:32](=[O:37])[C:33]([CH3:34])([CH3:35])[CH3:36])[C@H:22]([O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C@H:14]2[O:15][C:16](=[O:21])[C:17]([CH3:18])([CH3:19])[CH3:20])=[N:6][NH:7]3)=[CH:50][C:51]=1[CH3:56]
Reactant: C#Cc1cccc2[nH]nc(O[C@@H]3O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]3OC(=O)C(C)(C)C)c12
Reactant: Cc1cc(I)ccc1O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(C#Cc2cccc3[nH]nc(O[C@@H]4O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]4OC(=O)C(C)(C)C)c23)ccc1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
To a solution of 4-ethynyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indazole (66 mg) in triethylamine (1 mL) were added 4-iodo-2-methylphenol (25 mg), tetrakis(triphenylphosphine)palladium (0) (12 mg) and copper (I) iodide (4 mg), and the mixture was stirred at 80° C. under an argon atmosphere overnight. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethylacetate=3/1-2/1-1/1) to give the title compound (47 mg).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]([N:8]([C:10]1[C:11]([Cl:30])=[C:12]([C:26]([Cl:29])=[CH:27][CH:28]=1)[CH2:13][O:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[C:22]([CH3:25])[CH:21]=[CH:20]2)[CH3:9])=[O:7])([OH:3])=O.[NH2:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35]([NH:37][CH3:38])=[O:36].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>ClCCl>[Cl:30][C:11]1[C:10]([N:8]([C:6](=[O:7])[CH2:5][CH2:4][C:1](=[O:3])[NH:31][C:32]2[CH:41]=[CH:40][CH:39]=[C:34]([C:35](=[O:36])[NH:37][CH3:38])[CH:33]=2)[CH3:9])=[CH:28][CH:27]=[C:26]([Cl:29])[C:12]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[C:22]([CH3:25])[CH:21]=[CH:20]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CCC(=O)O)c3Cl)c2n1
Reactant: CNC(=O)c1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CNC(=O)c1cccc(NC(=O)CCC(=O)N(C)c2ccc(Cl)c(COc3cccc4ccc(C)nc34)c2Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.2 %

Procedure:
to amixture of 8-[3-[N-(3-carboxypropionyl)-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (139 mg), 3-amino-N-methylbenzamide (51.3 mg) and anhydrous dichloromethane (4 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (71.5 mg) and 1-hydroxybenzotriazole (54.6 mg). The mixture was stirred for 12 hours at ambient temperature ans washed with water. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was purifed by preparative thin-layer chromatography (chloroform-methanol) followed by pulverization with diethyl ether to give 8-[2,6-dichloro-3-[N-[3-[N-(3-methylcarbamoylphenyl)carbamoyl]propionyl]-N-methylamino]benzyloxy]-2-methylquinoline (103 mg) as an amorphous powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]1([NH:23][OH:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[N+:23]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[O-:24])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: ONC1CCCCC1
Product: [O-][N+](=Cc1ccc(OCc2ccccc2)cc1)C1CCCCC1

Procedure:
The title compound was prepared according to the procedure described in Example 42 using 4-benzyloxybenzaldehyde and N-cyclohexylhydroxylamine. The title compound was obtained in 81.2% yield as slightly yellowish solid, m.p. 129.0° C. (Rf =0.30 on a silica gel plate using hexanes:EtOAc, 1:1, v:v, as an eluant).
Reaction SMILES: [Br:1]C1C=NNC=1.[H-].[Na+].[CH2:9]([O:16][CH2:17][CH2:18]O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1>[Br:1][CH2:18][CH2:17][O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCCOCc1ccccc1
Reactant: Brc1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: BrCCOCc1ccccc1
Reaction time: 0.5 h

Procedure:
4-Bromopyrazole (2.205 g) was dissolved in tetrahydrofuran (20 ml). Under ice cooling, 60% sodium hydride (625 mg) was added thereto followed by stirring. After 30 min, benzyl 2-bromoethyl ether (3.872 g) obtained from 2-benzyloxyethanol in the same manner as the one of Production Example 1 was added thereto and the resultant mixture was stirred at room temperature overnight. Then the reaction solution was partitioned between ethyl acetate and water and the organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (2.287 g) as a colorless oil (yield: 53%).
Reaction SMILES: O[C:2]1([CH2:14][CH2:15][CH2:16][N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]([CH3:13])[CH2:5][CH2:4][CH2:3]1.C(OCC)C.N.[Li]>C(O)C>[CH2:18]([N:17]([CH2:16][CH2:15][CH2:14][CH:2]1[C:8]2[CH2:9][CH:10]=[CH:11][CH2:12][C:7]=2[CH:6]([CH3:13])[CH2:5][CH2:4][CH2:3]1)[CH2:20][CH3:21])[CH3:19]
Reactant: CCN(CC)CCCC1(O)CCCC(C)c2ccccc21
Agent: N
Agent: [Li]
Solvent: CCO
Solvent: CCOCC
Product: CCN(CC)CCCC1CCCC(C)C2=C1CC=CC2
Reaction time: 0.5 h

Procedure:
The crude 5-hydroxy-5-diethylaminopropyl-9-methyl-6,7,8,9-tetrahydro-5H-benzocycloheptene is dissolved in 100 ml. of diethyl ether and added to 500 ml. of liquid ammonia. The solution is treated with 20 g. of lithium in small portions. After 1/2 hr., the mixture is treated slowly dropwise with absolute ethanol until the color discharges completely. After removal of NH3, the residue is cooled, treated with water and extracted with ether. The dried extracts are freed of solvent leaving crude 5-diethylaminopropyl-9-methyl-1,4,6,7,8,9-hexahydro-5H-benzocycloheptene, which is converted to the corresponding tetrol as described hereinbefore.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=O)=[C:24]([CH:28]=[CH2:29])[N:23]=[C:22]3[O:30][CH2:31][CH3:32])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl.[NH2:40][OH:41]>O>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:40][OH:41])=[C:24]([CH:28]=[CH2:29])[N:23]=[C:22]3[O:30][CH2:31][CH3:32])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=Cc1nc(OCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c1C=O
Reactant: NO
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: C=Cc1nc(OCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c1C=NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
Intermediate (17b) (4.3 g, 10 mmol) was dissolved in pyridine (40 mL, 500 mmol). Hydroxylamine hydrochloride (1.7 g, 25 mmol) was added, followed by the addition of water (20 mL, 1000 mmol). The mixture was stirred at room temperature overnight. Water (30 mL) was added and the mixture was stirred for 20 minutes. The precipitant was filtered off and dried to yield intermediate (17c) (3.5 g). MS m/z: [M+H+] calcd for C26H29N3O4, 448.2. found 448.3.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1C=C([CH:10]=[CH:11][CH:12]=1)N)=[O:4].C(I)C.C(=O)([O-])[O-].[Na+].[Na+].[CH2:22]([N:24]([CH2:28][CH3:29])[C:25](=O)[CH3:26])[CH3:23]>O>[CH3:1][O:2][C:3]([NH:5][C:6]1[CH:26]=[C:25]([CH:10]=[CH:11][CH:12]=1)[N:24]([CH2:22][CH3:23])[CH2:28][CH3:29])=[O:4]
Reactant: COC(=O)Nc1cccc(N)c1
Reactant: CCN(CC)C(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCI
Product: CCN(CC)c1cccc(NC(=O)OC)c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of 4.5 g of 3-(methoxycarbonylamino)-aniline, 21.6 g of ethyl iodide, 14.4 g of sodium carbonate, and 90 ml of N,N-diethylacetamide was stirred for 1 hour at 110° C. The reaction mixture obtained was poured into 300 ml of water followed by stirring well and extracted with ethyl acetate. The extract was washed with water, dried by Glauber's salt, and the solvent was distilled off using a rotary evaporator to provide 6.0 g (yield: 100%) of an oily product.
Reaction SMILES: [CH:1]([C@:4]1([C:17]([N:19]2[CH2:24][CH:23]=[C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH:9]C(=O)OC(C)(C)C)[CH2:5]1)([CH3:3])[CH3:2]>Cl.CCOCC>[CH:1]([C@:4]1([C:17]([N:19]2[CH2:20][CH:21]=[C:22]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:23][CH2:24]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@]1(C(=O)N2CC=C(c3ccccc3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOCC
Product: CC(C)[C@]1(C(=O)N2CC=C(c3ccccc3)CC2)CC[C@@H](N)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
tert-Butyl {(1R,3S)-3-isopropyl-3-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-cyclopentyl}carbamate (0.23 g, 0.56 mmol) was dissolved in a 1.0 M solution of HCl in ether (4 mL). After being stirred at room temperature for 2 h, the solution was concentrated to give a colorless oil (170 mg). MS calculated for C20H28N2O: (M+H) 313; found 313.2.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([OH:13])=O)[C@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[S:28]1[C:32]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][N:40]([NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:41][C@H:42]([OH:52])[C@@H:43]([NH2:51])[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]([CH2:39][N:40]([NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:41][C@H:42]([OH:52])[C@@H:43]([NH:51][C:11](=[O:13])[C@H:6]([C@H:7]([CH2:9][CH3:10])[CH3:8])[NH:5][C:3]([O:2][CH3:1])=[O:4])[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: CC(C)(C)OC(=O)NN(Cc1ccc(-c2cncs2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2cncs2)cc1)NC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, 1.36 g (7.2 mmol) of N-methoxycarbonyl-(L)-iso-leucine, 2.59 g (13.5 mmol) of EDC and 1.22 g (9 mmol) of HOBT are dissolved in 20 ml of DMF. After 30 min, 3.79 ml (27 mmol) of TEA are added and a solution of 2.11 g (4.5 mmol) of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-amino-6-phenyl-2-azahexane (Example 2b) in 40 ml of DMF are added dropwise. After 3 hours, the reaction mixture is worked up analogously to Example 2c to form the title compound: m.p: 163-166° C.; Anal. (C33H45N5O6S (0.14 H2O)) calc. C, 61.71, H, 7.11, N, 10.90, S, 4.99, H2O 0.39: found C, 61.61, H, 7.10, N, 10.79, S, 4.76, H2O 0.4; HPLC20-100: tRet=16.0; FAB MS (M+H)+=640.
Reaction SMILES: O=P(Cl)(Cl)Cl.[Br:6][C:7]1[CH:8]=[C:9]([C:19]([O:21][CH3:22])=[O:20])[C:10]2[CH:11]=[CH:12][N:13]([CH:16]([CH3:18])[CH3:17])[C:14]=2[CH:15]=1.[OH-].[Na+].CN([CH:28]=[O:29])C>O>[Br:6][C:7]1[CH:8]=[C:9]([C:19]([O:21][CH3:22])=[O:20])[C:10]2[C:11]([CH:28]=[O:29])=[CH:12][N:13]([CH:16]([CH3:18])[CH3:17])[C:14]=2[CH:15]=1
Reactant: COC(=O)c1cc(Br)cc2c1ccn2C(C)C
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1cc(Br)cc2c1c(C=O)cn2C(C)C
Reaction time: 0.33 h
Yield: 91.3 %

Procedure:
To a stirred solution of DMF (1.04 lit) POCl3 (40.3 g, 263 mmol) was added at 0° C. and stirred for 20 min. Then methyl 6-bromo-1-isopropyl-1H-indole-4-carboxylate (65 g, 219.5 mmol) in DMF (260 mL) was added to the reaction mixture at 0° C. The reaction mixture was stirred at room temperature for 3 h. Diluted the reaction mixture with cold water and adjusted PH˜8 using with 2N NaOH solution, extracted with ethylacetate (4×1 lit). The organic layer washed with cold water, brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford desired product methyl 6-bromo-3-formyl-1-isopropyl-1H-indole-4-carboxylate (65 g, 91.3%). 1H NMR (CDCl3, 400 MHz): δ 1.588 (d, 6H, J=6.8 Hz), 3.994 (s, 3H), 4.634-4.701 (m, 1H), 7.760 (d, 1H, J=1.6 Hz), 7.958 (d, 1H, J=1.6 Hz), 8.122 (s, 1H), 10.446 (s, 1H). LC-MS (ES+) m/z=324.02 (M+H)