Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([N+:16]([O-])=O)[CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].[Cl-].[Na+]>C1COCC1.O.CO>[NH2:16][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14]
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(F)cc1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-fluoro-2-nitrophenylcarbamate (0.34 g) in THF (30 mL) was added a premixed solution of sodium hydrosulfite (2 g) and sodium bicarbonate (1 g) in water (50 mL). MeOH (10 mL) was also added to aid solution of the mixture, which was stirred at room temperature for 30 min, when sodium chloride was added to saturate the solution. The resulting mixture was extracted with EtOAc (2×). The combined organics were dried, filtered and evaporated to yield the titled compound (quant) that was used as such for the next step. 1H-NMR (300 MHz, CDCl3) δ 7.5 (dd, 1H), 6.6 (dd, 1H), 6.5 (m, 1H), 6.4 (br 1H), 4.7 (br 2H), 1.5 (s, 9H) ppm; MH+=227 (minor), 127 (-BOC), 171 (-tBu).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][N:10]([S:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N+:39]([O-:41])=[O:40])(=[O:32])=[O:31])[CH2:11][CH2:12][O:13][C:14]1[CH:19]=[C:18]([C:20](OCC)=[O:21])[N:17]=[C:16]([C:25](OCC)=[O:26])[CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].[Cl-].[Cl-].[Ca+2].O>C(O)C>[OH:26][CH2:25][C:16]1[CH:15]=[C:14]([O:13][CH2:12][CH2:11][N:10]([S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[N+:39]([O-:41])=[O:40])(=[O:31])=[O:32])[CH2:9][CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:19]=[C:18]([CH2:20][OH:21])[N:17]=1
Reactant: CCOC(=O)c1cc(OCCN(CCC(=O)OC(C)(C)C)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc(C(=O)OCC)n1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)CCN(CCOc1cc(CO)nc(CO)c1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 97.5 %

Procedure:
To a solution of 0.8 g of diethyl 4-{2-[(2-tert-butoxycarbonyl-ethyl)-(2-nitro-benzenesulfonyl)-amino]-ethoxy}-pyridine-2,6-dicarboxylate in 80 mL of ethanol were successively added 152 mg of sodium borohydride and 447 mg of CaCl2. The mixture was stirred at room temperature and 20 ml of water were then added at the end of the reaction. The ethanol was removed under reduced pressure, 100 ml of water were added to the residue obtained and the aqueous phase was extracted 3× with EtOAc. The organic phases were combined, washed with saturated NaCl solution, dried over MgSO4 and concentrated under reduced pressure. 670 mg of tert-butyl 3-[[2-(2,6-bis-hydroxymethyl-pyridin-4-yloxy)-ethyl]-(2-nitro-benzenesulfonyl)-amino]-propanoate were obtained. LC/MS (C): tr=3 min; [M+H]+: m/z 512.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24](O)=[O:25])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[N:4]=1)[CH3:2].[N:35]1(C(N2C=CN=C2)=O)[CH:39]=CN=[CH:36]1.CNC>CN(C=O)C>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]([N:35]([CH3:39])[CH3:36])=[O:25])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)O)ccn34)c12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: CN(C)C=O
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)N(C)C)ccn34)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.4 %

Procedure:
To 3-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-ylcarbamoyl) imidazo[1,2-a]pyridine-7-carboxylic acid (26 mg, 0.057 mmol; prepared as in Example 28, step A) in DMF (2 mL) was added di(1H-imidazol-1-yl)methanone (14 mg, 0.086 mmol). The reaction mixture was stirred at ambient temperature for 1 hour. Dimethylamine (286 μL, 0.57 mmol) was added to the reaction mixture. The reaction vial was sealed and the mixture was heated at 70° C. for 2 hours. The mixture was cooled to ambient temperature. The DMF was removed under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH 10:1) to provide the final product (10 mg). MS (ES+APCI) m/z=482 (M+H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[NH:10][C:4]=2[CH:3]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O.C(OCC)(=O)C.[Cu]I>[Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[N:10]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=3)[C:4]=2[CH:3]=1
Reactant: Cc1ccc(Br)nc1
Reactant: Cn1cc(-c2cc3cnc(Br)cc3[nH]2)cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(-n2c(-c3cnn(C)c3)cc3cnc(Br)cc32)nc1
Temperature: 210 °C
Yield: 46.6 %

Procedure:
6-Bromo-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine (Preparation 22, 84 mg 0.303 mmole) and 2-bromo-5-methylpyridine (78 mg, 0.45 mmole) were dissolved in DMA (2.1 ml) and potassium carbonate (60 mg, 0.42 mmole) and copper(I) iodide (12 mg, 0.066 mmole) were added. The reaction was placed under argon and heated by microwave at 210° C. for 60 minutes. Further 2-bromo-5-methylpyridine (49 mg) and potassium carbonate (40 mg) were added and the reaction again heated at 210° C. under microwave irradiation for 60 minutes. The reaction was taken up in ethyl acetate (30 mL) and the solution washed with water (3×10 mL) and brine. The aqueous was filtered through Celite and backwashed with ethyl acetate (10 mL). The combined organic layers were dried and concentrated in vacuo. The residue was purified using preparative TLC eluting with ethyl acetate to afford the title compound 52 mg (46%). 1H-NMR (CDCl3, 500 MHz): 2.48 (s, 3H), 3.88 (s, 3H), 6.70 (d, J=0.95 Hz, 1H), 7.09 (d, J=7.88 Hz, 1H), 7.24 (m, 1H), 7.25 (s, 1H), 7.44 (t, J=0.95 Hz, 1H), 7.66 (m, 1H), 8.53 (m, 1H), 8.65 (d, J=0.95 Hz, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([S:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[N:10][NH:11]2)=[CH:7][CH:6]=1.[N-:27]=[N+:28]=[N-:29].[Na+]>CS(C)=O.O>[N:27]([CH2:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([S:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[N:10][NH:11]2)=[CH:7][CH:6]=1)=[N+:28]=[N-:29]
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2cc(OCCCl)ccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCCOc1ccc2c(S(=O)(=O)c3cccc4ccccc34)n[nH]c2c1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 6-(2-chloro-ethoxy)-3-(naphthalene-1-sulfonyl)-1-H-indazole (0.19 g, 0.5 mmoles) and sodium azide (0.04 g, 0.62 mmoles) in DMSO (2 mL) was stirred together in a round bottom flask under nitrogen at 90° C. for 3 hours. Reaction mixture was cooled to room temperature, diluted with water, extracted with EtOAC, washed with water (2×), brine (1×), dried over Na2SO4, and concentrated under vacuum. Crude compound was purified by normal phase HPLC using as eluent 40% EtOAc/hexane to afford the title compound as an off white solid (0.17 g, 0.45 mmoles).
Reaction SMILES: [CH2:1]([CH:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)[OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH3:15][C:12]1[CH:13]=[CH:14][C:9]([C:7](=[O:8])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:10][CH:11]=1
Reactant: CCCCCCC(O)c1ccc(C)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCCCCCC(=O)c1ccc(C)cc1
Reaction time: 3 h

Procedure:
To a stirred solution of α-hexyl-4-methyl-benzenemethanol (2.10 g, 10.2 mmol.) in anhydrous dichloromethane (45 mL) under an atmosphere of dry nitrogen was added pyridinium chlorochromate (3.08 g, 14.3 mmol., 1.4 eq.). Stirring was continued at room temperature for 3 hours after which time analysis by thin layer chromatography revealed complete conversion of the starting alcohol. Following evaporation of the reaction solvent the desired ketone (1.929 g, 93%) was isolated by flash chromatography on silica gel, eluting with hexane-ethyl acetate (4:1). 1H nmr (200 MHz, CDCl3) 0.86-1.76 (m, 3H, (CH2)5CH3), 2.41 (s, 3H, ArCH3), 2.93 (t, J=3.6 Hz, 2H, COCH2), 7.25 (d, J=4.2 Hz, 2H, 2×ArH), 7.86 (d, J=4.2 Hz, 2H, 2×ArH).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:21][CH3:22])=[C:5]([CH:9]([CH2:19][CH3:20])[CH2:10][C:11]([C:15]([F:18])([F:17])[F:16])([OH:14])[CH2:12][OH:13])[CH:6]=[CH:7][CH:8]=1)[CH3:2].C(C1C(OC)=C(C(C)C(C)C(C(F)(F)F)(O)CO)C=CC=1)C.C1(O)C=CC=CC=1.[NH4+].[Cl-]>>[CH2:1]([C:3]1[C:4]([O:21][CH3:22])=[C:5]([CH:9]([CH2:19][CH3:20])[CH2:10][C:11]([OH:14])([C:15]([F:16])([F:18])[F:17])[CH:12]=[O:13])[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1cccc(C(CC)CC(O)(CO)C(F)(F)F)c1OC
Agent: CCc1cccc(C(C)C(C)C(O)(CO)C(F)(F)F)c1OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: Oc1ccccc1
Product: CCc1cccc(C(CC)CC(O)(C=O)C(F)(F)F)c1OC
Temperature: 25 °C

Procedure:
2.28 (7.12 mmol) of a mixture of 4-(3-ethyl-2-methoxyphenyl)-2-(trifluoromethyl)-hexane-1,2-diol and 4-(3-ethyl-2-methoxyphenyl)-3-methyl-2-(trifluoromethyl)-pentane-1,2-diol (prepared in analogy to the sequence described in Example 110: acetylation of the corresponding phenol, Fries displacement of the acetyl group, etherification of the phenol, Wittig reaction, ene reaction, reduction of the ester to the alcohol) are reacted conventionally with SO3/pyridine complex (3.4 g, 21.35 mmol). After three-hour stirring at room temperature the reaction mixture is poured onto a mixture of saturated NH4Cl solution and ice. It is extracted three times with diethyl ether. The combined organic extracts are washed twice with brine and dried (Na2SO4). Following removal of the solvent on a rotary evaporator, the residue is purified by means of chromatography. (silica gel, eluent: hexane/ethyl acetate). This gives 2.07 g (91.4%) of a mixture of the two aldehydes.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[O:4][CH2:3]1.C(O)(=O)C.[CH2:26]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47](=O)[C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:38][CH2:37]1)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([BH3-])#N.[Na+]>C(O)C>[CH2:26]([O:33][C:34]([N:36]1[CH2:37][CH2:38][CH:39]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C@@H:47]([NH:1][C@@H:2]2[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]3[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=3[O:4][CH2:3]2)[C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:40][CH2:41]1)=[O:35])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)COc2ccccc21
Reactant: CCOC(=O)C(=O)CCCCCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)[C@@H](CCCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Reaction time: 0.17 h
Yield: 6.4 %

Procedure:
A mixture of tert-butyl 3(S)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (2.4 g), ethanol (30 ml), acetic acid (0.5 g), ethyl 7-(1-benzyloxycarbonyl-4-piperidyl)-2-oxoheptanoate (3.2 g) and molecular sieves 3A (10 g) is stirred for 10 minutes. To the stirred mixture is added dropwise a solution of sodium cyanoborohydride (0.51 g) in ethanol (50 ml) for 3 hours at room temperature. After standing overnight at room temperature, the mixture is concentrated in vacuo and diluted with a mixture of water (50 ml) and ethyl acetate (200 ml). The resulting mixture is agitated thoroughly and filtered. The ethyl acetate layer is washed successively with 0.1N hydrochloric acid, 0.1N sodium hydroxide solution and water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue is chromatographed on silica gel using hexane-ethyl acetate (2:1) as an eluent. Evaporation of the first fraction affords tert-butyl 3(S)-[6(1-benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylhexyl]amino-4-oxo-2,3,4,5 -tetrahydro-1,5-benzoxazepine-5-acetate (0.35 g) as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[S:11][C:10]1([C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([CH2:48][C:49]2[CH:58]=[CH:57][C:52]3[O:53][CH2:54][CH2:55][O:56][C:51]=3[CH:50]=2)[CH:42]=1)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>ClCCl.C(#N)C>[Cl:47][C:44]1[CH:45]=[CH:46][C:41]([C@H:10]2[C@H:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:13]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[S:11]2)=[CH:42][C:43]=1[CH2:48][C:49]1[CH:58]=[CH:57][C:52]2[O:53][CH2:54][CH2:55][O:56][C:51]=2[CH:50]=1
Reactant: OC1(c2ccc(Cl)c(Cc3ccc4c(c3)OCCO4)c2)S[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CC#N
Solvent: CCOCC
Product: Clc1ccc([C@@H]2S[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc2c(c1)OCCO2
Temperature: 0 °C
Yield: 54 %

Procedure:
To a stirred −15° C. solution of lactol (125, 410 mg, 0.50 mmol) in dichloromethane/acetonitrile (4 mL/4 mL) was added triethylsilane (0.49 mL, 3.02 mmol) followed by boron trifluoride diethyl etherate (0.26 mL, 2.01 mmol) at a rate such that the reaction temperature was maintained between −15 and 0° C. The solution was allowed to warm to 0° C. over 0.5 h prior to quenching with saturated sodium bicarbonate solution. After removal of organic volatiles under a reduced pressure, the residue was partitioned between ethyl acetate and water. Following extraction of the aqueous layer with ethyl acetate, the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (silica gel, 3 to 25% ethyl acetate in hexane) to yield the title compound (126, 215 mg, 0.27 mmol, 53%) as a white solid.
Reaction SMILES: CN(C1C=CC=CN=1)C.Cl.C(N=C=NCCCN(C)C)C.[CH2:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][CH:32]=1)[CH:23]=[CH2:24].[CH2:40]([O:48][C:49]1[CH:72]=[CH:71][C:52]([C:53]([O:55][C:56]2[CH:68]=[CH:67][C:66]3[C:65]4[C:60](=[CH:61][C:62](O)=[CH:63][CH:64]=4)[CH:59]([CH3:70])[C:58]=3[CH:57]=2)=[O:54])=[CH:51][CH:50]=1)[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>O.C(Cl)Cl>[CH2:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([O:37][C:62]2[CH:63]=[CH:64][C:65]3[C:66]4[C:58](=[CH:57][C:56]([O:55][C:53](=[O:54])[C:52]5[CH:51]=[CH:50][C:49]([O:48][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[CH:72][CH:71]=5)=[CH:68][CH:67]=4)[CH:59]([CH3:70])[C:60]=3[CH:61]=2)=[O:36])=[CH:33][CH:32]=1)[CH:23]=[CH2:24]
Reactant: CCCCCCCCOc1ccc(C(=O)Oc2ccc3c(c2)C(C)c2cc(O)ccc2-3)cc1
Reactant: C=CCOCCCCOc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: C=CCOCCCCOc1ccc(C(=O)Oc2ccc3c(c2)C(C)c2cc(OC(=O)c4ccc(OCCCCCCCC)cc4)ccc2-3)cc1
Temperature: 5 °C
Reaction time: 12 h
Yield: 22 %

Procedure:
Dimethylaminopyridine 0.01 g and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride 0.8 g were added to a methylene chloride (50 ml) solution of 4-(4-allyloxybutyloxy)benzoic acid 0.84 g and 2-(4-octyloxybenzoyloxy)-7-hydroxy-9-methylfluorene (J1) 1.5 g while maintaining 5° C., and the mixture was further stirred at room temperature for 12 hours. Water 50 ml was added thereto, and the resulting organic layer was dried on anhydrous magnesium sulfate. A residue obtained by distilling the solvent off was refined by silica gel column chromatography to obtain 0.5 g of 2-[4-(4-allyloxybutyloxy)benzoyloxy]-7-(4-octyloxybenzoyloxy)-9-methylfluorene (J2).
Reaction SMILES: [C:1]([NH:3][C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[NH:5])#[N:2].Cl.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:20][NH2:21]>C1(C)C=C(C)C=C(C)C=1>[ClH:16].[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:20][NH:21][C:1]([NH:3][C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[NH:5])=[NH:2]
Reactant: CCCCCCCCNC(=N)NC#N
Reactant: NCc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: Cc1cc(C)cc(C)c1
Product: CCCCCCCCNC(=N)NC(=N)NCc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 144.6 %

Procedure:
To 20 g of N1 -cyano-N3 -octyl-guanidine and 20.2 g of 3,4-dichlorobenzylamine hydrochloride, 200 ml of mesitylene was added, which was heated and refluxed for 1.5 hours. Returning to room temperature after reaction, mesitylene was removed. To the residue, 200 ml of 10% ethanol aqueous solution was added, which was heated, and stirred for 3 hours at room temperature to be solidified. It was filtered off, and washed with 10% ethanol solution, water and isopropylether in turn, and 28.1 g of rough product was obtained. It was recrystallized in ethyl acetate, and 22.1 g of the captioned compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[O:6][CH:5]=[C:4]([C:7](Cl)=[O:8])[CH:3]=1.[OH-].[NH4+:11]>C1C=CC=CC=1>[CH3:1][C:2]1[O:6][CH:5]=[C:4]([C:7]([NH2:11])=[O:8])[CH:3]=1
Reactant: [NH4+]
Reactant: Cc1cc(C(=O)Cl)co1
Agent: [OH-]
Solvent: c1ccccc1
Product: Cc1cc(C(N)=O)co1
Reaction time: 3 h

Procedure:
24.7 g (171 mmol) of 5-methylfuran-3-carbonyl chloride were added dropwise to a stirred mixture of 80 ml of a 25% strength ammonium hydroxide solution and 80 ml of benzene at 25-40° C. The resulting mixture was stirred for 3 h and left to stand overnight. The next day, white crystals of the amide were filtered off, washed with cold water and dried to constant weight at 40-45° C. Yield 19.7 g (158 mmol, 92%), melting point 158° C.
Reaction SMILES: C1C=CC=CC=1.[Br:7]Br.P(Br)(Br)Br.[C:13]1(=[O:20])[NH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[Br:7][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:13]1=[O:20]
Reactant: BrBr
Reactant: O=C1CCCCCN1
Agent: BrP(Br)Br
Solvent: c1ccccc1
Product: O=C1NCCCCC1Br
Temperature: 10 °C
Reaction time: 1 h

Procedure:
A benzene (50 g; manufactured by JUNSEI CHEMICAL Co., Ltd.) solution in which 240 g (1.5 mol) of bromine (manufactured by JUNSEI CHEMICAL Co., Ltd.) were dissolved was cooled with ice to 10° C. To the cooled solution, 450 g (1.6 mol) of 90% phosphorus tribromide (manufactured by Wako Pure Chemical Industries Ltd.) were added while the temperature of the reaction solution was maintained at 10° C. or less, and the resultant reaction solution was stirred for 60 minutes. Into the reaction solution, a benzene (220 g) solution in which 85 g (0.75 mol) of commercially available 6-hexanolactam (trade name: ε-caprolactam; manufactured by Tokyo Chemical Industry Co., Ltd.) were dissolved was added dropwise through a dropping funnel over 30 minutes while maintaining the temperature of the reaction solution at 10° C. or less.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH2:23][C@@H:24]5[CH2:28][CH2:27][NH:26][CH2:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.Br[CH2:37][C:38]([NH2:40])=[O:39]>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH2:23][C@@H:24]5[CH2:28][CH2:27][N:26]([CH2:37][C:38]([NH2:40])=[O:39])[CH2:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:33])[F:34])[CH:3]=1
Reactant: NC(=O)CBr
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@@H]1CCNC1
Product: NC(=O)CN1CC[C@@H](CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)C1

Procedure:
2-[(3R)-3-{[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methyl}pyrrolidin-1-yl]acetamide was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(3R)-pyrrolidin-3-ylmethyl]-1,3-thiazolidine-2,4-dione and 2-bromoacetamide following General Procedure H.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:21]=[C:20]2[C:15]([C:16]([C:22]3[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)=[N:25][N:24]4[CH2:33][CH2:34][CH2:35][C:23]=34)=[CH:17][CH:18]=[N:19]2)=[CH:14][CH:13]=1)(C)(C)C>FC(F)(F)C(O)=O>[CH3:6][NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:21]=[C:20]2[C:15]([C:16]([C:22]3[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)=[N:25][N:24]4[CH2:33][CH2:34][CH2:35][C:23]=34)=[CH:17][CH:18]=[N:19]2)=[CH:14][CH:13]=1
Reactant: CN(CCCOc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CNCCCOc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1

Procedure:
A solution of methyl-{3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-propyl}-carbamic acid tert-butyl ester (100 mg, 0.2 mmol) in trifluoracetic acid (3 mL) is stirred at room temperature for 6 h. The mixture is concentrated in vacuo and traces of trifluoroacetic acid removed by repeated evaporation with chloroform. The residue is placed on an SCX column and washed with water, methanol, and 7 N ammonia in methanol. Concentration of the appropriate fraction yields the title compound, 40 mg (50%), as yellow oil.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:20]([OH:25])(=[O:24])[CH:21]([CH3:23])O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[CH:1]1([CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH:21]([C:20]([OH:25])=[O:24])[CH3:23])=[O:18])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)Cc1ccc(NCCC2CCCCC2)cc1
Reactant: CC(O)C(=O)O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: CC(OC(=O)Cc1ccc(NCCC2CCCCC2)cc1)C(=O)O

Procedure:
A flask containing 10.0 g. 4-(2-cyclohexylethylamino)phenylacetic acid, 3.3 g. lactic acid, 500 mg. toluenesulfonic acid and 500 ml. toluene equipped with a Soxhlet extractor charged with activated 4 A Linde molecular sieves. The solution is refluxed for 24 hours during which time the Soxhlet extractor is charged twice more with fresh sieves. The hot solution is filtered and left to cool, whereupon 1-carboxyethyl 4-(2-cyclohexylethylamino)phenylacetate separates as off-white crystals.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]3[CH:10]=[C:11]([C@H:13]4[CH2:18][CH2:17][C@H:16]([O:19][CH2:20][C:21](=[O:23])[CH3:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.[BH4-].[Na+]>C(O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]3[CH:10]=[C:11]([C@H:13]4[CH2:18][CH2:17][C@H:16]([O:19][CH2:20][CH:21]([OH:23])[CH3:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)CO[C@H]1CC[C@H](c2cc3ccc(OCC4CC4)cc3o2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)CO[C@H]1CC[C@H](c2cc3ccc(OCC4CC4)cc3o2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1-({trans-4-[6-(cyclopropylmethoxy)-1-benzofuran-2-yl]cyclohexyl}oxy)propan-2-one (556 mg) in ethanol (10 mL) was added sodium borohydride (123 mg) under ice-cooling. The mixture was stirred at 0° C. for 1 hr and extracted with ethyl acetate and 1M hydrochloric acid. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (555 mg).