Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:17])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][C:3]1([CH3:6])[CH2:5][CH2:4]1.[CH3:18][S:19]([N:22]1[CH2:27][CH:26]=[C:25]([C:28]2[CH:29]=[C:30]3[CH2:44][C:35]4([CH2:43][C:37]5([CH2:42][CH2:41][NH:40][CH2:39][CH2:38]5)[CH2:36]4)[O:34][C:31]3=[CH:32][N:33]=2)[CH2:24][CH2:23]1)(=[O:21])=[O:20].C(N(CC)CC)C.O1CCCC1>O>[CH3:18][S:19]([N:22]1[CH2:23][CH:24]=[C:25]([C:28]2[CH:29]=[C:30]3[CH2:44][C:35]4([CH2:36][C:37]5([CH2:38][CH2:39][N:40]([C:1]([O:2][C:3]6([CH3:6])[CH2:4][CH2:5]6)=[O:17])[CH2:41][CH2:42]5)[CH2:43]4)[O:34][C:31]3=[CH:32][N:33]=2)[CH2:26][CH2:27]1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCNCC3)C2)CC1
Reactant: CC1(OC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(OC(=O)N2CCC3(CC2)CC2(Cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4O2)C3)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1-Methylcyclopropyl 4-nitro-phenyl carbonate (58 mg) is added to a mixture of 5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (HCl salt; 66 mg), triethylamine (65 μL), and tetrahydrofuran (5 mL) at room temperature. The solution is stirred at 60° C. overnight. Water is added and the resulting mixture is extracted with ethyl acetate. The combined extracts are dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 4:1→1:4) to give the title compound. LC (method 1): tR=1.02 min; Mass spectrum (ESI+): m/z=488 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([S:6]([CH2:8][C:9]([OH:11])=O)=[O:7])=[CH:2]1.[NH2:12][CH:13]1[C:30](=[O:31])[N:15]2[C:16]([C:27]([OH:29])=[O:28])=[C:17]([CH2:20][S:21][C:22]3[NH:26][N:25]=[N:24][CH:23]=3)[CH2:18][S:19][C@H:14]12>>[S:1]1[CH:5]=[CH:4][C:3]([S:6]([CH2:8][C:9]([NH:12][CH:13]2[C:30](=[O:31])[N:15]3[C:16]([C:27]([OH:29])=[O:28])=[C:17]([CH2:20][S:21][C:22]4[NH:26][N:25]=[N:24][CH:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])=[O:7])=[CH:2]1
Reactant: O=C(O)CS(=O)c1ccsc1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3cnn[nH]3)CS[C@H]12
Product: O=C(CS(=O)c1ccsc1)NC1C(=O)N2C(C(=O)O)=C(CSc3cnn[nH]3)CS[C@H]12

Procedure:
380 mg. of 3-thienylsulfinylacetic acid of the R form and 7-amino-3-(1H-1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 369 mg. of 7-(3-thienylsulfinylacetamido)-3-(1H-1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid of the R form were obtained.
Reaction SMILES: C(O[C:6](=[O:35])[NH:7][CH2:8][C:9]1[C:10]([NH2:34])=[N:11][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=3[Cl:33])[CH2:22][CH2:21]2)=[CH:13][CH:14]=1)(C)(C)C.Cl.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[Cl:33][C:27]1[C:28]([Cl:32])=[CH:29][CH:30]=[CH:31][C:26]=1[N:23]1[CH2:22][CH2:21][N:20]([CH2:19][CH2:18][CH2:17][CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]3[CH2:8][NH:7][C:6](=[O:35])[NH:34][C:10]=3[N:11]=2)[CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)NCc1ccc(OCCCCN2CCN(c3cccc(Cl)c3Cl)CC2)nc1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C1NCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2N1
Temperature: 25 °C
Yield: 94 %

Procedure:
To a solution of crude (2-amino-6-{4-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-butoxy}-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester in dioxane (15 mL) was added 3 N HCl (15 mL). The resulting mixture was refluxed for 2 hours, cooled to RT, then neutralized with saturated Na2CO3. The neutralized solution was extracted with EtOAc and the organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound as a brown oil (0.367 g, 94% over two steps). 1H NMR (400 MHz, CDCl3): δ 7.21–7.10 (m, 3H), 7.00–6.91 (m, 1H), 6.00 (d, 1H), 5.40–5.21 (br s, 2H), 4.12 (t, 2H), 3.82 (s, 2H), 3.71 (s, 2H), 3.19–2.98 (m, 4H), 2.81–2.55 (m, 4H), 2.50 (t, 2H), 1.91–1.43 (m, 4H). MS ES: m/z=424.00, 425.99.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[C:11]([CH2:13][N:14]2[C:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]4=[O:33])=[N:24][CH:25]=3)=[CH:17][N:16]=[CH:15]2)[CH:10]=[CH:9][C:6]=1[C:7]#[N:8].[Cl:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38](Cl)=[O:39]>CN(C=O)C>[Cl:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38]([NH:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[C:11]([CH2:13][N:14]2[C:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]4=[O:33])=[N:24][CH:25]=3)=[CH:17][N:16]=[CH:15]2)[CH:10]=[CH:9][C:6]=1[C:7]#[N:8])=[O:39]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: N#Cc1ccc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)cc1OCCN
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)cc1OCCNC(=O)c1cccc(Cl)c1
Reaction time: 2 h

Procedure:
2-(2-Amino-ethoxy)-4-[5-(5-chloro-2-oxo-2H-[1,2']bipyridinyl-5'-ylmethyl)-imidazol-1-ylmethyl]-benzonitrile (L-824,459, 75 mg, 0.16 mmol) was dissolved in DMF (800 μl) and treated with 3-chlorobenzoylchloride (20 μl, 0.18 mmol). The reaction mixture was stirred at room temp. for 2 hours. The solvent was removed in vacuo and the crude product purified by flash chromatography [4% MeOH(NH4OH 5%)/CH2Cl2 ] to yield the final product.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10](Cl)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:9])([CH3:8])[CH3:7].[CH2:24]([NH:26][CH2:27][CH2:28][OH:29])[CH3:25]>C(Cl)Cl>[Si:10]([O:29][CH2:28][CH2:27][NH:26][CH2:24][CH3:25])([C:6]([CH3:9])([CH3:8])[CH3:7])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CCNCCO
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CCNCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
Imidazole (1.53 g, 22.44 mmol) and a solution of tert-butylchlorodiphenylsilane (4.63 g, 16.83 mmol) in DCM (10 ml) were added sequentially to a solution of 2-(ethylamino)ethanol (1.099 ml, 11.22 mmol) in DCM (30 ml) and the resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with DCM and washed with 1N aq. NaHSO4 and saturated aq. NaHCO3. The organic layer was dried (Na2SO4), concentrated under reduced pressure to give a residue which was purified by column chromatography (ISCO, 40 g silica gel column, eluting with 0→100% EtOAc/hexanes) to provide the title compound (2.95 g, yield: 80) %).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([NH:13][C:14](=[O:22])OC3C=CC=CC=3)=[CH:11][C:10]([C:23]([F:26])([F:25])[F:24])=[N:9]2)=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH2:40][CH2:41][O:42][CH3:43])[N:35]=[CH:34][N:33]=[C:32]2[S:44][C:45]1[CH:46]=[C:47]([CH:49]=[CH:50][CH:51]=1)[NH2:48]>CN(C)C1C=CN=CC=1.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([NH:13][C:14]([NH:48][C:47]3[CH:49]=[CH:50][CH:51]=[C:45]([S:44][C:32]4[C:31]5[C:36](=[CH:37][C:38]([O:39][CH2:40][CH2:41][O:42][CH3:43])=[C:29]([O:28][CH3:27])[CH:30]=5)[N:35]=[CH:34][N:33]=4)[CH:46]=3)=[O:22])=[CH:11][C:10]([C:23]([F:24])([F:25])[F:26])=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(Nc1cc(C(F)(F)F)nn1-c1ccc(F)cc1)Oc1ccccc1
Reactant: COCCOc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COCCOc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(F)(F)F)nn4-c4ccc(F)cc4)c3)c2cc1OC
Yield: 25 %

Procedure:
The title compound was prepared as described in Example 162B, using phenyl 1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate described in Example 171B (0.146 g, 0.4 mmol), 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described in Example 231A (0.143 g, 0.4 mmol), and 4-(dimethylamino)pyridine (0.025 g) in THF (6 mL), to afford 1-[1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}urea as solid (0.062 g, 25%). 1H NMR (300 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.79 (s, 1H), 8.68 (d, 1H), 7.78 (s, 1H), 7.68 (m, 2H), 7.45 (m, 4H), 7.37 (s, 1H), 7.33 (s, 1H), 7.27 (d, 1H), 6.87 (s, 1H), 4.33 (m, 2H), 4.02 (s, 3H), 3.76 (m, 2H), 3.34 (s, 3H); LC-MS (ESI) m/z 629 (M+H)+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH:10]1[CH2:20][CH2:19][CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:11]1>>[CH2:17]([O:16][C:14]([CH:13]1[CH2:19][CH2:20][N:10]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:11][CH2:12]1)=[O:15])[CH3:18]
Reactant: N#Cc1ccccc1F
Reactant: CCOC(=O)C1CCNCC1
Product: CCOC(=O)C1CCN(c2ccccc2C#N)CC1

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 2-fluorobenzonitrile and ethyl isonipecotate.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[CH3:11][NH2:12].S([O-])([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>O1CCCC1.ClCCl.CO>[CH3:11][NH:12][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CN
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: CNCc1ccc(C#N)cc1
Reaction time: 1 h

Procedure:
4-Cyanobenzaldehyde (12.0 g, 92.0 mmol), methylamine (69 ml of a 2.0M solution in tetrahydrofuran, 137 mmol) and magnesium sulphate (45 g) were stirred in dichloromethane (300 ml) at room temperature for 5 days. The mixture was filtered and the filtrate was concentrated under reduced pressure to leave a yellow oil. The oil was dissolved in methanol (200 ml) and sodium borohydride (4.10 g, 109 mmol) was added cautiously with vigorous stirring. Once the addition was complete the reaction was stirred for 1 hour and the mixture was concentrated under reduced pressure. The residue was dissolved in 1M aqueous sodium hydroxide solution (200 ml) and the mixture was stirred at room temperature for 1 hour. The resulting solution was extracted with dichloromethane (2×200 ml) and the combined organic phases were dried over magnesium sulphate, filtered and concentrated under reduced pressure to provide the title compound (13.4 g) as a pale yellow oil.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7]([NH2:9])=O)=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:10]1([C:1]2[CH:2]=[CH:3][C:4]([CH2:7][NH2:9])=[CH:5][CH:6]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NC(=O)c1ccc(-c2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc(-c2ccccc2)cc1

Procedure:
To a solution of 4-biphenylcarboxamide (Aldrich) (0.025 mole) in 150 mL of THF cooled to 10° C. was added a solution of 1.5 eq of LAH (1M in THF) dropwise. The reaction mixture turned from a white slurry to a green homogenous solution and then to a yellow homogeneous solution. The reaction was then quenched with 2.5 mL of 1N NaOH. The mixture was then filtered through Hyflo and extracted with ethyl acetate. The organic layer was then washed with 1N HCl. The pH of the resulting aqueous layer was adjusted to about 9 with 1N NaOH and extracted with ethyl acetate. The organic extracts were washed with water and brine, and then dried over Na2SO4, filtered and concentrated to give 4-(phenyl)benzyl amine as a white solid.
Reaction SMILES: CC(C)([O-])C.[Na+].[CH3:7][C:8]1[NH:9][C:10]2[C:15]([C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1)=[CH:14][C:13]([CH3:28])=[CH:12][CH:11]=2.Br[CH2:30][C:31]([O:33]CC)=[O:32]>C1COCC1.O.[OH-].[Na+]>[CH3:7][C:8]1[N:9]([CH2:30][C:31]([OH:33])=[O:32])[C:10]2[C:15]([C:16]=1[O:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=1)=[CH:14][C:13]([CH3:28])=[CH:12][CH:11]=2
Reactant: Cc1ccc2[nH]c(C)c(Oc3ccc(S(C)(=O)=O)cc3)c2c1
Reactant: CCOC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2c(c1)c(Oc1ccc(S(C)(=O)=O)cc1)c(C)n2CC(=O)O
Reaction time: 0.17 h

Procedure:
Sodium t-butoxide (220 mg) was added to a solution of the product from step (iii) (600 mg) in THF (20 ml) and stirred for 10 min. Ethyl bromoacetate (250 μl) was added and the reaction stirred for a further 1 h. The mixture was then diluted with water (10 ml), 1M aqueous sodium hydroxide (5 ml) added and stirred for 3 h. The mixture was extracted with EtOAc, washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified using reverse phase preparative chromatography (eluent MeCN/NH3(aq)) to give the title compound. Yield 450 mg.
Reaction SMILES: [CH:1]([Si:4]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[N:5]1[CH:9]=[CH:8][CH:7]=[CH:6]1)([CH3:3])[CH3:2].[Br:16]NC(=O)CCC(N)=O>C1COCC1>[Br:16][C:7]1[CH:8]=[CH:9][N:5]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:10]([CH3:12])[CH3:11])[CH:13]([CH3:15])[CH3:14])[CH:6]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cccc1
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc(Br)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 58.6 %

Procedure:
To a solution of 1-triisoproylsilyl-pyrrole (13.2 g, 0.059 mol) in 250 mL of THF at -78° C. was added 10.45 g (0.0587 mol) of N-bromosuccinamide (NBS), and the mixture was stirred at -78° C. for 3 h. The reaction mixture was warmed to room temperature and concentrated in vacuo, and the resulting residue in hexane was stirred overnight. The hexane solution was filtered through alumina eluting with hexane, the eluate was concentrated in vacuo, and the residue was distilled (b.p. 107°-108° C./0.2 mm) to afford 10.4 g (58.4%) of 3-bromo-1-triisopropylsilyl-pyrrole.
Reaction SMILES: [CH2:1]([N:5]([CH2:33][CH2:34][CH2:35][CH3:36])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[NH:11][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].Cl[CH2:38][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>>[CH2:33]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])[N:11]([CH2:38][CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[CH:12]=1)=[O:7])[CH2:34][CH2:35][CH3:36]
Reactant: CCCCN(CCCC)C(=O)c1c[nH]c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Reactant: ClCCCN1CCOCC1
Product: CCCCN(CCCC)C(=O)c1cn(CCCN2CCOCC2)c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 274A, 3-benzyl 1-methyl 4-(4-(dibutylcarbamoyl)-1H-imidazol-2-yl)isophthalate (130 mg, 0.26 mmol) and 4-(3-chloropropyl)morpholine (53 mg, 0.27 mmol) were converted to the title compound. (65 mg, 40%). 1H NMR (CD3OD) δ 8.67 (d, J=2.0 Hz, 1H), 8.33 (dd, J=8.0, 1.6 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.62 (s, 1H), 7.38-7.32 (m, 5H), 5.21 (s, 2H), 4.01 (s, 3H), 3.84-3.80 (m, 4H), 3.59-3.50 (m, 6H), 2.20-2.11 (m, 6H), 1.70-1.60 (m, 6H), 1.45-1.25 (m, 4H), 1.05-0.82 (m, 6H); MS(ESI+) m/z 619 (M+H)+.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2([C:23]1[C:24]([O:29][CH2:30][CH3:31])=[N:25][CH:26]=[CH:27][CH:28]=1)[OH:22]>N1C=CC=CC=1.ClCCl>[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3])[C:16](=[O:21])[C:15]2([C:23]1[C:24]([O:29][CH2:30][CH3:31])=[N:25][CH:26]=[CH:27][CH:28]=1)[O:22][C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCOc1ncccc1C1(O)C(=O)Nc2ccc(Cl)cc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOc1ncccc1C1(OC(=O)Oc2ccccc2)C(=O)N(C(=O)Oc2ccccc2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.3 %

Procedure:
2.6 ml (21 mmol) of phenyl chloroformate were slowly added dropwise to a solution, cooled to 0° C., of 3.00 g (9.8 mmol) of 5-chloro-3-(2-ethoxypyridin-3-yl)-3-hydroxy-1,3-dihydroindol-2-one from example a.1 in 10 ml of pyridine, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and extracted with water. The organic phase was washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was stirred with diethyl ether. 2.58 g of the title compound were obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:43]([C:44]([F:47])([F:46])[F:45])=[CH:42][CH:41]=[CH:40][C:3]=1[CH2:4][N:5]([CH2:26][CH:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16](COCC)[C:17]2[N:21]=[CH:20][NH:19][N:18]=2)[CH:11]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.Cl.C(OCC)C>ClCCl.C(OCC)C>[ClH:1].[Cl:1][C:2]1[C:43]([C:44]([F:45])([F:46])[F:47])=[CH:42][CH:41]=[CH:40][C:3]=1[CH2:4][N:5]([CH2:26][CH:27]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][C:17]2[N:21]=[CH:20][NH:19][N:18]=2)[CH:11]=1
Reactant: CCOCC(c1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1)c1nc[nH]n1
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: FC(F)(F)c1cccc(CN(CCCOc2cccc(Cc3nc[nH]n3)c2)CC(c2ccccc2)c2ccccc2)c1Cl
Reaction time: 8 h
Yield: 92.4 %

Procedure:
To a stirring solution of (2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(ethoxymethyl-1,2,4-triazol-3-ylmethyl)-phenoxy]-propyl)amine (mixture of regioisomers, 90 mg, 0.135 mmol) in dichloromethane (1.5 mL) was added triethylsilane (157 mg, 1.35 mmol). The reaction mixture was treated with TFA (0.5 mL) and then stirred overnight Solvent was removed and the residue was purified by preparative HPLC (YMC CombiPrep PDS, 75×30 mm, 25 mL/min, A: acetonitrile B: water, A: 60 to 100% during 10 min, UV detection at 254 nm) to give an oil. The oil was dissolved in diethyl ether and acidified with 1.0 M HCl/diethyl ether to give 40 mg (48% yield) of the title compound as a yellow oil. MS (ESI) 605.0 (M+).
Reaction SMILES: ClCCCl.[CH3:5][C:6]1[C:7]([OH:15])=[C:8]([CH3:14])[C:9]([CH3:13])=[C:10]([CH:12]=1)[OH:11].[F:16][C:17]([F:35])([F:34])[C:18]1[CH:19]=[C:20]([CH:24](O)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH:21]=[CH:22][CH:23]=1.B(F)(F)F.CCOCC>O>[F:16][C:17]([F:34])([F:35])[C:18]1[CH:19]=[C:20]([CH:24]([C:12]2[C:10](=[O:11])[C:9]([CH3:13])=[C:8]([CH3:14])[C:7](=[O:15])[C:6]=2[CH3:5])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH:21]=[CH:22][CH:23]=1
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: O=C(O)CCCCCC(O)c1cccc(C(F)(F)F)c1
Agent: FB(F)F
Solvent: O
Solvent: ClCCCl
Solvent: CCOCC
Product: CC1=C(C)C(=O)C(C(CCCCCC(=O)O)c2cccc(C(F)(F)F)c2)=C(C)C1=O
Temperature: 80 °C
Yield: 23.7 %

Procedure:
1,2-Dichloroethane (15 ml) was added to 0.76 g (5.0 mmole) of trimethylhydroquinone and 1.45 g (5.0 mmole) of 7-(3-trifluoromethylphenyl)-7-hydroxyheptanoic acid, and the mixture was warmed to 80° C. under stirring and admixed with 0.19 ml (5.0×0.3 mmole) of boron trifluoride ethyl etherate, followed by stirring at 80° C. for 2 hours. After the reaction solution was cooled by standing at room temperature, the solvent was distilled off, and the residue was dissolved in tetrahydrofuran (15 ml). A solution of 2.7 g (10.0 mmole) of ferric chloride in water (10 ml) was added to the solution, followed by stirring at room temperature for 20 minutes. The tetrahydrofuran was distilled off, and ethyl acetate was added to the residue to carry out extraction. The organic layer was separated out, washed with aqueous sodium chloride solution, dried (magnesium sulfate) and evaporated, and the residue was chromatographed on a silica gel column chromatography, followed by elution with isopropyl ether. The fractions containing the object compound were collected and concentrated under reduced pressure, and the residue was recrystallized from isopropyl ether-hexane to give 0.50 g (24%) of 7-(3-trifluoromethylphenyl)-7-(3,5,6-trimethyl-1,4-benzoquinon -2-yl)heptanoic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][CH2:13][C:12]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC(C)C)(C)C.P(Cl)(Cl)([Cl:31])=O>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][CH:13]=[C:12]2[Cl:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2c(cc1OCc1ccccc1)C(=O)CC=N2
Solvent: CC(C)NC(C)C
Product: COc1cc2nccc(Cl)c2cc1OCc1ccccc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
6-Benzyloxy-7-methoxy-4-quinolone (2.4 g), diisopropylamine (5 eq, 7.4 ml), and phosphorus oxychloride (2.5 eq, 2.0 ml) were added, and the mixture was stirred at 110° C. for one hr. The stirred mixture was concentrated under the reduced pressure. Chloroform and iced water were then added to the concentrate. The mixture was rendered weakly alkaline by the addition of 28% aqueous ammonia, followed by extraction with chloroform. The extract was washed with saturated brine and was dried over sodium sulfate, and the solvent was then removed by evaporation under the reduced pressure. The crude thus obtained was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (1.6 g, yield 63%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][NH:6][CH2:7][CH:8]=[CH:9][Cl:10])[CH3:2].C(N(CC)CC)C.[Cl:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24]>C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:11])[CH2:5][N:6]([CH2:7][CH:8]=[CH:9][Cl:10])[C:23](=[O:24])[CH2:22][CH2:21][CH2:20][Cl:19])[CH3:2]
Reactant: CCOC(=O)CNCC=CCl
Reactant: O=C(Cl)CCCCl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)CN(CC=CCl)C(=O)CCCCl
Temperature: 60 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
Into a 100 ml four-necked flask there were placed 17.8 g of N-(3-chloroallyl)glycine ethyl ester, 15.2 g of triethylamine and 50 ml of benzene, and then 16.9 g of γ-chlorobutyryl chloride was gradually dropwise added thereto at room temperature with thorough stirring. Thereafter, the mixture was stirred for 1 hour at 60° C. After cooling, the reaction solution was washed with water, the benzene layer was dried over anhydrous sodium sulfate and the benzene was removed under reduced pressure. The residue obtained was distilled under reduced pressure to obtain 23.7 g of the objective N-(3-chloroallyl)-N-γ-chlorobutyryl glycine ethyl ester (b.p.2 167 - 170° C, nD23.0 1.4884).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1.[Cl:25][CH2:26][C:27](Cl)=[O:28].C(N(CC)CC)C>ClCCl>[Cl:25][CH2:26][C:27]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)=[O:28]
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)c1cc2c(N)cccc2n1Cc1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(NC(=O)CCl)cccc2n1Cc1ccc(Cl)c(Cl)c1
Yield: 65 %

Procedure:
Ethyl 4-amino-N-(3,4-dichlorobenzyl)indole-2-carboxylate (2.03 g), chloroacetyl chloride (0.5 ml) and triethylamine (4.0 ml) were stirred in dichloromethane (50 ml) for 16 hours. The reaction was washed with water, dried (MgSO4) and concentrated in vacuo. The residue was triturated with toluene to give the product as a pale grey solid (1.61 g, 65%); NMR d (CD3SOCD3) 1.28 (t, 3H), 4.30 (q, 2H), 4.40 (s, 2H), 5.81 (s, 2H), 6.88 (dd, 1H), 7.30 (m, 3H), 7.50 (d, 1H), 7.76 (s, 1H), 7.78 (d, 1H), 10.19 (brs, 1H); M/z (−) 439 (M+), 4.37.