Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[C:3]=1[NH2:4].[C:32](O)(=O)[CH3:33]>>[Cl:1][C:2]1[C:3]2[N:4]=[C:32]([CH3:33])[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][S:25]([C:28]([F:30])([F:29])[F:31])(=[O:27])=[O:26])=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1c(Cl)cccc1NCc1ccc(Oc2ccc(OS(=O)(=O)C(F)(F)F)cc2)cc1
Reactant: CC(=O)O
Product: Cc1nc2c(Cl)cccc2n1Cc1ccc(Oc2ccc(OS(=O)(=O)C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-chloro-6-[4-(4-trifluoromethylsulfonyloxyphenoxy)benzylamino]aniline (300 mg) and acetic acid (5 ml) was heated under reflux for 6 hours. The reaction mixture was cooled to room temperature, excessive acetic acid was removed by distillation under reduced pressure, and toluene (100 ml) and a 5% sodium hydroxide solution (50 ml) were added thereto, followed by stirring for 10 minutes. The toluene layer was separated, washed with water, dried over anhydrous sodium sulfate and distilled under reduced pressure to eliminate toluene The residue was purified by silica gel column chromatography to give 4-chloro-2-methyl-1-[4-(4-trifluoromethylsulfonyloxyphenoxy)benzyl]benzimidazole (285 mg) as a colorless liquid. nD24 1.5655.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](O)=[O:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C[Si](C)(C)[N:52]1[CH2:56][CH2:55][CH2:54][C@H:53]1[C:57]([O:59][Si](C)(C)C)=[O:58]>C1COCC1.C(Cl)Cl>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][C:23]([N:52]3[CH2:56][CH2:55][CH2:54][C@H:53]3[C:57]([OH:59])=[O:58])=[O:24])=[CH:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)O)cc2)cc1
Reactant: C[Si](C)(C)OC(=O)[C@@H]1CCCN1[Si](C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)N3CCC[C@H]3C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)propanoic acid (15 mg, 0.044 mmol), TEA (0.019 mL, 0.133 mmol), and HATU (25.4 mg, 0.067 mmol) in THF (0.5 mL) and DCM (0.500 mL) was added (S)-trimethylsilyl 1-(trimethylsilyl)pyrrolidine-2-carboxylate (23.07 mg, 0.089 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated and the residue purified by HPLC to give the title compound. LCMS m/z=435.4 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[CH2:15][C:16]#[N:17])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[OH2:19]>C(=O)(O)[O-].[Na+]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[CH2:15][C:16]([NH2:17])=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: O
Reactant: CC(CC#N)c1ccc(N2CCN(C)CC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(CC(N)=O)c1ccc(N2CCN(C)CC2)cc1
Temperature: 90 °C
Yield: 74 %

Procedure:
A suspension of 3-(4-(4-methylpiperazin-1-yl)phenyl)butanenitrile (450 mg, 1.85 mmol) and poly phosphoric acid (4.5 g) was heated at 90° C. for 3 h. The reaction mixture was cooled to room temperature, diluted with cold water and basified with saturated sodium bicarbonate solution. The aqueous layer was extracted with DCM, washed with water and brine solution. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford 360 mg (74%) of 3-(4-(4-methylpiperazin-1-yl)phenyl)butanamide as light yellow color solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[CH3:23][O:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]([NH:38][C:39](=O)[O:40]C2C=CC=CC=2)[CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([NH:19][C:39]([NH:38][C:30]2[CH:31]=[C:32]([C:34]([F:36])([F:37])[F:35])[CH:33]=[C:28]([O:27][CH2:26][CH2:25][O:24][CH3:23])[CH:29]=2)=[O:40])[CH:20]=[CH:21][CH:22]=1
Reactant: COCCOc1cc(NC(=O)Oc2ccccc2)cc(C(F)(F)F)c1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Product: COCCOc1cc(NC(=O)Nc2cccc(Sc3ncnc4cc(OC)c(OC)cc34)c2)cc(C(F)(F)F)c1
Yield: 70 %

Procedure:
The title compound was prepared from 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (94 mg, 0.3 mmol) and 3-(2-methoxyethoxy)-5-(trifluoromethyl)phenylcarbamate from Example 117A (160 mg, 0.45 mmol) using Example 115C to give 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-(2-methoxyethoxy)-5-(trifluoromethyl)phenyl)urea (118 mg, 0.21 mmol, 69%). 1H NMR (300 MHz, DMSO-d6) δ 9.09 (s, 1H), 9.04 (s, 1H), 8.70 (s, 1H), 7.84 (s, 1H), 7.55 (d, 1H), 7.50-7.41 (m, 2H), 7.35 (s, 1H), 7.34 (s, 1H), 7.29-7.23 (m, 2H), 6.87 (s, 1H), 4.19-4.11 (m, 2H), 4.00 (s, 6H), 3.70-3.63 (m, 2H), 3.31 (s, 3H); LC-MS (ESI) m/z 575 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH2:13])[CH2:10][C@@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31])=O)C>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])[CH2:10][C@@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)C[C@@H]1CO
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](N2C(=O)c3ccccc3C2=O)C[C@@H]1CO
Reaction time: 6 h
Yield: 93.5 %

Procedure:
(2R,4S)-1-(tert-Butyloxycarbonyl)-2-hydroxymethyl-4-amino-pyrrolidine 41 (1.00 g, 4.63 mmol) was dissolved in dry methanol (20 ml) and treated with N-ethoxycarbonyl phthalimide (1.09 g, 5 mmol) at room temperature. The reaction mixture was stirred for 6 h and evaporated to dryness the residue was purified by flash chromatography over silica gel using CH2Cl2 →EtOAc as the eluent. The pure fractions were collected and evaporated to give 1.5 g (94%) of pure compound as foam. 1HNMR (CDCl3): 1.45 (s, 9H, Boc), 1.90 (dd, 1H), 2.34 (m, 1H), 3.40-3.62 (m, 3H), 4.00 (m, 2H), 4.28 (bs, 1H), 4.44 (m, 1H) and 7.3-7.6 (m, 4H, Ph).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH:9]=[CH:10][CH2:11][N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22].CO>C1COCC1.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][CH2:10][CH2:11][N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22]
Reactant: Cc1cccc(C)c1C=CCN1C(=O)c2ccccc2C1=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cccc(C)c1CCCN1C(=O)c2ccccc2C1=O
Reaction time: 24 h

Procedure:
The title compound of Example 32 (10 g, 34 mmole) dissolved in 120 ml of THF and 100 ml of MeOH was reduced in a standard Parr hydrogenation apparatus using 1 g of 5% Pd/C as catalyst. The reaction was run at room temperature under a pressure of 5 psi for 24 hours. The residue after removing all solvent under reduced pressure was chromotographed to yield the pale yellow crystalline product which was recrystallized from Skelly B. The melting point was 92°-93.5° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]3[N:10]=[C:11]([N:13]4[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C:21](=O)[CH3:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.[O:26]1[CH:30]=[CH:29][C:28]([NH2:31])=[N:27]1.[B][B][B][B][B][B][B][B][B][B].Cl>CO.C(O)(=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]3[N:10]=[C:11]([N:13]4[CH2:18][CH2:17][CH:16]([O:19][CH2:20][CH:21]([NH:31][C:28]5[CH:29]=[CH:30][O:26][N:27]=5)[CH3:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccon1
Reactant: CC(=O)COC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1
Agent: Cl
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CC(=O)O
Solvent: CO
Product: CC(COC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1)Nc1ccon1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-({1-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]piperidin-4-yl}oxy)propan-2-one (400 mg) and isoxazol-3-amine (0.129 mL) in methanol (6 mL) and acetic acid (0.300 mL) was added decaborane (213 mg), and the mixture was stirred at room temperature for 3 hr. 1M Hydrochloric acid was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min, and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (hexane/ethyl acetate). The obtained residue was applied to preparative HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)). Saturated aqueous sodium hydrogen carbonate solution was added to the obtained fraction, and the mixture was extracted with ethyl acetate and the extract was dried over anhydrous sodium sulfate. The residue was concentrated under reduced pressure to give the title compound (126 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:16][CH2:17]Cl)[C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:26]2[CH2:17][CH2:16][N:4]([C:5]3[CH:6]=[C:7]4[C:12](=[CH:13][CH:14]=3)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]4)[CH2:3][CH2:2]2)=[CH:23][CH:22]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=C1CCc2cc(N(CCCl)CCCl)ccc2N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CN2CCN(c3ccc4c(c3)CCC(=O)N4)CC2)cc1
Yield: 45.6 %

Procedure:
A mixture of 14.5 g of 6-[bis(2-chloroethyl)amino]-3,4-dihydrocarbostyril, 8.0 g of 4-methoxybenzylamine and 70 ml of methanol was stirred under reflux for 15 hours. After cooling, to the reaction mixture was added 3.06 g of sodium carbonate and the reaction mixture was stirred under reflux for 8 hours. After cooling, crystals which precipitated were collected by filtration and recrystallized from ethanol to give 8.1 g of 6-[4-(4-methoxybenzyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 196°-198° C., colorless needles.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2.C(O)(=O)C.[Br-:21].[Li+]>C1COCC1>[Br:21][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2
Reactant: O=C1CCc2cc(OCC3CO3)ccc2N1
Reactant: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C1CCc2cc(OCC(O)CBr)ccc2N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 10085.3 %

Procedure:
To a stirred solution of 6-(oxiran-2-ylmethoxy)-3,4-dihydroquinolin-2(1H)-one (0.2 g, 0.909 mmol) in dry THF (5 mL) was added acetic acid (0.162 g, 2.272 mmol) and lithium bromide (0.118 g, 1.363 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated to remove solvent and water was added (25 mL). The solid was filtered and dried to give crude 6-(3-bromo-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one as an off-white solid (0.25 g, 91.675 mmol). LCMS: RT 0.65 min; LCMS (ES-API), m/z 300.0 (M+H).
Reaction SMILES: CO[C:3](=[O:28])[CH:4]([N:8]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16](=[O:27])/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH2:10][CH2:9]1)[CH2:5][CH2:6][OH:7].ClC1C=C(/C=C/[C:39]([N:41]2CCC(=O)N(C3CCOC3=O)C[CH2:42]2)=O)C=CC=1Cl.CNC>C1COCC1>[Cl:26][C:21]1[CH:20]=[C:19](/[CH:18]=[CH:17]/[C:16]([N:11]2[CH2:12][CH2:13][C:14](=[O:15])[N:8]([CH:4]([CH2:5][CH2:6][OH:7])[C:3]([N:41]([CH3:42])[CH3:39])=[O:28])[CH2:9][CH2:10]2)=[O:27])[CH:24]=[CH:23][C:22]=1[Cl:25]
Reactant: O=C1OCCC1N1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Reactant: COC(=O)C(CCO)N1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)C(CCO)N1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Temperature: 50 °C
Yield: 96 %

Procedure:
A solution of 0.081 g (0.19 mmol) of (rac)-2-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-4-hydroxy-butyric acid methyl ester (with 50% of the lactone, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-(2-oxo-tetrahydro-furan-3-yl)-[1,4]diazepan-5-one) (intermediate 6) was suspended in 1 ml of THF, treated with 0.34 ml (1.89 mmol, 33% in EtOH) of dimethylamine and heated at 50° C. for 16 h. Evaporation of the solvent and drying gave 0.08 g (96%) of the titled compound as light yellow foam. MS: 442.3 (MH+, 2Cl).
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:52])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:51])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:50])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:49])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:48])[CH2:27][CH2:28][CH:29]=[C:30]([CH3:47])[CH2:31][CH2:32][CH:33]=[C:34]([CH3:46])[CH2:35][CH2:36][CH:37]=[C:38]([CH3:45])[CH2:39][CH2:40][CH:41]=[C:42]([CH3:44])[CH3:43])[CH2:3][C:4](O)=[O:5].[NH3:53].C1C=CC=CC=1.C(OCC)(=O)C>C(Cl)Cl>[CH3:1][CH:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:52])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:51])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:50])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:49])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:48])[CH2:27][CH2:28][CH:29]=[C:30]([CH3:47])[CH2:31][CH2:32][CH:33]=[C:34]([CH3:46])[CH2:35][CH2:36][CH:37]=[C:38]([CH3:45])[CH2:39][CH2:40][CH:41]=[C:42]([CH3:44])[CH3:43])[CH2:3][C:4]([NH2:53])=[O:5]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)CC(=O)O
Reactant: N
Solvent: ClCCl
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)CC(N)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
20 g of 3,7,11,15,19,23,27,31,35,39-decamethyl-6,10,14,18,22,26,30,34,38-tetracontanonaenic acid are dissolved in 100 ml of methylene chloride. To this solution, 6.9 g of N,N-dicyclohexylcarbodiimide are added with cooling at 0° C., and stirred for 1.0 hour. Ammonia gas is blown little by little into this solution during an hour. Stirring for 3.0 hours is performed at room temperature after the end of addition of ammonia. Mother liquor is condensed after filtering off N,N-dicyclohexylurea formed. The residue is subjected to silica gel column chromatography using benzene/ethyl acetate mixture for eluting solvent. The desired product was obtained as an oily substance light yellow in color (yield: 12.3 g). This oily substance was dissolved in 50 ml of acetone and left overnight in a refrigerator. The white crystals deposited were filtered off, dried and thus yielded 8.5 g of desired final product, acid amide derivative.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[N+:8]([CH3:11])([O-:10])=[O:9].Cl>C(O)C.[OH-].[Na+]>[O:1]1[CH:5]=[CH:4][C:3]([CH:6]=[CH:11][N+:8]([O-:10])=[O:9])=[CH:2]1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccoc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])C=Cc1ccoc1
Yield: 64.4 %

Procedure:
To a solution of 10.035 g (104.43 mmol) of 3-furaldehyde and 6.37 g (104 mmol) of nitromethane in 200 ml of ethanol, 11.0 ml of 10 N aqueous sodium hydroxide was added dropwise under ice-cooling, after which the reaction mixture was added dropwise to about 15% aqueous hydrochloric acid; the resulting precipitate was collected by filtration, washed with water and dried to yield 2-(3-furyl)-1-nitroethylene as a brown powder (yield 9.320 g). This crude product, without purification, was used for the next reaction.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)[NH2:2].[Cl:9][C:10]1[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=1)[C:13]([CH:15]([C:21](=O)[CH3:22])[CH2:16][C:17]([O:19][CH3:20])=[O:18])=O>C(O)C>[Cl:9][C:10]1[CH:11]=[C:12]([C:13]2[N:1]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=3)[N:2]=[C:21]([CH3:22])[C:15]=2[CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)CC(C(C)=O)C(=O)c1cccc(Cl)c1
Reactant: NNc1cccnc1
Solvent: CCO
Product: COC(=O)Cc1c(C)nn(-c2cccnc2)c1-c1cccc(Cl)c1
Temperature: 130 °C
Reaction time: 1.5 h

Procedure:
0.577 g (4.233 mmol) of 3-hydrazinopyridine in 5.00 ml of ethanol was added to 0.650 g (2.419 mmol) of methyl 3-(3-chlorobenzoyl)-4-oxopentanoate, and the mixture was stirred in a closed vessel in a microwave oven at 130° C. for 1.5 h. The solvent was removed under reduced pressure, and the residue was taken up in dichloromethane and washed twice with in each case 25 ml of water. The combined organic phases were dried over sodium sulfate, and the solvent was removed under reduced pressure. Chromatography of the residue gave 0.364 g (42% of theory) of a light-yellow oil. 1H-NMR (CDCl3): see Table 2.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][CH:4]=[N:3]1.C1COCC1.C([Li])CCC.Br[C:18]1[S:22][C:21]([C:23]2[N:27]3[N:28]=[C:29]([CH3:37])[CH:30]=[C:31]([CH:32]([CH2:35][CH3:36])[CH2:33][CH3:34])[C:26]3=[N:25][C:24]=2[CH3:38])=[C:20]([CH3:39])[CH:19]=1>C(Cl)Cl.[Cl-].[Cl-].[Zn+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:33]([CH:32]([C:31]1[C:26]2[N:27]([C:23]([C:21]3[S:22][C:18]([C:6]4[N:2]([CH3:1])[N:3]=[CH:4][N:5]=4)=[CH:19][C:20]=3[CH3:39])=[C:24]([CH3:38])[N:25]=2)[N:28]=[C:29]([CH3:37])[CH:30]=1)[CH2:35][CH3:36])[CH3:34]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C)c(C)nc12
Reactant: Cn1cncn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4ncnn4C)cc3C)c(C)nc12
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 59.9 %

Procedure:
To a −78° C. solution of 1-methyl-1,2,4-triazole (0.15 mL, 2.04 mmol) and THF (3 mL) is added a 1.34 M solution of n-Bu-Li in hexanes (1.60 mL, 2.14 mmol) over 20 minutes, then stirred at −78° C. for 1.5 hours. A 0.5 M solution of ZnCl2 in THF (4.28 mL, 2.14 mmol) is added and the solution warmed to ambient temperature. 3-(5-Bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.40 g, 1.019 mmol) and PdCl2(dppf) (0.037 g, 0.051 mmol) is added and the solution heated at 65° C. overnight diluted with CH2Cl2 (30 mL). The organic layer is washed with 10% citric acid (20 mL), water (20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO (20%-60% EtOAc/hexane gradient). The residue is dissolved in Et2O, treated with Darco®-60 for 15 minutes, dried with Na2SO4, and filtered to furnish the title compound (0.24 g, 0.61 mmol, 60%). 1H NMR (CDCl3), δ 0.88 (t, J=7.4 Hz, 6H), 1.75-1.93 (m, 4H), 2.20 (s, 3H), 2.50 (s, 3H), 2.51 (s, 3H), 3.28-3.37 (m, 1H), 4.14 (s, 3H), 6.69 (s, 1H), 7.45 (s, 1H), 7.87 (s, 1H). LC/MS (m/z): calcd. for C21H26N6S (M+H)+: 395.6; found: 395.2.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:32]=[CH:31][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]([CH2:26][C:27]([OH:29])=O)[C:17](=[O:30])[CH2:16]2)=[O:14])=[CH:11][CH:10]=1.[NH2:33][CH2:34][CH2:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:32]=[CH:31][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]([CH2:26][C:27]([NH:33][CH2:34][CH2:35][C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)=[O:29])[C:17](=[O:30])[CH2:16]2)=[O:14])=[CH:11][CH:10]=1
Reactant: NCCc1cccnc1
Reactant: O=C(O)CN1C(=O)CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CN1C(=O)CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc21)NCCc1cccnc1
Reaction time: 8 h

Procedure:
20 mg (0.042 mmol) of [4-(4-chlorobenzoyl)-2-oxo-2,3,4,5-tetrahydrobenzo[e][1,4]diazepin-1-yl]acetic acid trifluoroacetate was dissolved in 2 ml of dichloromethane. 7 mg (0.055 mmol) of 3-aminoethylpyridine, 11 mg (0.055 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.018 ml (0.126 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight The solvent was evaporated, and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: [CH2:1]([N:19]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[C:20](=[O:37])[CH2:21][O:22][C:23](=[O:36])[CH2:24][NH:25]C(OCC1C=CC=CC=1)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[ClH:56].CO>CCOC(C)=O.[Pd]>[ClH:56].[CH2:38]([N:19]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:20](=[O:37])[CH2:21][O:22][C:23](=[O:36])[CH2:24][NH2:25])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)COC(=O)CNC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)COC(=O)CN
Temperature: 25 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
10% Pd/C (150 mg) was added to a solution of N-[(phenylmethoxy)-carbonyl]glycine [2-(dioctadecylamino)-2-oxoethyl]ester (1.2 g; 1.4 mmol) in EtOAc (100 mL) and the suspension was stirred for 3 h under hydrogen atmosphere at room temperature. After filtration (through a Millipore® filter FT 0.45 μm) 1.2 M HCl in MeOH (1.3 mL; 1.6 mmol) was added dropwise to the resulting solution obtaining the precipitation of a white solid that was filtered to give the desired compound (830 mg; 1.2 mmol).Yield 86%. HPLC: 100% (area %). K.F.: 0.22%. The MS and IR spectra were consistent with the structure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:29]CC3C=CC(OC)=CC=3)([C:25]([F:28])([F:27])[F:26])[C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)=[CH:6][CH:5]=1.C(#N)C.O.OS([O-])(=O)=O.[K+]>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:45])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:29])([C:21]([F:22])([F:23])[F:24])[C:25]([F:27])([F:28])[F:26])=[CH:16][CH:15]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(OC(COc2ccc(C(OCc3ccc(OC)cc3)(C(F)(F)F)C(F)(F)F)cc2)c2ccccc2)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(OC(COc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)c2ccccc2)cc1
Reaction time: 3 h
Yield: 48.6 %

Procedure:
76 mg (0.12 mmol) of rac 4-(1-phenyl-2-{4-[2,2,2-trifluoro-1-(4-methoxy-benzyloxy)-1-trifluoromethyl-ethyl]-phenoxy}-ethoxy)-benzoic acid methyl ester in 4 ml of a mixture of acetonitrile:water (9:1) were treated with 250 mg (0.46 mmol) of ceric ammonium nitrate at room temperature overnight. An additional 100 mg (0.18 mmol) of ceric ammonium nitrate were added and stirring was continued for 3 h. EtOAc and 1M KHSO4 were added and the phases were separated. The inorganic one was extracted with EtOAc, the combined organic phases were washed with brine and dried (Na2SO4) and evaporated. Column chromatography on ISOLUTE Flash NH2 with a gradient of EtOAc/n-heptane to EtOAc gave 30 mg (48%) of rac 4-{1-phenyl-2-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenoxy]-ethoxy}-benzoic acid methyl ester as a colorless oil, MS: 513 (M−H)−.