Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:7]([O:9]/[C:10](=[CH:16]\[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]([CH3:42])[C:30]([O:32]C3C=CC([N+]([O-])=O)=CC=3)=O)[N:24]=2)=[CH:19][CH:18]=1)/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:8].O.C(OCC)(=O)C>CN(C)C=O>[CH2:7]([O:9]/[C:10](=[CH:16]\[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]([CH3:42])[C:30]([NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[O:32])[N:24]=2)=[CH:19][CH:18]=1)/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:8]
Reactant: CCOC(=O)/C(=C/c1ccc(-c2cccc(N(C)C(=O)Oc3ccc([N+](=O)[O-])cc3)n2)cc1)OCC
Reactant: CCCCCN
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OCC)C(=O)OCC)cc2)n1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 50.6 %

Procedure:
0.21 mL (1.8 mmol) of n-pentylamine is added to a solution of 0.45 g (0.9 mmol) of ethyl (Z)-2-ethoxy-3-(4-{6-[methyl-(4-nitrophenoxycarbonyl)amino]pyrid-2-yl}phenyl)acrylate (prepared according to Example 2d) in 15 mL of dimethylformamide. The tube is sealed and rapidly placed in an oil bath preheated to 80° C. The reaction mixture is stirred at 80° C. for 1 hour 30 minutes. After cooling, the reaction is worked up by addition of 10 mL of water and extraction with ethyl acetate. The organic phases are combined, washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvents are evaporated off. The crude product obtained is purified by chromatography on a column of silica eluted with a 70/30 heptane/ethyl acetate mixture to give 0.2 g (57%) of ethyl (Z)-2-ethoxy-3-{4-[6-(1-methyl-3-pentylureido)pyrid-2-yl]phenyl}acrylate in the form of a pale yellow solid.
Reaction SMILES: N[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].N([O-])=[O:12].[Na+]>OS(O)(=O)=O>[OH:12][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=N[O-]
Reactant: Nc1cncc(C(=O)O)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)c1cncc(O)c1

Procedure:
A mixture of 4.00 g (29.0 mmol) of 5-aminonicotinic acid in 400 ml of 0.1N H2SO4 at room temperature was diazotized with 2.2 g (31.8 mmol) of NaNO2 by the method of R. Graf (supra) to afford 5-hydroxynicotinic acid. The intermediate free acid was esterified in anhydrous methanolic HCl by the method of Urban (supra) to afford 2.34 g (53% overall yield) of 5-hydroxy nicotinic acid, methyl ester, mp 186°-187° C. (lit 182°-193° C.; Urban, supra). The IR data gave the characteristic 5-hydroxy band at 2550.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]([CH:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:45])[C@@H:30]([NH:35][C:36]([N:38]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:37])[CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:25][CH2:24]2)[CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=1)C1C=CC=CC=1>C1COCC1.CO.[Pd]>[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH:23]2[CH2:28][CH2:27][N:26]([C:29]([C@@H:30]([NH:35][C:36]([N:38]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:37])[CH2:31][CH:32]([CH3:34])[CH3:33])=[O:45])[CH2:25][CH2:24]2)=[CH:13][CH:12]=1
Reactant: CC(C)CCN(c1ccc(NC(=O)OCc2ccccc2)cc1)C1CCN(C(=O)[C@H](CC(C)C)NC(=O)N2CCCCCC2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CCN(c1ccc(N)cc1)C1CCN(C(=O)[C@H](CC(C)C)NC(=O)N2CCCCCC2)CC1
Reaction time: 1.25 h
Yield: 93 %

Procedure:
[(S)-{4-[(1-{2-[(Azepane-1-carbonyl)-amino]-4-methyl-pentanoyl}-piperidin-4-yl)-(3-methyl-butyl)-amino]-phenyl}-carbamic acid benzyl ester] (Example 34, 2.75 g, 4.34 mmol) was dissolved in THF/MeOH (50 mL, 1:1), treated with 20% Pd/C (0.26 g), and shaken under H2 (49 psi) for 1.25 hours. The reaction was filtered through Celite and concentrated to give 2.01 g (93%) of the desired product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](Cl)=[O:13])([CH3:4])([CH3:3])[CH3:2].[CH3:16][NH:17][NH2:18].C(N(CC)CC)C>C1COCC1>[C:1]([O:5][C:6](=[O:15])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:13])[N:17]([CH3:16])[NH2:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNN
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A solution of crude carbamoyl chloride 1 (9.35 g) in dry THF (40 ml) was added to an ice-cold solution of methylhydrazine (3.46 g; 4.00 ml; 0.075 mol) and triethylamine (6.33 g; 8.73 ml; 0.063 mol) in dry THF (40 ml). Stirring was continued at room temperature for 18 hours. The reaction mixture was filtered and evaporated, giving a light yellow solid. Recrystallization from hexane - chloroform gave 2 (6.62 g; 0.0272 mol; 68%) as a white solid, mp 89°-92°, TLC (silica gel; CH2CL2 --CH3OH, 10:1) Rf=0.45. MS m/e 243 (M+) Analysis: Calculated for C11H21N3O3 ; C,54.30; H, 8.70; N, 17.27. Found: C, 54.45; H, 8.96; N, 17.29, NMR (CDCl3): δ1.42 (9H,S); 1.7-2.3(4H.S); 3.00 (3H,S); 3.4-3.8(2H,m); 3.8(2H.bs); 4.4(1H.m) 1R(CHCl3): 35-3300, 1730, 1630 cm-1 [α]D =-55.7°±0.5°.
Reaction SMILES: [N+](C1C=C(S([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:18][CH:17]=2)(=O)=O)C=CC=1)([O-])=O.O[C:31]1[CH:38]=[CH:37][C:34]([CH:35]=[O:36])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:35]([C:34]1[CH:37]=[CH:38][C:31]([O:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:24])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[CH:20][CH:21]=2)=[CH:32][CH:33]=1)=[O:36]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCOS(=O)(=O)c2cccc([N+](=O)[O-])c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccc(CCOc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Yield: 79 %

Procedure:
26.7 g (63 mmole) 4-(tert-butoxycarbonylamino)phenethyl 3-nitro-benzenesulfonate, 8.5 g (69 mmole) p-hydroxybenzaldehyde, 9.54 g (69 mmole) potassium carbonate and acetonitrile was refluxed for 3 hours and thereafter stirred over night at room temperature. The precipitate was filtered off and the solvent was evaporated. Dichloromethane was added and the organic phase was washed with saturated sodium carbonate and thereafter with sodium hydroxide (0.1 M), dried (sodium sulfate), filtered and the solvent was evaporated to give 17 g (yield 79%) of tert-butyl N-{4-[2-(4-formylphenoxy)ethyl]phenyl}carbamate.
Reaction SMILES: FC(F)(F)OC1C=C(C2C=CC=C(CO)C=2)C=CC=1.C[O:21][C:22](=[O:53])[CH2:23][O:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([S:33][CH2:34][C:35]2[CH:36]=[C:37]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([O:47][C:48]([F:51])([F:50])[F:49])[CH:42]=3)[CH:38]=[CH:39][CH:40]=2)=[CH:27][C:26]=1[CH3:52]>>[CH3:32][O:31][C:29]1[C:28]([S:33][CH2:34][C:35]2[CH:36]=[C:37]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([O:47][C:48]([F:51])([F:50])[F:49])[CH:42]=3)[CH:38]=[CH:39][CH:40]=2)=[CH:27][C:26]([CH3:52])=[C:25]([CH:30]=1)[O:24][CH2:23][C:22]([OH:53])=[O:21]
Reactant: COC(=O)COc1cc(OC)c(SCc2cccc(-c3cccc(OC(F)(F)F)c3)c2)cc1C
Agent: OCc1cccc(-c2cccc(OC(F)(F)F)c2)c1
Product: COc1cc(OCC(=O)O)c(C)cc1SCc1cccc(-c2cccc(OC(F)(F)F)c2)c1

Procedure:
Preparation of (3′-Trifluoromethoxy-biphenyl-3-yl)-methanol (compound 16A) The title compound was prepared in the manner analogous to Example 3A using 3-hydroxymethylphenylboronic acid and 1-bromo-3-trifluoromethoxy-benzene. MS m/z 251 (M−1). Step 2. Preparation of 3-Chloromethyl-3′-trifluoromethoxy-biphenyl (compound 16B) The title compound was prepared in the manner analogous to Example 3B using 16A. MS m/z 251 (M−1). Step 2. Preparation of [5-Methoxy-2-methyl-4-(3′-trifluoromethoxy-biphenyl-3-ylmethylsulfanyl)-phenoxy]-acetic acid methyl ester (compound 16C) The title compound was prepared in the manner analogous to Example 1F using 16B and 1D. MS m/z 491 (M−1). Step 4. Preparation of [5-Methoxy-2-methyl-4-(3′-trifluoromethoxy-biphenyl-3-ylmethylsulfanyl)-phenoxy]-acetic acid (compound 16) The title compound was prepared in the manner analogous to Example 1 using 16C. mp 92-94° C.; 400 MHz 1H NMR (DMSO-d6) δ 12.96 (br(s), 1H), 7.55-7.24 (m, 8H), 7.01 (s, 1H), 6.52 (s, 1H), 4.68 (s, 2H), 4.03 (s, 2H), 3.72 (s, 3H), 1.99 (s, 3H); MS m/z 479 (M+1).
Reaction SMILES: CS(O[C:6]1[N:11]=[C:10]2[C:12]([Cl:16])=[N:13][CH:14]=[CH:15][C:9]2=[N:8][C:7]=1[CH3:17])(=O)=O.O1CCOCC1.[ClH:24]>CCOC(C)=O>[Cl:24][C:6]1[N:11]=[C:10]2[C:12]([Cl:16])=[N:13][CH:14]=[CH:15][C:9]2=[N:8][C:7]=1[CH3:17]
Reactant: Cc1nc2ccnc(Cl)c2nc1OS(C)(=O)=O
Reactant: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1nc2ccnc(Cl)c2nc1Cl
Temperature: 70 °C
Yield: 49.6 %

Procedure:
A glass microwave reaction vessel was charged with 5-chloro-2-methylpyrido[3,4-b]pyrazin-3-yl methanesulfonate (160 mg, 0.585 mmol), 1,4-Dioxane (1 mL) and hydrogen chloride (4 M in 1,4-dioxane, 0.73 mL, 2.92 mmol) (Sigma Aldich). The reaction mixture was stirred and heated in an oil bath at 70° C. for 1 h, then cooled to RT. The mixture was diluted with EtOAc (50 mL) and washed with sat. NaHCO3. The organic layer was dried (MgSO4), filtered and concentrated to give 3,5-dichloro-2-methylpyrido[3,4-b]pyrazine (62 mg, 0.290 mmol, 49% yield) as a brown solid. MS (ESI, pos. ion) m/z: 213.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:15]2=[N:16][C:17]3[C:18](=[C:19]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH:20]=[CH:21][CH:22]=3)[N:14]2[CH2:13][CH:12]([NH2:28])[CH2:11][CH2:10]1.C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37].C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:15]2=[N:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:18]=3[N:14]2[CH2:13][CH:12]([NH:28][C:36](=[O:38])[CH3:37])[CH2:11][CH2:10]1
Reactant: CCN(CC)c1cccc2nc3n(c12)CC(N)CCN3c1ccc(Cl)cc1Cl
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CC)c1cccc2nc3n(c12)CC(NC(C)=O)CCN3c1ccc(Cl)cc1Cl
Yield: 41.5 %

Procedure:
To a mixture of 1-(2,4-dichlorophenyl)-N7,N7-diethyl-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazole-4,7-diamine (59.5 mg, 0.142 mmol) and triethylamine (0.0396 mL, 0.284 mmol) in tetrahydrofuran (1.4 mL) was added acetic anhydride (0.161 mL, 0.170 mmol) at 0° C. After the resultant mixture was stirred at 0° C. for 1 hr, aqueous sodium bicarbonate was added and the mixture was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture to give a solid, which was recrystallized from ethyl acetate to afford the title compound as a colorless solid (27.1 mg, 0.0589 mmol, 41%).
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C:7]2[O:8][CH2:9][C:10]([CH3:13])([CH3:12])[N:11]=2)=[CH:3][CH:2]=1.C([Li])CCC.[CH3:25][S:26]SC.CCOCC>O1CCCC1.O>[CH3:25][S:26][C:3]1[CH:2]=[C:1]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][C:4]=1[C:7]1[O:8][CH2:9][C:10]([CH3:12])([CH3:13])[N:11]=1
Reactant: CSSC
Reactant: CC1(C)COC(c2ccc(-c3ccccc3)cc2)=N1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CSc1cc(-c2ccccc2)ccc1C1=NC(C)(C)CO1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
A stirred solution of 13.3 g of the biphenyl oxazoline of Example 1 in 210 mL tetrahydrofuran (THF) was treated with 36 mL of 1.6M n-butyllithium in hexanes at <-70° under nitrogen atmosphere. The mixture was kept at ca. -40° for 50 min., then 5.2 mL methyl disulfide was added and the mixture slowly warmed to room temperature. After 2 days the solution was poured into ether and water, the organic phase was washed successively with saturated sodium bicarbonate solution brine, then dried and evaporated. Trituration of the residue with n-chlorobutane plus hexanes gave 10.9 g of the title compound, mp 93°-95°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH2:11]Br)[CH:3]=1.[OH:13][CH2:14][C:15]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.[H-].[Na+]>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1)[CH2:11][O:13][CH2:14][C:15]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Reactant: O=[N+]([O-])c1cc(Br)cc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc([N+](=O)[O-])c2)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-Bromo-3-(bromomethyl)-5-nitrobenzene (2.12 g, 7.21 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (1.75 g, 6.0 mmol) were combined in dimethylformamide (18 mL) and cooled to 0° C. The reaction was treated with sodium hydride (288 mg, 12.0 mmol), stirred at 0° C. for 1 h, and at room temperature for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (20% ethyl acetate/hexanes) gave 1.4 g (38%). 1H-NMR (CDCl3, 500 MHz) δ 8.20 (s, 1H), 7.88 (s, 1H), 7.50 (s, 1H), 7.33-7.38 (m, 4H), 4.37 (s, 2H), 3.75-3.78 (m, 2H), 3.43 (s, 2H), 3.00-3.04 (m, 2H), 2.20-2.22 (m, 2H), 1.82-1.87 (m, 2H), 1.42 (s, 9H). Mass spec.: 507.10 (MH)+.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:19]([O:21]CC)=O)=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN[CH2:26][CH2:27]NC.C([Al](CC)CC)C>C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:19](=[O:21])[CH2:26][CH3:27])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNCCNC
Reactant: CCOC(=O)c1ccc(-c2ccccc2)c(-c2ccccc2)n1
Agent: CC[Al](CC)CC
Solvent: Cc1ccccc1
Product: CCC(=O)c1ccc(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
Following General Procedure O, ethyl 5,6-diphenylpyridine-2-carboxylate (Compound 21, 267 mg, 0.81 mmol) in toluene (5 ml), N,N′-dimethylethylenediamine (DMEDA, 85 mg, 0.97 mmol) and triethylaluminum (2.6 ml, 2.64 mmol, 1 M in hexane) were reacted to give the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](I)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])#[CH:11].[Cl-].[Li+].C(N(CC)CC)C>CN(C)C=O.[Cu](I)I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:11]#[C:10][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: Nc1ncc(F)cc1I
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: [Fe+2]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cc(F)cnc1N

Procedure:
But using 14 g of 5-fluoro-3-iodopyridin-2-ylamine, 12.47 ml of ethynyltrimethylsilane, 2.24 g of copper iodide, 2.74 g of lithium chloride, 41.33 ml of triethylamine and 2.15 g of [1,1′-bis(diphenylphosphino)ferrocene] palladium(II) chloride in 441 ml of dimethylformamide. After flash chromatography on a silica column (eluent: dichloromethane), 7.91 g of 5-fluoro-3-trimethylsilanylethynylpyridin-2-ylamine are thus obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])=[C:14]([CH3:22])[C:13]=2[CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>O1CCCC1.CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]([OH:21])[CH:18]([CH3:19])[CH3:20])=[C:14]([CH3:22])[C:13]=2[CH:23]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)C(C)C)oc2ccc(OCc3ccccc3)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(O)C(C)C)oc2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-[5-(Benzyloxy)-3-methyl-1-benzofuran-2-yl]-2-methylpropan-1-one (11.7 g) synthesized in the above-mentioned (1) was dissolved in a tetrahydrofuran (150 mL) and methanol (15 mL), and sodium borohydride (90%, 3.0 g) was added under ice-cooling. The ice bath was removed, the reaction mixture was stirred at room temperature for 2 hr. The mixture was ice-cooled again, water (10 mL) and 1N hydrochloric acid (100 mL) were carefully added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (11.3 g, quantitative) as a pale-yellow oil.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:15]=[CH:16][C:17]([OH:35])([C:31]([F:34])([F:33])[F:32])[CH2:18][C:19]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[O:29][CH3:30])([CH3:21])[CH3:20])[N:6]=1)=[O:4].[BH4-].[Na+].[Cl-].[Na+].C(OCC)(=O)C>C(O)C.[Ti]>[CH3:1][NH:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:15][CH2:16][C:17]([OH:35])([C:31]([F:32])([F:33])[F:34])[CH2:18][C:19]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[O:29][CH3:30])([CH3:21])[CH3:20])[N:6]=1)=[O:4]
Reactant: CNC(=O)c1ccc2c(N=CC(O)(CC(C)(C)c3cc(F)ccc3OC)C(F)(F)F)cccc2n1
Agent: [Ti]
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc2c(NCC(O)(CC(C)(C)c3cc(F)ccc3OC)C(F)(F)F)cccc2n1
Reaction time: 5 h

Procedure:
155 mg (0.315 mmol) of 5-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidenamino]quinoline-2-carboxylic acid methylamide is dissolved in 10 ml of ethanol and mixed with 0.09 ml (0.4 mmol) of titanium tetraethylate as well as 94 mg (2.6 mmol) of sodium borohydride. The reaction is halted after 5 hours by adding saturated sodium chloride solution and ethyl acetate. Insoluble components are filtered. The filtrate is extracted with ethyl acetate, the combined organic phases are dried on sodium sulfate, and the solvent is removed in a vacuum. After chromatography on silica gel with hexane-ethyl acetate (0-50%), 110 mg (71% of theory) of the product is obtained.
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:7][CH:6]=1.[OH-].[Na+]>CO>[CH3:17][O:16][CH2:15][CH2:14][O:13][CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:18])=[O:2])=[CH:6][CH:7]=1
Reactant: COCCOCOc1ccc(CC(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCCOCOc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of [4-(2-Methoxy-ethoxymethoxy)-phenyl]-acetic acid methyl ester (192 mg, 0.76 mmol) in MeOH (3 ml) is added 2 M NaOH (3 ml). The reaction mixture is stirred for 16 hours at room temperature. The solvent is removed in vacuo and the residue dissolved in EtOAc and washed with sat. aq. NH4C1 solution, dried (MgSO4) and concentrated in vacuo to yield [4-(2-Methoxy-ethoxymethoxy)-phenyl]-acetic acid
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([I:14])[C:11]=1[O:12][CH3:13])[NH2:8])([CH3:4])([CH3:3])[CH3:2].ClC[C:17]([N:19]=C=O)=[O:18].N12CCCN=C1CCCCC2>O1CCOCC1>[C:1]([C:5]1[CH:6]=[C:7]([NH:8][C:17]([NH2:19])=[O:18])[CH:9]=[C:10]([I:14])[C:11]=1[O:12][CH3:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=NC(=O)CCl
Reactant: COc1c(I)cc(N)cc1C(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: COc1c(I)cc(NC(N)=O)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-tert-butyl-5-iodo-4-methoxyaniline (915 mg, 3.0 mmol) in dioxane (20 mL) at 0° C. was added chloroacetyl isocyanate (0.256 mL, 3.00 mmol) dropwise to give a solution that was stirred at room temperature for 3 hours. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.904 mL, 6.00 mmol) was added and the solution was stirred for 18 hours and partitioned between ethyl acetate and 1 M HCl. The ethyl acetate was washed with H2O, brine and dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified on an Isco 40 g silica cartridge eluting with methanol/dichloromethane (0% to 5%) to give the title compound.
Reaction SMILES: [C:1]([O:7]CC)(=O)[CH2:2][C:3]([CH3:5])=[O:4].[CH2:10]([NH:12][CH2:13][CH3:14])[CH3:11]>>[CH2:10]([N:12]([CH2:13][CH3:14])[C:1](=[O:7])[CH2:2][C:3](=[O:4])[CH3:5])[CH3:11]
Reactant: CCNCC
Reactant: CCOC(=O)CC(C)=O
Product: CCN(CC)C(=O)CC(C)=O
Yield: 65.7 %

Procedure:
40 g (0.31 mol) of ethyl acetoacetate and 24 g (0.33 mol) of diethylamine were stirred in a Parr apparatus at 150° C. for 10'. The crude mixture was distilled at 115°-120° C./9 mmHg, to give 32 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1/[CH:12]=[CH:13]/[C:14]([O:16]CC)=O>Cl.O1CCOCC1>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[NH:1][C:14](=[O:16])[CH:13]=[CH:12]2
Reactant: CCOC(=O)/C=C/c1cc(C(F)(F)F)ccc1N
Agent: Cl
Solvent: C1COCCO1
Product: O=c1ccc2cc(C(F)(F)F)ccc2[nH]1
Temperature: 100 °C

Procedure:
To a stirring mixture of (E)-ethyl 3-(2-amino-5-(trifluoromethyl)phenyl)acrylate (4 g, 15.4 mmol) in 4N HCl in dioxane (20 mL) was added concentrated HCl (3 mL). The resulting mixture was warmed to 100° C. overnight. The reaction mixture was cooled to rt and then slowly quenched with a cold saturated NaHCO3 solution until pH>7. A normal aqueous extraction with EtOAc was followed. The crude mixture was taken directly to the next reaction without further purification. Retention time(min)=1.849, method [1], MS (ESI) 214.0 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[N:19][NH:20][C:21](=[O:33])[CH2:22][CH:23]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:24]Br)[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.[H-].[Na+].[Cl-].[NH4+]>O1CCCC1>[CH2:26]([CH:23]1[CH2:24][N:20]([N:19]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11][CH:10]=2)[C:21](=[O:33])[CH2:22]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(CC(CBr)Cc1ccccc1)NN=C(Cc1ccnc2ccccc12)c1ccccn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C1CC(Cc2ccccc2)CN1N=C(Cc1ccnc2ccccc12)c1ccccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-benzyl-4-bromo-butyric acid(1-pyridin-2-yl-2-quinolin-4-yl-ethylidene)-hydrazide (PREP. 70, 0.8 g, 1.6 mmol) in tetrahydrofuran (26 mL) at 0° C. is treated with NaH (60% in mineral oil, 0.086 g, 2.2 mmol). The mixture is warmed to room temperature and stirred for 2 h. Saturated ammonium chloride (2 mL) is added and volatiles removed in vacuo. The residue is chromatographed on SiO2 (90% ethyl acetate/hexanes followed by dichloromethane:methanol:ammonium hydroxide/94:5:1) to yield the title compound, 0.4 g (45%), as a yellowish foam.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3]1.[CH2:10]([N:12](CC)[CH2:13]C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.CNC>CN(C=O)C>[CH3:10][N:12]([CH3:13])[C:7]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)=[O:9]
Reactant: CCN(CC)CC
Reactant: Cn1cc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cnn(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl-1H-pyrazole-4-carboxylic acid (1.0 g, 7.93 mmol) was combined with DMF (10.0 ml) to give a light yellow solution. Triethylamine (3.3 ml, 23.8 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (2.8 g, 8.72 mmol) were added. The reaction mixture was set under argon and stirred for 1 h at RT. Then dimethylamine hydrochloride (679 mg, 8.33 mmol) was added. The reaction mixture was stirred over night. The solvent was evaporated and the residue was absorbed on silica gel and chromatographed (amine silica gel cartridge, CH2Cl2). The resulting brown oil was dried at the HV over night. Yield: 1.16 g (96%); brown oil; MS: m/z=154.1 [M+H]+.