Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]([CH2:28][CH2:29][CH2:30]O)[C:20]4=[O:32])[CH2:15][CH2:14]2)[CH2:5][CH2:4][CH:3]3[CH2:2]1.[S:33]1[CH2:37][C:36](=[O:38])[NH:35][C:34]1=[O:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]4[C:23]5[CH:22]=[CH:27][CH:26]=[CH:25][C:24]=5[N:21]([CH2:28][CH2:29][CH2:30][N:35]5[C:36](=[O:38])[CH2:37][S:33][C:34]5=[O:39])[C:20]4=[O:32])[CH2:15][CH2:14]2)[CH2:5][CH2:4][CH:3]3[CH2:2]1
Reactant: O=C1CSC(=O)N1
Reactant: O=c1n(CCCO)c2ccccc2n1C1CCN(C2CCC3CCc4cccc2c43)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1CSC(=O)N1CCCn1c(=O)n(C2CCN(C3CCC4CCc5cccc3c54)CC2)c2ccccc21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
1-[1-(1,2,2a,3,4,5-Hexahydroacenaphthylen-5-yl)piperidin-4-yl]-3-(3-hydroxypropyl)-1,3-dihydro-2H-benzimidazol-2-one and 2,4-thiazolidinedione (314 mg) were dissolved in THF (25 ml), 40% solution (1.22 ml) of triphenylphosphine (702 mg) and diethyl azodicarboxylate (DEAD) in toluene was added, and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (160 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([C:14]2[CH:23]=[CH:22][C:17]3[N:18]([CH3:21])[N:19]=[N:20][C:16]=3[CH:15]=2)[OH:13])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]>C(Cl)Cl.O=[Mn]=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:12]([C:14]2[CH:23]=[CH:22][C:17]3[N:18]([CH3:21])[N:19]=[N:20][C:16]=3[CH:15]=2)=[O:13])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(O)c2ccc3c(c2)nnn3C)ccc1OC
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCOc1cc(C(=O)c2ccc3c(c2)nnn3C)ccc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (3-ethoxy-4-methoxy-phenyl)-(1-methyl-1H-benzotriazol-5-yl)-methanol from above and MnO2 (2.5 g, 29 mmol) in methylene chloride (40 mL) was stirred at room temperature for 18 h. More MnO2 (1.5 g) was added and kept for overnight. The suspension was filtered thru a pad of Celite. Removal of solvent gave (3-ethoxy-4-methoxy-phenyl)-(1-methyl-1H-benzotriazol-5-yl)-methanone as an off-white solid (1.12 g, 58% yield 2 step): 1H NMR (CDCl3) δ 1.49 (t, J=7 Hz, 3H, CH3), 3.97 (s, 3H, CH3), 4.17 (q, J=7 Hz, 2H, CH2), 4.36 (s, 3H, CH3), 6.91 (d, J=8 Hz, 1H, Ar), 7.40 (dd, J=2, 8 Hz, 1H, Ar), 7.50 (d, J=2 Hz, 1H, Ar), 7.62 (d, J=8 Hz, 1H, Ar), 8.04 (dd, J=2, 9 Hz, 1H, Ar), 8.44-8.45 (m, 1H, Ar).
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:13]([NH:15][C@@H:16]([C:21]([NH:23][CH2:24][C:25]([NH:27][C@H:28]([C:36]([NH:38][C@H:39]([C:45]([NH:47][C@H:48]([C:53]([OH:55])=[O:54])[CH2:49][C:50](=[O:52])[OH:51])=[O:46])[CH2:40][CH2:41][C:42](=[O:44])[OH:43])=[O:37])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:35])[NH2:34])=[O:26])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.N1CCCCC1.C(O)(=O)C>CS(C)=O>[NH2:1][C@H:2]([C:13]([NH:15][C@@H:16]([C:21]([NH:23][CH2:24][C:25]([NH:27][C@H:28]([C:36]([NH:38][C@H:39]([C:45]([NH:47][C@H:48]([C:53]([OH:55])=[O:54])[CH2:49][C:50](=[O:51])[OH:52])=[O:46])[CH2:40][CH2:41][C:42](=[O:43])[OH:44])=[O:37])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:34])[NH2:35])=[O:26])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CC(C)C[C@@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(=O)O)C(=O)O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CC(C)C[C@@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(=O)O)C(=O)O

Procedure:
Fmoc-L-Trp-D-Leu-Gly-L-Arg-L-Glu-L-Asp-OH (50 mg), was dissolved in 0.5 ml of dimethylsulfoxide and 0.5 ml of piperidine was added to the solution. After reacting for an hour, the reaction mixture was neutralized with acetic acid under cooling.
Reaction SMILES: [OH-].[Na+:2].C[O:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]2[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[N:15]=[C:9]2[CH:8]=1)=[O:6]>C1COCC1.CO>[Na+:2].[Cl:22][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:9]3[CH:8]=[C:7]([C:5]([O-:6])=[O:4])[CH:12]=[CH:11][N:10]3[CH:13]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccn2cc(-c3cccc(Cl)c3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C([O-])c1ccn2cc(-c3cccc(Cl)c3)nc2c1
Reaction time: 4 h

Procedure:
Sodium hydroxide (1 mL, 2N) was added to a solution of 2-(3-chloro-phenyl)-imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (122 mg, 0.43 mmol) in THF (4 mL) and methanol (1 mL). The mixture was stirred for 4 hours then evaporated to dryness. Ethyl acetate was added and removed in vacuo three times to afford crude 2-(3-chloro-phenyl)-imidazo[1,2-a]pyridine-7-carboxylic acid sodium salt (quantitative yield) which was used without further purification. m/z (M+H)=273.1.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH:23]=O>CO>[OH:16][C:8]1[CH:7]=[CH:6][C:5]([C@@H:3]([OH:4])[C@@H:2]([NH:1][CH2:23][C:22]2[CH:25]=[C:26]([O:30][CH3:31])[C:27]([O:28][CH3:29])=[C:20]([O:19][CH3:18])[CH:21]=2)[CH3:17])=[CH:10][C:9]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: C[C@H](N)[C@H](O)c1ccc(O)c(NS(C)(=O)=O)c1
Reactant: COc1cc(C=O)cc(OC)c1OC
Solvent: CO
Product: COc1cc(CN[C@@H](C)[C@H](O)c2ccc(O)c(NS(C)(=O)=O)c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 35.4 %

Procedure:
Borane-pyridine complex (135 μL, 1.28 mmol) was added to a methanol solution (4 mL) of an amine (3) (111 mg, 0.43 mmol) and 3,4,5-trimethoxybenzaldehyde (111 mg, 0.55 mmol) at 40° C. and the mixture was stirred for 1.5 hours. The reaction mixture was allowed to cool to room temperature and extracted after addition of water with a mixed solvent (ethyl acetate: methanol=10:1), and the organic layer was washed with saturated aqueous sodium chloride solution. The organic layer was dried and concentrated, and the crude product obtained was purified by amine silica gel column chromatography (eluant:chloroform:methanol=7:1), to give a desired amine (7) as a white solid (67 mg, yield 36%).
Reaction SMILES: [F:1][CH2:2][C:3](=O)[CH3:4].[Cl:6][C:7]1[C:34]([Cl:35])=[CH:33][C:10]2[N:11]([C@H:15]3[O:27][C@@H:26]([CH2:28][O:29][C:30](=[O:32])[CH3:31])[C@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@@H:16]3[O:17][C:18](=[O:20])[CH3:19])[C:12]([NH2:14])=[N:13][C:9]=2[CH:8]=1.CC1C=CC(S(O)(=O)=O)=CC=1.C([BH3-])#N.[Na+]>C(OCC)(=O)C>[Cl:6][C:7]1[C:34]([Cl:35])=[CH:33][C:10]2[N:11]([C@H:15]3[O:27][C@@H:26]([CH2:28][O:29][C:30](=[O:32])[CH3:31])[C@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@@H:16]3[O:17][C:18](=[O:20])[CH3:19])[C:12]([NH:14][CH:3]([CH3:4])[CH2:2][F:1])=[N:13][C:9]=2[CH:8]=1
Reactant: CC(=O)CF
Reactant: CC(=O)OC[C@@H]1O[C@H](n2c(N)nc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@@H]1O[C@H](n2c(NC(C)CF)nc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reaction time: 6 h
Yield: 24.4 %

Procedure:
Fluoroacetone (5 g) and 5,6-dichloro-2-amino-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole (0.38 g, 0.82 mmol) were combined with tosic acid (0.050 g, 0.26 mmol) and stirred at reflux in a flask fitted with a Dean Stark trap. After four hours sodium cyanoborohydride (0.16 g, 2.4 mmol) was added and reflux was continued for six hours. The solution was diluted with ethyl acetate (200 mL) and washed with sat'd NaCl (2×50 mL) and water (50 mL). The organics were dried (Na2SO4), decanted, and concentrated. The crude product was purified on a silica gel column (230-400 mesh, 2.5×18 cm) with 1:25 methanol:CH2Cl2 gave 0.19 g of crude product This material was further purified on a chromatotron (2 mm rotor) with 1:1 ethyl acetate hexanes to give a light yellow solid (0.10 g, 0.20 mmol, 24%); MS (API+; m/z (rel. intensity) 520 (62.63, M+); 1H NMR (DMSO-d6) d 7.66 (s, 1H, Ar—H), 7.51 (s, 1H, Ar—H), 7.30 (d, 1 H, NH, J=7.6 Hz), 6.25 (d, 1H, H-1′, J=7.5 Hz), 5.31-5.23 (m, 1H, H-2′), 5.48-5.44 (m, 1H, H-3′), 4.63-4.26 (m, 6H, 2F, CH, H-4′ and 5′), 2.21 (s, 3H, OAc), 2.19 (s, 3H, OAc), 2.02 (s,3H, OAc), 1.24 (d, 3H, CH(CH3), J=7.5 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([NH:22][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])([C:13]([F:21])([F:20])[CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([N:22]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:24])[CH2:14][C:13]2([F:21])[F:20])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)(C(F)(F)COS(C)(=O)=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(C1)N(C(=O)OCc1ccccc1)CC2(F)F
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a solution of an optically-active compound of 3-benzyloxycarbonylamino-3-(1,1-difluoro-2-methanesulfonyloxyethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (565 mg) in N,N-dimethylformamide (17 ml) cooled to 0° C. was added sodium hydride (71 mg, with 40% mineral oil), and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the titled compound (397 mg).
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][N:6]1[CH:14]([CH3:16])[CH3:15].[OH-].[Na+]>CO>[CH:14]([N:6]1[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]1[CH2:4][C:3]([OH:17])=[O:2])([CH3:16])[CH3:15]
Reactant: COC(=O)CC1c2ccccc2CN1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)N1Cc2ccccc2C1CC(=O)O
Reaction time: 48 h
Yield: 85.3 %

Procedure:
To the compound of Step B (0.53 g., 2.30 mmol) in MeOH (5.1 mL) was added 1.0N NaOH (2.53 mL, 2.53 mmol). After two days, the solution was concentrated to dryness. The resulting residue was diluted with 1.0N HCl and water was loaded onto a strong cation exchange resin. The resin was washed with water, TBF/water (1:1) and then water. The product was then eluted from the resin with pyridine/water (1:9). The eluent was concentrated to dryness to afford about 0.43 g (85%) of the final compound. EIS-MS 220 [M+1].
Reaction SMILES: [CH:1]([NH:3]/[C:4](/[C:14](/[NH:24][CH:25]=O)=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])=[CH:5]\[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])=O.ClCCl.P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.N1C=CC=CC=1.C(OCC)(=O)C>[N+:3](/[C:4](/[C:14](/[N+:24]#[C-:25])=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])=[CH:5]\[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])#[C-:1]
Reactant: COc1ccccc1/C=C(NC=O)/C(=C/c1ccccc1OC)NC=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: [C-]#[N+]C(=C\c1ccccc1OC)/C(=C/c1ccccc1OC)[N+]#[C-]
Reaction time: 0.75 h
Yield: 59.1 %

Procedure:
1,1′-[(1Z,3Z)-2,3-diformylamino-1,3-butadiene-1,4-diyl]bis[methoxybenzene] (11.0 mg, 0.031 mmol) prepared in Reference Synthetic Example 4 was suspended in chloroform (200 μl) and pyridine (200 μl), and a dichloromethane solution of phosphorus oxychloride (6.4 μl, 0.069 mmol) was dropwise added under cooling with ice. After stirring for 45 minutes, the suspension was diluted with ethyl acetate, and poured into a saturated sodium hydrogen carbonate aqueous solution. Extraction with ethyl acetate was carried out twice, and the obtained organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give the desired compound 1,1′-[(1Z,3Z)-2,3-diisocyano-1,3-butadiene-1,4-diyl]bis[methoxybenzene] (xanthocillin X dimethyl ether) (5.8 mg, 59%) as pale green crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[C:8]([CH2:13][CH3:14])=[N:7]2.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:9]1[C:8]([CH2:13][CH3:14])=[N:7][C:6]2[C:11]([N:10]=1)=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1nc2cccc(Cl)c2[nH]c1=O
Product: CCc1nc2cccc(Cl)c2nc1Cl
Yield: 77.2 %

Procedure:
A thick slurry of 8-chloro-3-ethylquinoxalin-2(1H)-one (1.00 Kg, 4.79 mol) in POCl3 (2.68 L, 28.8 mol) was stirred at 100° C. for 2 h. At this time LC-MS analysis showed that the reaction was complete. After the removal of most of the POCl3 under reduced pressure, the residue was poured carefully into ice-water and neutralized with a combination of 2M aq. NaOH and saturated aq. NaHCO3. The resulting suspension was extracted with DCM (3×4 L). The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The crude was purified by flash column chromatography eluting with hexane/EtOAc (30/1) to give 3,5-dichloro-2-ethylquinoxaline (840 g) as a white solid. 1H NMR (DMSO-d6) δ ppm 8.01-8.08 (m, 2H), 7.84 (t, J=8.0 Hz, 1H), 3.10-3.17 (d, J=7.3 Hz, 2H), 1.36 (t, J=7.3 Hz, 3H). Mass Spectrum (ESI) m/z=227.1 (M+1).
Reaction SMILES: [C:1]([O:7][CH2:8]C)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[C:10](OC)(=O)[CH2:11][SH:12].[Na]>ClCCl>[OH:4][C:3]1[CH:5]=[C:11]([CH3:10])[S:12][C:2]=1[C:1]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CS
Reactant: CCOC(=O)CC(C)=O
Agent: [Na]
Solvent: ClCCl
Product: COC(=O)c1sc(C)cc1O
Yield: 52.3 %

Procedure:
Prepared by the method described in Example 1 from ethyl acetoacetate (130 g, 1.0 mole), methyl thioglycolate (212 g, 2.0 moles) and sodium (53 g, 2.3 moles). The crude product is shaken with two portions of dichloromethane, filtered, and the filtrate stripped of solvent under reduced pressure to afford the product (90.1 g); mp 50°-53° C.
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][CH:7]=[C:6]2[O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22]([NH2:26])=[CH:23]2)=[CH:18][CH:17]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:48][C:49]1[CH:57]=[CH:56][C:52]([C:53](O)=[O:54])=[CH:51][C:50]=1[C:58]([F:61])([F:60])[F:59].CCN(C(C)C)C(C)C>CN(C=O)C.O>[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][CH:7]=[C:6]2[O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22]([NH:26][C:53](=[O:54])[C:52]3[CH:56]=[CH:57][C:49]([Cl:48])=[C:50]([C:58]([F:61])([F:59])[F:60])[CH:51]=3)=[CH:23]2)=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: COc1cc2nccc(Oc3ccc4ccc(N)cc4c3)c2cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc4ccc(NC(=O)c5ccc(Cl)c(C(F)(F)F)c5)cc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 7-(6,7-dimethoxyquinolin-4-yloxy)naphthalen-2-amine (0.137 g, 0.40 mmol) in 10 mL of DMF was added EDCI (0.077 g, 0.40 mmol), HOBt (0.054 g, 0.40 mmol), and 4-chloro-3-(trifluoromethyl)benzoic acid (0.099 g, 0.44 mmol). DIPEA (0.140 mL, 0.80 mmol) was added and the solution was stirred for 16 h at RT under an atmosphere of nitrogen. The reaction was diluted with water and extracted with EtOAc 3×. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified using a Gilson Prep HPLC system. The fractions were collected, combined, treated with NaHCO3(aq) and extracted with EtOAc 3×. The organic layer was dried (Na2SO4), filtered and concentrated to afford the desired compound. MS (ESI, pos. ion) m/z: 553.0 (M+1). Mass Calc'd for C29H20ClF3N2O4: 552.934.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]([C:11]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:13]=2[N:12]=1)[CH3:10])C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:26][C:23]1[CH:24]=[CH:25][C:13]2[N:12]=[C:11]([C@@H:9]([NH:7][CH3:6])[CH3:10])[N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:14]=2[CH:22]=1
Reactant: C[C@@H](c1nc2ccc(F)cc2n1-c1ccccc1)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@@H](C)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.6 %

Procedure:
To a solution of [(S)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]methylcarbamic acid tert-butyl ester (0.264 g, 0.72 mmol) in DCM (8 mL) was added TFA (4 mL) and the mixture stirred at RT for 1.5 h. The volatiles were removed under in vacuo and the resulting residue partitioned between DCM and a saturated aqueous solution of NaHCO3. The two phase system was stirred for 10 minutes and then the aqueous phase extracted with DCM. The combined organic fractions were dried (MgSO4) and concentrated in vacuo to afford the title compound as a colourless oil (102 mg, 53%). LCMS (Method J): RT 1.80 min [M+H]+ 270.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][CH2:10][CH2:9][CH2:8]2.[NH2:13][C:14]1[N:19]=[C:18]([NH2:20])[C:17]([CH2:21]O)=[CH:16][N:15]=1>>[NH2:13][C:14]1[N:19]=[C:18]([NH2:20])[C:17]([CH2:21][C:5]2[CH:6]=[C:7]3[C:12](=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:11][CH2:10][CH2:9][CH2:8]3)=[CH:16][N:15]=1
Reactant: COc1cccc2c1NCCC2
Reactant: Nc1ncc(CO)c(N)n1
Product: COc1cc(Cc2cnc(N)nc2N)cc2c1NCCC2

Procedure:
8-Methoxy-1,2,3,4-tetrahydroquinoline (J. L. Neumeyer and J. G. Cannon, J. Pharm. Sci., 51, 804 (1962)) (2.88 g) was treated by the method of Example 1 with 2,4-diamino-5-hydroxymethylpyrimidine. The product crystallized from the reaction mixture as an off-white solid, which was washed with water and treated with ammonia, followed by recrystallization from absolute ethanol (5.0 g). A slight impurity was removed on a silica gel column, which was eluted with 19:1 methylene chloride:methanol, taken to dryness, and recrystallized once more from absolute ethanol; m.p., 201°-203° C. Anal. Calcd. for C15H19N5O: C, 63.14; H, 6.71; N, 24.54. Found: C, 63.23; H, 6.75; N, 24.47.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:21]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:22])=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]2[CH3:20].CI.[C:30](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:30][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:21]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:22])=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]2[CH3:20]
Reactant: O=C([O-])[O-]
Reactant: CC1=CC(C)(C)Nc2ccc(-c3ccccc3O)c(C(=O)N3CCCC3)c21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1ccc2c(c1C(=O)N1CCCC1)C(C)=CC(C)(C)N2
Temperature: 50 °C
Reaction time: 8 h
Yield: 63.1 %

Procedure:
A mixture of 6-(2-hydroxyphenyl)-5-[(pyrrolidin-1-yl)carbonyl]-2,2,4-trimethyl-1,2-dihydroquinoline (Compound No. 8-1, 65.0 mg, 0.179 mmol), methyl iodide (11.1 μL, 0.178 mmol) and potassium carbonate (49.5 mg, 0.358 mmol) was suspended in anhydrous N,N-dimethylformamide (1.5 mL), and the reaction mixture was stirred at 50° C. overnight. After cooling down, it was diluted with ethyl acetate (100 mL). The whole was washed with water (100 mL) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (42.5 mg) as a colorless solid. (Yield 63%)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:20]([O:13][C:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]([F:11])([F:12])[F:10])=[CH:7][C:2]=1[Br:1])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(OC(F)(F)F)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)(F)Oc1ccc(OCc2ccccc2)c(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
To a suspension of 2-bromo-4-(trifluoromethoxy)phenol (3 g, 11.7 mmol) and potassium carbonate (3.23 g, 23.4 mmol) in N,N-dimethylformamide (35 mL) was added benzyl bromide (2.1 mL, 17.5 mmol) dropwise and stirred at room temperature for 16 hours. Reaction mixture was diluted with ethyl acetate and washed with water, saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel column chromatography eluting with ethyl acetate:hexane (2:98, by volume) afforded the title compound, 3.3 g, 81% yield.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]2)(=O)=O)=CC=1.[N+:20]([C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)([O-:22])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:19][C:15]1([CH3:18])[O:14][CH:13]([CH2:12][N:25]2[CH:24]=[C:23]([N+:20]([O-:22])=[O:21])[CH:27]=[N:26]2)[CH2:17][O:16]1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC1(C)OCC(Cn2cc([N+](=O)[O-])cn2)O1
Yield: 88.9 %

Procedure:
A solution of (2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (1.57 g, 5.5 mmol), 4-nitro-1H-pyrazole (0.57 g, 5.0 mmol) and cesium carbonate (4.89 g, 15.0 mmol) in acetonitrile (30 mL) was stirred at 70° C. under N2 overnight. The reaction mixture was filtered, and the resulting filtrate was concentrated. The residue was diluted with ethyl acetate (50 mL), washed with water (50 mL×2) and brine (50 mL), dried over sodium sulfate, filtered, and concentrated to afford 1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-4-nitro-1H-pyrazole (1.01 g, crude), which was directly used in the next step without further purification. MS (ES+) C9H13N3O4 requires: 227, found: 228 [M+H]+.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[C:15]([S:16][CH3:17])=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[CH3:22]O>>[F:6][C:7]1[C:15]([S:16][CH3:17])=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=[CH:12][C:8]=1[C:9]([O:11][CH3:22])=[O:10]
Reactant: CSc1c(C(F)(F)F)ccc(C(=O)O)c1F
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C(F)(F)F)c(SC)c1F

Procedure:
5 ml of concentrated sulfuric acid were added to 20.0 g (78.7 mmol) of 2-fluoro-3-methylthio-4-(trifluoromethyl)benzoic acid in 200 ml of methanol, and the mixture was heated under reflux until HPLC analysis showed complete conversion. The mixture was cooled and the solvent was removed. The residue was taken up in water, and the mixture was extracted twice with ethyl acetate. The combined organic phases were washed once with saturated aqueous NaHCO3 solution. Finally, the organic phase was dried and the filtrate was concentrated. This gave 20.5 g of methyl 2-fluoro-3-methylthio-4-(trifluoromethyl)benzoate.