Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH:10]1([CH2:13]O)[CH2:12][CH2:11]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:13][CH:10]2[CH2:12][CH2:11]2)[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: OCC1CC1
Reactant: Oc1cc(Br)cc(Br)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Brc1cc(Br)cc(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3,5-Dibromo-phenol (5 g; 19.9 mmol), cyclopropylcarbinol (1.4 g; 19.9 mmol) and tributylphosphine (8.8 mL; 35.7 mmol) were dissolved in THF (500 mL) in a dried reaction flask under an atmosphere of nitrogen. 1,1′-(Azodicarbonyl)dipiperidine (9.0 g; 35.7 mmol) dissolved in THF (100 mL) was added to the reaction mixture, which was stirred at room temperature for 16 hours. The reaction mixture was partly evaporated, filtered, evaporated to dryness and purified by flash chromatography (ethyl acetate:heptane 0:1→1:10). Yield: 5.45 g; 90%.
Reaction SMILES: [O:1]=[C:2]([NH:5][C:6]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[N:26]=[CH:25][CH:24]=[CH:23]2)([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9]CC)=O)[CH2:3][CH3:4].[H][H]>C(O)(=O)C>[O:9]=[C:7]1[C:6]([NH:5][C:2](=[O:1])[CH2:3][CH3:4])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:17][C:18]2=[CH:19][CH:20]=[CH:21][C:22]3=[C:27]2[N:26]1[CH2:25][CH2:24][CH2:23]3
Reactant: CCOC(=O)C(Cc1cccc2cccnc12)(NC(=O)CC)C(=O)OCC
Reactant: [H][H]
Solvent: CC(=O)O
Product: CCOC(=O)C1(NC(=O)CC)Cc2cccc3c2N(CCC3)C1=O
Yield: 77.8 %

Procedure:
A mixture of diethyl ((1-oxopropyl)amino)(8-quinolinylmethyl)-propanedioate (17.47 g, 0.047 mol) and platnium oxide (0.72 g) in glacial acetic acid (150 mL) was hydrogenated (50 lb initial pressure) until hydrogen uptake ceased (1.8 equiv). The mixture was filtered through celite and the solvent removed under reduced pressure. The product was crystallized from ethyl acetate to give 12.08 g of crystals, mp 136°-140° C. A sample was recrystallized from ethyl acetate for analysis; mp 137°-141° C. Anal. Calcd. for C18H22N2O4 ; C, 65.44; H, 6.71; N, 8.48. Found: C, 65.66; H, 6.64; N, 8.43.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Reactant: O=C1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(Br)cc(NC2CCCCC2)c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (0.3 g, 1.33 mmol) and cyclohexanone (0.64 g, 6.6 mmol) in methanol (3 mL), acetic acid (0.159 g, 2.6 mmol) was added and reaction stirred at room temperature for 3 h. Then sodium cyanoborohydride (0.208 g, 3.3 mmol) was added and reaction stirred overnight. On completion, solvent was removed under reduced pressure and was used directly in the next step.
Reaction SMILES: [O:1]=[S:2]1(=[O:35])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[C:11]([C:31]([F:34])([F:33])[F:32])=[N:12][C:13]([NH:16][C:17]34[CH2:26][CH:21]5[CH2:22][CH:23]([CH2:25][C:19]([C:27]([O:29]C)=[O:28])([CH2:20]5)[CH2:18]3)[CH2:24]4)=[N:14][CH:15]=2)=[O:9])[CH2:4][CH2:3]1.CO.[OH-].[Na+]>O1CCCC1>[O:35]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([C:8]([C:10]2[C:11]([C:31]([F:34])([F:33])[F:32])=[N:12][C:13]([NH:16][C:17]34[CH2:24][CH:23]5[CH2:22][CH:21]([CH2:20][C:19]([C:27]([OH:29])=[O:28])([CH2:25]5)[CH2:18]3)[CH2:26]4)=[N:14][CH:15]=2)=[O:9])[CH2:6][CH2:7]1
Reactant: COC(=O)C12CC3CC(CC(Nc4ncc(C(=O)N5CCS(=O)(=O)CC5)c(C(F)(F)F)n4)(C3)C1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(c1cnc(NC23CC4CC(C2)CC(C(=O)O)(C4)C3)nc1C(F)(F)F)N1CCS(=O)(=O)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
To a mixture of methyl 3-({5-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]-4-(trifluoromethyl)pyrimidin-2-yl}amino)adamantane-1-carboxylate (500 mg) and methanol (2 mL), and tetrahydrofuran (2 mL) was added a 1 M aqueous sodium hydroxide solution (1.9 mL) at room temperature, followed by stirring at 60° C. for 3 hours. The solvent was evaporated under reduced pressure, and to the obtained residue were added water and 1 M hydrochloric acid, followed by stirring at room temperature for 30 minutes. The obtained precipitate was filtered and washed with water to obtain 3-({5-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]-4-(trifluoromethyl)pyrimidin-2-yl}amino)adamantane-1-carboxylic acid (446 mg) as a white powder.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:22]4[CH:23]=[CH:24][C:25]([N:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]5)=[CH:26][CH:27]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)cc2)CC1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (73.0 mg, 0.286 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (29.0 mg, 0.0530 mmol) as the ligand in a manner analogous to Step 2d. The reaction product was isolated as pale yellow solid (0.022 g, 18%). MP=242-244° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.47 (dd, J=6.7, 1.1 Hz, 1H), 8.25-8.20 (m, 2H), 8.10-8.06 (m, 2H), 7.63 (dd, J=7.4, 1.1 Hz, 1H), 7.51-7.46 (m, 2H), 7.01-6.95 (m, 2H), 6.67 (s, 1H), 3.20-3.15 (m, 4H), 3.10 (s, 3H), 2.62-2.58 (m, 4H), 2.36 (s, 3H). MS=463 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5]Br.[CH2:11]([O:13][P:14]([O:18]CC)[O:15][CH2:16][CH3:17])[CH3:12]>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][P:14](=[O:18])([O:15][CH2:16][CH3:17])[O:13][CH2:11][CH3:12]
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1cc(F)cc(F)c1)OCC
Temperature: 135 °C
Reaction time: 8 h

Procedure:
3,5-difluorobenzyl bromide (3.0 mL, 23.2 mmol) was combined with triethylphosphite (9.1 mL, 53.3 mmol) and the mixture heated and stirred at 135° C. overnight. The mixture was put under hi-vacuum and heated to 70° C. for 12 hours. The final product was a clear oil (5.78 g, 94% yield). 1H NMR (400.14 MHz, CDCl3) δ 6.83 (m, 2H), 6.71 (dt, J=9.00, 2.28 Hz), 4.06 (m, 4H), 3.12 (d, J=21.94 Hz, 2H), 1.28 (t, J=7.09 Hz, 6H). 31P{1H} NMR (161.97 MHz, CDCl3): δ 25.22.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[C:5]([C:18]3[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:25][N:26]([CH3:54])[C:27](=[O:53])[C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)=[O:36])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[OH:24][C:20]1[CH:19]=[C:18]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[N:3]=[C:2]([C:41]2[CH:40]=[CH:39][C:38]([NH:37][C:35](=[O:36])[NH:34][C:31]4[CH:30]=[CH:29][C:28]([C:27]([N:26]([CH3:54])[CH3:25])=[O:53])=[CH:33][CH:32]=4)=[CH:43][CH:42]=2)[N:11]=[C:10]3[N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:23]=[CH:22][CH:21]=1
Reactant: Oc1cccc(-c2cccc3c(N4CCOCC4)nc(Cl)nc23)c1
Reactant: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)c4cccc(-c5cccc(O)c5)c4n3)cc2)cc1
Temperature: 95 °C
Reaction time: 2 h
Yield: 10.9 %

Procedure:
To a 50 mL round bottom flask, 3-(2-chloro-4-morpholin-4-ylquinazolin-8-yl)-phenol (80 mg, 0.000234 mol), N,N-dimethyl-4-{3-{4-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ureido}-benzamide (114 mg, 0.00028 mol), cesium carbonate (153 mg, 0.00047 mol), DMF (7 mL) and water (1 mL) were added. The reaction mixture was degassed with nitrogen for 5-10 min. To the same reaction flask, Pd(PPh3)2Cl2 (8 mg, 0.0000011 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude product. The crude product was purified using column chromatography (60-120 silica gel, 2-5% MeOH in chloroform) to yield the title compound [15 mg, 6%]. 1H NMR: (300 MHz, DMSO-d6): δ 9.49 (s, 1H), 9.00 (s, 1H), 8.97 (s, 1H), 8.31 (d, J=8.4 Hz, 2H), 8.00 (d, J=8.4 Hz, 1H), 7.82 (d, J=7.2 Hz, 1H), 7.50-7.59 (m, 5H), 7.29-7.35 (m, 3H), 7.16-7.22 (m, 2H), 6.83 (d, J=8.1 Hz, 1H), 3.83 (m, 8H), 2.97 (s, 6H); LC-MS (ESI): Calculated mass: 588.2; Observed mass: 588.8 [M+H]+ (RT: 0.64 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9](=[N:15]O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[N:18]1([C:23]2[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:28][C:27]([C:26]3[CH:25]=[CH:24][C:23]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[CH:30][CH:29]=3)=[N:15][C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: NCc1ccc(N2CCCC2)cc1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(Cl)cc1
Product: CCOC(=O)c1nc(-c2ccc(N3CCCC3)cc2)[nH]c1-c1ccc(Cl)cc1

Procedure:
Ethyl 3-(4-chlorophenyl)-2-hydroxyimino-3-oxopropionate and 4-(1-pyrrolidinyl)benzylamine are reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 5-(4-chlorophenyl)-2-(4-(1-pyrrolidinyl)phenyl)imidazole-4-carboxylate. Ethyl 5-(4-chlorophenyl)-2-(4-(1-pyrrolidinyl)-phenyl)imidazole-4-carboxylate is reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 5-(4-chlorophenyl)-2-(4-(1-pyrrolidinyl)phenyl)imidazole-4-carboxylic acid. 5-(4-Chlorophenyl)-2-(4-(1-pyrrolidinyl)phenyl)imidazole-4-carboxylic acid is reacted and treated in the same manner as in Example 1 to give 5-(4-chlorophenyl)-2-(4-(1-pyrrolidinyl)phenyl)-N-(2-thiazolyl)imidazole-4-carboxamide.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[C:9]([NH:14][C:15](=[O:20])[O:16][CH:17]([CH3:19])[CH3:18])[CH:10]=[C:11]([F:13])[CH:12]=1.CN(CCN(C)C)C.CN(C)[CH:31]=[O:32]>C1COCC1>[F:6][C:7]1[CH:8]=[C:9]([NH:14][C:15](=[O:20])[O:16][CH:17]([CH3:18])[CH3:19])[CH:10]=[C:11]([F:13])[C:12]=1[CH:31]=[O:32]
Reactant: CC(C)OC(=O)Nc1cc(F)cc(F)c1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)OC(=O)Nc1cc(F)c(C=O)c(F)c1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.5M in hexane, 112 mL, 0.279 mol) was added dropwise at −78° C. to a solution of isopropyl 3,5-difluoro-phenylcarbamate (20 g, 0.093 mol) and N,N,N,N-tetramethylethylenediamine (32 mL, 0.214 mol) in 93 mL of THF, and stirred for 30 min. Dimethylformamide (10.8 mL, 0.140 mol) was then added dropwise at −78° C., stirred for 1 h, and allowed to warm to −20° C. The reaction was then quenched with saturated aqueous ammonium chloride (100 mL). The reaction mixture was extracted with ethyl acetate, the extracts washed with brine, dried (MgSO4), and concentrated. The crude product was triturated with hexane to provide the title compound. The combined hexane washings were concentrated and purified by flash column chromatography (30% ethyl acetate/hexane) to provide additional product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=O)=[CH:5][CH:4]=1.[CH2:16]([NH2:24])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]2[NH:24][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:5][CH:4]=1
Reactant: NCCc1ccccc1
Reactant: COc1ccc(C2CCCCC2=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(C2CCCCC2NCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(4-methoxyphenyl)-cyclohexanone (prepared following the procedure described in W. E. Bachmann et al., J. Am. Chem. Soc., 1950, 72, 1995) (2.0 g, 9.79 mmol), phenethylamine (1.19 g, 9.79 mmol), toluene (40 ml) and a catalytical amount of p-toluenesulfonic acid was refluxed in a Dean-Stark apparatus overnight. After removal of the solvent, the residue was dissolved in MeOH (25 ml) and sodium borohydride (excess) was added. After stirring for 1 h at RT, the solvent was evaporated, H2O was added to the residue. Extraction with CH2Cl2, drying of the organic layer over Na2SO4, evaporation of the solvent and chromatography of the residue over SiO2 (Merck 230-400 mesh) eluting with AcOEt gave (1RS,2RS)-[2-(4-methoxy-phenyl)-cyclohexyl]-phenethyl-amine (1.5 g, 50%, light yellow oil, MS: m/e=310.2 (M+H+)) and (1RS,2SR)-[2-(4-methoxy-phenyl)-cyclohexyl]-phenethyl-amine (0.95 g, 31%, light yellow oil, MS: m/e=310.2 (M+H+)).
Reaction SMILES: [CH:1]12[O:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[CH:2]2[C:3](=[O:12])O[C:5]1=[O:11].[CH2:13]([CH2:15][NH2:16])[OH:14]>CO>[OH:14][CH2:13][CH2:15][N:16]1[C:3](=[O:12])[CH:2]2[CH:6]([CH:7]3[O:10][CH:1]2[CH:9]=[CH:8]3)[C:5]1=[O:11]
Reactant: O=C1OC(=O)C2C3C=CC(O3)C12
Reactant: NCCO
Solvent: CO
Product: O=C1C2C3C=CC(O3)C2C(=O)N1CCO
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 41.7 %

Procedure:
The anhydride, 4,10-dioxa-tricyclo[5.2.1.02,6]dec-8-ene-3,5-dione, (2.00 g, 12.0×10−3 mol) was suspended in 50 mL of MeOH and the mixture cooled to 0° C. A solution of ethanolamine (0.72 mL, 12.0×10−3 mol) in 20 mL of MeOH was added dropwise (10 min) and the resulting solution was stirred for 5 min at 0° C., then 30 min at room temperature and finally refluxed for 4 h. After cooling to room temperature the solvent was removed under reduced pressure, the white residue was dissolved in 150 mL of CH2Cl2 and washed with 3×100 mL of water. The organic layer was dried over MgSO4 and filtered. Removal of the solvent under reduced pressure furnished the desired product (1.04 g 5.0×10−3 mol, 42% yield) as white solid that was used for the next step without further purifications. An analytical sample was obtained by flash chromatography (CC, SiO2, 100% ethyl acetate, Rf(6)=0.26). m.p. 139-141° C. (dec). IR (neat): 3472, 1681, 1435, 1405, 1335, 1269, 1168, 1100, 1053, 1013, 959, 916, 875, 850, 807, 722, 705, 654 cm−1. 1H NMR (400.03 MHz, CDCl3, 298 K) δ=1.90 (bs, 1H, OH); 2.90 (s, 2H, CH), 3.69-3.72 (m, 2H, CH2), 3.76-3.78 (m, 2H, CH2), 5.28 (t, J=0.9 Hz, 2H, CH), 6.52 (t, J=0.9 Hz, 2H, CHvinyl). 13C{1H} NMR (100.59 MHz, CDCl3, 298 K) δ=41.77 (2C, NCH2), 60.18 (2C, OCH2), 47.50 (2C, CH), 81.04 (2C, CH), 136.60 (2C, CHvinyl), 176.97 (2C, C). Anal. Calcd. for C10H11NO4: C, 57.41; H, 5.30; N, 6.70. Found C, 57.16; H, 5.37; N, 6.62.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[C:12]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:11]=[CH:10][CH:9]=2)=[O:4].[Br:23]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([Br:23])[C:8]2[C:13]([C:14]=1[OH:15])=[C:12]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:11]=[CH:10][CH:9]=2)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ncc2cccc(Oc3ccccc3)c2c1O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1nc(Br)c2cccc(Oc3ccccc3)c2c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.8 %

Procedure:
A mixture of 4-hydroxy-5-phenoxy-isoquinoline-3-carboxylic acid methyl ester (1.55 mmol, 458 mg), N-bromosuccinimide (1.7 mmol, 306 mg), benzoyl peroxide (0.08 mmol, 19 mg), and CCl4 (10 mL) was refluxed with stirring for 2 h. After cooling to ambient temperature the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using hexanes:ethyl acetate=9:1 as the eluent to give the title compound as an off-white solid (225 mg); MS-(+)-ion: M+1, 79Br/81Br=373.9 and 375.8.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH2:3][N:4]=[C:5]([NH2:20])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][S:13][CH2:14][CH2:15][C:16]([O:18]C)=O)[N:11]=1.[CH3:23][NH2:24]>CCO>[CH3:23][NH:24][C:16](=[O:18])[CH2:15][CH2:14][S:13][CH2:12][C:10]1[N:11]=[C:7]([NH:6][C:5]([NH2:20])=[N:4][CH2:3][C:2]([F:1])([F:22])[F:21])[S:8][CH:9]=1
Reactant: CN
Reactant: COC(=O)CCSCc1csc(NC(N)=NCC(F)(F)F)n1
Solvent: CCO
Product: CNC(=O)CCSCc1csc(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl 3-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-ylmethylthio]propionate (0.5 g.) in EtOH (20 ml.) was treated with 33% w/v ethanolic methylamine (7 ml.) and stirred for 18 hours at room temperature. The solution was evaporated and the residue crystallised from aqueous EtOH to give N-methyl-3-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-ylmethylthio]propionamide (0.35 g.), m.p. 152°-154° (73%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1[CH3:21].[H][H]>C(O)C.C(O)(=O)C.O=[Pt]=O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1[CH3:21]
Reactant: [H][H]
Reactant: COC(=O)c1cc(Br)ccc1C=Cc1cccc(OC)c1C
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)c1cc(Br)ccc1CCc1cccc(OC)c1C
Temperature: 38 °C

Procedure:
To 5-bromo-2-[2-(3-methoxy-2-methylphenyl)-vinyl]-benzoic acid methyl ester (5) (4.99 g; 13.8 mmol), stirring in ethyl alcohol (70 mL) and acetic acid (23 mL), was added PtO2 (0.075 g; 2.4%). The solution was stirred in a hydrogen atmosphere (balloon pressure) and the temperature of the solution was raised to 38° C. The reaction was monitored closely by TLC and the mixture was cooled after three hours. The reaction mixture was filtered and evaporated to give compound 6 as a residue. The residue was carried on to the next step without further purification.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][OH:8])=[CH:5][CH:4]=[C:3]([OH:9])[CH:2]=1.C1(C)C=CC(S(O[CH2:20][CH2:21][CH:22]([C:27]([F:30])([F:29])[F:28])[CH2:23][CH2:24][CH2:25][CH3:26])(=O)=O)=CC=1.[OH-].[Na+].Cl>C(O)C>[F:28][C:27]([F:29])([F:30])[CH:22]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:21][CH2:20][O:9][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][OH:8])=[CH:1][CH:2]=1
Reactant: CCCCC(CCOS(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Reactant: OCc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCC(CCOc1ccc(CO)cc1)C(F)(F)F
Reaction time: 6 h
Yield: 96.8 %

Procedure:
In a round-bottomed flask, a solution of 2.4 g of p-hydroxybenzyl alcohol in 10 ml of ethanol and 5.3 g of (+)-3-trifluoromethylheptyl p-toluenesulfonate were placed, and a solution of 0.8 g of sodium hydroxide in 10 ml of ethanol was added thereto dropwise, followed by 6 hours of heat-refluxing, cooling by standing and acidification with hydrochloric acid. The organic layer was extracted with diethyl ether. The resultant ether solution was dried with sodium sulfate and subjected to distilling-off of the solvent and purification by silica gel column chromatography to obtain 4.4 g of (+)-p-(3-trifluoromethylheptyloxy)benzyl alcohol. [α]D28 +1.0°, [α]43527 +2.4° (c 5.0, chloroform).
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.[CH2:22]([O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][N:15]1[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12][CH:11]([CH2:10][CH2:9][OH:1])[C:16]1=[O:17])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: OCc1cccc(OCc2ccccc2)c1
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccccc2NC1=O
Product: O=C1C(CCO)Oc2ccccc2N1Cc1cccc(OCc2ccccc2)c1

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine by Methods F and G, alkylating with the methanesulfonate ester of 3-benzyloxybenzyl alcohol, in 67% overall yield as a viscous liquid, after flash chromatography eluting with 30-100% EtOAc in hexane, IR (CHCl3) 3434, 2933, 1681, 1500, 1401, 1256, 1054, 751 cm-1 ; 1H NMR (CDCl3) δ 1.77 (br s, 1H plus HDO), 2.20-2.34 (m, 2H), 3.91 (t, J=5.5 Hz, 2H), 4.82 (dd, J=7.5, 5.7 Hz, 1H), 5.02 (s, 2H), 5.11 (ABq, JAB =16.0 Hz, 2H), 6.85-7.01 (m, 7H), 7.22-7.41 (m, 6H); MH+ at m/z=390; Anal. Calc'd for C24H23NO4 : C, 74.02; H, 5.95; N, 3.60. Found: C, 73.61; H, 6.03; N, 3.55.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([Cl:12])=[CH:10][C:9](=[O:13])[N:8]([CH3:14])[CH:7]=1)=[O:5])[CH3:2].C1C(=O)N([Cl:22])C(=O)C1>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:11]([Cl:12])=[C:10]([Cl:22])[C:9](=[O:13])[N:8]([CH3:14])[CH:7]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1cn(C)c(=O)cc1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(C)c(=O)c(Cl)c1Cl
Reaction time: 1 h
Yield: 94.8 %

Procedure:
A mixture of 4-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester (1.00 g, 4.64 mmol) and NCS (0.68 g, 5.10 mmol) in DMF (30 mL) was stirred for 1 hour. The reaction mixture was diluted with EtOAc and washed with 0.1 N HCl solution. The organic layer was dried (MgSO4) and concentrated under reduced pressure to give 1.10 g (95%) of 4,5-dichloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester.
Reaction SMILES: CC1C=CC(S(C(C2C=CC=C(I)C=2)[N+]#[C-])(=O)=O)=CC=1.[I:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([NH:39][CH:40]=O)[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[CH:24][CH:23]=1.IC1C=C(C(NC=O)S(C2C=CC(C)=CC=2)(=O)=O)C=CC=1>>[CH3:38][C:35]1[CH:34]=[CH:33][C:32]([S:29]([CH:28]([C:25]2[CH:24]=[CH:23][C:22]([I:21])=[CH:27][CH:26]=2)[N+:39]#[C-:40])(=[O:31])=[O:30])=[CH:37][CH:36]=1
Reactant: Cc1ccc(S(=O)(=O)C(NC=O)c2ccc(I)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)C(NC=O)c2cccc(I)c2)cc1
Agent: [C-]#[N+]C(c1cccc(I)c1)S(=O)(=O)c1ccc(C)cc1
Product: [C-]#[N+]C(c1ccc(I)cc1)S(=O)(=O)c1ccc(C)cc1

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 53 but using {(4-iodophenyl)[(4-methylphenyl)sulfonyl]methyl}formamide (Intermediate 60) in place of {(3-iodophenyl)[(4-methylphenyl)sulfonyl]methyl}formamide (Intermediate 52). Brown gum (3.1 g, 20%);
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>C(OCC)C>[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:2]2[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([CH3:10])[N:3]=2)=[CH:14][CH:13]=1
Reactant: Nc1ccc(F)cc1
Reactant: Cc1cc(CO)nc(Cl)n1
Solvent: CCOCC
Product: Cc1cc(CO)nc(Nc2ccc(F)cc2)n1

Procedure:
50 mg (0.32 mmol) of the compound from example 5A and 350 mg (3.15 mmol) of 4-fluoroaniline are stirred together at 160° C. for 2 h. The reaction mixture is then poured into 10 ml of diethyl ether. The precipitate is filtered off and discarded and the filtrate is then purified chromatographically on silica gel 60 (mobile phase: gradient dichloromethane→dichloromethane/ethanol 50:1).