Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([OH:21])[CH:15]=2)=[CH:9][C:8]=1[CH3:22])[CH3:2].[Br:24][C:25]1[CH:26]=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:28]=[CH:29][C:30]=1F.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.O>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([O:21][C:30]3[CH:29]=[CH:28][C:27]([C:32]([F:35])([F:34])[F:33])=[CH:26][C:25]=3[Br:24])[CH:15]=2)=[CH:9][C:8]=1[CH3:22])[CH3:2]
Reactant: CCOC(=O)CCc1ccc(Oc2ccc(C)c(O)c2)cc1C
Reactant: Fc1ccc(C(F)(F)F)cc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)CCc1ccc(Oc2ccc(C)c(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Temperature: 100 °C
Reaction time: 6 h
Yield: 87.5 %

Procedure:
A mixture of 3-[4-(3-hydroxy-4-methyl-phenoxy)-2-methyl-phenyl]-propionic acid ethyl ester (Example 82, Step J) (1.05 g, 3.34 mmol), 3-bromo-4-fluorobenzotrifluoride (0.81 g, 3.34 mmol) and 325 mesh potassium carbonate (0.55 g, 3.97 mmol) in dry DMSO (15 mL) is heated to 100° C. and stirred for 6 hours under N2. The reaction is cooled and acidified with 1 N HCl. The mixture is diluted with water and extracted with Et2O. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 9/1 hexanes/ethyl acetate to afford 1.57 g (88%) of the title compound. Rf=0.38 (4/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C26H24O4F3Br 536, found 554 and 556 (M+NH4, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:16][CH2:15][CH2:14][CH:13]2[CH2:12][NH:11][CH2:10][CH2:9]3)[CH:5]=[CH:6][CH:7]=1.[CH2:17](I)[CH:18]=[CH2:19].C(=O)(O)[O-].[Na+]>>[OH:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:16][CH2:15][CH2:14][CH:13]2[CH2:12][N:11]([CH2:19][CH:18]=[CH2:17])[CH2:10][CH2:9]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(C23CCCC2CNCC3)c1
Reactant: C=CCI
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCN1CCC2(c3cccc(O)c3)CCCC2C1

Procedure:
Following the procedure set forth in Example 36, 4a-(3-hydroxyphenyl)-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine was reacted with allyl iodide in the presence of sodium bicarbonate to provide 4a-(3-hydroxyphenyl)-2-(2-propenyl)-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine. M.P. 106°-108° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:12])=[C:4]([CH2:10][OH:11])[C:5]([F:9])=[C:6]([F:8])[CH:7]=1.CCN(C(C)C)C(C)C.Br[CH2:23][CH2:24][O:25][CH2:26][CH2:27]Br>CN(C=O)C.CCOC(C)=O>[F:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([N:1]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[C:3]([F:12])[C:4]=1[CH2:10][OH:11]
Reactant: Nc1cc(F)c(F)c(CO)c1F
Reactant: BrCCOCCBr
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: OCc1c(F)c(F)cc(N2CCOCC2)c1F
Temperature: 80 °C
Yield: 48 %

Procedure:
To a solution of (3-amino-2,5,6-trifluorophenyl)methanol (200 mg, 1.1 mmol) in DMF (3 mL) was added DIEA (1.6 mL) and 2-bromoethylether (5 eq) and the reaction heated to 80° C. for 18 h. The reaction was allowed to cool to rt, diluted with EtOAc and washed with H2O then saturated NH4Cl (aq). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was purified by column chromatography (petroleum ether: EtOAc) to give (2,3,6-trifluoro-5-morpholinophenyl)methanol (110 mg, 48%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[C:16](Cl)(=[O:18])[CH3:17]>C(Cl)Cl.O>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:16](=[O:18])[CH3:17])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: Nc1cccc(Br)n1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(Br)n1
Reaction time: 8 h
Yield: 85.3 %

Procedure:
To a solution of 6-bromopyridin-2-amine (10 g, 0.060 mol) and Et3N (25 g, 0.27 mol) in CH2Cl2 (300 mL) was added acetyl chloride (13 g, 0.17 mol) at 0° C. The mixture was stirred overnight. The reaction mixture was diluted with water and extracted with ethyl acetate (200 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give N-(6-bromopyridin-2-yl)acetamide (11 g, 88%). 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J=8.0 Hz, 1H), 7.97 (brs, 1H), 7.55 (t, J=8.0 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 2.19 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].N1C=CC=CC=1.[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH2:27]>C(#N)C>[C:19]([NH:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)C1=C(N)CCCC1
Reactant: ClCc1ccccc1
Reactant: O
Solvent: CC#N
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(NC(=O)c2ccccc2)CCCC1
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
In a 2000 ml flask were charged ethyl 2-aminocyclohexene-1-carboxylate (80.0 g, 472.8 mmol), pyridine (37.4 g, 472.8 mmol), and acetonitrile (190 ml), and the mixture was dissolved by heating to 40° C. While keeping the mixture at 40-50° C., a solution (126 ml) of benzyl chloride (63.14 g, 449.2 mmol) in acetonitrile was added dropwise. The mixture was stirred at 50-60° C. for 1.5 hr, cooled, and water (631 ml) was added dropwise at 20-30° C. over 30 min. After stirring at the same temperature for 30 min, the precipitate was collected by filtration and washed with water (631 ml). The obtained powder was dried under reduced pressure at 60° C. yield 119.62 g, 97%.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8](=[O:11])[NH:9][CH:10]=1.[C:30]([O:35][CH3:36])(=[O:34])[CH:31]([CH3:33])O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.O.O1CCCC1>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH:31]([C:30]([O:35][CH3:36])=[O:34])[CH3:33])=[N:9][CH:10]=1
Reactant: COC(=O)C(C)O
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccc(=O)[nH]c3)c(Cl)cc2F)c1=O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C(C)Oc1ccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
To a mixture of 60 mg of 5-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridone, 1.0 ml of tetrahydrofuran, 25 mg of methyl lactate, and 64 mg of triphenylphosphine, 123 mg of a 40% solution of diisopropyl azodicarboxylate in toluene, and the mixture was stirred for 2 hours at room temperature. The reaction solution was poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 20 mg of 5-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-{1-(methoxycarbonyl)ethoxy}pyridine [present compound 7-12].
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH2:13]([O:15][C:16](=[O:21])[CH2:17][C:18](=[NH:20])[NH2:19])[CH3:14]>C(O)C>[CH2:13]([O:15][C:16]([C:17]1[CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[C:2]([F:12])([F:11])[F:1])[C:17]([C:16]([O:15][CH2:13][CH3:14])=[O:21])=[C:18]([NH2:19])[NH:20][C:18]=1[NH2:19])=[O:21])[CH3:14]
Reactant: CCOC(=O)CC(=N)N
Reactant: O=Cc1ccccc1C(F)(F)F
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1ccccc1C(F)(F)F
Yield: 70 %

Procedure:
Upon boiling a solution of 8.7 g 2-trifluoromethylbenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 ml of ethanol for 2 hours, 2,6-diamino-4-(2-tri-fluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 191°C (ethanol) is obtained.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:16]([C:18]2[CH:19]=[C:20]([C:27]3[C:35]([C:36]([N:38]4[C@H:47]([CH2:48][N:49]5[CH2:54][CH2:53][O:52][CH2:51][CH2:50]5)[CH2:46][C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[CH2:39]4)=[O:37])=[CH:34][C:30]4[O:31][CH2:32][O:33][C:29]=4[CH:28]=3)[N:21]3[C:26]=2[CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:17])=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[OH-].[K+].[Cl:63]CCl>CO>[ClH:63].[OH:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]([C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:16]([C:18]2[CH:19]=[C:20]([C:27]3[C:35]([C:36]([N:38]4[C@H:47]([CH2:48][N:49]5[CH2:54][CH2:53][O:52][CH2:51][CH2:50]5)[CH2:46][C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[CH2:39]4)=[O:37])=[CH:34][C:30]4[O:31][CH2:32][O:33][C:29]=4[CH:28]=3)[N:21]3[C:26]=2[CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:17])=[CH:13][CH:14]=1
Reactant: ClCCl
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N(C(=O)c2cc(-c3cc4c(cc3C(=O)N3Cc5ccccc5C[C@H]3CN3CCOCC3)OCO4)n3c2CCCC3)c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cl
Product: O=C(c1cc(-c2cc3c(cc2C(=O)N2Cc4ccccc4C[C@H]2CN2CCOCC2)OCO3)n2c1CCCC2)N(c1ccccc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.9 g of the compound obtained in Step C (2.3 mmol) in 4 mL of methanol there is added 0.646 g (11.5 mmol) of potassium hydroxide dissolved in 8 mL of methanol. The batch is stirred at ambient temperature for 30 minutes. The reaction mixture is then diluted with dichloromethane and washed successively with 1M HCl solution, saturated aqueous NaHCO3 solution and then brine until a neutral pH is reached. The organic phase is then dried over magnesium sulphate, filtered and evaporated. The crude product thereby obtained is purified by chromatography over silica gel (dichloromethane/methanol gradient). The solid is then dissolved in dichloromethane, and 2 mL of 1M ethereal HCl are added. The batch is stirred for 1 hour and then evaporated to dryness. The hydrochloride thereby obtained is dissolved in a mixture of water/acetonitrile until dissolution is complete, and is then lyophilised.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:19])[C@H:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[NH2:13].[CH:20]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26])=[O:21]>O1CCCC1>[CH3:9][O:10][C:11](=[O:19])[CH:12]([NH:13][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][CH:30]=[C:22]([CH:20]=[O:21])[CH:23]=1)[CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C[C@H](N)C(=O)OC
Reactant: O=Cc1cccc(C(=O)Cl)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CC(NC(=O)c1cccc(C=O)c1)C(=O)OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.4 %

Procedure:
A mixture of 30 ml of tetrahydrofuran, 12 ml of triethylamine and 4.11 g of aspartic acid dimethyl ester hydrochloride was added dropwise to a solution of 3.50 g of 3-formylbenzoic acid chloride in 30 ml of tetrahydrofuran at 10° C. After stirred at room temperature for 6 hours, insolubles were filtered and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 3.01 g of oily 2-[3-formyl-(benzoylamino)]succinic acid dimethyl ester [Compound No. (p)].
Reaction SMILES: [Cl:1]C(OC(Cl)C)=O.C([N:21]1[CH2:24][CH:23]([O:25][CH2:26]/[C:27](/[CH3:30])=[CH:28]/[CH3:29])[CH2:22]1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)C>ClCCl>[ClH:1].[CH3:30]/[C:27](=[CH:28]\[CH3:29])/[CH2:26][O:25][CH:23]1[CH2:24][NH:21][CH2:22]1
Reactant: C/C=C(\C)COC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: CCO
Product: C/C=C(\C)COC1CNC1
Product: Cl
Reaction time: 2 h

Procedure:
1-Chloroethyl chloroformate (107 μL, 1.0 mmol) was added to a solution of (E)-1-benzhydryl-3-(2-methylbut-2-enyloxy)azetidine (290 mg, 0.941 mmol) in dichloromethane (10 mL) at 0° C. The reaction mixture was stirred for 2 hours. Ethanol (10 mL) was then added and the reaction mixture was stirred for an additional 2 hours at 0° C. and 16 hours at room temperature. After concentration to dryness, the crude mixture was triturated in pentane (5 mL) and petroleum ether (5 mL) to afford a colorless oil (211 mg, quantitative).
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:51])([CH2:49][CH3:50])[CH2:4][C:5]1[N:6]=[C:7]([CH2:29][CH:30]([NH:44][C:45](=[O:48])[O:46][CH3:47])[C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][N:38]=3)=[CH:33][CH:32]=2)[N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1>O1CCOCC1.CO>[CH3:2][C:3]([CH3:51])([CH2:49][CH3:50])[CH2:4][C:5]1[N:6]=[C:7]([CH2:29][CH:30]([NH:44][C:45](=[O:48])[O:46][CH3:47])[C:31]2[CH:32]=[CH:33][C:34]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][N:38]=3)=[CH:35][CH:36]=2)[NH:8][CH:9]=1
Reactant: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(NC(=O)OC)c2ccc(-c3ccc(F)cn3)cc2)n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCC(C)(C)Cc1c[nH]c(CC(NC(=O)OC)c2ccc(-c3ccc(F)cn3)cc2)n1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Hydrogen chloride (4N, 2 mL) in dioxane was added to a solution of methyl {2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-[4-(5-fluoropyridin-2-yl)phenyl]ethyl}carbamate in methanol (4 mL) at ambient temperature. The solution was stirred at 50° C. for 2 hr. Concentration of the solution afforded the title compound as a white solid. 1H NMR (500 MHz, CD3OD) δ 8.51 (d, J=3.0 Hz, 1H), 7.95 (d, J=8.5 Hz, 2H), 7.88 (dd, J=4.0, 9.0 Hz, 1H), 7.66 (td, J=3.0, 8.5 Hz, 1H), 7.44 (d, J=8.0 Hz, 2H), 7.13 (s, 1H), 5.15 (t, J=7.7 Hz, 1H), 3.59 (s, 3H), 3.51 (dd, J=8.5, 15.0 Hz, 1H), 3.41 (dd, J=7.0, 14.5 Hz, 1H), 2.49 (dd, J=14.7, 18.7 Hz, 2H), 1.20 (q, J=7.5, 15.2 Hz, 2H), 0.84 (t, J=7.5 Hz, 3H), 0.80 (s, 3H), 0.79 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.CC1C=CC(S(O[C@@H:28]2[CH2:32][CH2:31][O:30][CH2:29]2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C@H:28]3[CH2:32][CH2:31][O:30][CH2:29]3)=[CH:11][CH:10]=2)[O:5]1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CCOC2)cc1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2ccc(O[C@H]3CCOC3)cc2)OC1(C)C
Temperature: 85 °C
Yield: 36.3 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (5 g, 22.8 mmole), (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (6.6 g, 22.8 mmol) and K2CO3 (8.0 g, 58 mmole) in DMF (25 mL) was heated at 85° C. for 15 h. The reaction mixture was diluted with ethyl acetate, washed with water, dried over MgSO4, filtered, and concentrated under vacuum The residue was purified by flash chromatography (silica gel, elute: 5% ethyl acetate in hexane) to give the title compound (2.4 g, 30% yield). MS (ESI) m/z: Calc. 290.2 (M+). Found: 291.1 (M+1).
Reaction SMILES: [Na].[I:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8](O)[N:7]=[C:6]2O.[ClH:15].C(N(CC)CC)C.P(Cl)(Cl)([Cl:25])=O>>[Cl:15][C:8]1[N:7]=[C:6]([Cl:25])[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([I:2])[CH:4]=2)[N:9]=1
Reactant: Oc1nc(O)c2cc(I)ccc2n1
Reactant: Cl
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na]
Solvent: CCN(CC)CC
Product: Clc1nc(Cl)c2cc(I)ccc2n1
Yield: 90 %

Procedure:
To a suspension of 6-iodo-quinazoline-2,4-diol sodium salt (849 mg, 2.74 mmol) in phosphorus oxychloride (20 mL), was added triethylamine hydrochloride (1.70 g, 12.32 mmol). The reaction mixture was heated at 100 C for 16 hours, then concentrated in vacuum. Ice chips were added to the remaining residue, which was diluted with dichloromethane, washed with water and saturated aqueous sodium bicarbonate, then dried over magnesium sulfate to give 2,4-dichloro-6-iodo-quinazoline as an off-white solid (799 mg, 90%). HNMR (500 MHz, DMSO) 7.82 (d, 1H), 8.45 (d, 1H), 8.63 (s, 1H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[C:4]=1[C:5](O)=[O:6].C(Cl)(=O)C([Cl:23])=O.CO>C(Cl)Cl.CN(C=O)C>[CH3:1][S:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[C:4]=1[C:5]([Cl:23])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CSc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)O
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CSc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the mixture containing 2-(methylthio)-4,6-bis(trifluoromethyl)benzoic acid D54 (225 mg) in dry DCM (4 ml), containing dry DMF (1drop), was treated with oxalyl chloride (87 ul, 1.0 mmol) and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure to afford a crude product which was treated with dry methanol (2 ml) and stirred at room temperature overnight. The solvent was then carefully removed under reduced pressure. The residue was chromatographed on silica gel, eluting with 0-10% ethyl acetate in pentane to afford the title product 2-(methylthio)-4,6-bis(trifluoromethyl)benzoyl chloride (60 mg). 1H NMR (CDCl3) δ: 2.62 (3H, s), 7.77 (1H, s), 7.82 (1H, s). Further elution gave methyl 2,4-bis(trifluoromethyl)benzoate (100 mg).
Reaction SMILES: C([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6](OCC)=O)(=O)C.BrC[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl>[O-]CC>[NH2:4][CH:5]([CH2:6][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CCOC(=O)CCCCCCBr
Agent: CC[O-]
Agent: Cl
Product: CCOC(=O)CCCCCCC(N)C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
Diethyl acetamidomalonate (16.7 g) and ethyl 7-bromoheptanoate (16.6 g) were dissolved in ethanolic ethoxide (prepared from sodium (1.51 g) and absolute ethanol (30 ml)) and the mixture was refluxed for 27 hours. The cooled solution was poured into ice-water, the product was extracted into ether, and the dried extract was evapoated to give crude diethyl acetamido-(6-ethoxycarbonylhexyl) malonate as a pale yellow oil, δ2.2(3H, singlet, --COCH3), 4.17(6H, multiplet, 3×--OCH2 --CH3). This amide was refluxed with concentrated hydrochloric acid (111 ml) for 51/2 hours, the cooled solution was washed with ether, and the aqueous layer was decolorised with activated charcoal and evaporated to dryness in vacuo. The residual colourless glass was dissolved in the minimum quantity of absolute ethanol and added dropwise to a stirred, cooled (-10° C.) mixture of absolute ethanol (125 ml) and thionyl chloride (15.7 g). The resulting solution was set aside at room temperature for 1 hour, refluxed for 11/2 hours, cooled, and poured into ice-water, adjusting the pH to 9 with aqueous sodium hydroxide. The mixture was extracted with ether, and the dried extract was concentrated and distilled, giving diethyl 2-aminononanedioate (55% yield) as a colourless oil, b.p. 114°-115°/0.02-03 mm.
Reaction SMILES: C1(C)[CH:6]=[CH:5][C:4]([S:7](O)(=O)=O)=CC=1.[CH2:12]([OH:15])[CH2:13][OH:14].[CH3:16]CCC=S>C1CCCCC1>[CH3:16][S:7][CH2:4][CH2:5][CH:6]1[O:15][CH2:12][CH2:13][O:14]1
Reactant: OCCO
Reactant: CCCC=S
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Product: CSCCC1OCCO1
Reaction time: 0.5 h

Procedure:
Into a 100 ml reaction flask equipped with spin bar, reflux condenser, heating mantle and hot plate with magnetic stirring apparatus is placed 5 ml cyclohexane, 0.2 grams para-toluenesulfonic acid and 3.1 grams (0.05 moles) of 1,2-ethanediol. Over a period of 30 minutes, 5.2 grams (0.05 moles) of 3-methylthiopropionaldehyde is added to the reaction mass. The reaction mass is then heated to reflux and during reflux, water of formation is removed. The refluxing continues for a period of 9 hours. At the end of the 9 hour period, the reaction mass is cooled and transferred to a separatory funnel and washed with one 50 ml portion of saturated sodium chloride solution. The reaction mass is then dried over anhydrous sodium sulfate, filtered and distilled on a Microvigreux column yielding the following fractions:
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[CH3:13][C:14]([CH3:16])=[O:15].[OH-:17].[Na+]>CO.O>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:13][C:14](=[O:15])[CH:16]=[CH:9][C:8]2[CH:11]=[CH:12][C:5]([C:1]([O:3][CH3:4])=[O:17])=[CH:6][CH:7]=2)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(C)=O
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(C=CC(=O)C=Cc2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.6 %

Procedure:
4-Carbmethoxybenzaldehyde (1ae, 0.62 g, 3.8 mmol) and acetone (19, 0.14 ml, 1.9 mmol) were combined in methanol (20 ml) and stirred under a nitrogen atmosphere for 15 min at room temperature. A solution of sodium hydroxide (0.15 g, 3.8 mmol) in water (5 ml) was added the mixture stirred for 18 hr at room temperature under a nitrogen atmosphere. The resulting precipitate was filtered and recrystallized from xylene to give 0.29 g (44%) of a yellow solid: mp 206-210° C. [expected mp 221-223° C.]; 1H NMR: δ 3.92 (s, 6H), 7.12 (d, 2H, J=16.1 Hz), 7.65 (d, 4H, J=8.1 Hz), 7.73 (d, 2H, J=15.9 Hz), 8.06 (d, 4H, J=8.0 Hz); 13C NMR: δ 52.3, 127.1, 128.1, 130.1, 131.6, 138.8, 142.1, 166.2, 188.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([I:18])[S:17][C:10]=12.FC1C=CC([NH:27][C:28]([C:30]2([C:33](O)=[O:34])[CH2:32][CH2:31]2)=[O:29])=CC=1.C1(C(O)=O)(C(O)=O)CC1.[F:45][C:46]1[CH:52]=[CH:51][C:49](N)=[CH:48][CH:47]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:19]([C:49]2[CH:51]=[CH:52][C:46]([F:45])=[CH:47][CH:48]=2)[C:33]([C:30]2([C:28]([NH2:27])=[O:29])[CH2:31][CH2:32]2)=[O:34])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([I:18])[S:17][C:10]=12
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(Cl)c1
Agent: O=C(O)C1(C(=O)O)CC1
Product: NC(=O)C1(C(=O)N(c2ccc(F)cc2)c2ccc(Oc3ccnc4cc(I)sc34)c(Cl)c2)CC1

Procedure:
Prepared from 3-chloro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (0.300 g, 0.499 mmol) and 1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxylic acid (0.167 g, 0.749 mmol; prepared from cyclopropane-1,1-dicarboxylic acid and 4-fluoroaniline using the methods described in WO 2005/030140 and by Shih and Rankin, Synth. Comm. 1996, 26(4), 833-836) according to the procedure for Example 72, Step B. The crude was purified by Biotage 40S (2:1EtOAc/Hexane). After concentration the product was a brown oil (160 mg, 26%). LRMS (ESI pos) m/e 608 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])=[CH:4][C:3]=1[S:21][CH2:22][C:23]([O:25]CC)=[O:24].Cl>O1CCOCC1.C(OCC)(=O)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])=[CH:4][C:3]=1[S:21][CH2:22][C:23]([OH:25])=[O:24]
Reactant: CCOC(=O)CSc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(O)CSc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 80.3 %

Procedure:
8 mg Ethyl 2-(1-hydroxy-4-(thiophene-2-sulfonamido)naphthalen-2-ylthio)acetate (9a) was dissolved in 0.5 ml dioxane, to which was added 0.5 ml HCl solution (4 N). The reaction mixture was heated at 100° C. with M.W. for 10 min and diluted to 20 ml with ethyl acetate. Washed with water and brine, the organic solution was dried over Na2SO4 and filtered. The filtrate was concentrated to dryness affording title compound 6 mg (80%) as a pale yellow solid, m.p.: 175-177° C.