Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[O:41])[CH2:3][O:4][N:5]=[C:6]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH:33]([CH3:35])[CH3:34])=[CH:27][C:26]=1[O:36][CH2:37][CH:38]([CH3:40])[CH3:39])[C:7]1[CH:8]=[CH:9][C:10]([O:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[C:11]([CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])[CH:12]=1.[OH-].[Na+].C(Cl)(Cl)Cl.Cl>C(O)C.O>[NH2:1][C:2](=[O:41])[CH2:3][O:4][N:5]=[C:6]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH:33]([CH3:34])[CH3:35])=[CH:27][C:26]=1[O:36][CH2:37][CH:38]([CH3:40])[CH3:39])[C:7]1[CH:8]=[CH:9][C:10]([O:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[C:11]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:12]=1
Reactant: CCOC(=O)CCc1cc(C(=NOCC(N)=O)c2ccc(OCC(C)C)cc2OCC(C)C)ccc1OCC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: O
Product: CC(C)COc1ccc(C(=NOCC(N)=O)c2ccc(OCC(C)C)c(CCC(=O)O)c2)c(OCC(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.2 %

Procedure:
In 10 ml of ethanol is dissolved 1.08 g of ethyl 3-{5-[[(2-amino-2-oxoethoxy)imino](2,4-diisobutoxyphenyl)methyl]-2-isobutoxyphenyl}propanoate, to which is added 1.1 ml of 5 mol/L sodium hydroxide solution. The mixture is stirred at ambient temperature for 3 hours. Chloroform and water are added to the reaction mixture, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; chloroform:ethanol=10:1) to obtain 0.68 g of 3-{5-[[(2-amino-2-oxoethoxy)imino](2,4-diisobutoxyphenyl)methyl]-2-isobutoxyphenyl}propanoic acid as a white foaming product.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:7][C:6]=1[CH3:16])(=O)C.[OH2:17].[OH2:18].O.O.O.O.O.S([O-])([O-])(=O)=O.[Mg+2].O.[Mn]([O-])(=O)(=O)=O.[K+]>[OH-].[Na+]>[F:11][C:9]1[CH:10]=[C:5]([NH2:4])[C:6](=[CH:7][C:8]=1[S:12](=[O:14])(=[O:15])[NH2:13])[C:16]([OH:18])=[O:17]
Reactant: CC(=O)Nc1cc(F)c(S(N)(=O)=O)cc1C
Reactant: O
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Product: Nc1cc(F)c(S(N)(=O)=O)cc1C(=O)O
Reaction time: 4 h

Procedure:
A mixture of 25.0 g (0.102 molecule) of purified sulphonamide (4), 36.7 g of magnesium sulphate heptahydrate and of 560 ml of water was stirred and heated to 80°. Potassium permanganate (48.1 g) was added, in portions, keeping the temperature between 80° and 85°. The mixture was taken to 90° during 4 hours, filtered hot and the cake, (collected into a mass), of manganese dioxide was washed with water. The filtrate was acidified with concentrated hydrochloric acid and the precipitate of compound 5 was recovered. The moist compound 5 of the above reaction and 4.0 g., previously obtained, were heated under reflux for three hours in 215 ml of 3N sodium hydroxide. The reaction mixture was filtered and the filtrate was acidified with concentrated hydrochloric acid. The separating solid was recovered on a filter, washed with water, then dried in vacuo at 80°; yield: 20.1 g (70.5%).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:9](N(OC)C)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]([Mg]Br)([CH3:25])=[CH2:24]>C1COCC1.CN1C2C(N=C(N)NC=2NCC1CNC1C=CC(C(NC(C(O)=O)CCC(O)=O)=O)=CC=1)=O>[CH:1]1([CH2:7][C@H:8]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])[C:9](=[O:10])[C:23]([CH3:25])=[CH2:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C=C(C)[Mg]Br
Reactant: CON(C)C(=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: CN1c2c([nH]c(N)nc2=O)NCC1CNc1ccc(C(=O)NC(CCC(=O)O)C(=O)O)cc1
Solvent: C1CCOC1
Product: C=C(C)C(=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
To (S)-tert-butyl (3-cyclohexyl-1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate (12.2 g, 38.9 mmol) in THF (150 mL) at 0° C. was added isopropenylmagnesium bromide (71.2 mL of a 1.5 N solution in methyl-THF, 0.107 mol) dropwise. After stirring at 0° C. for 2 h the mixture was quenched with heptane/citric acid (1:1). The product was extracted with EtOAc (2×), washed with brine, dried with sodium sulfate, filtered, and concentrated. The crude product was triturated from cold (0° C.) methanol to provide (S)-tert-butyl (1-cyclohexyl-4-methyl-3-oxopent-4-en-2-yl)carbamate (5.36 g, 49%) as a colorless crystalline solid. MS (EI) for C17H29NO3, found 196.2 [M-Boc]+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:12][CH2:13][CH2:14][OH:15]>N1C=CC=CC=1>[Cl:12][CH2:13][CH2:14][O:15][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: OCCCl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Para-toluenesulphonyl chloride (20.5 g) was added to a mixture of 2-chloroethanol (8.6 g) and pyridine (50 ml). After stirring for one hour at 0° C., the mixture was added to ice and the organic phase was extracted with ether. The extract was washed with dilute hydrochloric acid, dried with magnesium sulphate, and evaporated, to yield 2-chloroethyl-p-toluenesulphonate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[N+:14]([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C1COCC1.O>[NH2:14][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:6]=1[O:5][C:4]1[CH:3]=[C:2]([CH3:1])[CH:19]=[C:18]([CH3:20])[CH:17]=1)[C:10]#[N:11]
Reactant: Cc1cc(C)cc(Oc2ccc(C#N)cc2[N+](=O)[O-])c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)cc(Oc2ccc(C#N)cc2N)c1
Temperature: 90 °C
Reaction time: 24 h
Yield: 95.2 %

Procedure:
A solution of compound 21 (15.00 g, 55.91 mmol) in THF (250 mL) was added a solution of sodium hydrosulfite (58.41 g, 335.5 mmol) in water (75 mL). The reaction mixture was stirred at 90° C. After 24 hrs, the starting material was consumed as monitored with TLC (10% EtOAc in hexanes) and reaction mixture was removed from heat. The reaction mixture was concentrated in vacuo until product precipitated in remaining water. The precipitate was collected via vacuum filtration and washed with water. The product was dried overnight in vacuum at 40° C. to afford compound 22. (12.681 g, 95.2% yield, 99.9% HPLC purity). 1H NMR (500 MHz, DMSO-d6): δ 7.08 (d, J=2 Hz, 1H), 6.91 (dd, J1=8 Hz, J2=2 Hz, 1H), 6.80 (s, 1H), 6.73 (d, J=8 Hz, 1H), 6.63 (s, 2H), 5.47 (s, 2H), 2.24 (s, 6H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9].[Cl:10][CH2:11][C:12](O)=O>Cl.O.C(=O)(O)[O-].[Na+]>[Cl:10][CH2:11][C:12]1[N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:9]=1
Reactant: CNc1ccccc1N
Reactant: O=C(O)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cn1c(CCl)nc2ccccc21
Temperature: 55 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
N-methyl-phenylenediamine (1 g, 8.2 mmol) and chloroacetic acid (0.9 g, 9.4 mol) were dissolved in 5 N aqueous hydrochloric acid (10 mL) and stirred at 55° C. overnight. The reaction mixture was then diluted with water and basified with solid sodium bicarbonate to give a precipitate which was filtered, washed with water and dried to provide the desired compound (1.3 g, 87%).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[F:21][C:22]([C:28]([F:52])([F:51])[C:29]([F:50])([F:49])[C:30]([F:48])([F:47])[C:31]([F:46])([F:45])[C:32]([F:44])([F:43])[C:33]([F:42])([F:41])[C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])(O)[C:23]([F:26])([F:25])[F:24].C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[C:1]([O:20][C:22]([F:21])([C:28]([F:51])([F:52])[C:29]([F:49])([F:50])[C:30]([F:47])([F:48])[C:31]([F:45])([F:46])[C:32]([F:43])([F:44])[C:33]([F:42])([F:41])[C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])[C:23]([F:26])([F:25])[F:24])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: OC(F)(C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OC(F)(C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 92.9 %

Procedure:
With 57 g of oleic acid were mixed 93 g of perfluorooctylethanol and 340 ml of toluene, and 3 g of p-toluenesulfonic acid was slowly added with stirring. The resulting mixture was vigorously refluxed for about 1 hour and 30 minutes to carry out the reaction until water was removed azeotropically. After completion of the reaction, the reaction mixture was cooled and then concentrated under reduced pressure to remove the toluene, and the residue was dissolved in 300 ml of n-hexane. The resulting solution was purified by a column chromatography to obtain 129 g (yield: 88%) of perfluorooctylethyl oleate.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH2:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20](=[O:22])[CH3:21])[CH:18]=2)[C:13]([CH2:23][CH3:24])=[N:12]1)[CH3:10]>CN(C)C=O>[CH2:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20](=[O:22])/[CH:21]=[CH:3]/[N:4]([CH3:5])[CH3:6])[CH:18]=2)[C:13]([CH2:23][CH3:24])=[N:12]1)[CH3:10]
Reactant: CCc1nn(CC)c2cc(C(C)=O)ccc12
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CCc1nn(CC)c2cc(C(=O)/C=C/N(C)C)ccc12
Temperature: 120 °C
Reaction time: 16 h
Yield: 1.7 %

Procedure:
1,1-dimethoxy-N,N-dimethylmethanamine (0.891 g, 0.0075 mol) was added to a solution of 1-(1,3-Diethyl-1H-indazol-6-yl)-ethanone (0.187 mg, 8.64 mmol) in N,N-dimethylformamide (8 mL), and the resulting mixture was shaken at 120° C. for 16 hours. 1,1-dimethoxy-N,N-dimethylmethanamine (0.618 g, 0.0052 mol) was added, and the reaction was refluxed at 140° C. for a further 16 hours. The solvent was removed in vacuo, and the residue extracted with ethyl acetate (30 mL) and water (10 mL). The aqueous layer was re-extracted with ethyl acetate (30 mL). The organic layers were combined, dried, filtered and concentrated. The resulting crude product was purified by silica-gel chromatography, using an eluent gradient of 0.25-0.5% methanol in dichloromethane (mobile phase contained 0.5% ammonium hydroxide solution) to afford 35 mg of (2E)-1-(1,3-diethyl-1H-indazol-6-yl)-3-(dimethylamino)prop-2-en-1-one.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)\[C:4]#[N:5].[Br:12][C:13]1[S:14][CH:15]=[C:16]([CH2:18]Br)[N:17]=1.[I-].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(#N)C>[Br:12][C:13]1[S:14][CH:15]=[C:16]([CH2:18][O:1]/[N:2]=[C:3](/[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)\[C:4]#[N:5])[N:17]=1
Reactant: BrCc1csc(Br)n1
Reactant: N#C/C(=N\O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CC#N
Product: N#C/C(=N\OCc1csc(Br)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a mixture of (2Z)-(hydroxyimino)(phenyl)acetonitrile (2.9 g, 19.84 mmol, 1 eq.), 2-bromo-4-(bromomethyl)thiazole (5.10 g, 19.84 mmol, 1 eq.), potassium iodide (329 mg, 1.98 mmol, 0.1 eq.) and caesium carbonate (9.70 g, 29.76 mmol, 1.5 eq.) was added 80 ml of acetonitrile and 10 ml of DMF. The reaction was stirred 2 h at room temperature. The solvent was then evaporated and the residue dissolved in EtOAc, subsequently washed with H2O and brine. After separation, the organic phase was dried over MgSO4 then concentrated. The residue was purified by chromatography on silica gel to give (2Z)-{[(2-bromo-1,3-thiazol-4-yl)methoxy]imino}(phenyl)acetonitrile (5.70 g, 88% yield, only 1 oxime isomer).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[CH3:20][S-:21].[Na+]>CCO>[Cl:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][CH2:3][CH2:2][S:21][CH3:20])[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7]2
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2n1CCCBr
Reactant: C[S-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc2cc(Cl)ccc2n1CCCSC
Yield: 97.6 %

Procedure:
A solution of ethyl 1-(3-bromopropyl)-5-chloro-1H-indole-2-carboxylate (38.5 g, 0.112 mol) and sodium methanethiolate (9.4 g, 0.135 mol) in 500 mL of EtOH was stirred at RT for 16 hours. The mixture was concentrated in vacuo and the residue was diluted with 200 mL of water and then extracted with EtOAc (100 mL×2). The combined organic layers were washed with 100 mL of brine and 100 mL of water, and then dried over Na2SO4 and concentrated in vacuo to afford 34.1 g of the crude ethyl 5-chloro-1-[3-(methylsulfanyl)propyl]-1H-indole-2-carboxylate, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([F:14])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:17])=O>CN(C)C=O>[F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([F:14])[C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: O=C(O)c1c(F)ccc([N+](=O)[O-])c1F
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1c(F)ccc([N+](=O)[O-])c1F
Temperature: 80 °C
Yield: 99.1 %

Procedure:
To 2,6-difluoro-3-nitro-benzoic acid (48, 5.50 g, 27.1 mmol), thionyl chloride (20 mL, 300 mmol) is added, followed by N,N-dimethylformamide (0.1 mL, 2.0 mmol) and the reaction is heated in an oil bath at 80° C. After overnight reaction, the reaction mixture is concentrated under vacuum, azeotroped with toluene (2×) to provide the desired compound (49, 5.95 g).
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([NH2:10])=[CH:8][C:7]([O:11][CH3:12])=[C:6]([O:13][CH3:14])[CH:5]=1)=O.B(F)(F)F.CCOCC.[CH:24]([NH2:26])=O>>[CH3:1][C:2]1[C:4]2[C:9](=[CH:8][C:7]([O:11][CH3:12])=[C:6]([O:13][CH3:14])[CH:5]=2)[N:10]=[CH:24][N:26]=1
Reactant: COc1cc(N)c(C(C)=O)cc1OC
Reactant: NC=O
Agent: FB(F)F
Solvent: CCOCC
Product: COc1cc2ncnc(C)c2cc1OC
Temperature: 25 °C

Procedure:
2-Amino-4,5-dimethoxyacetophenone (5.0 g) and boron trifluoride etherate (1.5 mL) were heated in formamide (80 mL) at 140° C. for 18 h. The reaction mixture was cooled to room temperature and extracted three times with benzene. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. Flash chromatography on silical gel, eluting with a mixture of 98/2 dichloromethane/methanol gave 4-methyl-6,7-dimethoxyquinazoline (D-1) as a yellow solid, 3.43 g; 1H NMR (CDCl3, 300 MHz) 8.99 (s, 1H), 7.30 (s, 1H), 7.18 (s, 1H), 4.05 (s, 6H), 2.87 (s, 1H) ppm; MS (ES) 205 (M+H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)[CH:9]=[CH:10][CH:11]=1)=[C:2]=[O:3].[CH2:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[C:31]=1[NH:37][C:38]([NH2:40])=[S:39])[CH3:29]>>[CH2:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[C:31]=1[NH:37][C:38]([NH:40][C:2]([NH:1][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:26])([F:25])[F:27])=[CH:19][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:3])=[S:39])[CH3:29]
Reactant: O=C=NCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Reactant: CCc1cccc(C)c1NC(N)=S
Product: CCc1cccc(C)c1NC(=S)NC(=O)NCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1

Procedure:
The title compound was prepared as described in Example 75 using 3-(3-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (CA44) and 1-(2-ethyl-6-methylphenyl)thiourea (CA39) isolated as a white solid (0.137 g, 45%): 1H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 10.13 (s, 1H), 9.42 (s, 1H), 8.16-8.05 (m, 2H), 8.05-7.96 (m, 2H), 7.62 (ddd, J=7.9, 2.0, 1.0 Hz, 2H), 7.49 (t, J=7.6 Hz, 1H), 7.39 (dt, J=7.7, 1.4 Hz, 1H), 7.21-7.12 (m, 1H), 7.13-7.05 (m, 2H), 7.00 (t, J=5.7 Hz, 1H), 3.47 (q, J=6.7 Hz, 2H), 2.90 (t, J=6.9 Hz, 2H), 2.47 (dd, J=7.6, 2.9 Hz, 2H), 2.14 (s, 3H), 1.14-1.08 (m, 3H); 19F NMR (376 MHz, DMSO-d6) δ −56.97; ESIMS m/z 569 ([M+H]+), 567 ([M−H]−).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[C:11]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]=1[C:24]([F:27])([F:26])[F:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:33]([O:35]CC)=[CH2:34])CCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:17]([O:16][C:11]1[C:10]([C:24]([F:27])([F:26])[F:25])=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=[CH:13][C:12]=1[C:33](=[O:35])[CH3:34])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: FC(F)(F)c1c(OCc2ccccc2)ccc(Br)c1OCc1ccccc1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(=O)c1ccc(OCc2ccccc2)c(C(F)(F)F)c1OCc1ccccc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 60 %

Procedure:
Add tetrakis(triphenylphosphine)palladium (2.93 g, 2.54 mmol) to a solution of 1,3-bis-benzyloxy-4-bromo-2-trifluoromethyl-benzene (11.10 g, 25.4 mmol) and tributyl-(1-ethoxy-vinyl)-stannane (10.08 g, 27.92 mmol) in dioxane (250 mL) and stir. Purge reaction vessel with argon. Heat to 100° C. After 6 hours, cool to ambient temperature and concentrate under reduced pressure. Add 2N aqueous hydrochloric acid (50 mL), and tetrahydrofuran (200 mL) and stir. After 30 minutes add water and extract with ethyl acetate. Combine organic layers, dry with sodium sulfate, filter and concentrate under reduced pressure to yield a residue. Purify the residue by flash chromatography eluting with a gradient of 0-20% ethyl acetate:hexanes to yield the title compound as a clear oil (6.10 g, 60%): 1H NMR (CD3CN) δ 2.48 (s, 3H), 4.89 (s, 2H), 5.25 (s, 2H), 7.08 (d, 1H), 7.33-7.48 (m, 10H), 7.83 (d, 1H).
Reaction SMILES: P([O:5][CH2:6][C@H:7]1[O:11][C@@H:10]([N:12]2[CH:19]=[C:18]([CH:20]3[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[CH2:24][CH2:23][C:22]4[CH:31]=[CH:32][CH:33]=[CH:34][C:21]3=4)[C:16](=[S:17])[NH:15][C:13]2=[O:14])[C@H:9]([OH:35])[C@@H:8]1[OH:36])(O)(O)=O.ClC(Cl)(P(=O)(O)O)P(=O)(O)O>>[CH:30]1[C:25]2[CH:24]=[CH:23][C:22]3[CH:31]=[CH:32][CH:33]=[CH:34][C:21]=3[CH:20]([C:18]3[C:16](=[S:17])[NH:15][C:13](=[O:14])[N:12]([CH:19]=3)[C@@H:10]3[O:11][C@H:7]([CH2:6][OH:5])[C@@H:8]([OH:36])[C@H:9]3[OH:35])[C:26]=2[CH:27]=[CH:28][CH:29]=1
Reactant: O=c1[nH]c(=S)c(C2c3ccccc3CCc3ccccc32)cn1[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: O=P(O)(O)C(Cl)(Cl)P(=O)(O)O
Product: O=c1[nH]c(=S)c(C2c3ccccc3C=Cc3ccccc32)cn1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
monoanhydride of 5-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-4-thiouridine-5'-phosphate with dichloromethylenebisphosphonic acid;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:23]#[N:24])[CH:5]=[CH:6][C:7]=1[F:8]>C(O)C>[NH2:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]([C:23]#[N:24])=[C:10]2[NH:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1ccc(F)c(F)c1
Solvent: CCO
Product: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(F)c(F)c1
Reaction time: 2 h
Yield: 88.9 %

Procedure:
A mixture of 4.53 g (13.9 mmol) 4-[(3,4-difluorophenyl)amino]-6-nitro-3-quinolinecarbonitrile, 200 ml ethanol and 15.72 g (69.4 mmol) SnCl2 dihydrate was heated to reflux under N2. Removed heat at 1.5 hours, added ice water and made basic with sodium bicarbonate. Stirred for 2 hours and extracted with chloroform. Stirred organic layer with Darco, dried with sodium sulfate and filtered. Stripped solvent and dried in vacuo, giving 3.660 g of yellow-green solid: mass spectrum (electrospray m/e): M+H=297.1.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:23]=[C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=O.[NH2:30][C@H:31]1[CH2:36][C:35]2[C:37]([N:41]3[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]3)=[CH:38][CH:39]=[CH:40][C:34]=2[O:33][CH2:32]1>CN(C)C=O>[CH3:47][N:44]1[CH2:45][CH2:46][N:41]([C:37]2[C:35]3[CH2:36][C@H:31]([NH:30][C:17](=[O:19])[C:16]4[CH:20]=[CH:21][C:22]([N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[CH:23][C:15]=4[O:14][CH3:13])[CH2:32][O:33][C:34]=3[CH:40]=[CH:39][CH:38]=2)[CH2:42][CH2:43]1
Reactant: COc1cc(N2CCOCC2)ccc1C(=O)O
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CO3)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: COc1cc(N2CCOCC2)ccc1C(=O)N[C@@H]1COc2cccc(N3CCN(C)CC3)c2C1
Temperature: 25 °C
Reaction time: 120 h
Yield: 32.7 %

Procedure:
A stirred solution of 1,1′-carbonyldiimidazole (222 mg, 1.37 mmol) and 2-methoxy-4-morpholinobenzoic acid (176 mg, 0.740 mmol) in anhydrous N,N-dimethylformamide (5 mL) was heated at 75° C. for 2 h, and was then allowed to cool. A solution of (S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (183 mg, 0.740 mmol) in anhydrous N,N-dimethylformamide (4 mL) was added. The reaction mixture was stirred at room temperature for 5 days. The solvent was removed in vacuo, and the residue was partitioned between ethyl acetate (50 mL) and a 2 M NH3 solution (15 mL). The organic layer was dried (MgSO4), and the solvent was removed in vacuo. The residue was purified by column chromatography on silica (eluent: chloroform/ethanol, 93:7+0.5% conc. NH3) affording 113 mg (30% yield) of the title compound as an uncolored foam: [α]21D−141° (c 0.5, chloroform); EIMS (70 eV) m/z (relative intensity) 466 (20, M+).
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]1[CH:23]=[CH:22][C:7]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]3[S:19]C(=S)N[C:16]3=[O:21])[S:12][CH:13]=2)=[CH:6][CH:5]=1.Cl>>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([SH:19])[C:16]([OH:21])=[O:1])[S:12][CH:13]=2)=[CH:22][CH:23]=1
Reactant: [OH-]
Reactant: O=C1NC(=S)SC1=Cc1cc(Cc2ccc(Cl)cc2)cs1
Agent: Cl
Agent: [Na+]
Product: O=C(O)C(S)=Cc1cc(Cc2ccc(Cl)cc2)cs1
Temperature: 45 °C
Yield: 95 %

Procedure:
To a 20-mL scintillation vial fitted with a magnetic stir bar under a N2 atmosphere was added 3.5 mL of NaOH (2.0 M), and heated to 45° C. 5-((4-(4-chlorobenzyl)thiophen-2-yl)methylene)-2-thioxothiazolidin-4-one was added to the 2 M NaOH solution. After complete dissolution, the temperature of the reaction vial was increased to 60° C. over a 30 min period. The vial was subsequently cooled to 5° C. and cold 10% (v/v) aq. HCl solution was added until a precipitate formed (approx. pH 2-3). The resulting precipitate was collected by filtration, washed several times with water, and dried thoroughly under vacuum at 40° C. to give 3-(4-(4-chlorobenzyl)thiophen-2-yl)-2-mercaptoacrylic acid (379 mg, 95% yield). Note: 1H NMR showed a number of peaks in the aromatic region. The presence of the signal for the vinyl proton and the loss of the rhodanine moiety (i.e.; absence of the proton attached to the nitrogen in the rhodanine moiety) was used as an indicator of the desired compound. The material was used in the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]1[CH2:6][C@@H:5]1[CH:7]1[CH2:12][CH2:11][N:10](C(OCC2C=CC=CC=2)=O)[CH2:9][CH2:8]1>[Pd].CO>[NH:10]1[CH2:11][CH2:12][CH:7]([C@H:5]2[CH2:6][C@H:4]2[CH2:3][CH2:2][OH:1])[CH2:8][CH2:9]1
Reactant: O=C(OCc1ccccc1)N1CCC([C@H]2C[C@H]2CCO)CC1
Agent: [Pd]
Solvent: CO
Product: OCC[C@@H]1C[C@@H]1C1CCNCC1

Procedure:
Benzyl 4-((1R,2S)-2-(2-hydroxyethyl)cyclopropyl)piperidine-1-carboxylate (7.50 g, 24.7 mmol) and palladium on activated carbon (10%, wet, 1.00 g) in methanol (130 mL) were stirred under an atmosphere of hydrogen (1 atm) at RT for 48 h. The mixture was filtered through Celite® and the filter cake washed with methanol. The filtrate was concentrated to dryness under reduced pressure to afford the compound as a white solid. 1H NMR (500 MHz, CDCl3) δ 3.74 (m, 2H), 3.15-3.05 (m, 2H), 2.56 (m, 2H), 1.91-1.87 (m, 2H), 1.76-1.72 (m, 3H), 1.36-1.28 (m, 3H), 0.92-0.87 (m, 1H), 0.84-0.76 (m, 1H), 0.67-0.61 (m, 1H), 0.60-0.56 (m, 1H), −0.18 (q, J=4.5 Hz, 1H).