Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]([CH3:20])[CH3:19])/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[NH2:21][C:22]1[S:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[S:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=[C:22]1[NH:21][C:13](=[O:15])/[C:12](/[C:4]1[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=1)=[N:16]/[O:17][CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)O/N=C(/C(=O)O)c1ccc(S(C)(=O)=O)c(Cl)c1
Reactant: Nc1nc2ccccc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)O/N=C(/C(=O)Nc1nc2ccccc2s1)c1ccc(S(C)(=O)=O)c(Cl)c1
Reaction time: 2 h
Yield: 54.2 %

Procedure:
This estimated 80% pure (E)-(3-chloro-4-methanesulfonyl-phenyl)-isopropoxyimino-acetic acid (prepared as in Example 6, 99 mg, 0.31 mmol), 2-aminobenzothiazole (512 mg, 0.34 mmol) and N,N-diisopropylethylamine (162 μL, 0.93 mmol) were combined in acetonitrile (1.25 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (118 mg, 0.31 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 50% ethyl acetate/hexanes) to afford (E)-N-benzothiazol-2-yl-2-(3-chloro-4-methanesulfonyl-phenyl)-2-isopropoxyimino-acetamide (76 mg, 54%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C19H18ClN3O4S2 [M+] 451.04, found 452 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.39 (d, J=6.3 Hz, 6 H, 2×CH3), 3.32 (s, 3 H, SO2CH3), 4.65 (m, J=6.3 Hz, 1 H, OCH), 7.36 (brt, J=7.8 Hz, 1H, Ar), 7.49 (brt, J=7.8 Hz, 1H, Ar), 7.64 (dd, Jo=8.2, Jm=1.6 Hz, 1 H, Ar), 7.74 (d, Jm=1.6 Hz, 1 H, Ar), 7.84 (m, 2H, Ar), 8.24 (d, Jo=8.2 Hz, 1 H, Ar), 10.20 (s, 1 H, NH).
Reaction SMILES: C([O:5][C:6](=[O:43])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]4[N:29]=[C:30]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[O:31][C:32]=4[C:33]([F:36])([F:35])[F:34])=[O:27])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[C:37]1([C:30]2[O:31][C:32]([C:33]([F:34])([F:35])[F:36])=[C:28]([C:26]([NH:25][C:22]3[CH:21]=[CH:20][C:19]([CH:16]4[CH2:15][CH2:14][N:13]([C:10]5[CH:9]=[CH:8][C:7]([C:6]([OH:43])=[O:5])=[CH:12][CH:11]=5)[CH2:18][CH2:17]4)=[CH:24][CH:23]=3)=[O:27])[N:29]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N2CCC(c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cc3)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(N2CCC(c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
The above 4-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidin-1-yl)-benzoic acid tert-butyl ester (40 mg) was dissolved in a mixture of methylene chloride (2 mL) and trifluoroacetic acid (2 mL). The mixture was stirred at room temperature for 1 hr and solvents were evaporated. The residue was extracted with ethyl acetate and water. The organic layer was dried and solvents were evaporated. The residue was triturated with ethyl acetate to give a solid as 4-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidin-1-yl)-benzoic acid (25 mg). LC-MS for C29H24F3N3O4 (m/e) calcd 535, obsd 536 (M+H). 1H-NMR is consistent with the desired structure.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1.[C:22]([O:27][CH2:28][CH3:29])(=[O:26])[C:23]([CH3:25])=O.C(O)(=O)C.[BH]C#N.[Na]>C(O)C>[C:14]([O:13][C:11]([CH2:10][N:7]1[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3][CH:2]([NH:1][CH:23]([C:22]([O:27][CH2:28][CH3:29])=[O:26])[CH3:25])[C:8]1=[O:9])=[O:12])([CH3:16])([CH3:17])[CH3:15]
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(N)CSc2ccccc21
Reactant: CCOC(=O)C(C)=O
Agent: [BH]C#N
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(C)NC1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Reaction time: 2 h
Yield: 50.3 %

Procedure:
1.5 g of 3-amino-5-t-butoxycarbonylmethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and 2.0 g of ethyl pyruvate were dissolved in 15 ml of ethanol. After the addition of 0.3 ml of acetic acid, the resulting mixture was stirred for 2 hours. Then, a solution of 420 mg of sodium boron cyanide hydride in 8 ml of ethanol was slowly added dropwise thereto. After this mixture was allowed to stand overnight, the solvent was distilled off under reduced pressure and the residue was dissolved in ethyl acetate. The resulting solution was washed with water, dried and then concentrated. The residue was purified by silica gel column chromatography using a 3:1 mixture of benzene and ethyl acetate as the eluent. Thus, there was obtained 1.0 g of the desired compound in the form of an oily material.
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].N1C=CC=CC=1.[N+:11]([C:14]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:15]=1[CH2:16]Cl)([O-:13])=[O:12]>C1COCC1.ClCCl>[C:1]([S:3][CH2:16][C:15]1[CH:18]=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:14]=1[N+:11]([O-:13])=[O:12])(=[O:4])[CH3:2]
Reactant: CC(O)=S
Reactant: O=[N+]([O-])c1ccc(CCl)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)SCc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 80.1 %

Procedure:
Redistilled thioacetic acid (25.73 cm3, 0.36 mol) and then dry pyridine (19.9 cm3, 0.246 mol) were added to a stirred solution of 2,4-dinitrobenzyl chloride (13.0 g, 60.0 mmol) in dry THF (180 cm3) at room temperature. After 2 h, the products were filtered and the filtrate was concentrated under reduced pressure. The residual solid obtained was dissolved in dichloromethane (300 cm3) and the resulting solution was washed in turn with saturated aqueous sodium hydrogen carbonate (300 cm3), 1.0 mol dm-3 sulfuric acid (200 cm3) and saturated aqueous sodium hydrogen carbonate (200 cm3). The dried (MgSO4) organic layer was evaporated under reduced pressure and the residue was crystallized from ethyl acetate--petroleum ether (b.p. 60°-80° C.) to give S-(2,4-dinitrobenzyl) thioacetate 16b as a pale yellow solid (12.32 g, 80%) (Found: C, 42.3; H, 3.1; N, 10.9. C9H8N2O5S requires: C, 42.2; H, 3.15; N, 10.9%), m.p. 78°-79° C.; δH [CDCl3 ] 2.35 (3 H, s), 4.49 (2 H, s), 7.91. (1 H, d, J 8.5), 8.41 (1 H, dd, J 2.4 and 8.5), 8.88 (1 H, d; J 2.3); δC [CDCl3 ] 30.2, 30.7, 120.7, 127.6, 134.2, 140.6, 147.1, 148.0, 194.7.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([F:10])[C:7]=1[CH:8]=[O:9].Cl[C:15]1[N:20]=[C:19]([NH2:21])[N:18]=[C:17]([N:22]([CH3:24])[CH3:23])[CH:16]=1>CCOC(C)=O>[NH2:21][C:19]1[N:20]=[C:15]([C:4]2[CH:3]=[C:2]([F:1])[C:7]([CH:8]=[O:9])=[C:6]([F:10])[CH:5]=2)[CH:16]=[C:17]([N:22]([CH3:24])[CH3:23])[N:18]=1
Reactant: CN(C)c1cc(Cl)nc(N)n1
Reactant: O=Cc1c(F)cc(B(O)O)cc1F
Solvent: CCOC(C)=O
Product: CN(C)c1cc(-c2cc(F)c(C=O)c(F)c2)nc(N)n1
Yield: 79.2 %

Procedure:
The title compound was prepared following the General Procedure A using: (3,5-difluoro-4-formylphenyl)boronic acid (2.37 g, 12.8 mmol) and 6-chloro-N4,N4-dimethyl-2,4-pyrimidinediamine (2.2 g, 12.8 mmol). The solid was dissolved in EtOAc and precipitated with hexanes. The resulting solid was collected via vacuum filtration to afford the title compound (2.82 g, 80%) as a yellow solid. LC-MS (ES) m/z=279 [M+H]+.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O[C:16]([CH3:27])([CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:17]>CS(O)(=O)=O>[CH3:17][C:16]1([CH3:27])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: CC(C)(O)CCCc1ccccc1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1(C)CCCc2ccccc21
Temperature: 105 °C
Yield: 89.9 %

Procedure:
A mixture of P2O5 (55.3 g, 0.390 mol) in 400 ml of methanesulfonic acid was heated to 105° C. under argon until all of the solid had dissolved. The resulting solution was cooled to room temperature and 2-hydroxy-2-methyl-5-phenylpentane (63.0 g, 0.354 mol) added slowly with stirring. After 4 hours the reaction was quenched by carefully pouring the solution onto 1 L of ice. The resulting mixture was extracted with Et2O (4×125 ml)and the combined organic layers washed with water, saturated aqueous NaHCO3, water, and saturated aqueous NaCl before being dried over MgSO4. Concentration of The solution under reduced pressure, followed by distillation afforded 51.0 g (90%) of the product as a clear colorless oil, bp. 65-67° C./1.1 mmHg. 1H NMR (CDCl3): δ 7.32 (1H, d, J=7.4 Hz), 7.16-7.05 (3H, m), 2.77 (2H, t, J=6.3 Hz), 1.80 (2H, m), 1.66 (2H, m), 1.28 (6H, s).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[N:8]([C:16](=[O:29])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([O:26]CC)=[O:25])[CH:19]=1)[CH2:7][CH2:6]2.[OH-].[Na+].Cl>C(O)C>[CH3:1][S:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([F:13])([F:14])[F:15])[N:8]([C:16](=[O:29])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([OH:26])=[O:25])[CH:19]=1)[CH2:7][CH2:6]2
Reactant: CCOC(=O)c1cccc(NC(=O)N2CCc3cc(SC)c(C(F)(F)F)cc32)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cccc(C(=O)O)c1)CC2
Yield: 82.6 %

Procedure:
To a suspension of 5-methylthio-6-trifluoromethyl-1-(3-ethoxy carbonyl phenyl carbamoyl)indoline (3g, 7.1 mmol) in ethanol (30 ml) was added aqueous sodium hydroxide solution (SM) (7.1 ml, 35.5 mmol) and heated gently for 2 hours. It was then allowed to cool and acidified with aqueous hydrochloric acid (5M) forming a white precipitate which was filtered and dried to yield the product as a white solid (2.324 g, 83%), mp>200° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:12]=[C:13]([NH2:20])[N:14](C(C)(C)C)[N:15]=2)[CH:6]=[CH:7][CH:8]=1.[C:21]([NH:29][C:30]1[CH:39]=[CH:38][C:33]([C:34](OC)=[O:35])=[CH:32][CH:31]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C[Al](C)C>C1(C)C=CC=CC=1.C(Cl)Cl.C(O)=O>[C:21]([NH:29][C:30]1[CH:31]=[CH:32][C:33]([C:34]([NH:20][C:13]2[NH:14][N:15]=[C:11]([CH2:10][CH2:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:12]=2)=[O:35])=[CH:38][CH:39]=1)(=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1ccc(NC(=O)c2ccccc2)cc1
Reactant: COc1cccc(CCc2cc(N)n(C(C)(C)C)n2)c1
Agent: C[Al](C)C
Solvent: O=CO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cccc(CCc2cc(NC(=O)c3ccc(NC(=O)c4ccccc4)cc3)[nH]n2)c1
Temperature: 82 °C
Reaction time: 8 h

Procedure:
5-[2-(3-Methoxyphenyl)ethyl]-2-tert-butyl-pyrazol-3-amine (0.2 g, 0.73 mmol) was dissolved in toluene (10 ml) and to this was added methyl 4-benzamidobenzoate (200 mg, 0.80 mmol) and AlMe3 (0.93 ml, 1.8 mmol). The reaction was stirred overnight. The reaction was diluted with DCM (15 ml) and quenched with damp sodium sulfite. The reaction mixture was stirred for 20 mins before being filtered and the solvent removed in vacuo to yield a yellow gum. This gum was dissolved in formic acid (12 ml) and heated at 82° C. overnight. The reaction was evaporated to dryness and the resulting product was passed through a SCX column, eluting initially with methanol followed by 2N ammonia/methanol. After removal of the solvent, a yellow solid was obtained which was triturated with hot acetonitrile to afford a white solid. The solid was filtered and dried (66 mg, 21%); 1H NMR (400.132 MHz, DMSO) δ 2.91 (s, 4H), 3.74 (s, 3H), 6.46 (brs, 1H), 6.77 (d, 1H), 6.83 (s, 2H), 7.20 (t, 1H), 7.64-7.54 (m, 3H), 7.90 (d, 2H), 8.02-7.97 (m, 4H), 10.46 (s, 1H), 10.55 (s, 1H), 12.15 (s, 1H); MS: m/z 441 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:14][C:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:21](=[O:23])[CH3:22])[CH2:16][CH2:17][C:18]([OH:20])=[O:19].[OH-].[Na+]>C(O)C.O>[Cl:10][C:11]1[CH:12]=[C:13]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:14][C:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:21](=[O:23])[CH:22]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: CC(=O)C(CCC(=O)O)(Cc1ccc(Cl)c(Cl)c1)c1ccccc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCC(Cc1ccc(Cl)c(Cl)c1)(C(=O)C=Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
p-Chlorobenzaldehyde (3.5 g., 0.025 mole) in ethanol (10 ml.) is added to a solution of 4-(3,4-dichlorobenzyl)-4-phenyl-5-oxohexanoic acid (5.48 g., 0.015 mole) and sodium hydroxide (0.80 g., 0.02 mole) in water (50 ml.). The resulting mixture is heated on a steam bath for 24 hours. Then the reaction solution is cooled to room temperature, diluted with water (250 ml.), and extracted with ether to remove the excess p-chlorobenzaldehyde. The aqueous phase is then acidified with dilute hydrochloric acid (15 ml.). The organic material which separates is extracted into ether, washed with saturated brine, and dried over Na2SO4. The ether is removed in vacuo, and trituration of the residue with ethanol (25 ml.) produces 1.6 g. of solid. Recrystallization from butyl chloride gives material with m.p. 155°-156.5°C.
Reaction SMILES: [Mg:1].Br[CH2:3][CH2:4][CH:5]=[CH2:6].Br[CH:8]=[CH:9][CH2:10][CH3:11].O1CCOCC1>C1COCC1.BrC(Br)C>[CH2:3]([Mg:1][CH2:11][CH2:10][CH:9]=[CH2:8])[CH2:4][CH:5]=[CH2:6]
Reactant: CCC=CBr
Reactant: C=CCCBr
Reactant: [Mg]
Agent: CC(Br)Br
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: C=CCC[Mg]CCC=C

Procedure:
A mixture of magnesium turnings (0.5 g, 0.02 mole) and dry THF (5 mL) were placed in a dry, three-necked round-bottomed flask under argon. To this was added dropwise a solution of 2.3 g (0.7 mole) of 4-bromobutene in 5 mL of dry THF. After about 1/3 of the bromobutene was added, the reaction had not initiated. Two drops of dibromoethane was added and the reaction heated to reflux until Grignard formation was initiated. Heating was stopped and the remainder of the halide was added dropwise to maintain a gentle reflux. After all of the halide was added, the reaction was heated briefly then treated with 1.5 g (0.017 mole) of dioxane with stirring. An immediate white precipitate was formed. This suspension was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:12]=[C:11]([C:21]([NH2:23])=[O:22])[C:7]=3[NH:8][C:9]=2[CH:10]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32]O)[CH2:27][CH2:26]1>>[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][O:1][C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[N:14]=[C:13]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[CH:12]=[C:11]([C:21]([NH2:23])=[O:22])[C:7]=4[NH:8][C:9]=3[CH:10]=2)[CH2:27][CH2:26]1
Reactant: NC(=O)c1cc(-c2ccccc2)nc2c1[nH]c1cc(O)ccc12
Reactant: CN1CCN(CCO)CC1
Product: CN1CCN(CCOc2ccc3c(c2)[nH]c2c(C(N)=O)cc(-c4ccccc4)nc23)CC1

Procedure:
This was similarly prepared from 7-hydroxy-2-phenyl-5H-pyrido[3,2-b]indole-4-carboxamide and 2-(4-methylpiperazin-1-yl)ethanol. MS (ESI) m/z 430.1 (M+H). 1H NMR (400 MHz, MeOD) δ ppm 8.20-8.27 (1H, m), 8.12 (1H, s), 8.04-8.09 (2H, m), 7.46-7.53 (2H, m), 7.37-7.42 (1H, m), 7.12-7.16 (1H, m), 6.87-6.94 (1H, m), 4.18-4.27 (2H, m), 2.87 (2H, t, J=5.41 Hz), 2.42-2.77 (6H, m), 2.27 (3H, s).
Reaction SMILES: [C:1]([NH2:11])(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:21])=CC=1.Br[CH:35]([CH3:43])[C:36](=O)[CH2:37][C:38]([O:40][CH3:41])=[O:39]>O1CCCC1>[CH3:43][C:35]1[S:21][C:1]([CH:2]=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[N:11][C:36]=1[CH2:37][C:38]([O:40][CH3:41])=[O:39]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)CC(=O)C(C)Br
Reactant: NC(=O)C=Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)Cc1nc(C=Cc2ccccc2)sc1C
Yield: 86.9 %

Procedure:
Cinnamamide (3.27 g) was dissolved in tetrahydrofuran (33 ml), and Lawesson's reagent (4.94 g) was added. The mixture was refluxed for 3 h and methyl 4-bromo-3-oxopentanoate (6.97 g) was added. The mixture was further refluxed for 11 h. Tetrahydrofuran was evaporated under reduced pressure and ethyl acetate (300 ml) was added to the obtained residue. The mixture was washed with water (200 ml) and then with saturated brine (200 ml), and dried (Na2SO4). Ethyl acetate was evaporated under reduced pressure and the obtained residue was purified by column chromatography to give methyl (5-methyl-2-styrylthiazole-4-yl)acetate (2.9 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[CH:15]1([CH2:18][NH2:19])[CH2:17][CH2:16]1>>[CH:15]1([CH2:18][NH:19][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=2)[CH2:17][CH2:16]1
Reactant: NCC1CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Product: O=[N+]([O-])c1ccc(NCC2CC2)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 1A from 4-fluoro-1-nitro-2-(trifluoromethyl)benzene and (cyclopropylmethyl)amine: MS (APCI) m/z 261 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]([SH:15])[CH2:13][SH:14])[CH:6]=[C:7]([O:10][CH3:11])[C:8]=1[OH:9].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH:21]=O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1C=CC=CC=1>C1C=CC=CC=1.O>[CH3:29][O:28][C:24]1[CH:23]=[C:20]([CH:21]2[S:15][CH:12]([C:5]3[CH:6]=[C:7]([O:10][CH3:11])[C:8]([OH:9])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:13][S:14]2)[CH:19]=[C:18]([O:17][CH3:16])[C:25]=1[O:26][CH3:27]
Reactant: COc1cc(C(S)CS)cc(OC)c1O
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: c1ccccc1
Product: COc1cc(C2CSC(c3cc(OC)c(OC)c(OC)c3)S2)cc(OC)c1O

Procedure:
1-(3,5-dimethoxy-4-hydroxyphenyl)-1,2-ethanedithiol (40) (2.10 g, 8.54 mmole), 3,4,5-trimethoxybenzaldehyde (24) (1.28 g, 6.57 mmole) and 0.857 g of pyridinium paratoluene sulfonate are added to 60 ml dry benzene and refluxed with Dean-Stark removal of the benzene-water azeotrope overnight. The benzene is removed in vacuo, and the remaining oil is extracted into 10% NaOH which was washed with diethylether. The basic layer is reacidified with 10% HCl and the desired product is extracted into ethyl acetate. The organic layer is dried over MgSO4, filtered, and evaporated in vacuo to an oil which is purified by flash column chromatography with 2:1 hex/ethyl acetate as eluent. The product mixture contains a 1.0/1.2 cis/trans ratio after the first recrystallization (1.287 g, 59%). The trans isomer is isolated after six additional recrystallizations from methanol.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][OH:7])[CH:2]=[CH2:3].N1C=CC=CC=1.C1COCC1.[Br:19][CH:20]([CH3:24])[C:21](Cl)=[O:22]>C(OCC)(=O)C>[Br:19][CH:20]([CH3:24])[C:21]([O:7][CH2:6][CH2:5][O:4][CH2:1][CH:2]=[CH2:3])=[O:22]
Reactant: CC(Br)C(=O)Cl
Reactant: C=CCOCCO
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=CCOCCOC(=O)C(C)Br
Temperature: 0 °C
Yield: 64.5 %

Procedure:
A 50-mL two-necked flask is purged with nitrogen and then charged with 2-allyloxyethanol (2.5 mL, 23.4 mmol), pyridine (3 mL) and THF (10 mL). The solution is cooled to 0° C., and 2-bromopropionyl chloride (2 mL, 19.52 mmol) is added dropwise slowly. The resulting mixture is stirred at that temperature for an hour, then ethyl acetate (10 mL) is added, and the resulting pyridine hydrochloride is filtered off. The filtrate is washed with dilute hydrochloric acid (10 mL), then with an aqueous solution of NaHCO3 (10 mL) and further with brine (10 mL). The organic layer is dried over Na2SO4 and the volatile matter is distilled off under reduced pressure. The crude product thus obtained is distilled under reduced pressure to give allyloxyethyl 2-bromopropionate (78.5-81 (1.3 mmHg), 2.986 g) of the formula shown below.
Reaction SMILES: [H-].[Na+].[CH:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH2:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:14])=[O:11])=[CH:5][CH:4]=1.F[C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][N:24]=1>CN(C=O)C.C(Cl)Cl.O>[NH:9]([C:10](=[O:11])[CH:12]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][N:24]=1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])[C:6]1[CH:5]=[CH:4][CH:3]=[CH:8][CH:7]=1
Reactant: O=C(CC(=O)Nc1ccccc1)Nc1ccccc1
Reactant: COC(=O)c1ccc(F)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(C(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)nc1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 27.3 %

Procedure:
To a suspension of NaH (32 mg, 60% wt. dispersion in mineral oil, 0.80 mmol) in DMF (0.5 mL) at room temperature was added malondianilide (169 mg, 0.67 mmol). The solution was stirred for 20 min and a solution of methyl 6-fluoronicotinate (129 mg, 0.62 mmol) in DMF (1 mL) was added. The reaction mixture was heated to 100° C. for 1 h, cooled to room temperature, and diluted with CH2Cl2 and water. The aqueous phase was extracted with CH2Cl2 (3×) and the combined extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated. Purification by reverse phase HPLC (40% to 90% MeCN in water) gave methyl 6-[2-anilino-1-(anilinocarbonyl)-2-oxoethyl]nicotinate (66 mg, TFA salt, 21%) as a white solid: ESIMS calcd 390.1 (M++H), found 390.1 (M++H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](F)[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1.[OH-:13].[K+].[CH3:15]O>>[Br:1][C:2]1[CH:3]=[C:4]([O:13][CH3:15])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1
Reactant: CO
Reactant: O=[N+]([O-])c1c(F)cc(Br)cc1F
Reactant: [OH-]
Agent: [K+]
Product: COc1cc(Br)cc(F)c1[N+](=O)[O-]
Temperature: 90 °C
Yield: 63 %

Procedure:
To a solution of 5-bromo-1,3-difluoro-2-nitrobenzene (2.7 g, 11.3 mmol) in methanol (20 mL) was added potassium hydroxide (680 mg, 12 mmol). The reaction mixture was refluxed at 90° C. for 1 h. It was then concentrated, diluted to ethyl acetate and washed by water and brine. The mixture was then purified by flash column to give the product as red oil (1.8 g, 63%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.94 (s, 3H) 7.01 (s, 1H) 7.04 (d, J=8 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[NH:5][C:6]1[C:15]([Cl:16])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)[CH3:2].[B-](F)(F)(F)[F:19].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:17])[NH:5][C:6]1[C:15]([Cl:16])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[F:19])[CH3:2]
Reactant: F[B-](F)(F)F
Reactant: CCOC(=O)Nc1cc2ccccc2cc1Cl
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CCOC(C)=O
Product: CCOC(=O)Nc1c(Cl)cc2ccccc2c1F
Temperature: 25 °C

Procedure:
A mixture of 2.50 g (10 mmol) of N-(3-chloro-2-naphthyl)carbamic acid ethyl ester and 7.1 g of Selectfluor® (20 mmol) in 30 mL of CH2CN is heated to reflux under an atmosphere of nitrogen for 16 hours. After cooling to room temperature, the solids are filtered and the solvent is evaporated to give a residue that is diluted with 200 mL of EtOAc. The mixture is washed 3 times with 50 mL of H2O, once with 50 mL of saturated brine and dried over MgSO4. Evaporation of the solvents gives a residue that is purified by flash chromatography on silica gel (100% CH2Cl2) to give N-(1-fluoro-3-chloro-2-naphthyl)carbamic acid ethyl ester.