Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)=O.[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]3[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:13]=3[C:12]=2I)=[CH:7][CH:6]=1.C([Li])CCC.[CH3:28][O:29][C:30](Cl)=[O:31]>C1COCC1.CC(C)=O>[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]3[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:13]=3[C:12]=2[C:30]([O:29][CH3:28])=[O:31])=[CH:7][CH:6]=1
Reactant: COc1ccc2sc(-c3ccc(F)cc3)c(I)c2c1
Reactant: COC(=O)Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2ccc(F)cc2)sc2ccc(OC)cc12
Temperature: -78 °C
Reaction time: 15 h

Procedure:
To a cooled solution (−78° C., dry ice, acetone) containing 2-(4-fluorophenyl)-3-iodo-5-methoxybenzo[b]thiophene (1.0 g, 2.6 mmol,) and THF (26 mL) was added n-butyllithium (2.0 mL, 1.0 M THF) over 5 min. The solution was maintained at −78° C. for 1 h. Methylchloroformate (0.80 mL, 10.4 mmol) was then added quickly in a steady stream via syringe. The solution was removed from cooling and allowed to stand at ambient temperature for 15 h. The solution was concentrated and purified on silica gel (0-10% ethyl acetate/hexanes, 40 min. gradient) to afford methyl 2-(4-fluorophenyl)-5-methoxybenzo[b]thiophene-3-carboxylate as a yellow residue. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 7.88 (d, J=2.44 Hz, 1H), 7.66 (d, J=8.85 Hz, 1H), 7.47 (dd, J=8.85, 5.19 Hz, 2H), 7.12 (t, J=8.70 Hz, 2H), 7.05 (dd, J=8.70, 2.59 Hz, 1H), 3.91 (s, 3H), 3.74 (s, 3H). LCMS: retention time: 3.355 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% CH3CN/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% CH3CN/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 317 (MH+).
Reaction SMILES: [H-].[Na+].[C:3]1([S:9]([C:12]2[CH:21]=[CH:20][C:15]3[NH:16][CH2:17][CH2:18][O:19][C:14]=3[CH:13]=2)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:22]([N:29]1[CH2:33][CH2:32][CH:31](OS(C)(=O)=O)[CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C)C=O>[C:3]1([S:9]([C:12]2[CH:21]=[CH:20][C:15]3[N:16]([CH:31]4[CH2:32][CH2:33][N:29]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:30]4)[CH2:17][CH2:18][O:19][C:14]=3[CH:13]=2)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc2c(c1)OCCN2
Reactant: CS(=O)(=O)OC1CCN(Cc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(c1ccccc1)c1ccc2c(c1)OCCN2C1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40.2 %

Procedure:
To a suspension of sodium hydride (0.033 g. of a 60% dispersion in mineral oil, 0.834 mmol) in 3 mL dimethylformamide was added portionwise 7-benzenesulfonyl-3,4-dihydro-2H-benzo[1,4]oxazine (0.200 g, 0.726 mmol), and the resulting suspension was stirred at room temperature for 10 minutes. Racemic methanesulfonic acid 1-benzyl-pyrrolidin-3-yl ester (0.259 g., 1.018 mmol) was added dropwise and the reaction mixture was heated to 65° C. for 21 hours. The reaction mixture was then poured into 100 mL water, and extracted three times with 50 mL ethyl acetate. The organic fraction was washed twice with 50 mL 10% aq. hydrogen chloride and once with 50 mL saturated sodium bicarbonate. The organic fraction was then dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography (2%-5% methanol in dichlormethane) to give 0.127 g (0.292 mmol, 40%) of 7-benzenesulfonyl-4-(1-benzyl-pyrrolidin-3-yl)-3,4-dihydro-2H-benzo[1,4]oxazine as a red oil. MS: 474 (M+ACN)+.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:30][C:29]([CH3:31])=[N:28][C:27]=2[C:32](O)=[O:33])=[CH:22][CH:21]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:32]([C:27]3[N:28]=[C:29]([CH3:31])[S:30][C:26]=3[C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)=[O:33])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)s2)OCCO1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(Cl)cc2)s1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3nc(C)sc3-c3ccc(Cl)cc3)cn2)s1

Procedure:
Following general procedure X followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(4-chloro-phenyl)-2-methyl-thiazole-4-carboxylic acid. LC-MS-conditions 05c: tR=0.77 min; [M+H]+=457.15.
Reaction SMILES: [CH3:1][S-:2].[Na+].F[C:5]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][C:6]=1[C:7]#[N:8].O>CS(C)=O>[I:13][C:10]1[CH:11]=[CH:12][C:5]([S:2][CH3:1])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: C[S-]
Reactant: N#Cc1cc(I)ccc1F
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CSc1ccc(I)cc1C#N
Yield: 93.4 %

Procedure:
Sodium thiomethoxide (0.142 g) was added to a solution of 2-fluoro-5-iodobenzonitrile (0.5 g) in DMSO (1 mL) and the mixture stirred. An exotherm was noted. After stirring for 90 min, water was added and the solid that precipitated was collected, washed with water and dried at 50° C. under vacuum to leave the subtitle compound as an off-white solid (0.52 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[Cl:12][C:5]1[CH:4]=[CH:3][C:2]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:7][C:6]=1[C:8]([F:11])([F:10])[F:9]
Reactant: C1CNCCN1
Reactant: FC(F)(F)c1cc(Br)ccc1Cl
Product: FC(F)(F)c1cc(N2CCNCC2)ccc1Cl
Yield: 78.2 %

Procedure:
Beginning with 5-bromo-2-chlorobenzotrifluoride (602 mg) and piperazine (1 g), 480 mg of the title compound was recovered by the procedure described in Example 1.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[CH3:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18]2.N1CCCCC1>C(O)C>[CH3:13][C:7]1[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])=[CH:10][NH:9][C:8]=1[CH:11]=[C:18]1[C:17]2[C:21](=[CH:22][CH:23]=[C:15]([CH3:14])[CH:16]=2)[NH:20][C:19]1=[O:24]
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Reactant: Cc1ccc2c(c1)CC(=O)N2
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1ccc2c(c1)C(=Cc1[nH]cc(CCC(=O)O)c1C)C(=O)N2
Yield: 42.2 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (90 mg), 74 mg 5-methyl-2-oxindole, and 75 μL piperidine in 2 mL of ethanol were heated at 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven to give 65 mg (42%) of the title compound as a brown solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:24][CH2:25][CH3:26])[C:5]([CH2:7][O:8][C:9](=[O:23])[CH2:10][CH2:11][NH:12]C(OCC1C=CC=CC=1)=O)=[O:6])[CH2:2][CH3:3].Cl>O1CCOCC1>[CH2:24]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([CH2:7][O:8][C:9](=[O:23])[CH2:10][CH2:11][NH2:12])=[O:6])[CH2:25][CH3:26]
Reactant: CCCN(CCC)C(=O)COC(=O)CCNC(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CCCN(CCC)C(=O)COC(=O)CCN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled stirred solution of 3-tert-butoxycarbonylamino-propionic acid dipropylcarbamoylmethyl ester (step 1) (36.5 g, 110 mmol) in dry dioxane under N2 was added dropwise 4N HCl in dioxane (18.12 ml, 597 mmol). The resulting mixture was allowed to warm to RT and stirred overnight. The solvent was removed in vacuo and the crude product was suspended in EtOAc (500 ml) and sonicated for 1 h. The resulting white precipitate was isolated by filtration and was dried under vacuum at 40° C. for 1 h to afford a pale yellow solid. Recrystallisation from EtOAc afforded the title compound; LC-MS Rt 0.77 mins; 231.2 [M+H]+, Method 2minLC_v003.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:20][OH:21])[CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.Cl[C:23]1[CH:24]=[C:25]2[N:32]([CH3:33])[C@@H:31]([CH3:34])[CH2:30][N:26]2[C:27](=[O:29])[N:28]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1)[CH2:20][O:21][C:23]1[CH:24]=[C:25]2[N:32]([CH3:33])[C@@H:31]([CH3:34])[CH2:30][N:26]2[C:27](=[O:29])[N:28]=1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Reactant: OCc1cc(F)c(Oc2cncc(C(F)(F)F)c2)c(F)c1
Product: C[C@H]1Cn2c(cc(OCc3cc(F)c(Oc4cncc(C(F)(F)F)c4)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3,5-difluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol and (S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](O)=[CH:12][CH:13]=[N:14]2)=[CH:9][CH:8]=1>>[Cl:3][C:11]1[C:10]2[C:15](=[CH:16][C:7]([Cl:6])=[CH:8][CH:9]=2)[N:14]=[CH:13][CH:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc2cc(Cl)ccc12
Product: Clc1ccc2c(Cl)ccnc2c1
Temperature: 25 °C
Yield: 88.6 %

Procedure:
Phosphorus oxychloride (4 mL, 429 mmol) was added to 7-chloro-4-hydroxyquinoline 2.86 g, 15.9 mmol) in a round bottom flask equipped with a reflux condenser. The mixture was heated to reflux for 2 h, then allowed to cool to room temperature. The solution was concentrated in vacuo to a thick oil, then dumped over cracked ice. The resulting solution was neutralized with saturated NaHCO3 (aq). The slurry was filtered and washed with water. The solids were dried under vacuum, afforded 4,7-dichloroquinoline as a white solid (2.79 g, 88.5% yield).
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]2[CH:11]=[CH:10][CH:9]=[CH:8]2)=[CH:4][CH:3]=1.CN(C)[CH:16]=[C:17]([N:23]=[CH:24]N(C)C)[C:18]([O:20][CH2:21][CH3:22])=[O:19].FC(F)(F)C(O)=O>C(O)(=O)C>[F:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]2[C:11]3[CH:16]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:23]=[CH:24][C:10]=3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=CN(C)C)N=CN(C)C
Reactant: Fc1ccc(Cn2cccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2c(ccn2Cc2ccc(F)cc2)cn1
Yield: 19 %

Procedure:
A solution of 1-(4-fluorobenzyl)-1H-pyrrole (11.1 g, 63.4 mmol), ethyl 3-dimethylamino-2-(dimethylamino-methyleneamino)-acrylate (14.84 g, 69.7 mmol) [prepared according to W. Kantlehner, F. Wagner, H. Bredereck, Liebigs Ann. Chem. 1980, 344-357] and trifluoroacetic acid (19.4 mL, 253.6 mmol) in acetic acid (80 mL) was stirred for 16 h at ambient temperature. Then the solution was heated to reflux for 4 hr. After cooling down, it was concentrated. The residue was poured into satd. potassium carbonate solution (1000 mL) and extracted with ethyl acetate (3×500 mL). The combined organic extracts were washed with brine (2×500 mL), dried over sodium sulfate, and concentrated. Purification by column chromatography with toluene:acetonitrile (2:1) provided the title compound. (3.6 g, 19% yield). 1H NMR (CDCl3) δ ppm 9.15 (s, 1H), 8.23 (s, 1H), 7.37 (d, 1H, J=3.0 Hz), 7.0-7.11 (m, 4H), 6.83 (d, 1H, J=3.0 Hz), 5.40 (s, 2H), 4.52 (q, 2H, J=7.0 Hz), 1.48 (t, 3H, J=7.0 Hz). LCMS (APCI, M+H+): 299.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].N1C=CC=CC=1.[NH2:12][C:13]1[N:17]([C:18]2[C:23]([Cl:24])=[CH:22][C:21]([S:25][C:26]([F:29])([F:28])[F:27])=[CH:20][C:19]=2[Cl:30])[N:16]=[CH:15][C:14]=1[C:31]#[N:32]>C(Cl)(Cl)Cl>[C:1]([NH:12][C:13]1[N:17]([C:18]2[C:23]([Cl:24])=[CH:22][C:21]([S:25][C:26]([F:27])([F:28])[F:29])=[CH:20][C:19]=2[Cl:30])[N:16]=[CH:15][C:14]=1[C:31]#[N:32])(=[O:4])[CH2:2][CH3:3]
Reactant: N#Cc1cnn(-c2c(Cl)cc(SC(F)(F)F)cc2Cl)c1N
Reactant: CCC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCC(=O)Nc1c(C#N)cnn1-c1c(Cl)cc(SC(F)(F)F)cc1Cl
Reaction time: 20 h
Yield: 83.1 %

Procedure:
First 10 ml (0.11 mole) of propionyl chloride and then 1.8 ml (0.02 mole) of pyridine in 15 ml of chloroform are added to a suspension of 3.5 g (0.01 mole) of 5-amino-4-cyano-1-(2,6-dichloro-4-trifluoromethylthio-phenyl)pyrazole in 30 ml of chloroform at 0° C., with stirring. A clear solution is obtained, and, when the addition has ended, stirring is continued at room temperature for 20 hours. The solution thus obtained is evaporated to dryness. For working up, the residue is taken up in 50 ml of ethanol, aqueous ammonia is added until the reaction is alkaline, the mixture is heated under reflux for 10 minutes, the volatile constituents are removed in vacuo, the residue is taken up in 100 ml of chloroform, the mixture is washed with water, then with 2N aqueous hydrochloric acid and again with water and dried over sodium sulphate and the solvent is removed in vacuo. 3.4 g (83% of theory) of 5-propionylamino-4-cyano-1-(2,6-dichloro-4-trifluoromethylthio-phenyl)-pyrazole of melting point 153° C. to 156° C. are obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[N:9]=[C:10]([CH2:13][C:14]#[N:15])[S:11][CH:12]=2)=[C:5]([CH3:7])[N:6]=1.C(N(CC)C(C)C)(C)C.[N:25]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:26]=[O:27]>C(Cl)Cl>[C:14]([CH2:13][C:10]1[S:11][CH:12]=[C:8]([C:4]2[S:3][C:2]([NH:1][C:26]([NH:25][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:27])=[N:6][C:5]=2[CH3:7])[N:9]=1)#[N:15]
Reactant: Cc1nc(N)sc1-c1csc(CC#N)n1
Reactant: CCOC(=O)CCN=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)Nc1nc(C)c(-c2csc(CC#N)n2)s1
Temperature: 50 °C
Reaction time: 36 h

Procedure:
(2′-Amino-4′-methyl-4,5′-bi-1,3-thiazol-2-yl)acetonitrile, prepared in Step I, described above (236.3 mg; 1 mmol; 1 eq.), is suspended in DCM (5 ml). N,N-Diisopropylethylamine (377 μl; 2.20 mmol; 2.20 eq.) is added, followed by a solution of ethyl 3-isocyanatopropionate (143.1 mg; 1 mmol; 1 eq.) in DCM (3 ml). The reaction mixture is heated at 50° C. overnight. As the reaction is not complete, a second batch of ethyl 3-isocyanatopropionate (Aldrich) (143.1 mg; 1 mmol; 1 eq.) is added. After 36 hours the reaction is complete. The solvents are evaporated. EtOAc is added and the mixture is washed with brine, dried over MgSO4 and evaporated. The resulting crude product is purified by preparative HPLC, affording Compound (50) as white-off solid (76.6 mg; 20%). 1H NMR (DMSO-d6, 300 MHz) δ 1.21 (t, J=7.5 Hz, 3H), 2.44 (s, 3H), 2.58 (m, 2H), 3.39 (q, J=6 Hz, 2H), 4.10 (q, J=7.5 Hz, 2H), 4.62 (s, 2H), 6.72 (t, J=6 Hz, 1H), 7.64 (s, 1H), 10.49 (br s, 1H). M− (ESI): 378.17; M+ (ESI): 380.10. HPLC (method A), Rt: 2.60 min (purity: 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH3:10].C([Li])CCC.[CH3:16][S:17]SC>C1COCC1>[CH3:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[S:17][CH3:16]
Reactant: CSSC
Reactant: COc1ccc(Br)c(C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(SC)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
To the cold (−78° C.) solution of 2-bromo-5-methoxy toluene (8 g, 0.04 mol) in dry THF (80 mL) under inert atmosphere, butyl lithium solution (1.6M solution in hexane; 36.8 mL, 0.058 mol) was added dropwise and the mixture was stirred for 1 h at same temperature. Dimethyl disulphide (7.7 mL, 0.08 mol) was then added dropwise and the reaction mixture was allowed to warm to room temperature over a period of 2 h. The reaction mixture was quenched with sat. ammonium chloride solution and extracted in diethyl ether. The combined organic extracts were washed with water and brine and dried. The solvent was evaporated in vacuo to yield 6.5 g of 2-methyl-4-methoxy thioanisole, which was used as such in Step 2 MS m/z 168 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([CH2:22][N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[S:11][C:12]=1[S:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1.ClC1C=CC=C(C(OO)=[O:40])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([CH2:22][N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[S:11][C:12]=1[S:13]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)=[O:40]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cccc(Sc2sc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2F)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cccc(S(=O)c2sc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2F)c1
Reaction time: 6 h
Yield: 80.6 %

Procedure:
To a solution of tert-butyl ({4-(2-fluorophenyl)-5-[(3-methoxyphenyl)thio]-2-thienyl}methyl)methylcarbamate (277 mg) in ethyl acetate (5 mL) was added 3-chloroperbenzoic acid (144 mg) and the mixture was stirred for 6 hr. The reaction mixture was treated with aqueous sodium thiosulfate solution, and extracted with ethyl acetate. The extract was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→4:1) to give the title compound as a colorless oil (yield 231 mg, yield 81%).
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[CH3:12][NH2:13].C1COCC1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[CH3:12][NH:13][C:2]1[C:3]([NH2:4])=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CNc1ccc([N+](=O)[O-])cc1N
Temperature: 120 °C

Procedure:
In a 350 mL pressure flask, 2-fluoro-5-nitroaniline (10 g, 0.064 mol), methylamine as a 2M solution in THF (65 mL, 0.13 mol) and potassium carbonate (18 g, 0.13 mol) in 1-Methyl-2-pyrrolidinone (80 mL) were combined. The flask was sealed and heated to 120 degrees C. overnight. The reaction was monitored by TLC. When reaction was judged to be complete based upon consumption of 2-fluoro-5-nitroaniline, it was cooled to room temperature and poured into 2-3 times the total reaction volume of water. When a precipitate was formed, it was filtered and dried. The product was carried on without purification. 1H NMR (300 MHz, d6DMSO) δ 7.54 (dd, J=8.79, 2.64 Hz, 1H), 7.39 (d, J≦2.64 Hz, 1H), 6.41 (d, J=8.79 Hz, 1H), 6.11 (d, J=4.39 Hz, 1H), 5.07 (s, 2H), 2.83 (d, 1H), 4.83 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.[N+:14]([O-])([OH:16])=[O:15].OS(O)(=O)=O>>[CH3:13][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1
Reactant: CC(=O)Nc1ccc(N(C)C)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1ccc(N(C)C)cc1[N+](=O)[O-]

Procedure:
N-[4-(dimethylamino)phenyl]acetamide obtained in step I above was nitrated using nitric acid (1.2 eq)+H2SO4 (1.0 eq) at 0 to 5° C. for 2 hrs. After the completion of the reaction, reaction mixture was added to ice and pH was adjusted to 8, extracted with dichloromethane, which was evaporated to dryness to obtain N-[4-(dimethylamino)-2-nitrophenyl]acetamide.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH3:15][Si:16]([CH3:33])([CH3:32])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O.O>[CH3:15][Si:16]([CH3:32])([CH3:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Reactant: C[Si](C)(C)CCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)C=Cc1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1

Procedure:
A mixture of 5.0 g. ethyl 4-aminocinnamate, 9.14 g. of 14-(trimethylsilyl)tetradecyl bromide and 3.6 g. of powdered anhydrous potassium carbonate in hexamethylphosphoramide is heated for 20 hours at 60° C. The mixture is then cooled, diluted with water and extracted with ether. The combined ether extracts are dried, filtered and evaporated to provide ethyl 4-[14-(trimethylsilyl)tetradecylamino]cinnamate. The ester is hydrolyzed with.sodium hydroxide in a 1:9 water:ethanol solution at steam bath temperature for 10 hours. The hot solution is then acidified with acetic acid, cooled and filtered and the solid is washed with water. Recrystallization from chloroform yields the title product as a white solid.
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][C:5]1[CH:13]=[CH:12][C:11]2[N:10]3[CH:14]=[CH:15][CH:16]=[C:9]3[C:8](=O)[C:7]=2[CH:6]=1>N1C=CC=CC=1>[Cl:4][C:5]1[CH:13]=[CH:12][C:11]2[N:10]3[CH:14]=[CH:15][CH:16]=[C:9]3[C:8](=[N:2][OH:3])[C:7]=2[CH:6]=1
Reactant: NO
Reactant: O=C1c2cc(Cl)ccc2-n2cccc21
Agent: Cl
Solvent: c1ccncc1
Product: ON=C1c2cc(Cl)ccc2-n2cccc21
Yield: 84.6 %

Procedure:
Add 3.9 g (56.1 mmol) of hydroxylamine hydrochloride to a solution of 4.6 g (22.6 mmol) of 7-chloropyrrolo[1,2-a]indol-9-one in 80 ml of pyridine, then heat the reaction mixture at reflux for 3 hours. After cooling, the pyridine is removed under reduced pressure and the residue is taken up in water and extracted with 300 ml of diethyl ether. The ethereal phase is washed with 100 ml of 0.5N hydrochloric acid and then with water, dried over magnesium sulfate, rendered colourless with animal charcoal and then concentrated under reduced pressure to yield 4.18 g of the title product.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][C:31](=[O:38])[NH:32][C:33]2[NH:34][CH2:35][CH2:36][N:37]=2)=[CH:23][CH:22]=1)[C:13]([O:15]C(C)(C)C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O.O>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][C:31](=[O:38])[NH:32][C:33]2[NH:37][CH2:36][CH2:35][N:34]=2)=[CH:23][CH:22]=1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC2=NCCN2)cc1)NC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(CCCOc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1)NC1=NCCN1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
200 mg of tert-butyl (2S)-2-benzyloxycarbonylamino-3-(4-(3-(4,5-dihydro-1H-imidazol-2-ylcarbamoyl)-propoxy)phenyl)propionate were dissolved in 5 ml of trifluoroacetic acid/water (95/5) and the solution was stirred at room temperature for 15 min. The reaction solution was then concentrated in vacuo. The residue was dissolved in water and the solution was freeze-dried. Yield: 100%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:25](Br)[CH2:26][OH:27]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:25][CH2:26][OH:27])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCN1CCN(c2ccc(F)cc2)CC1
Yield: 79 %

Procedure:
To a mixture of 1-(4-fluorophenyl)piperazine (7.24 g), potassium carbonate powder (13.9 g) and N,N-dimethylformamide (30 ml) was added dropwise ethylene bromohydrin (10.0 g) under stirring. The mixture was stirred at room temperature for 3 hours, diluted with 100 ml of water and extracted with ethyl ether. The ethyl ether layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel chromatography [eluent: hexane-ethyl acetate (1:3)] to give 7.12 g (79.0%) of 4-(4-fluorophenyl)-1-piperazineethanol as an oil. IR(Neat): 3150 cm-1. NMR (CDCl3)δ: 2.47-2.80(6H, m), 2.97-3.20(4H, m), 3.10(1H, s), 3.65(2H, t, J=5.5), 6.71-7.13(4H, m).