Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH:53]1([CH2:56][NH:57][CH2:58][C:59]2[NH:60][C:61](=[O:69])[C:62]3[CH2:68][O:67][CH2:66][CH2:65][C:63]=3[N:64]=2)[CH2:55][CH2:54]1>CN(C=O)C>[CH:53]1([CH2:56][N:57]([CH2:58][C:59]2[NH:60][C:61](=[O:69])[C:62]3[CH2:68][O:67][CH2:66][CH2:65][C:63]=3[N:64]=2)[C:15](=[O:17])[CH2:14][N:11]2[CH2:10][CH2:9][CH:8]([C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)[CH2:55][CH2:54]1
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: O=c1[nH]c(CNCC2CC2)nc2c1COCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(F)cc1)C1CCN(CC(=O)N(Cc2nc3c(c(=O)[nH]2)COCC3)CC2CC2)CC1
Reaction time: 0.5 h
Yield: 21.9 %

Procedure:
[4-(4-Fluoro-benzoyl)-piperidin-1-yl]-acetic acid (169 mg, 0.64 mmol) was added with HATU (364 mg, 0.96 mmol) in DMF (2 mL) and DIEA (0.28 mL, 1.60 mmol) was added. This was sonicated, stirred for 30 min and then 2-[(cyclopropylmethyl-amino)-methyl]-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (150 mg, 0.64 mmol) in 1 mL DMF was added to the mixture. The mixture was stirred at room temperature for 16 h, concentrated to dryness, purified by silica gel column (eluted with 0-10% methanol in dichloromethane) then triturated with methanol to give a white solid as the title compound (66 mg, 0.14 mmol, 21% yield). m/z=483.3 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[CH3:16])[CH3:2].[CH:18]1([S:24]([C:27]2[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=2[CH:29]=O)(=[O:26])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>ClCCl>[CH:18]1([S:24]([C:27]2[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=2[CH2:29][C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=3)[N:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:17])[C:7]=2[CH3:16])(=[O:25])=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=Cc1ccccc1S(=O)(=O)C1CCCCC1
Reactant: CCOC(=O)Cn1c(C)cc2cc(F)ccc21
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)C2CCCCC2)c2cc(F)ccc21
Reaction time: 2 h
Yield: 51.4 %

Procedure:
To a stirred solution of [5-fluoro-2-methyl-1H-indol-1-yl]acetic acid ethyl ester (0.85 g, 3.62 mmol) at room temperature in dichloromethane (20 mL) was added 2-(cyclohexylsulfonyl)benzaldehyde (1.00 g, 3.97 mmol) followed by triethylsilane (2.9 mL, 18.3 mmol). TFA (0.85 mL, 11.0 mmol) was then added dropwise over 15 minutes, and after the addition was complete, the resulting mixture was stirred for 2 hours. Saturated aqueous NaHCO3 was then added to the solution, and the separated organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The resulting solid was purified by trituration with light petroleum then recrystallised from an ethyl acetate/hexanes mixture to afford ethyl 2-(3-(2-(cyclohexylsulfonyl)benzyl)-5-fluoro-2-methyl-1H-indol-1-yl)acetate (0.875 g, 1.86 mmol, 51%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[O:14][C:13](=[O:15])[C:12]([C:16]([OH:18])=[O:17])=[CH:11][C:10]=2[CH:19]=1)(=[O:3])[CH3:2].[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1O)#[N:21].N1C=CC=CC=1>O1CCOCC1>[C:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[O:14][C:13](=[O:15])[C:12]([C:16]([O:18][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[C:20]#[N:21])=[O:17])=[CH:11][C:10]=2[CH:19]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1ccc2oc(=O)c(C(=O)O)cc2c1
Reactant: N#Cc1ccccc1O
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CC(=O)OCc1ccc2oc(=O)c(C(=O)Oc3ccccc3C#N)cc2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To the suspension of the acid chloride of 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylic acid (4 mmol) obtained according to Pochet et al. (Bioorg. Med. Chem. 2000, 8, 1489) in anhydrous dioxane (10 mL) was added 2-cyanophenol (5 mmol) and pyridine (0.4 mL). After 12 h stirring at room temperature, the solvent was evaporated under vacuum and the residue was suspended in methanol. The resulting precipitate was collected by filtration, washed with methanol and dried. The solid was crystallyzed in ethyl acetate (40%); mp: 181-183° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[CH2:8][C:9]1[N:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][CH:10]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.O>CN(C=O)C>[N:19]1([CH2:8][C:9]2[N:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COC(=O)c1cccc(CCl)n1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CN2CCCC2)n1
Temperature: 80 °C
Yield: 67.4 %

Procedure:
K2CO3 (66 g, 0.48 mol) was added to a solution of methyl 6-(chloromethyl)picolinate 67 (45.0 g) and pyrrolidine 68 (34 g, 0.48 mol) in DMF (300 mL). The reaction mixture was heated at 80° C. for 12 h. H2O (300 mL) was added and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo to give 69 (36 g).
Reaction SMILES: C[O:2][C:3](=[O:36])[C@H:4]([CH2:32][CH2:33][S:34][CH3:35])[NH:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:9][C:8]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([F:30])([F:29])[F:28].[Li+].[OH-].O>C1COCC1>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([NH:5][C@H:4]([C:3]([OH:36])=[O:2])[CH2:32][CH2:33][S:34][CH3:35])=[O:31])=[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:28])([F:29])[F:30])[CH:9]=2)[CH:16]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(COc2cccnc2)cc1-c1ccccc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CSCC[C@H](NC(=O)c1ccc(COc2cccnc2)cc1-c1ccccc1C(F)(F)F)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
The product of Example 304F (291 mg, 0.56 mmol) was dissolved in THF(4 mL) and saturated aqueous LiOH (1 mL). Water (1 mL) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was thoroughly evaporated and formic acid was added to pH3 The reaction was evaporated to dryness and ethyl acetate (10 mL) was added followed by a minimum quantity of H2O (−1 mL) to completely solubilize the free acid and the water soluble salts, respectively. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×). The ethyl acetate layers were combined and dried over Na2SO4, filtered, and evaporated and then lyophilized to give the title compound (242 mg, 86%) as an amorphous white solid. 1H NMR (300 MHz, CD3OD) δ 8.30 (bs, 1H), 8.14 (m, 1H), 7.76-7.33 (m, 9H), 5.28 (s, 2H), 4.87-4.40 (m, 1H), 2.40-2.06 (m, 2H), 2.04-1.94 (m, 4H contains methionine SMe), 1.92-1.80 (m, 1H). MS (CI) 505 (M+H)+ 505. Anal calcd for C25H23O4N2SF3: 0.65H2O solvate: C, 58.17; H, 4.74; N, 5.43. Found: C, 58.17; H, 4.80; N, 5.31. HRMS FAB Calcd m/z MH+ for C25H23O4N2SF3 505.1409, found 505.1408.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]2)=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc([N+](=O)[O-])cc2)CC1

Procedure:
A stirred solution of the t-butyl piperidin-4-ylcarbamate (1 equiv.), 4-fluoronitrobenzene (1 equiv.), and potassium carbonate (1 equiv.) in ethanol was heated at reflux temperature under nitrogen for 18 h, cooled, diluted with water and extracted with CH2Cl2. The combined extracts were dried over MgSO4 and concentrated in vacuo to give a solid residue. The solid was triturated with 20:80 ethyl acetate:hexanes and filtered. The filtercake was air-dried to afford t-butyl 1-(4-nitrophenyl)piperidin-4-ylcarbamate.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[S:23][C:17]=2[C:16]([CH2:31][CH:32]([CH3:34])[CH3:33])=[N:15]1.CC1C=CC(S(=O)([S:44][CH2:45][CH2:46][CH2:47][O:48][Si](C(C)(C)C)(C)C)=O)=CC=1>O1CCCC1>[OH:48][CH2:47][CH2:46][CH2:45][S:44][C:21]1[C:18]2[C:19](=[O:20])[N:14]([CH3:13])[N:15]=[C:16]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:17]=2[S:23][C:22]=1[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)Cc1nn(C)c(=O)c2cc(Cc3ccccc3)sc12
Reactant: Cc1ccc(S(=O)(=O)SCCCO[Si](C)(C)C(C)(C)C)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)Cc1nn(C)c(=O)c2c(SCCCO)c(Cc3ccccc3)sc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of butyl lithium in hexanes (2.5M, 1.3 ml) was added to a solution of diisopropylamine (0.45 ml) in tetrahydrofuran (6 ml) at 0° C. under nitrogen. After 30 minutes, 5 ml of the resulting solution was added to a solution of 5-methyl-7-(2-methylpropyl)-2-phenylmethylthieno[2,3-d]pyridazin-4(5H)-one (example 15, 0.50 g) and S-[3-{[(1,1-dimethylethyl)dimethylsilyl]oxy}propyl] 4methylbenzenesulfonothioate, (J. Med. Chem. 1995, 38, 2557., 0.85 g) in tetrahydrofuran (10 ml) at −78° C. under nitrogen. The reaction mixture was warmed to room temperature, quenched with saturated aqueous ammonium chloride solution (25 ml) and extracted with ethyl acetate (50 ml). The organic extracts were washed twice with saturated aqueous ammonium chloride solution, twice with saturated sodium hydrogen carbonate solution, then with brine, dried, filtered and evaporated. The residue was dissolved in acetonitrile (20 ml) and treated with 40% hydrofluoric acid (1 ml). After 16 hours, saturated sodium hydrogen carbonate solution (50 ml) was added and the mixture was extracted with ethyl acetate (50 ml). The organic extracts were washed with brine, dried, filtered and evaporated. The residue was purified by column chromatography, eluting with ethyl acetate:isohexane (1:2 then 1:1) to give the title compound (0.51 g) as a solid.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[C:6]([O:12][CH3:13])[C:5]=1[N:14]=[CH:15]OCC.O.[NH2:21][NH2:22]>C(O)C>[NH2:21][N:22]1[C:3](=[O:2])[C:4]2[C:5](=[C:6]([O:12][CH3:13])[C:7]([Cl:11])=[CH:8][C:9]=2[Cl:10])[N:14]=[CH:15]1
Reactant: CCOC=Nc1c(OC)c(Cl)cc(Cl)c1C(=O)OC
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1c(Cl)cc(Cl)c2c(=O)n(N)cnc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of the imidate 5-2 (400 mg, 1.31 mmol) in ethanol (12 mL), was added under an argon atmosphere, hydrazine hydrate (1.8 mL, 57.8 mmol). After 15 min, the solution was warmed to room temperature and stirred for a further 2 h. The thick suspension was diluted with ethanol and filtered. The solid was washed with cold ethanol and dried under vacuum to give 3-amino-5,7-dichloro-8-methoxy-3H-quinazolin-4-one (5-3) as a white fluffy solid (289 mg, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[S:16][C:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:14][C:13]=2[CH3:23])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(N(CC)C(C)C)(C)C.CN(C1C=CC=CN=1)C.[F:42][C:43]([F:49])([F:48])[S:44](Cl)(=[O:46])=[O:45]>ClCCl>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[S:16][C:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:44]([C:43]([F:49])([F:48])[F:42])(=[O:46])=[O:45])[CH2:19][CH2:18]3)=[N:14][C:13]=2[CH3:23])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1nc(C2CCNCC2)sc1COc1ccc(C#N)c(Cl)c1
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: CN(C)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(C2CCN(S(=O)(=O)C(F)(F)F)CC2)sc1COc1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
500 mg 2-Chloro-4-(4-methyl-2-piperidin-4-yl-thiazol-5-ylmethoxy)-benzonitrile was dissolved in 20 ml dichloromethane. 0.25 ml N,N-Diisopropylethylamine and 50 mg dimethylaminopyridine were added. Then 0.26 ml trifluoromethanesulfonylchloride were added to the ice cooled reaction mixture. The cooling bath was removed and the reaction mixture stirred at room temperature overnight. The reaction mixture was washed with 10 ml saturated NaHCO3 solution and then dried over MgSO4. The solvent was removed in Vacuo. The resulting crude material was purified by reversed phase HPLC to obtain 350 mg 2-Chloro-4-[4-methyl-2-(1-trifluoromethanesulfonyl-piperidin-4-yl)-thiazol-5-ylmethoxy]-benzonitrile as amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[CH3:9][Al](C)C.C[Si](Cl)(C)C.Cl>CCCCCC.C1COCC1>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH2:3]1
Reactant: CC1=CC(=O)CCC1
Reactant: C[Al](C)C
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1(C)CCCC(=O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
1.1 g (10 mmol) of 3-methyl-cyclohex-2-en-1-one and 28 mg (0.2 mmol) of CuBr are introduced into 15 ml of THF. 11 ml (11 mmol) of a 10% trimethylaluminum solution in hexane and 2.16 g (20 mmol) of trimethylsilyl chloride are added at 0° C. and stirred for 3 hours at room temperature. It is hydrolyzed with 10 ml of 1N hydrochloric acid, extracted with ethyl acetate, and the solvent is evaporated. 1.21 g (97% of theory) of 3,3-dimethylcyclohexanone is obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[S:9][CH:8]=[N:7][C:6]=1[CH3:10].[C:11]([C:14]1[S:15][C:16]([CH2:20][CH2:21][O:22][CH3:23])=[C:17]([CH3:19])[N:18]=1)(=[O:13])[CH3:12]>>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:11]([C:14]2[S:15][C:16]([CH2:20][CH2:21][O:22][CH3:23])=[C:17]([CH3:19])[N:18]=2)([OH:13])[CH3:12])=[N:7][C:6]=1[CH3:10]
Reactant: COCCc1sc(C(C)=O)nc1C
Reactant: COCCc1scnc1C
Product: COCCc1sc(C(C)(O)c2nc(C)c(CCOC)s2)nc1C

Procedure:
From 5-(2-methoxyethyl)-4-methylthiazole and 2-acetyl-5-(2-methoxyethyl)-4-methylthiazole.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[C:18]1([NH:24][CH2:25][CH2:26][NH2:27])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([NH:27][CH2:26][CH2:25][NH:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: NCCNc1ccccc1
Reactant: CS(=O)c1nc(N)nc(-c2cccs2)c1C#N
Solvent: C1COCCO1
Product: N#Cc1c(NCCNc2ccccc2)nc(N)nc1-c1cccs1

Procedure:
From 2-amino-4-methanesulfinyl-6-thiophen-2-yl-pyrimidine-5-carbonitrile and N-phenylethylenediamine in dioxane. ES-MS m/e (%): 337 (M+H+, 100).
Reaction SMILES: I/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1.[C:17]([C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=1)#[CH:18]>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2][C:18]#[C:17][C:19]2[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)=[CH:11][CH:12]=1
Reactant: Clc1ccc(-c2ccccc2/C=C/I)cc1
Reactant: C#Cc1ccc(C(=O)OC)cc1
Product: O=C(O)c1ccc(C#CC=Cc2ccccc2-c2ccc(Cl)cc2)cc1
Yield: 42.2 %

Procedure:
In a similar manner to that of Example 1(e), by reaction of 2.40 g (7.0 mmol) of 2-((E)-2-iodovinyl)-4'-chlorobiphenyl obtained in Example 23(b) with 1.03 g (6.4 mmol) of methyl 4-ethynylbenzoate, 970 mg (41%) of the expected compound are obtained in the form of a pale yellow solid with a melting point of 135° C.
Reaction SMILES: [H-].[Na+].[Br:3][CH2:4][CH2:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][OH:11])=[CH:8][CH:7]=1.I[CH3:15].O>C1COCC1>[CH3:15][O:11][CH2:10][C:9]1[CH:12]=[CH:13][C:6]([CH2:5][CH2:4][Br:3])=[CH:7][CH:8]=1
Reactant: OCc1ccc(CCBr)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCc1ccc(CCBr)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
To a suspension of 60% NaH in paraffin (13.9 mmol; 0.56 g) in THF (20 ml) cooled to 0° C. was first added, dropwise, a solution of 4-(2-bromoethyl)benzyl alcohol (9.25 mmol; 1.99 g) in THF (20 ml) in an ice bath, followed by iodomethane (13.9 mmol; 1.972 g; 0.86 ml). The mixture was stirred at room temperature for 1 hour 30 minutes, after which it was poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated NaCl solution (3×20 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was chromatographed on a column of alumina, eluting with ethyl acetate, to give 1.38 g of product as an oil (65%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([NH:22][C:23](=O)[CH2:24][N:25]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=3)[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:51])=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([NH:22][C:23](=[S:51])[CH2:24][N:25]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=3)[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1NC(=O)CN(C(=O)OC(C)(C)C)c1ccc(F)c(F)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1NC(=S)CN(C(=O)OC(C)(C)C)c1ccc(F)c(F)c1
Temperature: 100 °C
Yield: 82.2 %

Procedure:
To a solution of 4-(3-{2-[tert-butoxycarbonyl-(3,4-difluoro-phenyl)-amino]-acetylamino}-4-methyl-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (160 mg) in toluene (4 ml) was added Lawesson's reagent (100 mg) and the reaction heated at 100° C. for 2.5 hr. After cooling to room temperature, the solvent was removed in vacuo to afford a yellow powder. Purification by NPHPLC (0-5% MeOH in CH2Cl2) afforded 4-(3-{2-[tert-butoxycarbonyl-(3,4-difluoro-phenyl)-amino]-thioacetylamino}-4-methyl-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (120 mg). This was taken up in CH2Cl2 (1 ml) and trifluoroacetic acid (0.63 ml) added. After 2 hr stirring the reaction was poured into aqueous K2CO3 and the organic layer was separated, washed with aqueous K2CO3 and brine, dried (Na2SO4) and concentrated to leave yellow crystals. They were purified further by reverse phase HPLC to afford the title compound (14 mg).
Reaction SMILES: C(O)(=O)C.[F:5][CH:6]([F:16])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1>[Fe].C(OCC)(=O)C>[F:5][CH:6]([F:16])[C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[NH2:13]
Reactant: O=[N+]([O-])c1cccc(C(F)F)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1cccc(C(F)F)c1
Yield: 97.2 %

Procedure:
100 mg of Fe was added intio 3 ml of acetic acid and refluxed for 15 minutes. After lowering the temperature into room temperature, the mixture was added with 1-(difluoromethyl)-3-nitrobenzene (0.2 g, 1.15 mmol) and refluxed again for 1 hour. After addition of 20 ml ethyl acetate, impurities were removed using cellite and the organic layer was concentrated under vacuum. After column chromatography (ethylacetate/n-hexane, 1/15), the title compound (0.16 g, 50%) was obtained.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:13][C@@H:12]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:11][C@H:10]1[C:24](=[O:28])[NH:25][CH2:26][CH3:27])=O)(C)(C)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:26]([NH:25][C:24]([C@@H:10]1[CH2:11][C@H:12]([S:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[CH2:13][NH:9]1)=[O:28])[CH3:27]
Reactant: CCNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.5 %

Procedure:
41.19 ml of a 4N ethyl acetate solution of hydrogen chloride were added to a solution of 13.00 g of (2S, 4S)-1-t-butoxycarbonyl-2-ethylcarbamoyl-4-(4-methoxybenzylthio)pyrrolidine dissolved in 100 ml of ethyl acetate, and the mixture was stirred at room temperature for 3 hours. At the end of this time, the reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The aqueous layer was saturated with ammonium chloride and extracted with tetrahydrofuran. The combined extracts were washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation under reduced pressure. The residue was subjected to column chromatography through silica gel (eluted with a 87:13 by volume mixture of ethyl acetate and methanol) to afford 8.00 g of the title compound as pale brown crystals, melting at 67°-68° C.
Reaction SMILES: [CH2:1]([S:6][C:7]1[S:11][C:10]([CH2:12][NH:13][OH:14])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C[Si]([N:19]=[C:20]=[S:21])(C)C>O1CCOCC1>[OH:14][N:13]([CH2:12][C:10]1[S:11][C:7]([S:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:8][CH:9]=1)[C:20]([NH2:19])=[S:21]
Reactant: C[Si](C)(C)N=C=S
Reactant: CCCCCSc1ccc(CNO)s1
Solvent: C1COCCO1
Product: CCCCCSc1ccc(CN(O)C(N)=S)s1

Procedure:
To a solution of N-[5-n-pentylthiothien-2-ylmethyl]-hydroxylamine (4.36 g) in dioxan (60 ml) at room temperature under nitrogen, was added trimethylsilylisothiocyanate (3.11 g) and the solution heated at reflux for 1 hour. The cooled solution was quenched with saturated aqueous ammonium chloride, dried over MgSO4 and evaporated under reduced pressure to give a brown oil. The oil was flash chromatographed on a Sorbsil C60-40/60H column using ether to give a pale yellow solid, recrystallized from n-hexane to give a cream crystalline solid m.p. 112°-114° C.
Reaction SMILES: CO.[OH-].[K+].[C:5]1([C:12]([O:14]C)=[O:13])([C:8]([O:10]C)=[O:9])[CH2:7][CH2:6]1.S(=O)(=O)(O)O>O>[C:5]1([C:12]([OH:14])=[O:13])([C:8]([OH:10])=[O:9])[CH2:7][CH2:6]1
Reactant: COC(=O)C1(C(=O)OC)CC1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1(C(=O)O)CC1
Reaction time: 1.5 h

Procedure:
In a 4 liter multinecked flask, 800 ml of aqueous saturated K2 SO4 solution (from previous batches, neutralized), 500 ml of methanol and 330 g of KOH (85%, 5.0 mol) are heated and then, at 68° C., over a period of 90 minutes, a 316.2 g amount of dimethyl cyclopropane-1,1-dicarboxylate (2.0 mol) is added gradually. During the postreaction time of 4 hours, some of the methanol distills. After the reaction solution has cooled it is acidified, with cooling, with a 281 g amount of sulfuric acid (96% strength, 2.75 mol) which has previously been diluted with 100 ml of water. The K2SO4 which crystallizes is filtered via a sintered disk, washed with methanol and dried: 380 g (87.2% of the theoretical yield).