Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:6]=[CH:7][C:8]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[C:15]([C:17]2[C:18](=[O:24])[NH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[CH:14]=[C:13]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:12]=1[O:29][CH3:30].[CH3:36][O-:37].[Na+]>CO>[C:25]([C:13]1[C:12]([O:29][CH3:30])=[C:11](/[CH:10]=[CH:9]/[C:8]2[CH:7]=[CH:6][C:5]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:4][C:3]=2[CH2:2][O:37][CH3:36])[CH:16]=[C:15]([C:17]2[C:18](=[O:24])[NH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[CH:14]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2CBr)cc(-c2ccc(C)[nH]c2=O)cc1C(C)(C)C
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1cc(NS(C)(=O)=O)ccc1/C=C/c1cc(-c2ccc(C)[nH]c2=O)cc(C(C)(C)C)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
step 3—To a solution of 320 (70 mg, 0.125 mmol) in MeOH (10 mL) was added sodium methoxide (10 mL, 5 mmol, 0.5 M MeOH solution). The reaction was stirred at RT overnight. The reaction mixture was concentrated, diluted with EtOAc and acidified with 6N HCl (1 mL). The organic extract was dried (Na2SO4), filtered and concentrated. The crude product was purified on a preparative SiO2 TLC plate developed with 2:1 EtOAc/hexane to afford 28 mg of I-208 as an off-white solid.
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:32])[F:31])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([NH:41][CH2:42][C:43](O)=[O:44])(OC(C)(C)C)=O>>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:31])[F:32])[CH:24]=2)[CH2:19][CH2:18][N:17]([C:43](=[O:44])[CH2:42][NH2:41])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: FC(F)(F)Oc1cccc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)c1
Agent: Cl
Product: NCC(=O)N1CC[C@H](OCc2cccc(OC(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound (27.7 mg) obtained in Example 27 and Boc-glycine (21.0 mg) were reacted and treated in the same manner as in the method described in Example 29 to obtain the title compound.
Reaction SMILES: C([O:3][C:4](=[O:12])[CH:5]([CH2:9][CH:10]=[CH2:11])[CH2:6][CH:7]=[CH2:8])C.[OH-].[Na+]>CO.O>[CH2:6]([CH:5]([CH2:9][CH:10]=[CH2:11])[C:4]([OH:12])=[O:3])[CH:7]=[CH2:8]
Reactant: C=CCC(CC=C)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCC(CC=C)C(=O)O
Temperature: 25 °C
Reaction time: 15 h
Yield: 54.2 %

Procedure:
To a stirred solution of 2-allylpent-4-enoic acid ethyl ester (prepared above, 9.0 g, 54 mmol) in 50 mL of methanol and 2 mL of water was added sodium hydroxide (2.5 g, 63 mmol, available from EMD). The solution was stirred for 15 hours, then heated at reflux temperature for 2 hours. After cooling the reaction mixture to room temperature, solvent was removed at reduced pressure. To the residue were added 75 mL of diethyl ether and 10 mL of concentrated hydrochloric acid. The mixture was stirred at room temperature for 10 minutes, then the layers were separated and the diethyl ether layer was dried over magnesium sulfate. After filtration to remove the magnesium sulfate, solvent was removed at reduced pressure to leave 4.1 g of 2-allylpent-4-enoic acid as a colorless oil whose structure was confirmed by NMR analyses.
Reaction SMILES: [CH2:1]([NH:7][C:8]([N:10]1[C:16](=[O:17])[CH2:15][C:14]([CH3:19])([CH3:18])[NH:13][C:12]([CH3:21])([CH3:20])[CH2:11]1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:22]([O-])=O.[Na+].C=O.[OH-].[NH4+]>C(O)=O>[CH2:1]([NH:7][C:8]([N:10]1[C:16](=[O:17])[CH2:15][C:14]([CH3:19])([CH3:18])[N:13]([CH3:22])[C:12]([CH3:20])([CH3:21])[CH2:11]1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCNC(=O)N1CC(C)(C)NC(C)(C)CC1=O
Reactant: O=C[O-]
Agent: C=O
Agent: [NH4+]
Agent: [Na+]
Solvent: O=CO
Product: CCCCCCNC(=O)N1CC(C)(C)N(C)C(C)(C)CC1=O

Procedure:
A mixture of 25 parts of 4-n-hexylcarbamoyl-2,2,7,7-tetramethyl-1,4-diazacycloheptan-5-one, 11.2 parts of sodium formate, 25 parts of formaldehyde and 2 parts of formic acid were heated at steam bath temperature for 2 hours. 250 Parts of ammonium hydroxide were then added and the solution extracted with chloroform to yield, after drying, 20 parts of a heavy oil which was further purified by column chromatography (silica) to give pure 4-n-hexylcarbamoyl-1,2,2,7,7-pentamethyl-1,4-diazacycloheptan-5-one. This material had the following elemental analysis by weight:
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:12]N(C)C)=[C:9]([OH:11])[CH:10]=1)(=O)C.[OH-].[K+]>[Pd]>[NH2:4][C:5]1[CH:10]=[C:9]([OH:11])[C:8]([CH3:12])=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(CN(C)C)c(O)c1
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Product: Cc1ccc(N)cc1O
Reaction time: 3 h
Yield: 68.4 %

Procedure:
In the hydrogenolysis step, 8.0 g (38 mmol) of 5-acetamido-2-[(N,N-dimethylamino)methyl]phenol was dissolved in 54 ml (162 mmol) of 3N potassium hydroxide solution in a Parr bottle. Palladium on activated carbon (0.8 g; 3% Pd/C) was added to the solution. The reaction mixture was shaken under hydrogen on a Parr apparatus for 3 hours at 70°-80° C. and 60 psi. The catalyst (Pd/C) was removed by filtration and the filtrate brought to about pH 12 with 6M HC1 (15-20 ml). The off-white crystalline product precipitated out of solution. The solution was cooled and the precipitate filtered, washed with water, and dried overnight in a vacuum oven to give 3.2 g (68% yield) of 5-amino-o-cresol, m.p. 158°-160° C.). The purity of 5-amino-o-cresol prepared by this procedure was determined to be 97% by perchloric acid titration.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[C:7]([CH:13]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:2].[CH3:19][Mg+].[Br-]>CCOCC>[OH:2][CH:1]([C:3]1[CH:13]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[C:5]([CH:4]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:19]
Reactant: CCOC(=O)c1cc(C=O)cc(C(=O)OCC)c1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Product: CCOC(=O)c1cc(C(=O)OCC)cc(C(C)O)c1
Reaction time: 5 h
Yield: 38.2 %

Procedure:
To a stirred solution of diethyl 5-formylisophthalate (2.83 g, 11.3 mmol) in ether (20 mL) was added MeMgBr (3.8 ml of 3.0 M solution, 11.3 mmol) dropwise. The resulting yellow suspension was stirred for 5 h and quenched with saturated aqueous NH4Cl. The resulting mixture was extracted with EtOAc (2×20 mL). The combined organic layer was washed with brine, dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (20% EtOAc in hexanes) to provide diethyl 5-(1-hydroxyethyl)isophthalate (1.15 g, 40%) as a white solid. 1H NMR (CDCl3): d 8.60-8.61 (m, 1H), 8.26-8.27 (m, 2H), 5.02-5.09 (m, 1H), 4.45 (q, J=7.2 Hz, 2H), 1.56 (d, J=6.3 Hz, 3H), 1.45 (t, J=7.2, 3H).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C:10]=3[N:9](COCC[Si](C)(C)C)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([C:7]2[C:15]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[NH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(-c3ccccc3)nn(COCC[Si](C)(C)C)c2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(-c2n[nH]c3c2CCNC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 3-phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (298 mg, 0.69 mmol) was dissolved in DCM (8 mL) with TFA (0.5 mL, 6.98 mmol) and was allowed to stir under N2 pressure at rt overnight. Solvent was removed and the residue partitioned between 2M Na2CO3 and DCM, then extracted with DCM three times. The combined organic layers were dried over Na2SO4 and concentrated. The resulting product was used as is in the next step.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][C:18]=2[N:19]=1.[CH3:29][O:30][CH2:31][CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:29][O:30][CH2:31][CH2:32][NH:33][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[CH:22][C:21]([O:24][C:25]([F:27])([F:28])[F:26])=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: Cn1c(Nc2nc3cc(OC(F)(F)F)ccc3s2)nc2cc(C(=O)O)ccc21
Reactant: COCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)c1ccc2c(c1)nc(Nc1nc3cc(OC(F)(F)F)ccc3s1)n2C

Procedure:
1-Methyl-2-(5-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (2-methoxy-ethyl)-amide (35 mg) was prepared by following General Procedure F using 1-methyl-2-(5-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benz-imidazole-5-carboxylic acid (41 mg), 2-methoxy-ethylamine (0.1 ml), HBTU (38 mg), and DIEA (0.1 ml). LCMS: m/z 467.
Reaction SMILES: [C:1]12([C:11]3O[N:14]=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:16][NH2:17].ClCCl>>[C:1]12([C:11]3[CH:12]=[C:13]([NH2:14])[NH:17][N:16]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: c1cc(C23CC4CC(CC(C4)C2)C3)on1
Reactant: NN
Solvent: ClCCl
Product: Nc1cc(C23CC4CC(CC(C4)C2)C3)n[nH]1
Yield: 96.3 %

Procedure:
A solution of 2.40 g (11.80 mmol) of 5-adamantylisoxazole and 1.18 g (23.60 mmol) of hydrazine hours. The solvent was removed in vacuo and the residue was taken up in 50 mol of dichloromethane. The solution was concentrated in vacuo to yield 2.47 g (96%) of a light brown oil. The crude material was purified by chromatography on silica gel to yield 200 g (78%) of a pale yellow solid: Rf 0.45 in 2/2/1 ligroin/CH2Cl2 /CH3OH; 1H NMR (CDCl3) δ 1.51 (S, 6H, the δ hydrogens of the adamantyl ring), 1.65 (S, 6H, the β hydrogens of the adamantyl ring, 1.81 (S, 3H, the three bridgehead protons), 5.16 (S, 1H, --C=CH--). All the analytical data are identical to those obtained from an authenticated sample.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]([S:12]([CH3:14])=[O:13])[C:5]2=[O:15].NC1C=C([Cl:23])C=CC=1C(=O)CS(C)=O.N([O-])=O.[Na+]>Cl>[Cl:23][C:11]1[CH:10]=[C:9]2[C:4]([C:5](=[O:15])[C:6]([S:12]([CH3:14])=[O:13])=[N:7][NH:8]2)=[CH:3][CH:2]=1
Reactant: CS(=O)c1n[nH]c2ccc(Cl)cc2c1=O
Reactant: CS(=O)CC(=O)c1ccc(Cl)cc1N
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Product: CS(=O)c1n[nH]c2cc(Cl)ccc2c1=O

Procedure:
This was prepared in analogous fashion to 6-chloro-3-(methylsulfinyl)-4(1H)-cinnolinone by diazotizing a suspension of 11 g of 2'-amino-4'-chloro-2-(methylsulfinyl) acetophenone in 250 ml of 1N HCl with 3.5 g of NaNO2. The material was recrystallized from dimethyl formamide m.p. 285°-90°; yield 10 g (87%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH2:14][C:15]([F:23])([CH2:21][CH3:22])[C:16](OCC)=[O:17])[CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[C:5]([N+:24]([O-])=O)=[CH:4][N:3]=1.Cl>C(O)(=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:24][C:16](=[O:17])[C:15]([CH2:21][CH3:22])([F:23])[CH2:14][N:8]([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[C:6]=2[N:7]=1
Reactant: CCOC(=O)C(F)(CC)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Agent: Cl
Solvent: CC(=O)O
Product: CCC1(F)CN(C2CCCC2)c2nc(Cl)ncc2NC1=O
Temperature: 60 °C
Reaction time: 18 h
Yield: 48 %

Procedure:
To a suspension of ethyl 2-(((2-chloro-5-nitropyrimidin-4-yl)(cyclopentyl)amino)methyl)-2-fluorobutanoate (2.6 g, 6 mmol), reduced iron (840 mg, 15 mmol) in acetic acid (20 ml) was added dropwise concentrated hydrochloric acid (2 ml) at 0° C. The reaction mixture was stirred at 60° C. for 18 h. It was then concentrated in vacuo, diluted to EtOAc, basified with 10% NaOH solution at 0° C. The whole was filtered through celite, washed with EtOAc. The filtrate was then separated. The organic layer was dried over Na2SO4. The solution was concentrated in vacuo followed by precipitation from ether to afford the product (0.9 g, 48% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.90 (t, J=7.3 Hz, 3 H) 1.53-1.91 (m, 10 H) 3.53-3.69 (m, 1 H) 3.78 (d, J=13.4 Hz, 1 H) 5.05 (t, J=8.5 Hz, 1 H) 7.96 (s, 1 H) 10.31 (d, J=1.5 Hz, 1 H). [M+H] calc'd for C14H18ClFN4O, 313; found 313.
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[CH:4][C:5](=[O:10])[C:6]([F:9])([F:8])[F:7].[CH3:13][NH:14][CH3:15]>C(O)C>[CH3:13][N:14]([CH3:15])[C:3]([S:2][CH3:1])=[CH:4][C:5](=[O:10])[C:6]([F:9])([F:8])[F:7]
Reactant: CSC(=CC(=O)C(F)(F)F)SC
Reactant: CNC
Solvent: CCO
Product: CSC(=CC(=O)C(F)(F)F)N(C)C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
The product of Example 1, 1,1-bismethylthio-4,4,4-trifluoro-1-buten-2-one, (2.16 g, 0.01 mol) and dimethylamine (0.45 g, 0.01 mol) were dissolved in ethanol (30 ml). The resulting solution was heated to 50° C. and maintained at that temperature with stirring for 1 hour. After this time, the resulting mixture was cooled to ambient temperature (20° C.) and the solvent was removed by evaporation under reduced pressure yielding a yellow residue. Chromatographic purifications of the solid using a silica column eluted with dichloromethane/methanol (30:1) gave the product, 1-dimethylamino-1-methylthio-4,4,4-trifluoro-1-buten-3-one, as a yellow oil in a yield of 2.1 g (98%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([O:21][CH2:22][CH3:23])=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13]CC2C=CC=CC=2)[CH:8]=1)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:22]([O:21][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:24])[CH3:23]
Reactant: CCOC(=O)C(=Cc1cccc(OCc2ccccc2)c1)OCC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1cccc(O)c1)OCC
Yield: 92.4 %

Procedure:
Compound (a) (10.4 g; 31.8 mmole) was hydrogenated at atmospheric pressure in ethyl acetate using Pd/C (dry, 10%) as a catalyst. The reaction mixture was filtered through celite and the solvent was evaporated in vacuo. The starting material was not completely consumed, therefore the hydrogenation was repeated to give 7 g (yield 92%) of the desired product.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:22]2[C:9](=[CH:10][C:11]3[CH:12]=[C:13]4[C:18](=[C:19]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:20]=3[CH:21]=2)[CH:17]=[CH:16][CH:15]=[CH:14]4)[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[Br:30]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:30][C:12]1[C:11]2[CH:10]=[C:9]3[C:8]4[C:3]([C:2]([CH3:29])([CH3:1])[C:22]3=[CH:21][C:20]=2[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[CH:17]2)=[CH:4][CH:5]=[CH:6][CH:7]=4
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)c2ccccc2-c2cc3cc4ccccc4c(-c4ccccc4)c3cc21
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)c2ccccc2-c2cc3c(Br)c4ccccc4c(-c4ccccc4)c3cc21
Temperature: 60 °C
Yield: 68.1 %

Procedure:
13,13-dimethyl-11-phenyl-13H-indeno[1,2-b]anthracene (6.3 g, 0.017 mol) and N-bromosuccinimide (3.76 g, 0.017 mol) were dissolved in carbon tetrachloride (150 ml), and the reaction mixture was stirred under reflux for 4 hours at 60° C. After the reaction was terminated, the reaction solution was extracted with distilled water, and purified by column chromatography to give 6-bromo-13,13-dimethyl-11-phenyl-13H-indeno[1,2-b]anthracene (5.2 g, yield=68%).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[N+:16]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH2:24])=[NH:23])([O-:18])=[O:17]>>[OH:13][C:11]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:24]=[C:22]([C:21]2[CH:25]=[CH:26][CH:27]=[C:19]([N+:16]([O-:18])=[O:17])[CH:20]=2)[N:23]=1
Reactant: N=C(N)c1cccc([N+](=O)[O-])c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1cnc(-c2cccc([N+](=O)[O-])c2)nc1O
Yield: 86 %

Procedure:
The title compound was prepared by (a) reaction of diethyl ethoxymethylenemalonate (5 g, 24 mmol) with 3-nitrobenzamidine (5 g, 25 mmol) to afford 86% of ethyl 4-hydroxy-2-(3'-nitrophenyl)pyrimidine-5-carboxylate in analogy to Example 15, (b) reaction of ethyl 4-hydroxy-2-(3'-nitrophenyl)pyrimidine-5-carboxylate (6 g, 21 mmol) with (chloromethylene)dimethylammonium chloride (4 g, 31 mmol) concentration of reaction mixture, followed by hexane and ether wash afford 45% of ethyl 4-chloro-2-(3'-nitrophenyl)pyrimidine-5-carboxylate, (c) reaction of ethyl 4-chloro-2-(3'-nitrophenyl)pyrimidine-5-carboxylate (1.9 g, 6 mmol) with hydrazine (0.6 g, 18 mmol) to afford 33% of ethyl 4-hydrazino-2-(3'-nitrophenyl)pyrimidine-5-carboxylate in analogy to Example 18, (d) reaction of ethyl 4-hydrazino-2-(3'-nitrophenyl)pyrimidine-5-carboxylate (1.8 g, 6 mmol) with citraconic anhydride in analogy to Example 21, to afford 80% (0.5 g) of the title compound; m.p. 118-120° C.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:18]([O:19][C:20](=O)[CH3:21])[C@H:17]([O:23][C:24](=O)[CH3:25])[C@H:16]([CH3:27])[O:15][C@@H:6]1[S:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=O)[CH3:2].C[O-].[Na+].CO.[H-].[Na+].[CH:35]1[CH:40]=[CH:39][C:38]([CH2:41]Br)=CC=1>CN(C=O)C.O.CCCCCC>[CH2:1]([O:4][C@H:5]1[C@H:18]([O:19][CH2:20][C:21]2[CH:5]=[CH:18][CH:17]=[CH:16][CH:27]=2)[C@H:17]([O:23][CH2:24][C:25]2[CH:41]=[CH:38][CH:39]=[CH:40][CH:35]=2)[C@H:16]([CH3:27])[O:15][C@@H:6]1[S:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=1)[C:2]1[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)O[C@H](Sc2ccc(C)cc2)[C@H]1OC(C)=O
Reactant: BrCc1ccccc1
Agent: C[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccc(S[C@H]2O[C@@H](C)[C@@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 152.4 %

Procedure:
p-Methylphenyl 2,3,4-Tri-O-acetyl-1-thio-β-L-fucopyranoside (ibid, Brukart, M. D. et al. 1997) (2.5 g, 6.31 mmol) was treated with NaOMe-MeOH. The product was further treated with 85% NaH (463 g, 22.7 mmol) and BnBr (5.8 mL, 37.86 mmol) in DMF (25 mL). After reaction was finished, hexane (30 mL) and water (300 mL) were added into the vigorously stirred solution. The solid product was filtered, washed with water (2×5 mL) and hexane-AcOEt (15:1, 2×5 mL). The crude product was suspended in a hot (70° C.) mixture of AcOEt-Hexane (10:1), and stirred for 10 min, cooled to rt, filtered to gave pure 50 (2.6 g, 76%) as solid: [α]D22 +8° (c, 0.5, CHCl3); HRMS (M+Cs) calcd for C34H36O4SCs 672.1290. found 672.1287.
Reaction SMILES: Br[CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CCCC[SnH](CCCC)CCCC.[C:22](#[N:25])[CH:23]=[CH2:24].CC(N=NC(C#N)(C)C)(C#N)C>C1(C)C=CC=CC=1>[CH:2]1([CH2:24][CH2:23][C:22]#[N:25])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: BrC1CCCCCC1
Reactant: C=CC#N
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: N#CCCC1CCCCCC1

Procedure:
3-Cycloheptylpropionitrile is prepared in this example according to the procedure of Example 1 using a solution of 2-bromocycloheptane (25.57 g; 144.38 mmole); Bu3SnH (50.42 g; 173.26 mmole), acrylonitrile (15.32 g; 288.77 mmole), and AIBN (1.13 g) in toluene (300 ml). Yield is 16 g; mp oil.
Reaction SMILES: [CH3:1][CH:2]1[O:6][CH2:5][S:4][C:3]1=[N:7][OH:8].[CH3:9][N:10]([S:14][S:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)[C:11](F)=[O:12].C(N(CC)CC)C>O1CCOCC1>[CH3:9][N:10]([S:14][S:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)[C:11]([O:8][N:7]=[C:3]1[CH:2]([CH3:1])[O:6][CH2:5][S:4]1)=[O:12]
Reactant: CC1OCSC1=NO
Reactant: Cc1ccc(SSN(C)C(=O)F)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1ccc(SSN(C)C(=O)ON=C2SCOC2C)cc1

Procedure:
4-[[O-[N-Methyl-N-(4-methylphenylthiosulfenyl)carbamoyl]oximino]]-5-methyl-1,3-oxathiolane was prepared by the procedure described in Example I by reacting 4.0 g (0.03 m) of 5-methyl-4-oximino-1,3-oxathiolane, 6.95 g (0.03 m) of N-methyl-N-(4-methylphenylthiosulfenyl) carbamoyl fluoride and 3.07 g (0.03 m) of triethylamine in 50 ml of dioxane. The crude residual oil (7.3 g) was purified by dry column chromatography using silica gel.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:16]O>>[NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: Nc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a mixture of 2-amino-4-(trifluoromethyl)benzoic acid (150 g, 0.73 mol) in MeOH (2.5 L) was added conc. HCl (0.5 L, 16.5 mol). The reaction mixture was allowed to stir at reflux. After 3 h, an additional portion of HCl (0.5 L, 16.5 mol) was added and the reaction was allowed to continue to stir at 80° C. for 60 h. The reaction mixture was allowed to cool to rt and was concentrated. Water (0.5 L) was added to the residue, and the solution was basified with 10% aqueous NaOH solution. The resulting precipitate was filtered to give methyl 2-amino-4-(trifluoromethyl)benzoate (120 g, 75%) as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]1([PH:9](=[O:13])[O:10][CH2:11][CH3:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:14](I)[CH3:15]>C1COCC1>[CH2:14]([P:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:13])[O:10][CH2:11][CH3:12])[CH3:15]
Reactant: CCI
Reactant: CCO[PH](=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(CC)c1ccccc1
Yield: 52.2 %

Procedure:
A slurry of sodium hydride (0.13 g of a 60% suspension in mineral oil, 3.2 mmol) in anhydrous THF (10 ml) was treated dropwise with a solution of ethyl phenylphosphinate (0.50 g, 2.9 mmol) over one hour via a syring pump. The mixture was allowed to stir an additional 30 minutes before the addition of ethyl iodide (0.26 ml, 3.2 mmol). After 45 minutes the reaction was quenched with 10% aqueous ammonium chloride (5 ml) and poured into a separatory funnel containing ethyl acetate (50 ml). The organic phase was washed with water, saturated aqueous sodium bicarbonate and brine before being dried over magnesium sulfate, filtered and concentrated to afford 0.30 g (52%) of the title compound as a colorless mobile oil following flash chromatography on silica gel (50% ethyl acetate/hexane); MS: 199 m/z (M+H)+.
Reaction SMILES: [ClH:1].[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>>[ClH:1].[C:2]1([N:8]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH2:28])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CCc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCC(=O)O)c3ccccc3)ccc21

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[2-(4-amidinophenyl)ethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide hydrochloride and sodium hydroxide solution.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([C:14]1[C:15]([F:30])=[C:16]([NH:22]C(=O)OC(C)(C)C)[CH:17]=[C:18]([F:21])[C:19]=1[F:20])=[O:13])=[CH:7][CH:6]=2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:22][C:16]1[C:15]([F:30])=[C:14]([C:12]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]=[CH:3][C:2]([Cl:1])=[N:11]3)=[O:13])[C:19]([F:20])=[C:18]([F:21])[CH:17]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)c(C(=O)c2ccc3ncc(Cl)nc3c2)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(F)c(F)c(C(=O)c2ccc3ncc(Cl)nc3c2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
To a solution of tert-butyl (3-(3-chloroquinoxaline-6-carbonyl)-2,4,5-trifluorophenyl)carbamate (128 mg, 0.29 mmol, 1.0 eq.) in DCM (5 mL) was added TFA (5 mL). After the resulting mixture was stirred at rt for 0.5 h, the solvent was evaporated. The resulting residue was washed with saturated NaHCO3 and extracted with EA (20 mL×3). The combined organic layers were dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash column chromatography (PE/EA=2/1, v/v) to afford (3-amino-2,5,6-trifluorophenyl)(3-chloroquinoxalin-6-yl)methanone (40 mg, 40.9%).