Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].Cl.O[Li].O.C([O-])=O.[NH4+].[C:18](ON1C(=O)CCC1=O)([O:20][CH2:21][CH:22]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19].C([O-])(O)=O.[Na+]>C1COCC1.CO.O.O.CO.CC(C)=O.O.[Pd]>[N:1]1([C:18]([O:20][CH2:21][CH:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]3[C:34]2=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:19])[CH2:9][CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: O=C(O)[C@@H]1CCCCN1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CCCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 20 h
Yield: 71.5 %

Procedure:
The carboxylate salt 2-16 (0.084 g, 0.204 mmol) was dissolved in THF/MeOH/H2O (6:3:1, 9 mL) and the solution cooled to 0° C. LiOH.H2O (0.045 g, 1.07 mmol) dissolved in 0.4 mL H2O was added. The mixture was stirred at 0° C. for 20 hours. The solvent was removed under reduced pressure to give a white solid (Rf=0.31, CH2Cl2:MeOH 10:1). The white solid was dissolved in MeOH followed by addition of ammonium formate (0.106 g, 1.68 mmol) and Pd/C (10%, 0.049 g) under N2. The mixture was refluxed for 3 hours. The solution was then cooled, filtered through celite and syringe filter and the filtrate concentrated on a rotary evaporator to afford a white solid. The solid was dissolved in acetone/H2O (2:1, 9 mL) and cooled to 0° C., followed by the addition of Fmoc-OSu (0.067 g, 0.199 mmol) and NaHCO3 (0.16 g, 1.90 mmol). The turbid reaction mixture was stirred at 0° C. for 1 hour and was then allowed to stir at room temperature overnight. Acetone was mostly removed under reduced pressure. The aqueous residue was diluted with H2O (2 mL), diethyl ether (9 mL) added and the mixture stirred at room temperature for 1 hour. The layers were separated and the ether layer was washed three times with saturated NaHCO3. The aqueous phases were combined, acidified with 1N HCl and extracted three times with ethyl acetate (75 mL total volume). The combined organic extracts were dried over MgSO4, concentrated on a rotary evaporator, and dried under vacuum to afford a white solid. The crude product was purified by three crystallizations from n-hexane/chloroform to afford 0.05 g (53% yield) of 2-18 as white fluffy crystals: m.p. 206-208° C.; Rf=0.44, 10:1 CH2Cl2:MeOH; [α]23D=−36.0 (c 0.50, acetone); 1H NMR (300 MHz, CDCl3/CD3OD) δ 7.77 (d, J=7.5 Hz, 2H, ArH), 7.62 (d, J=6.9 Hz, 2H, ArH), 7.43-7.29 (m, 4H, ArH), 4.36-4.22 (m, 3H), 4.07-4.02 (m, 1H), 3.93-3.86 (m, 1H), 3.09-2.82 (m, 2H), 2.44-2.38 (m, 1H), 2.02-1.97 (m, 1H), 1.50-1.43 (m, 1H), 1.47 (s, 9H); 13C NMR (75 MHz, CDCl3/CD3OD) δ 173.38 (C), 155.83 (C), 154.21 (C), 143.23 (C), 140.69 (C), 127.07 (CH), 126.46 (CH), 124.42 (CH), 119.27 (CH), 80.00 (C), 66.35 (CH2), 49.73 (CH), 47.77 (CH), 46.57 (CH), 44.33 (CH2), 41.68 (CH2), 30.63 (CH2), 27.51 (CH3); MS-ESI m/z 243.1 [M−Fmoc]−, 465.1 [M−H]−, 931.2 [2M−H]−.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH:21](OCC)(OCC)OCC>C(O)C.Cl>[CH2:14]([N:13]1[C:3]2[CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:11]=[CH:12][C:2]=2[N:1]=[CH:21]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1ccc(N)c(NCc2ccccc2)c1
Reactant: CCOC(OCC)OCC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc2ncn(Cc3ccccc3)c2c1
Temperature: 25 °C
Yield: 48.1 %

Procedure:
A solution of ethyl 4-amino-3-(benzylamino)benzoate (0.24 g, 0.89 mmol) and triethyl orthoformate (0.8 mL, 4.8 mmol) in ethanol (10 mL) and conc. HCl (7 drops) was heated to reflux for 24 hr. The solution was cooled to room temperature and concentrated, then diluted with ethyl acetate (100 mL) and washed with dilute aq. NaHCO3 (1×100 mL). Then organic layer was dried (MgSO4), filtered and then concentrated and the resulting residue was purified by flash chromatography (50% ethyl acetate/hexane then ethyl acetate) to provide 0.12 g (48%) of ethyl 3-benzyl-3H-benzo[d]imidazole-5-carboxylate as an off white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[CH:33]=[CH:32][S:31][CH:30]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:38].[CH3:39][C:40]1([CH3:49])[CH2:45][CH:44]([NH2:46])[CH2:43][C:42]([CH3:48])([CH3:47])[NH:41]1>C(#N)C>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:46][CH:44]3[CH2:45][C:40]([CH3:49])([CH3:39])[NH:41][C:42]([CH3:48])([CH3:47])[CH2:43]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[CH:33]=[CH:32][S:31][CH:30]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:38]
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: Cc1ccc(NC(=O)c2ccsc2)cc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: CC#N
Product: Cc1ccc(NC(=O)c2ccsc2)cc1-c1nc(NC2CC(C)(C)NC(C)(C)C2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 16 %

Procedure:
The title compound was prepared from N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide and 2,2,6,6-tetramethyl-4-piperidinamine according to General Procedure for Sulfoxide/Sulfone Displacement, described above. The concentrated reaction mixture was slurried with acetonitrile and filtered. The solid was recrystallized from methanol/water to afford the desired product as a crystalline solid (0.2 g, 16%). HPLC indicated >99% pure: LC-MS m/z 629 (M+H)+, 1.86 min (ret time).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].Cl.[CH2:8]([S:10][C:11](=[NH:13])[NH2:12])[CH3:9].O.[OH-].[Na+]>C(Cl)Cl.C(#N)C>[CH2:5]([O:4][C:2]([NH:12][C:11]([NH2:13])=[SH:10][CH2:8][CH3:9])=[O:3])[CH3:6]
Reactant: CCSC(=N)N
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)NC(N)=[SH]CC
Reaction time: 1.33 h

Procedure:
302 g. (2.78 moles) of ethyl chloroformate was added to 2 moles of S-ethylisothiourea hydrochloride in 800 ml. of water and 200 ml. of acetonitrile. A 25% solution of sodium hydroxide was added dropwise so rapidly that, with external cooling, a temperature of +25° C. was not exceeded. The solution of sodium hydroxide was added for as long as the pH value did not rise above 8. Stirring was effected for a further 80 minutes during which control of the pH value was continued. If necessary, a little more solution of sodium hydroxide was added. A two phase system, aqueous and organic, resulted. The product was isolated from the organic phase by extraction with methylene chloride and concentration in vacuo to a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4[NH:19][CH:20]=[CH:21][C:15]=4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1.[NH:23]1[CH:27]=[N:26][N:25]=[N:24]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4[N:19]([C:27]5[NH:26][N:25]=[N:24][N:23]=5)[CH:20]=[CH:21][C:15]=4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1
Reactant: CC1c2cc[nH]c2CCN1C(=O)c1cc2ncc(Cl)cn2n1
Reactant: c1nnn[nH]1
Product: CC1c2ccn(-c3nnn[nH]3)c2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 52, (6-chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-methyl-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-5-yl)-methanone is reacted with 1H tetrazole to provide the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@@H:7]1[CH2:12][CH2:11][C@H:10]([O:13]C(=O)C2C=CC([N+]([O-])=O)=CC=2)[CH2:9][CH2:8]1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[OH:13][C@@H:10]1[CH2:9][CH2:8][C@H:7]([N:3]2[CH2:4][CH2:5][CH2:6][C:2]2=[O:1])[CH2:12][CH2:11]1
Reactant: O=C(O[C@H]1CC[C@@H](N2CCCC2=O)CC1)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C1CCCN1[C@H]1CC[C@@H](O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve cis-4-nitro-benzoic acid 4-(2-oxo-pyrrolidin-1-yl)-cyclohexyl ester (87.9 g, 264 mmol) in methanol (1.35 L) and water (150 mL) and treat with potassium carbonate (109.5 g, 800 mmol). Stir at room temperature overnight to give a white precipitate. Evaporate to dryness. Remove excess water by mixing with ethanol and concentrating to dryness under vacuum. Repeat this procedure. Stir in tetrahydrofuran (1 L) for 1 hour then filter. Evaporate the filtrate to an oil and crystallize from diethyl ether (100 mL) to afford 40 g (83%) of the title compound.
Reaction SMILES: C[N:2]1[C:8](=O)[O:7][C:5](=O)[C:4]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:3]12.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[NH:15][NH2:16].C(O)C>C(OCC)(=O)C>[CH3:8][NH:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[C:5]([NH:16][NH:15][C:14]([O:18][CH2:19][CH3:20])=[O:17])=[O:7]
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Reactant: CCOC(=O)NN
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)NNC(=O)c1ccccc1NC
Yield: 50.5 %

Procedure:
A mixture of 8.86 g of N-methylisatoic anhydride, 5.73 g of ethyl carbazate and 25 ml of ethanol was heated to reflux for 2 hours. After the reaction mixture was allowed to around room temperature, ethyl acetate was added thereto and the mixture was washed with water two times. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was washed with methyl tert-butyl ether to obtain 5.99 g of N-(2-methylaminobenzoyl)-N′-ethoxycarbonylhydrazine of the formula:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH:26]([CH2:30][OH:31])[CH:27]([CH3:29])[CH3:28])=[O:24])[C:5]1=[O:32].[N:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:11]2[CH:12]=[C:13]3[C:8]([C:7]([OH:22])=[C:6]([C:23]([NH:25][CH:26]([CH2:30][OH:31])[CH:27]([CH3:29])[CH3:28])=[O:24])[C:5](=[O:32])[N:4]3[CH2:3][CH2:2][NH:1][C:39]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[O:40])=[N:9][CH:10]=2)=[CH:20][CH:19]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CC(C)C(CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN)c1=O
Product: CC(C)C(CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCNC(=O)N2CCOCC2)c1=O

Procedure:
This compound was prepared from 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[1-(hydroxymethyl)-2-methylpropyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide and 4-morpholinecarbonyl chloride employing methods similar to those described in Example 450 and was obtained as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 0.88-0.96 (m, 6 H), 1.92-2.04 (m, 2 H), 3.12-3.21 (m, 4 H), 3.27-3.31 (m, 2 H), 3.44-3.51 (m, 5 H), 3.51-3.61 (m, 1 H), 3.86 (ddd, J=14.64, 5.30, 5.19 Hz, 1 H), 4.14 (s, 2 H), 4.29 (t, J=6.25 Hz, 2 H), 4.88 (t, J=5.05 Hz, 1 H), 6.77 (t, J=5.76 Hz, 1 H), 7.11-7.18 (m, 2 H), 7.39-7.45 (m, 2 H), 8.25 (d, J=1.54 Hz, 1 H), 8.54 (d, J=0.98 Hz, 1 H), 10.44 (d, J=9.13 Hz, 1 H); ES+ MS: 556 (M+H+).
Reaction SMILES: [CH2:1]([C:11]1[S:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([F:23])[CH:17]=2)=[N:14][N:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:24](O)(=[O:29])[CH2:25][CH2:26][CH2:27][CH3:28].C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CC=2)CCCC1>ClCCl>[CH2:1]([C:11]1[S:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:24](=[O:29])[CH2:25][CH2:26][CH2:27][CH3:28])=[C:18]([F:23])[CH:17]=2)=[N:14][N:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCC(=O)O
Reactant: CCCCCCCCCCc1nnc(-c2ccc(O)c(F)c2)s1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: CCCCCCCCCCc1nnc(-c2ccc(OC(=O)CCCC)c(F)c2)s1
Temperature: 25 °C
Yield: 56 %

Procedure:
40 ml of dichloromethane was added to a mixture of 2.0 g (5.94 mM) of 2-decyl-5-(3-fluoro-4-hydroxyphenyl)-1,3,4-thiadiazole and 0.61 g (5.97 mM) of pentanoic acid. Under stirring at room temperature, 1.21 g (5.86 mM) of N,N'-dicyclohexylcarbodiimide (DCC) and 0.05 g of 4-pyrrolidinopyridine were successively added to the above mixture, followed by stirring for 19 hours at room temperature. After the reaction, precipitated N,N'-dicyclohexylurea was recovered by filtration, washed with dichloromethane and added to the filtrate. The resultant dichloromethane solution was subjected to distillation under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (eluent: benzene) and recrystallized from ethanol to obtain 1.40 g of 2-decyl-5-(3-fluoro-4-pentanoyloxyphenyl)-1,3,4-thiadiazole (Yield: 56.9%). ##STR132##
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[OH-].[Na+]>C(O)C.O.CO>[CH2:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Solvent: O
Product: C=CCOc1ccc(C(=O)O)cc1
Temperature: 80 °C
Yield: 28.2 %

Procedure:
18.0 g (93.6 mmol) of the resulting compound (11) was dissolved in 600 ml of ethanol. The solution was poured into a solution of 12.0 g (300 mmol) of sodium hydroxide dissolved in 80 ml of water and 100 ml of methanol. The whole was refluxed at 80° C. for 2 hours. After removal of the solvent by distillation, the resulting white solid was dissolved in water and the solution was rendered acidic by adding hydrochloric acid, whereby white precipitate formed. The precipitate was extracted with methylene chloride. After removal of the solvent by distillation, the residue was purified by silica gel column chromatography to obtain 4.7 g of p-allyloxybenzoic acid (12) (yield: 88.1%).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]([F:44])([F:43])[CH2:21][NH:22][C:23]([C:25]1([CH2:38][CH2:39][CH2:40][CH2:41]Br)[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24]>>[F:19][C:20]([F:43])([F:44])[CH2:21][NH:22][C:23]([C:25]1([CH2:38][CH2:39][CH2:40][CH2:41][N:16]2[CH2:17][CH2:18][N:13]([C:9]3[CH:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:12]=[CH:11][N:10]=3)[CH2:14][CH2:15]2)[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc(-c2ccnc(N3CCNCC3)c2)cc1
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3cc(-c4ccccc4)ccn3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 b from 1-(4-phenyl-pyridin-2-yl)-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[C:6]([Cl:9])=[N:5][S:4][N:3]=1.[C:10]([CH:12]([OH:26])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:14]=1)#[N:11].C(N(CC)CC)C.Cl.C(N(CC)CC)C>C(OCC)(=O)C.O>[Cl:9][C:6]1[C:7](=[O:8])[C:2]([O:26][CH:12]([C:10]#[N:11])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:14]=2)=[N:3][S:4][N:5]=1
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Reactant: O=c1c(Cl)nsnc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: N#CC(Oc1nsnc(Cl)c1=O)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 7.3 grams (0.04 mole) of 3,5-dichloro-4H-1,2,6-thiadiazin-4-one and 9.0 grams (0.04 mole) of a α-cyano-3-phenoxybenzyl alcohol in 130 ml of ethyl acetate was added dropwise a solution of 4.1 grams (0.04 mole) of triethylamine in approximately 40 ml of ethyl acetate. Upon complete addition the reaction mixture was stirred at ambient temperature for 16 hours, then diluted with 100 ml of water to dissolve triethylamine hydrochloride. The organic layer was removed and washed with 100 ml of water, then with 100 ml of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to a residual solid. The solid was triturated with absolute ethanol and collected by filtration. The filter cake was washed with hexane and recrystallized from glacial acetic acid. The yield was 5.8 grams (39%) of 3-chloro-5-(α-cyano-3-phenoxybenzyloxy)-4H-1,2,6-thiadiazin-4-one; m.p. 146.5°-147.7° C. The nmr and the ir spectra were consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O.Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26](=[O:28])[CH3:27]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26](=[O:28])[CH3:27]
Reactant: CC(=O)c1ccccc1Br
Reactant: OB(O)c1ccc(F)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)c1ccccc1-c1ccc(F)cc1F
Temperature: 70 °C
Yield: 49.1 %

Procedure:
2,4-Difluorophenylboronic acid (9.47 g, 60 mmol), tetrabutylammonium bromide (16.1 g, 50 mmol), and potassium carbonate (20.7 g, 150 mmol) were added to a flask followed by water (50 mL). The contents were mixed until most of the dissolvable solids were in solution. To the remaining slurry was added 2′-bromoacetophenone (9.95 g, 50 mmol) and palladium acetate (1.12 g, 5 mmol). The stirred contents were heated to 70° C. under a nitrogen atmosphere for 12 hours. Thin layer chromatography analysis indicated the formation of a single product. The reaction was allowed to cool to room temperature. Ethyl acetate (500 mL) was added and the organic phase was extracted with water (3×100 mL). The combined aqueous phase was extracted once with additional ethyl acetate and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to provide a crude oil. The product was purified by preparative liquid chromatography on a Biotage® 40 Mi column of prepacked silica gel (90 g), eluting with a gradient of 5%-20% methyl tert-butyl ether in hexane, to afford the title compound (5.7 g, 49%) as a yellow oil;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29][CH3:30])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([OH:24])=O)[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CCOC(C)=O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29][CH3:30])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:39][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:24])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: NCc1ccccc1
Reactant: CSc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CSc1nc(-c2cc(C(=O)NCc3ccccc3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C

Procedure:
3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (0.15 g, 0.342 mmol) was dissolved in CH2Cl2 (10 mL) and stirred under argon at room temperature. N-Benzylamine (0.11 g, 1.03 mmol) was added followed by EDC (0.082 g, 0.41 mmol) and HOBT (0.055 g, 0.41 mmol). The reaction was stirred overnight. The solvents were pumped off in vacuo, and the residue taken up in EtOAc and washed twice with H2O, once with brine, dried over anhydrous Na2SO4 filtered and evaporated. The residue was flash chromatographed on silica gel (20 g) eluted with 0-1.5% MeOH/CH2Cl2 to give the title compound. mp (dec) 124-130° C. LC-MS m/z 529 (M+H)+, 2.36 min (ret time).
Reaction SMILES: [C:1]([CH:5]=[C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([NH:17][CH2:18][CH:19]([OH:26])[C:20]2[N:21]=[C:22]([CH3:25])[S:23][CH:24]=2)[CH3:16])=[CH:10][CH:9]=1)[CH3:7])([O:3][CH3:4])=[O:2].[C:27]([O:31][CH3:32])(=[O:30])[CH:28]=O>>[C:1]([CH:5]=[C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH:15]([N:17]2[CH2:18][CH:19]([C:20]3[N:21]=[C:22]([CH3:25])[S:23][CH:24]=3)[O:26][CH:28]2[C:27]([O:31][CH3:32])=[O:30])[CH3:16])=[CH:12][CH:13]=1)[CH3:7])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C=O
Reactant: COC(=O)C=C(C)c1ccc(CC(C)NCC(O)c2csc(C)n2)cc1
Product: COC(=O)C=C(C)c1ccc(CC(C)N2CC(c3csc(C)n3)OC2C(=O)OC)cc1

Procedure:
Prepared by analogy to Example 18 by reaction of N-[2-(4-(2-carbomethoxy-1-methylethenyl)phenyl)-1-methylethyl]-2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine with methyl glyoxylate, followed by purification of the base on a silica gel column using petroleum ether/ethyl acetate=7:3 as eluant.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@@H:14]([N:16]([CH:24]2[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[CH2:26][CH2:25]2)[C:17]([C@@H:19]2[CH2:23][CH2:22][CH2:21][O:20]2)=[O:18])[CH2:13][C@H:9]1[C:10](O)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:32]([NH2:34])[CH3:33]>>[C:1]([N:8]1[CH2:15][C@@H:14]([N:16]([CH:24]2[CH2:29][CH2:28][C:27]([CH3:30])([CH3:31])[CH2:26][CH2:25]2)[C:17]([C@@H:19]2[CH2:23][CH2:22][CH2:21][O:20]2)=[O:18])[CH2:13][C@H:9]1[C:10]([NH:34][CH2:32][CH3:33])=[O:11])([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: CC1(C)CCC(N(C(=O)[C@@H]2CCCO2)[C@H]2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)CC1
Reactant: CCN
Product: CCNC(=O)[C@@H]1C[C@H](N(C(=O)[C@@H]2CCCO2)C2CCC(C)(C)CC2)CN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the procedure described in Step D of Example A1, using (4S)-1-BOC-4-{(4,4-dimethylcyclohexyl)[(2S)-tetrahydrofuran-2-ylcarbonyl]amino}-L-proline (0.96 g, 2.2 mmol) prepared in Step B of Example A2 and commercially available ethylamine (0.95 g, 93%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[C:29]([O:36][CH3:37])[CH:28]=1>CN(C=O)C>[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[C:29]([O:36][CH3:37])[CH:28]=1
Reactant: COc1cc(F)ccc1B(O)O
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Solvent: CN(C)C=O
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 4-fluoro-2-methoxyphenylboronic acid (CAS RN 179899-07-1) and using DMF as reaction solvent. Off-white solid (38%). MS (ESI): m/z=473.4 [M+H]+.
Reaction SMILES: [Na].C([S:5][CH2:6][C:7]([NH:9][C:10]1[CH:19]=[CH:18][C:13]([S:14]([OH:17])(=[O:16])=[O:15])=[CH:12][CH:11]=1)=[O:8])(=O)C.[OH-].[Na+:21].[OH-].[K+]>>[Na+:21].[SH:5][CH2:6][C:7]([NH:9][C:10]1[CH:19]=[CH:18][C:13]([S:14]([O-:17])(=[O:15])=[O:16])=[CH:12][CH:11]=1)=[O:8]
Reactant: CC(=O)SCC(=O)Nc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Agent: [Na+]
Agent: [Na]
Product: O=C(CS)Nc1ccc(S(=O)(=O)[O-])cc1

Procedure:
By substituting the sodium salt of N-[2-(acetylthio)acetyl]sulfanilic acid and sodium hydroxide in place of the potassium salt and potassium hydroxide, respectively, according to the above procedure, there is provided N-(2-MERCAPTOACETYL)SULFANILIC ACID SODIUM SALT.