Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13]O)[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[SH:17][C:18]1[S:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][S:17][C:18]2[S:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=3[N:22]=2)[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Sc1nc2ccccc2s1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CO)COC1(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1[C@@H](CSc2nc3ccccc3s2)COC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
To a stirred, cooled (0° C.) solution of (S)-4-hydroxymethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.36 g), 2-mercaptobenzothiazole (1.48 g) and triphenylphosphine (2.32 g) in THF (80 ml) under an argon atmosphere was added diethyl azodicarboxylate (4.1 ml; 40% solution in toluene). The mixture (soon turning to a yellow suspension, slowly warming up to r.t.) was stirred for 18 h overnight, then diluted with EtOAc and washed with sat. aq. Na2CO3. The aqueous phase was back extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2; gradient: cyclohexane ->cyclohexane/EtOAc 85:15) to give (R)-4-(benzothiazol-2-ylsulfanyl-methyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (2.1 g) as light yellow viscous oil.
Reaction SMILES: BrC1C(=O)C(C(O)=O)=CN(C(C)C)C=1C.[Br:16][C:17]1[C:18](=[O:32])[C:19]([C:29]([OH:31])=O)=[CH:20][N:21]([CH:24]2[CH2:28][CH2:27][O:26][CH2:25]2)[C:22]=1[CH3:23].Cl.CS(C1C=CC(CN)=CC=1)(=O)=O.[CH3:46][S:47]([C:50]1[CH:51]=[CH:52][C:53]([CH2:56][NH2:57])=[N:54][CH:55]=1)(=[O:49])=[O:48].BrBr>>[CH3:46][S:47]([C:50]1[CH:51]=[CH:52][C:53]([CH2:56][NH:57][C:29]([C:19]2[C:18](=[O:32])[C:17]([Br:16])=[C:22]([CH3:23])[N:21]([CH:24]3[CH2:28][CH2:27][O:26][CH2:25]3)[CH:20]=2)=[O:31])=[N:54][CH:55]=1)(=[O:49])=[O:48]
Reactant: Cc1c(Br)c(=O)c(C(=O)O)cn1C1CCOC1
Reactant: CS(=O)(=O)c1ccc(CN)nc1
Agent: BrBr
Agent: CS(=O)(=O)c1ccc(CN)cc1
Agent: Cc1c(Br)c(=O)c(C(=O)O)cn1C(C)C
Product: Cc1c(Br)c(=O)c(C(=O)NCc2ccc(S(C)(=O)=O)cn2)cn1C1CCOC1

Procedure:
Preparation 22 is prepared following the procedure for preparation 5, substituting preparation 3c with preparation 14b and 4-methylsulfonylbenzylamine hydrochloride with C-(5-methanesulfonyl-pyridin-2-yl)-methylamine. ESI mass spectrum: [M+H]+=470 (bromine isotope pattern); Retention time HPLC: 0.77 min (Z018_S04).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CNc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CNc1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
4-Bromo-N-methylaniline (0.7 mL, 5.4 mmol), (4-chlorophenyl)boronic acid (967 mg, 6.2 mmol), Pd(dppf)Cl2 (440 mg, 0.5 mmol), and K2CO3 (1.5 g, 10.8 mmol) were dissolved in 1,4-dioxane (40 mL) and water (10 mL) and the resulting mixture was heated to 80° C. After 16 h the resulting mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].[CH2:9]([Mg]Br)[CH3:10].B.O1CCCC1.[OH-].[Na+]>C(OCC)C.Cl.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[N:6]1[CH:7]=[CH:8][C:3]([C:1]2([NH2:2])[CH2:10][CH2:9]2)=[CH:4][CH:5]=1
Reactant: N#Cc1ccncc1
Reactant: CC[Mg]Br
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: NC1(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 2.6 %

Procedure:
To 4-cyanopyridine (1.04 g, 10 mmol) in diethyl ether (50 mL), tetraisopropoxytitanium (3.27 mL, 11 mmol) and ethylmagnesium bromide (6.3 mL, 22 mmol, 3 M in diethyl ether) were added dropwise in a nitrogen stream at −78° C., and after 10 minutes, the reaction solution was warmed to room temperature and stirred for 1.5 hours and then stirred with a borane-tetrahydrofuran complex (21.5 mL, 20 mmol. 0.93 M in tetrahydrofuran) for 1 hour. After completion of the reaction, the reaction solution was diluted with diethyl ether (10 mL), and dilute hydrochloric acid (30 mL, 1 M) was added dropwise. After addition of aqueous sodium hydroxide (100 mL, 10% w/v), the reaction solution was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=9/1) to give the desired product (2.6% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[OH:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>>[N:24]1[CH:25]=[CH:26][CH:27]=[C:22]([O:21][C:16]2[N:15]=[C:14]([NH:13][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)[CH:19]=[N:18][CH:17]=2)[CH:23]=1
Reactant: Oc1cccnc1
Reactant: COc1cc(Nc2cncc(Cl)n2)cc(OC)c1OC
Product: COc1cc(Nc2cncc(Oc3cccnc3)n2)cc(OC)c1OC
Yield: 26 %

Procedure:
Using Method X with 150 mg of 2-(3,4,5-trimethoxyphenylamino)-6-chloropyrazine and 3-hydroxypyridine, the title compound was obtained (46 mg). Yield: 26%. 1H NMR (250 MHz, DMSO-d6) δ 3.41 (s, 6H), 3.54 (s, 3H), 6.71 (s, 2H), 7.47 (ddd, 1H, J1=0.6 Hz, J2=4.7 Hz, J3=8.4 Hz), 7.69 (ddd, 1H, J1=1.4 Hz, J2=2.8 Hz, J3=8.4 Hz), 7.82 (s, 1H), 7.98 (s, 1H), 8.43 (dd, 1H, J1=1.4 Hz, J2=4.7 Hz), 8.54 (dd, 1H, J1=0.5 Hz, J2=2.8 Hz), 9.61 (s, 1H). 13C NMR (62.9 MHz, DMSO-d6) δ 55.32, 60.04, 95.95, 120.94, 124.52, 128.42, 128.91, 132.34, 136.10, 142.68, 145.66, 150.31, 150.38, 152.71, 156.84. m/z 355.1 [(M+H)+ calcd for C18H18N4O4 354.1].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([CH:21]=O)([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:23]([C:26]2[CH:27]=[N:28][C:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:30][CH:31]=2)(=[O:25])=[O:24])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.[NH:38]1[CH2:42][CH2:41][C@@H:40]([OH:43])[CH2:39]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([CH2:21][N:38]5[CH2:42][CH2:41][C@@H:40]([OH:43])[CH2:39]5)([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:23]([C:26]2[CH:27]=[N:28][C:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:30][CH:31]=2)(=[O:24])=[O:25])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1
Reactant: O[C@@H]1CCNC1
Reactant: O=C[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2
Product: O=S(=O)(c1ccc(N2CCOCC2)nc1)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(CN2CC[C@@H](O)C2)C1

Procedure:
The title compound was prepared by the method of Preparation 62 using (R)-1-(4-fluorophenyl)-6-[6-morpholin-4-yl-pyridine-3-sulfonyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carbaldehyde and (R)-pyrrolidin-3-ol. LCMS (Method F): 595 (M+H)+, Retention time 3.2 minutes.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C:17]3[N:18]([CH3:33])[N:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[CH:21]=3)[CH:13]=2)[CH:8]=[CH:7]1)C.[Li+].[OH-]>>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]2[CH:21]=[C:17]([CH2:16][O:15][C:12]3[CH:13]=[C:14]4[C:9]([CH:8]=[CH:7][N:6]4[CH2:5][C:4]([OH:34])=[O:3])=[CH:10][CH:11]=3)[N:18]([CH3:33])[N:19]=2)=[CH:23][C:24]=1[C:29]([F:30])([F:31])[F:32]
Reactant: CCOC(=O)Cn1ccc2ccc(OCc3cc(-c4ccc(F)c(C(F)(F)F)c4)nn3C)cc21
Agent: [Li+]
Agent: [OH-]
Product: Cn1nc(-c2ccc(F)c(C(F)(F)F)c2)cc1COc1ccc2ccn(CC(=O)O)c2c1

Procedure:
In analogy to the procedure described for example 1 f], {6-[5-(4-fluoro-3-trifluoromethyl-phenyl)-2-methyl-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester was treated with LiOH to obtain {6-[5-(4-fluoro-3-trifluoromethyl-phenyl)-2-methyl-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid as brown solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH:15]([CH3:17])[CH3:16])[C:11]([Cl:18])=[CH:10][C:9]=1[NH:19][C:20](=[O:43])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[C:33]([CH2:34][O:35]C3CCCCO3)=[CH:32][N:31]=[N:30]2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:18][C:11]1[C:12]([NH:14][CH:15]([CH3:17])[CH3:16])=[CH:13][C:8]2[N:7]=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N:29]4[C:33]([CH2:34][OH:35])=[CH:32][N:31]=[N:30]4)[CH:24]=3)[CH2:21][C:20](=[O:43])[NH:19][C:9]=2[CH:10]=1
Reactant: CC(C)Nc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[4-chloro-5-isopropylamino-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert-butyl ester (Example M113) (0.37 g, 0.60 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (209 mg, 82%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[OH:24][C:25]([CH3:35])([CH3:34])[CH2:26][NH:27][C:28]1[CH2:32][S:31][C:30](=[O:33])[N:29]=1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:32]2/[C:28]([NH:27][CH2:26][C:25]([OH:24])([CH3:35])[CH3:34])=[N:29][C:30](=[O:33])[S:31]/2)[CH2:8][CH2:7]1
Reactant: CC(C)(O)CNC1=NC(=O)SC1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CC(C)(O)CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 56.4 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1.11 g) in 2-propanol (10 mL) were added 4-[(2-hydroxy-2-methylpropyl)amino]-1,3-thiazol-2(5H)-one (616 mg) and piperidinium acetate (475 mg). The reaction mixture was stirred at 80° C. for 2 hr, and the solvent was evaporated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (940 mg).
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][NH:3][CH2:2]1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[C:29]([CH3:42])=[C:30]([CH3:41])[C:31]4[O:35][C:34]([CH3:37])([CH3:36])[CH:33](O)[C:32]=4[C:39]=3[CH3:40])[CH2:24][CH2:23]2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>CCCCCC.CO>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:22]2[CH2:23][CH2:24][N:25]([C:28]3[C:29]([CH3:42])=[C:30]([CH3:41])[C:31]4[O:35][C:34]([CH3:36])([CH3:37])[CH:33]([N:3]5[CH2:2][CH2:1][C:7]6[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=6[CH2:5][CH2:4]5)[C:32]=4[C:39]=3[CH3:40])[CH2:26][CH2:27]2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: c1ccc2c(c1)CCNCC2
Reactant: COc1ccc(C2CCN(c3c(C)c(C)c4c(c3C)C(O)C(C)(C)O4)CC2)cc1OC
Solvent: CCCCCC
Solvent: CO
Product: COc1ccc(C2CCN(c3c(C)c(C)c4c(c3C)C(N3CCc5ccccc5CC3)C(C)(C)O4)CC2)cc1OC
Yield: 54 %

Procedure:
Using 2,3,4,5-tetrahydro-1H-3-benzazepine and 5-(4-(3,4-dimethoxyphenyl)piperidino)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-ol obtained in Reference Example 19, the title compound was synthesized in the same manner as in Example 57. Yield 54%. mp. 136–138° C. (hexane-methanol).
Reaction SMILES: CS[C:3]1[N:8]2[CH:9]=[N:10][CH:11]=[C:7]2[CH:6]=[N:5][N:4]=1.[NH2:12][C:13]1[CH:17]=[CH:16][NH:15][N:14]=1>C1(C)C=CC=CC=1>[NH:15]1[CH:16]=[CH:17][C:13]([NH:12][C:3]2[N:8]3[CH:9]=[N:10][CH:11]=[C:7]3[CH:6]=[N:5][N:4]=2)=[N:14]1
Reactant: CSc1nncc2cncn12
Reactant: Nc1cc[nH]n1
Solvent: Cc1ccccc1
Product: c1cc(Nc2nncc3cncn23)n[nH]1
Temperature: 0 °C

Procedure:
A mixture of 6.0 gm. of 4-(methylthio)-imidazo[1,5-d]-as-triazine, 4.15 gm. of 3-aminopyrazole and 150 ml. of toluene is refluxed for 26 hours. The mixture is evaporated and the residue is heated with a mixture of 150 ml. of ethanol and 40 ml. of dimethylformamide. The mixture is cooled to 0° C. and the desired product is collected as a solid, m.p. 271°-274° C.
Reaction SMILES: C[O:2][C:3](=[O:42])[CH:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1([C:24](=[O:41])[N:25]([C:32]1[O:40][C:36]2=[CH:37][CH:38]=[CH:39][C:35]2=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]=[CH:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:14][CH:13]=1.[OH-].[Na+]>CCO.C1COCC1.O>[O:40]1[C:36]2=[CH:37][CH:38]=[CH:39][C:35]2=[CH:34][CH:33]=[C:32]1[N:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:24]([C:5]1([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([CH:18]=[CH:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[CH:16][CH:17]=2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:4]1[C:3]([OH:42])=[O:2])=[O:41]
Reactant: COC(=O)C1C=CC=CC1(CCc1ccc(C=CC(C)(C)C)cc1)C(=O)N(c1ccccc1)c1ccc2cccc-2o1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)C=Cc1ccc(CCC2(C(=O)N(c3ccccc3)c3ccc4cccc-4o3)C=CC=CC2C(=O)O)cc1
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To a stirred solution of (R)-4-[2-(4-Benzofuran-2-yl-phenylcarbamoyl)-2-[4-(3,3-dimethyl-but-1-enyl)-phenyl-ethyl]-benzoic acid methyl ester (0.29 g, 0.52 mmol) in EtOH/THF/H2O (4:2:1) (12 mL) at rt, was added aq. 40% NaOH (2.5 ml), The reaction mixture was stirred for overnight, After completion of the reaction, the solvent was removed under reduced pressure. The crude was taken to pH=2 with 4N HCl and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated, the resulting compound was dried under vacuum to afford 4-[2-(4-Benzofuran-2-yl-phenylcarbamoyl)-2-[4-(3,3-dimethyl-but-1-enyl)-phenyl-ethyl]-benzoic acid as a solid (0.27 g, 98%):
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[N:11]=[C:10]([CH3:20])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[Na+].[CH3:22][S:23]([O-])(=[O:25])=[O:24].O>CN(C=O)C>[CH3:22][S:23]([C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[N:11]=[C:10]([CH3:20])[CH:9]=2)[CH:5]=[CH:4][N:3]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)[O-]
Reactant: Cc1cccc(-n2nc(C)cc2-c2ccnc(Cl)c2)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(-n2nc(C)cc2-c2ccnc(S(C)(=O)=O)c2)c1
Temperature: 140 °C
Yield: 39.3 %

Procedure:
A mixture of 2-chloro-4-[1-(3-methylphenyl)-3-methyl-1H-pyrazol-5-yl]pyridine (Example 45; 1.0 g, 0.0035 mol) and methanesulfonic acid sodium salt (3.24 g, 0.021 mol) in 15 mL of DMF was heated at 140° C. for 24 hours. After the mixture was cooled, water was added and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude was purified by chromatography on silica gel (ethyl acetate/hexane, 1:1) to give 0.45 g (40% yield) of product as a yellow solid: mp: 140-142° C.; Anal. Calc'd. for C17H17N3SO2: C, 62.36; H, 5.23; N, 12.83; S, 9.79. Found: C, 62.16; H, 5.31; N, 12.74; S, 9.86.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH:5]([CH:11]1[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH2:12]1)C(OCC)=O)C.O=C1C(CCC)CCC(CC(O)=O)C1>>[O:17]=[C:13]1[CH2:14][CH2:15][CH2:16][CH:11]([CH2:5][C:4]([OH:18])=[O:3])[CH2:12]1
Reactant: CCOC(=O)C(C(=O)OCC)C1CCCC(=O)C1
Agent: CCCC1CCC(CC(=O)O)CC1=O
Product: O=C(O)CC1CCCC(=O)C1
Yield: 70 %

Procedure:
Step 2 (3-Oxo-cyclohexyl)-acetic acid was prepared in 70% yield from 2-(3-oxo-cyclohexyl)-malonic acid diethyl ester by the method described above for the synthesis of (3-oxo-4-propyl-cyclohexyl)-acetic acid: 1H NMR (300 MHz, CDCl3) δ 2.58–1.92 (m, 7H), 1.80–1.61 (m, 1H), 1.52–1.42 (m, 1H); ESI MS m/z 155 [M−H]−.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][OH:3].[S:8](Cl)([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9].C(N(CC)CC)C.O>C(OCC)C>[S:8]([O:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: CCOC(=O)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOCC
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)COS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of ethyl glycolate (500 mg, 4.8 mmol) and tosyl chloride (915 mg, 4.8 mmol) in anhydrous diethyl ether (2 ml) at 0° C. was treated dropwise with triethylamine (1.34 ml, 9.6 mmol). The temperature was maintained at 0° C. with stirring for a further 2 h. After this time, water was added and the phases separated. The aqueous phase was extracted with fresh diethyl ether. The combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo. The crude product was purified by column chromatography over silica gel (Rf=0.29, 25% ethyl acetate in hexane) affording the tosylate 2 as a colorless oil which solidified on standing as a white solid (868 mg, 70%). [This procedure was repeated on 2× scale (1.8 g, 73%)]. δH (400 MHz, CDCl3) 1.22-1.27 (3H, m, CH3), 2.46 (3H, s, ArCH3), 4.16-4.22 (2H, m, CH2CH3), 4.58-4.59 (2H, m, OCH2), 7.36 (2H, d, J=8.2 Hz, ArH), 7.84 (2H, d, J=8.2 Hz, ArH); δc (100.6 MHz, CDCl3) 14.2, 21.9, 62.1, 64.9, 128.3, 130.1, 132.9, 145.5, 166.2; MS (ES+) 276.0 (100%, [M+H2O]+) (ion not detected in ES−).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[SH:11].[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](O)=O>C(Cl)(Cl)Cl>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]2[S:11][C:17]([C:13]3[S:12][CH:16]=[CH:15][CH:14]=3)=[N:1][C:2]=2[CH:7]=1)([O-:10])=[O:9]
Reactant: Nc1cc([N+](=O)[O-])ccc1S
Reactant: O=C(O)c1cccs1
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc2sc(-c3cccs3)nc2c1

Procedure:
2-Amino-4-nitrobenzenethiol, 9.6 g (0.054 mole) and thiophene-2-carboxylic acid, 10.0 g (0.075 mole) are added to a solution of 54 g of PPE in 130 cc CHCl3. The mixture is heated at reflux for 2 hours. It is then concentrated in vacuo and the residue poured over ice. The pH is adjusted to 10 with 50% NaOH solution, and the precipitate filtered and washed with H2O. Drying in vacuo yields 15 g of the title compound.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:18])[N:6]([CH3:17])[CH2:7][CH2:8][CH2:9][NH:10]C(=O)C(F)(F)F)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH:1]([O:4][C:5](=[O:18])[N:6]([CH2:7][CH2:8][CH2:9][NH2:10])[CH3:17])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N(C)CCCNC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)OC(=O)N(C)CCCN
Temperature: 25 °C
Reaction time: 17 h
Yield: 109.1 %

Procedure:
A suspension of methyl-[3-(2,2,2-trifluoro-acetylamino)-propyl]-carbamic acid isopropyl ester (9.0 g, 33.15 mmol), and potassium carbonate [584-08-7] in 50% (v/v) methanol/water (200 mL) was stirred at ambient temperature, under N2 blanket for 17 h, filtered, and the filtrate evaporated to reduce its volume. The resultant aqueous product solution was place in a continuous extractor and extracted with ethyl acetate to 2d. The ethyl acetate extract was dried (CaSO4) and evaporated to afford 6.3 g of clear yellow oil. LRMS (ESI) m/z 175.1 [(M+H)]+, calc'd for C8H18N2O2: 174.24.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[I-].[CH2:12]([C:16]1([CH2:27][CH:28]([CH3:30])[CH3:29])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N+:18]([CH3:25])=[C:17]1[CH3:26])[CH:13]([CH3:15])[CH3:14].C>O>[CH2:12]([C:16]1([CH2:27][CH:28]([CH3:30])[CH3:29])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH3:25])[C:17]1=[CH:26][CH:3]=[O:4])[CH:13]([CH3:15])[CH3:14]
Reactant: CN(C)C=O
Reactant: CC1=[N+](C)c2ccccc2C1(CC(C)C)CC(C)C
Agent: C
Agent: [I-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)CC1(CC(C)C)C(=CC=O)N(C)c2ccccc21
Temperature: 25 °C

Procedure:
To 10 mL of dry dimethylformamide in a flask cooled with an ice bath was added dropwise with stirring phosphoryl chloride (1.76 g, 0.0115 mole). After a few minutes 3,3-diisobutyl-1,2-dimethyl-(3H)-indolium iodide (3.85 g, 0.01 mole) was added portionwise over 5 min. The resulting solution was allowed to stir at room temperature for at least 3 hours. This solution was then slowly poured into 250 mL of water stirring in a beaker. After a few minutes 3,3-diisobutyl-2-dimethylaminovinyl-1-methyl-(3H)-indolium iodide separated as its monohydrate via elemental analysis and NMR of a small sample which was removed. This aqueous suspension was then heated to boiling with stirring to dissolve this intermediate product giving a yellow solution with a little purple scum floating on the top. A little Norit was added and after a minute or so the solution was filtered. The yellow filtrate was made strongly basic with 20% sodium hydroxide solution and stirred with warming at 50°-60° C. for a few minutes. The formylmethylene product separated and slowly became crystalline. After cooling to room temperature, the product was filtered, washed well with water, and dried to give 2.3 g (80.6%). The IR and NMR were good. (MW 285.43)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[S:22][CH:23]=[C:24]([CH3:26])[CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:26][C:24]1[CH:25]=[C:21]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)[S:22][CH:23]=1
Reactant: Cc1csc(OB([O-])[O-])c1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COC(=O)C1=Cc2cc(-c3cc(C)cs3)ccc2S(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
In toluene/ethanol/water (10/1/1.2 ml) was dissolved methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (800 mg), and to the solution were added 4-methyl-2-thienyl borate (524 mg) and potassium carbonate (935 mg). The mixture was stirred at room temperature for 30 minutes, and to the mixture was added tetrakistriphenylphosphinepalladium (152 mg). The mixture was stirred at 100° C. for 16 hours and cooled to room temperature. To the mixture was added water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=3/1) to give methyl 7-(4-methyl-2-thienyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (510 mg).