Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH:34]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][CH2:35]1>>[CH:34]1([C:38]([N:29]2[CH2:28][CH2:27][CH:26]([N:23]3[C:19]4=[N:20][CH:21]=[N:22][C:17]([O:16][C:15]5[CH:14]=[CH:13][C:12]([S:9]([CH3:8])(=[O:11])=[O:10])=[CH:33][CH:32]=5)=[C:18]4[CH:25]=[N:24]3)[CH2:31][CH2:30]2)=[O:39])[CH2:37][CH2:36][CH2:35]1
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Reactant: O=C(Cl)C1CCC1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)C3CCC3)CC2)cc1

Procedure:
Cyclobutyl-{4-[4-(4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-yl}-methanone was prepared according to General Procedure I by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with cyclobutanecarbonyl chloride (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 1.74-2.21 (m, 10H), 2.82-2.87 (m, 1H), 3.30 (methyl sulfonyl and water peak), 3.84-3.87 (m, 1H), 4.49-4.52 (m, 1H), 5.06-5.08 (m, 1H), 7.62-7.65 (m, 2H), 8.05-8.07 (m, 2H), 8.38 (s, 1H), 8.57 (s, 1H). Mass spectrum MH+=456, M+Na=478.
Reaction SMILES: [N:1]12[CH2:8][CH2:7]N([CH2:5][CH2:6]1)CC2.[C:9]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](NC2C=C(C)C(C)=CC=2I)[CH:16]=1)(=[O:12])C=C>CN(C=O)C>[CH3:14][C:15]1[CH:16]=[C:17]2[C:6](=[CH:5][C:20]=1[CH3:19])[NH:1][CH:8]=[C:7]2[C:9]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: C1CN2CCN1CC2
Reactant: C=CC(=O)OCc1cccc(Nc2cc(C)c(C)cc2I)c1
Solvent: CN(C)C=O
Product: Cc1cc2[nH]cc(C(=O)OCc3ccccc3)c2cc1C
Temperature: 120 °C
Yield: 140.6 %

Procedure:
8.60 g of 1,4-diazabicyclo[2.2.2]octane is added to a solution of 25.5 g of the compound obtained in step 1 in 120 ml of DMF. It is degassed with nitrogen, then 0.703 g of palladium acetate is added and the reaction mixture is heated at 120° C. for 7 hours. EtOAc is added, then it is washed with water and with brine, dried over Na2SO4 and evaporated. After trituration of the solid residue with iso ether, 12.3 g of the expected compound is obtained in the form of a beige powder.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH2:4].[H-].[Na+].Cl[C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]2[S:23][C:24]([I:26])=[CH:25][C:16]=12>O1CCCC1>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH:4][C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]2[S:23][C:24]([I:26])=[CH:25][C:16]=12
Reactant: N#Cc1cnc2sc(I)cc2c1Cl
Reactant: COc1cc(N)c(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Nc2c(C#N)cnc3sc(I)cc23)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.8 %

Procedure:
A mixture of 2,4-dichloro-5-methoxyaniline (1.1 g, 5.7 mmol) and 60% sodium hydride (285 mg, 9.9 mmol) in 30 mL of tetrahydrofuran is heated at reflux for 1 hour. The solution is cooled and 4-chloro-2-iodothieno[2,3-b]pyridine-5-carbonitrile (1.0 g, 3.12 mmol) is added. The reaction mixture is heated at reflux for 5 hours then allowed to stir at room temperature overnight. The resultant dark solution is partitioned between ethyl acetate and water. The organic layer is washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 0.5:9.5 methanol:dichloromethane to provide 0.28 g of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[2,3-b]pyridine-5-carbonitrile as an off white solid, mp 231-233° C. An additional 0.09 g is obtained by chromatography of a mixture of unreacted starting material and product using a gradient of 9:1 to 1:1 hexane:ethyl acetate. 1H NMR (DMSO-d6) δ 3.87 (s, 3H), 7.36 (s, 1H), 7.76 (s, 1H), 8.11 (s, 1H), 8.39 (s, 1H), 9.76 (s, 1H); MS 473.8 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:9]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:19](O)([C:21]([F:24])([F:23])[F:22])=O>>[N:13]1([C:9]2[CH:8]=[C:3]([C:4]([O:6][CH3:7])=[O:5])[C:2]3[NH:1][C:19]([C:21]([F:24])([F:23])[F:22])=[N:12][C:11]=3[CH:10]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: COC(=O)c1cc(N2CCOCC2)cc(N)c1N
Reactant: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(N2CCOCC2)cc2nc(C(F)(F)F)[nH]c12
Temperature: 25 °C

Procedure:
A mixture of methyl 2,3-diamino-5-(4-morpholinyl)benzoate (4.0 g) in CF3COOH (20 mL) was heated at reflux temperature for 8 h. When TLC analysis indicated consumption of starting material, the mixture was cooled to room temperature and the solvent was removed in-vacuo. The residue was diluted with aqueous NaHCO3 and extracted with EtOAc (250 mL×3).The combined organic layers were washed with brine (250 mL×2), dried over anhydrous Na2SO4. After filtration, the solvent was removed by rotary evaporator. The residue was then purified by silica gel chromatography eluted with EtOAc:petroleum ether=1:4 to afford the desired product as a pale solid. (4.3 g, 82.7%). 1H NMR (300 MHz, DMSO-d6): δ ppm 13.47 (s, 1H), 7.71 (s, 1H), 7.56 (s, 1H), 3.96 (s, 3H), 3.79 (t, 4H, J=4.5 Hz), 3.17 (s, 4H). LC-MS: m/e=330.1 [M+1]+.
Reaction SMILES: [C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](Cl)=[O:9])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](=[O:9])[C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][C:17]=2[O:21][CH3:22])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: COc1cccc(OC)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COc1ccc(C(=O)C2CCN(C(C)=O)CC2)c(OC)c1
Temperature: 25 °C

Procedure:
18.7 g of 1acetylisonipecotoyl chloride, Example 1(b) are added slowly to a stirred mixture of 40.0 g of m-dimethoxybenzene and 19.2 g of aluminum chloride in 75 ml of carbon disulfide. The reaction mixture is stirred at ambient temperature for an hour, poured into ice-water and extracted with chloroform, the combined extracts are dried and the chloroform is removed, leaving a yellow oil. The oil is triturated with ether to give a white solid, which is recrystallized twice from ethyl acetate to give the pure solid, mp 132°-134° C., 1-acetyl-4-(2,4-dimethoxybenzoyl)piperidine.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([O:16][C:17]3[CH:32]=[CH:31][C:20]([C:21]([O:23]CC4C=CC=CC=4)=[O:22])=[CH:19][CH:18]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2>[Pd].C(OCC)(=O)C>[CH3:1][C:2]1([CH3:33])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]([O:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:31][CH:32]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)Oc3ccc(C(=O)OCc4ccccc4)cc3)ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)CCC(C)(C)c2cc(C(=O)Oc3ccc(C(=O)O)cc3)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 150 mg (0.3394 mmol) of benzyl 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthoyloxy)benzoate and 50 mg of 10% palladium on carbon in 5 ml of ethyl acetate was stirred under a hydrogen atmosphere at room temperature for 4 hours. The reaction mixture was then filtered and the filtrate was concentrated in-vacuo. The residue was dissolved in ether and extracted with aqueous NaOH solution. The aqueous extract was then acidified with glacial acetic acid and extracted with ether. The ether extract was washed with saturated NaCl solution and then concentrated in-vacuo. The resultant residue was recrystallized from ethyl acetate to give the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][C:5]=1[OH:15])([O-])=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)C.O>[NH2:1][C:4]1[CH:9]=[C:8]([O:10][C:11]([F:12])([F:13])[F:14])[CH:7]=[CH:6][C:5]=1[OH:15]
Reactant: O=[N+]([O-])c1cc(OC(F)(F)F)ccc1O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cc(OC(F)(F)F)ccc1O
Temperature: 80 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
To a mixture of 2-nitro-4-(trifluoromethoxy)phenol (2 g, 0.0089 mol) in ethanol (50 mL) and water (25 mL) was added sodium thiosulfate (6.2 g, 0.0356 mol) at room temperature. The heterogeneous mixture was stirred at 80° C. under an atmosphere of nitrogen for 1 hour. The reaction mixture was cooled to room temperature, and ethanol was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate (3×70 mL), and the organic layer was washed with brine and dried under sodium sulfate. The solvent was removed under reduced pressure to give yellow solid of 2-amino-4-(trifluoromethoxy)phenol (0.9 g, 0.005 mol). TLC (methanol/dichloromethane=5:95) Rf 0.29 MS: MH+: 194.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[O:10][C:9](=[O:11])[NH:8][C:5]2=[N:6][CH:7]=1.[Li]N([Si](C)(C)C)[Si](C)(C)[CH3:15].COS(OC)(=O)=O>C1COCC1>[CH3:15][N:8]1[C:5]2=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=[C:4]2[O:10][C:9]1=[O:11]
Reactant: [Li]N([Si](C)(C)C)[Si](C)(C)C
Reactant: O=c1[nH]c2ncc(Br)cc2o1
Solvent: C1CCOC1
Solvent: COS(=O)(=O)OC
Product: Cn1c(=O)oc2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4.7 g of 6-bromo-oxazolo[4,5-b]pyridin-2(3H)-one (0.022 mole) in 90 ml of THF is added 24 ml of LiN(TMS)2 (0.024 mole) in THF. The homogenous solution is maintained under nitrogen at room temperature for 20 min., 3.03 g (0.024 mole) of dimethylsulfate is added and the reaction mixture allowed to stir overnight. The reaction mixture is then quenched with 20 ml of sat. ammonium chloride and extracted with 3×80 ml ethyl acetate. The ethyl acetate is then washed with 3×30 ml sat. ammonium chloride, dried over sodium sulfate and concentrated to obtain off white product which is used directly in the next step.
Reaction SMILES: S([C:5]1C=CC(C)=CC=1)(O)(=O)=O.[C:12]1([C:18]2([C:24]([OH:26])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C[Si](Cl)(C)C>CO>[CH3:5][O:25][C:24]([C:18]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]1)=[O:26]
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)C1(c2ccccc2)CCNCC1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
To a solution of 4-phenyl-piperidine-4-carboxylic acid tosylate (4.6 g, 20 mmol) in MeOH (25 mL) is added TMSCl (10 mL) and the reaction mixture is stirred at 50° C. for 15 h. The reaction mixture is cooled and evaporated. The residue is taken up in MeOH (5 mL), poured into sat. Na2CO3 (100 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic extracts are dried (Na2SO4), filtered and evaporated to provide the title compound.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:21]#[N:22])=[N:6][N:7]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[CH:8]=1)(=O)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:43](Br)([F:45])[F:44]>ClCCl>[C:21]([C:5]1[C:4]([C:1]([CH3:2])=[C:43]([F:45])[F:44])=[CH:8][N:7]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:17])[F:18])=[CH:11][C:10]=2[Cl:20])[N:6]=1)#[N:22]
Reactant: FC(F)(Br)Br
Reactant: CC(=O)c1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(=C(F)F)c1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C#N
Temperature: 90 °C
Reaction time: 12 h

Procedure:
4-Acetyl-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (0.5 g), triphenylphosphine (1.884 g), dibromodifluoromethane (0.33 ml) and dichloromethane (50 ml) were placed in a stainless steel bomb and heated and stirred at 90° C. for 12 hours. The reaction mixtiure was evaporated and the residue was purified by column chromatography on silica gel eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a white solid, m.p. 66-68° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])[C:4]([O:14][CH3:15])=[C:3]1[C:16]([O:18]CC)=[O:17].[OH-].[Na+].C(O)C>O>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])[C:4]([O:14][CH3:15])=[C:3]1[C:16]([OH:18])=[O:17]
Reactant: C=CCOC(=O)Nc1cn(C)c(C(=O)OCC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCOC(=O)Nc1cn(C)c(C(=O)O)c1OC
Temperature: 25 °C
Reaction time: 120 h
Yield: 71.5 %

Procedure:
A mixture of 0.93 g (3.3 mmol) of ethyl 1-methyl-4-[(allyloxycarbonyl)amino]-3-methoxy-1H-pyrrole-2-carboxylate (prepared according to the method described in K. Narkunan, M. A. Ciufolini, Synthesis, 2000, 673-676), 3.3 ml of a 2 molar sodium hydroxide aqueous solution and 3.3 ml of ethanol is stirred at room temperature for 5 days. Water is added and the ethanol is evaporated. After extraction with diethyl ether, the aqueous phase is acidified to pH 2 with concentrated hydrochloric acid. Extraction with ethyl acetate, drying and concentration give 0.6 g (71% yield) of a light brown solid. (M−1=253).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[N:5]=[C:4]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:13]=2)[CH:3]=1.[C@H:30]1([NH2:37])[CH2:35][CH2:34][C@H:33]([NH2:36])[CH2:32][CH2:31]1.C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:13]=2)[N:5]=[C:6]([NH:36][C@H:33]2[CH2:34][CH2:35][C@H:30]([NH2:37])[CH2:31][CH2:32]2)[N:7]=1
Reactant: CS(=O)(=O)c1nc(Cl)cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)n1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: N[C@H]1CC[C@H](Nc2nc(Cl)cc(-c3cn(S(=O)(=O)c4ccccc4)c4ncccc34)n2)CC1

Procedure:
A mixture of Example 42b (5 g, 11.14 mmol), trans-cyclohexane-1,4-diamine (2.54 g, 22.28 mmol), triethylamine (3.10 mL, 22.28 mmol) and dioxane (120 mL) in a 250 mL of flask was heated at 60° C. for 90 minutes. The reaction mixture was concentrated and used directly for the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@H:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11])=[CH:6][CH:5]=1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(N)cc1
Yield: 78 %

Procedure:
A solution of C1 (1.0 g, 3.8 mmol) in MeOH (20 mL) was charged to a Parr reactor, and the contents of the reactor were treated with 10% Pd/C (800 mg, 0.376 mmol). The contents of the reactor were then hydrogenated at 45 Psi hydrogen pressure and 25° C. for 4 hours. The contents of the reactor were filtered through Celite® and washed with DCM. The combined filtrates were concentrated to provide C2 as a sticky orange residue. Yield: 690 mg, 78% yield. GC_MS=236. 1H NMR (500 MHz, d6-DMSO) δ: 7.07 (d, 1H), 6.88 (d, 2H), 6.43 (d, 2H), 4.85 (s, 2H), 4.40 (m, 1H), 1.31 (s, 9H), 1.18 (d, 3H).
Reaction SMILES: [CH3:1]N(CCN)C.CN(C)[CH2:9][CH2:10][NH:11][C:12]([CH:14]([OH:32])[C@H:15]1[O:19][C@@H:18]([N:20]2[C:29]3[N:28]=[CH:27][N:26]=[C:24]([NH2:25])[C:23]=3[N:22]=[CH:21]2)[C@H:17]([OH:30])[C@@H:16]1[OH:31])=[O:13]>>[CH2:10]([NH:11][C:12]([CH:14]([OH:32])[C@H:15]1[O:19][C@@H:18]([N:20]2[C:29]3[N:28]=[CH:27][N:26]=[C:24]([NH2:25])[C:23]=3[N:22]=[CH:21]2)[C@H:17]([OH:30])[C@@H:16]1[OH:31])=[O:13])[CH:9]=[CH2:1]
Reactant: CN(C)CCN
Reactant: CN(C)CCNC(=O)C(O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Product: C=CCNC(=O)C(O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Yield: 84 %

Procedure:
with dimethylaminoethylamine: adenosine-5'-carboxylic acid N-(2-dimethylaminoethyl)-amide; m.p. 136°-138° C.; yield 84% of theory.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[CH:29]([C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]([OH:40])=[O:39])=[CH:33][CH:32]=1)=O>>[C:38]([CH2:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:29][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[CH:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:32][CH:33]=1)([OH:40])=[O:39]
Reactant: CCNc1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=Cc1ccc(CC(=O)O)cc1
Product: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)O)cc2)c1
Yield: 57.6 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (70 mg) and (4-formylphenyl)acetic acid (150 mg) according to an analogous synthetic method to Example 212,the title compound (56 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[O:16]1[CH2:20][CH2:19][C:18](=O)[CH2:17]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[N:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:4][C:3]3[C:13](=[O:14])[NH:15][C:18]4([CH2:19][CH2:20][O:16][CH2:17]4)[NH:1][C:2]=3[CH:6]=2)=[CH:12][CH:11]=1
Reactant: O=C1CCOC1
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1NC2(CCOC2)Nc2cc(-c3ccncc3)sc21
Temperature: 80 °C
Reaction time: 5 h
Yield: 11.5 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.108 g, 0.500 mmol), dihydro-3(2H)-furanone (0.215 g, 2.50 mmol), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (3.0 mL) was stirred for 5 h at 80° C. in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (100 mL). Extraction with ethyl acetate-tetrahydrofuran (2:1, 100 mL, 50 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. This oil was purified by column chromatography (Combiflash, 12 g silica gel, dichloromethane to 90:10 dichloromethane/methanol) to afford the title compound (0.0165 g, 11%) as a yellow solid:
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]#[N:16])=[CH:10][CH:9]=1.[N:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[F:30])=[N+:18]=[N-:19]>C(O)(C)(C)C>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[N:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:22][C:21]=3[F:30])[C:15]=2[NH2:16])=[CH:10][CH:9]=1
Reactant: N#CCc1ccc(N)cc1
Reactant: [N-]=[N+]=Nc1ccc(C(F)(F)F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Nc1ccc(-c2nnn(-c3ccc(C(F)(F)F)cc3F)c2N)cc1
Yield: 21.3 %

Procedure:
To a stirred and ice-cooled solution of potassium tert-butoxide (1.728 g, 14.626 mmol) in tert-butanol (50 ml), commercial 4-aminophenylacetonitrile (1.418 g, 10.7258 mmol) and 1-azido-2-fluoro-4-trifluoromethyl-benzene (2.000 g, 9.7507 mmol) are added under a nitrogen atmosphere and the reaction mixture is allowed to attain spontaneously room temperature (1 h) and finally refluxed for 6 h. The resulting reaction mixture is concentrated, added water, and extracted with ethylacetate (3×100 ml). The combined organic layers are dried over MgSO4, filtered and evaporated, to afford a dark brown gummy material (3.289 g, 100% mass balance). The crude residue is purified by column chromatography over silica gel (230-400 mesh), eluting with 25% ethylacetate in petroleum ether, to obtain the title compound as a light yellow solid (0.700 g, 21% yield). M.p. 163.6-165.0° C. LC-ESI-HRMS of [M+H]+ shows 338.1021 Da. Calc. 338.102882 Da, dev. −2.3 ppm.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O.[SH:16][CH2:17][C:18]([O:20][CH3:21])=[O:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:10]1([C:8]2[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[S:16][C:17]=2[C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(c1ccccc1)c1ccccc1F
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc2ccccc2c1-c1ccccc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 23 %

Procedure:
To a stirring solution of (2-fluorophenyl)(phenyl)methanone 87 (2 g, 9.99 mmol) and methyl 2-mercaptoacetate in DMF (30 mL) was added potassium carbonate (4.14 g, 30.0 mmol) and the reaction mixture was stirred at 70° C. for 16 h. The solvent was removed under reduced pressure and the resulting residue was diluted with ethyl acetate and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford methyl 3-phenylbenzo[b]thiophene-2-carboxylate 88 as a white oily solid (0.62 g, 23% yield) after purification by ISCO (0 to 40% ethyl acetate in hexane). LRMS (ESI): (calc) 268.33 (found) 269.156 (MH)+
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>C1(C)C(C)=CC=CC=1>[OH:11][C:10]1[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7](=[O:20])(=[O:21])[N:6]([CH3:22])[C:5]=1[C:3]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)=[O:4])=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: Nc1ccccn1
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccc3ccccc3c2S1(=O)=O
Reaction time: 8 h

Procedure:
A mixture consisting of 9.53 gm (0.03 mol) of 4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methylester-1,1-dioxide, 3.8 gm (0.04 mol) of 2-aminopyridine and 250 ml of anhydrous xylene was refluxed for 14 hours in a Soxhlet apparatus equippedwith a 4-A-molecular sieve. After cooling and standing overnight, the crystals which had formed were suction-filtered off and recrystallized from ethylene chloride, yielding 5.4 gm (42% of theory) of the crystallinecompound of the formula ##SPC14##
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24](O)=[O:25])[CH:19]=2)[CH2:14][CH2:13]1)=[O:10].Cl.[O:28]([NH2:30])[CH3:29]>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]([NH:30][O:28][CH3:29])=[O:25])[CH:19]=2)[CH2:14][CH2:13]1)=[O:10]
Reactant: CON
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3ccnc(C(=O)O)c3)CC2)c(Cl)c1Cl
Agent: Cl
Product: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)ccn1

Procedure:
The title compound was synthesized by an analogous method to Example 8 starting from 4-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)pyridine-2-carboxylic acid (Example 293) and methoxylamine hydrochloride.