Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:24]I.[Cl-].[NH4+]>CN(C=O)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH3:24])[C@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2c(c1)[C@H](NC(=O)OC(C)(C)C)CC2
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)[C@H](N(C)C(=O)OC(C)(C)C)CC2
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A solution of (R)-methyl 3-(tert-butoxycarbonylamino)-2,3-dihydro-1H-indene-5-carboxylate (stage (ii) A-07) (60 g, 20.62 mmol, 1.0 eq.) in DMF (20 ml) was added dropwise at 0° C. to a suspension of NaH (1.24 g, 30.93 mmol, 1.5 eq., 60% in mineral oil) in DCM (20 ml) and stirring was carried out for 30 minutes. Methyl iodide (2.6 ml, 41.24 mmol, 2.0 eq.) was then added at 0° C. and stirring was carried out for 3 hours at RT. After monitoring by TLC, sat. ammonium chloride solution (200 ml) was added and extraction with ethyl acetate (3×250 ml) was carried out. The combined org. phases were washed with water and sat. NaCl solution (in each case 400 ml), dried over sodium sulfate, concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 10% ethyl acetate in hexane). Yield: 95% (6.0 g, 19.67 mmol).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[CH3:19][S:20]([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)(=[O:22])=[O:21]>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:26]3[CH2:27][CH2:28][CH:23]([S:20]([CH3:19])(=[O:22])=[O:21])[CH2:24][CH2:25]3)[S:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)C1CCNCC1
Reactant: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Product: CS(=O)(=O)C1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-carbaldehyde (General Procedure D-2) and 4-methanesulfonyl-piperidine (Example 34) using General Procedure B-3 yielded 2-chloro-6-(4-methanesulfonyl-piperidin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[NH:21][C:22]2[C:31]3[C:26](=[N:27][C:28]([CH3:32])=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)=[CH:9][CH:8]=1)C.CCO>[OH-].[Na+]>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]([S:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:33])=[O:3])=[CH:8][CH:9]=2)=[C:15]([NH:21][C:22]2[C:31]3[C:26](=[N:27][C:28]([CH3:32])=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH:16]=1
Reactant: CCOC(=O)COc1ccc(Sc2ccc(C)cc2Nc2ccnc3nc(C)ccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(Sc2ccc(OCC(=O)O)cc2)c(Nc2ccnc3nc(C)ccc23)c1
Temperature: 25 °C
Reaction time: 110 h

Procedure:
The product from Example 64 (0.246 g 0.535 mmol) was dissolved in 10 mL of 5% NaOH and 10 mL of EtOH and heated to 100° C. for 2 hrs and then stirred at room temperature for 110 hrs. At this time all the solvent was removed under vacuum and the brown oil was redissolved in water, to which 2 mL of HCl was added and a yellow precipitate formed. Precipitate collected by filtration and solid dried in under vacuum overnight (150 mg, 64%) 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.33 (s, 3H), 2.75 (s, 3H), 5.42 (s, 2H), 6.46 (d, J=7.35 Hz, 1H), 6.52 (s, 1H), 6.75 (d, J=8.46 Hz, 2H), 6.99 (d, J=8.46 Hz, 1H), 7.15-7.40 (m, J=8.46 Hz, 4H), 7.85 (s, 1H), 8.62 (s, 1H), 9.08 (d, J=8.09 Hz, 1H), 9.90 (s, 1H); MS (ESI) m/z 432 (M+H)+, (ESI−) m/z 430(M−H)−.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[CH2:2].[CH3:9][C:10]1[NH:11][CH:12]=[CH:13][N:14]=1.C(O)(=O)C.C>C(Cl)Cl>[CH3:9][C:10]1[N:11]([CH2:2][CH2:1][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH:12]=[CH:13][N:14]=1
Reactant: C=Cc1ccncc1
Reactant: Cc1ncc[nH]1
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1nccn1CCc1ccncc1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
A stirred solution containing 52.5 g (0.50 mol) of 4-vinylpyridine, 36.9 g (0.45 mol) of 2-methylimidazole and 1.1 g of glacial acetic acid was heated to an internal temperature of 130° C. under a nitrogen atmosphere, maintained at this temperature for 5 hours, and then allowed to stand overnight at room temperature. The resultant solidified mass was dissolved in 150 ml of methylene dichloride, treated with charcoal, filtered through Celite and then concentrated in vacuo. The crude residue was crystallized from a mixture of methylene chloride and pentane in a ratio of 1:2.5 as the eluent to yield a solid.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:35])=[O:34])=[CH:29][CH:28]=2)([OH:26])[CH2:21][CH:22]2[CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mn]([O-])(=O)(=O)=[O:37].[K+]>CO.O.C(OCC)(=O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:27]2[CH:28]=[CH:29][C:30]([S:33]([CH3:35])(=[O:37])=[O:34])=[CH:31][CH:32]=2)([OH:26])[CH2:21][CH:22]2[CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)c1ccc(C(O)(CC2CCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(O)(CC2CCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 123 %

Procedure:
To a stirred solution of 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclobutyl-1-(4-methylsulfinyl-phenyl)-ethanol (512 mg, 1 mmol) in methanol (50 mL) and water (10 mL) was added potassium permanganate (126 mg, 0.8 mmol) at room temperature. The mixture was stirred at room temperature for 2 h, diluted with ethyl acetate (150 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclobutyl-1-(4-methylsulfonyl-phenyl)-ethanol (520 mg, quant.) as a light yellow solid: LC/MS m/e calcd for C26H25FN2O5S2 [M+H]+ 529.63, observed 529.0.
Reaction SMILES: [F:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[C:10]1(=[O:16])[O:15][C:13](=[O:14])[CH2:12][CH2:11]1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClC(Cl)C(Cl)Cl>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[C:3]([OH:9])[C:2]=1[F:1]
Reactant: O=C1CCC(=O)O1
Reactant: Oc1cccc(Cl)c1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)C(Cl)Cl
Product: O=C(O)CCC(=O)c1ccc(Cl)c(F)c1O
Temperature: 130 °C
Yield: 18.9 %

Procedure:
To a stirred and cooled solution of 2-fluoro-3-chloro-phenol (21.9 g, 0.15 mol) and succinic anhydride (15.3 g, 0.15 mol) in 1,1,2,2-tetrachloroethane (135 mL) was added anhydrous aluminum chloride (38.7 g, 0.29 mol) portion-wise. The reaction mixture was stirred at room temperature for 3 hours and then heated at 130° C. for 2 hours. After being cooled to room temperature, to the reaction mixture were added concentrated hydrochloric acid and ice alternatively in small portions. The resulting mixture was extracted with ethyl acetate (75 mL×3). The combined organic layers were evaporated. The solid residue was basified by slow addition of an aqueous solution of 2N sodium hydroxide solution under cooling conditions, and then extracted with ethyl acetate (30 mL×3). The aqueous layer was acidified by dropwise addition of concentrated hydrochloric acid to a pH of about 2, and then extracted with ethyl acetate (50 mL×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Column chromatography (silica gel, 100-120 mesh, 15% ethyl acetate in hexane) gave 4-(4-chloro-3-fluoro-2-hydroxy-phenyl)-4-oxo-butyric acid (7.0 g, 19%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.59 (t, J=6.26 Hz, 2H), 3.31 (t, J=6.28 Hz, 2H), 7.15 (d, J=6.56 Hz, 1H), 7.74 (d, J=6.56 Hz, 1H), 11.90-12.31 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([C:4]([NH:6][C:7]1[S:8][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[N:10][N:11]=1)=[O:5])[NH2:3].[CH2:16]=O.[OH-].[K+]>CO>[CH3:1][N:2]1[C:4](=[O:5])[N:6]([C:7]2[S:8][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[N:10][N:11]=2)[CH2:16][NH:3]1
Reactant: CN(N)C(=O)Nc1nnc(C(C)(C)C)s1
Reactant: C=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1NCN(c2nnc(C(C)(C)C)s2)C1=O
Reaction time: 0.33 h

Procedure:
2-Methyl-4-(5-t-butyl-1,3,4-thiadiazol-2-yl)-semicarbazide (0.1 mole) dissolved in methanol (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. Aqueous formaldehyde (0.2 mole; 37% concentration) is then added to the reaction vessel with stirring. Dilute aqueous potassium hydroxide is added to the reaction mixture to adjust the pH to between 7 and 8 and stirring is continued for a period of about 20 minutes resulting in the formation of a solid precipitate. The precipitate is recovered by filtration, is recrystallized and is dried under vacuum to yield the desired product 2-methyl-4-(5-t-butyl-1,3,4-thiadiazol-2-yl)-1,2,4-triazolidin-3-one.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:14]([CH3:16])[CH3:15])[C:6]([O:8][CH3:9])=[O:7])#[N:2].[OH-].[Na+].FC(F)(F)C(OC1[C:29]([F:30])=[C:28]([F:31])[C:27]([F:32])=[C:26]([F:33])[C:25]=1[F:34])=O.C(N(CC)CC)C>CO.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:14]([CH3:16])[CH3:15])[C:6]([O:8][C:9]1[C:29]([F:30])=[C:28]([F:31])[C:27]([F:32])=[C:26]([F:33])[C:25]=1[F:34])=[O:7])#[N:2]
Reactant: COC(=O)c1ccc(OC(C)C)c(C#N)c1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)Oc1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
20.5 g (0.093 mol) of methyl 3-cyano-4-isopropoxybenzoate 4 was dissolved in 200 mL of a 6:4 mixture of methanol and water. To this was added 5.61 g (0.14 mol) of NaOH and the mixture stirred for 2 hours at room temperature. The solution was then filtered through a silica gel plug and the solvents removed under vacuum. The resulting solid was re-dissolved in 200 mL of CH2Cl2 and treated with 19.3 mL (0.11 mol) of perfluorophenyl 2,2,2-trifluoroacetate 5 and 19.5 mL (0.14 mol) of triethylamine. After stirring overnight, the solution was filtered and any solids rinsed with CH2Cl2. The combined organic fractions were run through a short silica gel column and then evaporated to dryness to give 29 g (83.5% yield) of 6 which was characterized by LCMS and HNMR.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].Br[CH2:22][C:23]1[O:24][CH:25]=[CH:26][C:27]=1[C:28]([O:30][CH3:31])=[O:29]>>[CH3:31][O:30][C:28]([C:27]1[CH:26]=[CH:25][O:24][C:23]=1[CH2:22][N:8]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19])=[O:29]
Reactant: COC(=O)c1ccoc1CBr
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: COC(=O)c1ccoc1Cn1c(Oc2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O
Yield: 33.5 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 2-bromomethyl-3-methoxycarbonylfurane were reacted by the same way with the example 1 to obtain the titled compound (133 mg, yield: 33.5%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([C:16]3[N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]([F:30])([F:29])[F:28])[N:19]=[C:18]([C:31](O)=[O:32])[CH:17]=3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].C(Cl)(=O)C(Cl)=O.[CH3:40][S:41]([NH2:44])(=[O:43])=[O:42].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.ClCCCl.CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([C:16]3[N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]([F:30])([F:28])[F:29])[N:19]=[C:18]([C:31]([NH:44][S:41]([CH3:40])(=[O:43])=[O:42])=[O:32])[CH:17]=3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(N)(=O)=O
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(=O)O)nn3-c3ccccc3C(F)(F)F)s2)c1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
To round bottom flask was added 5-[5-(3-Methanesulfonyl-phenyl)-thiophen-2-yl]-1-(2-trifluoromethyl-phenyl)-1H-pyrazole-3-carboxylic acid (302 mg, 615 mmol), oxalyl chloride (0.54 mL), anhydrous DCM (10 mL), and anhydrous DMF (100 μL). The reaction solution was stirred at room temperature for approximately 1 hr prior to concentration in vacuo. The resulting crude acid chloride intermediate was used in the next reaction without further purification. To a glass vial was added acid chloride (615 μmol theoretical), methanesulfonamide (117 mg, 1.23 mmol), 1,2-dichloroethane (9 mL), DIEA (200 μL), and DMAP (10 mg). The reaction solution was stirred at 45° C. for 3 hrs. The reaction solution was diluted with DCM (60 mL) and transferred to a separatory funnel. The solution was washed with aq NH4Cl (50 mL×2) and with aq NaCl (50 mL). The organic phase was dried over Na2SO4, filtered, concentrated on the Rotavapor and chromatographed through a 25 g SiO2 column using a mobile phase gradient of 100% Hx to 70% EtOAc to afford 182 mg (52% yield) of the title compound. 1H NMR (400 MHz, CDCl3) δ 9.07 (s, 1H), 8.02 (s, 1H), 7.91 (m, 1H), 7.84 (d, 1H), 7.74-7.80 (m, 2H), 7.69 (d, 1H), 7.55 (t, 1H), 7.48 (m, 1H), 7.23 (s, 1H), 7.21 (d, 1H), 6.77 (d, 1H), 3.42 (s, 3H), 3.07 (s, 3H); 19F NMR (400 MHz, CDCl3) δ −60.5 ppm MS (ES) 570.2 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[N:4]([CH3:11])[CH:5]=[C:6]([OH:10])[C:7](=[O:9])[CH:8]=1.[C:13]([CH:17](OC)[OH:18])([F:16])([F:15])[F:14].C(=O)([O-])[O-].[K+].[K+]>>[F:12][CH:2]([F:1])[C:3]1[N:4]([CH3:11])[C:5]([CH:17]([OH:18])[C:13]([F:16])([F:15])[F:14])=[C:6]([OH:10])[C:7](=[O:9])[CH:8]=1
Reactant: COC(O)C(F)(F)F
Reactant: Cn1cc(O)c(=O)cc1C(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cn1c(C(F)F)cc(=O)c(O)c1C(O)C(F)(F)F
Temperature: 100 °C
Yield: 4.5 %

Procedure:
A suspension of 2-difluoromethyl-5-hydroxy-1-methyl-1H-pyridin-4-one (0.50 g, 2.85 mmol), CF3CH(OH)OCH3 (2.37 g, 18.2 mmol) and potassium carbonate (0.122 g, 0.88 mmol) in a sealed parallel reactor test tube was heated to about 100° C. The progress of the reaction was monitored by HPLC Method 1 (Example 24), and only one major product peak was detected (HPLC peak percent area was about 20% after 1.5 h, and 38% after 3 h). The reaction mixture was heated for another 21 h, then cooled down to RT, and some white solid separated. The solid was collected by suction filtration. HPLC analysis of the solid dissolved in methanol showed the presence of 2-difluoromethyl-5-hydroxy-1-methyl-1H-pyridin-4-one and 6-difluoromethyl-3-hydroxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one in 18/82 ratio. A portion of the solid was purified by column chromatography on silica gel (conc. NH4OH/isopropanol 10/100 v/v as eluant) to afford 6-difluoromethyl-3-hydroxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one (35 mg). HPLC Method 1 (Example 24), RT=11.3 min, HPLC purity (peak percent area): 97.9% at λ=280 nm. 1H NMR (DMSO-d6+1 drop of D2O) δ ppm: 7.12 (t, J=52.8 Hz, 1H), 6.56 (s, 1H), 5.83 (b, 1H), 3.79 (s, 3H). 19F NMR (DMSO-d6+1 drop of D2O) δ ppm: −73.3 (3F), −117.8 (2F). MS-ESI (m/z) 274.1 [M+1]+, 256.1, 228.1, 208.1 (100%), 180.1.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][C:7]1[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][C:8]=1[OH:9].[OH-].[Na+].Cl.CN([CH:21]=[O:22])C>O>[OH:9][C:8]1[C:7]([CH3:6])=[C:13]([OH:14])[CH:12]=[CH:11][C:10]=1[CH:21]=[O:22]
Reactant: CN(C)C=O
Reactant: Cc1c(O)cccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(O)ccc(C=O)c1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To an ice-cooled solution of POCl3 (4.9 g, 32.2 mmol) in dry DMF (10.0 mL, 64.4 mmol) was slowly added a solution of 2-methylresorcinol (2.0 g, 16.1 mmol) in dry DMF (5.0 mL). After stirring at room temperature for 12 h, the mixture was cooled to 0° C. and then carefully treated with iced water (15 mL). 2 M sodium hydroxide was added to adjust pH to 10. The resulting mixture was heated to reflux for 10 min. Then, the mixture was acidified by 3 M HCl (pH=3). The resulting solid was collected by filtration, and the precipitate was washed with water (10 mL×3). The obtained orange solid (4.0 g, 46%) was dried in vacuo and used for the next reaction without further purification. 1H-NMR (DMSO-d6, 400 MHz): δ9.71 (1H, s), 7.43 (1H, d, J=8.5 Hz), 6.55 (1H, d, J=8.5 Hz), 1.97 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)[CH:5]=[C:4]([NH2:17])[C:3]=1[NH2:18].[N:19]#[C:20]Br>CO>[CH3:1][C:2]1[C:3]2[NH:18][C:20]([NH2:19])=[N:17][C:4]=2[CH:5]=[C:6]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)[CH:7]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(N)c1N
Reactant: N#CBr
Solvent: CO
Product: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc2nc(N)[nH]c12
Reaction time: 1.5 h
Yield: 101.2 %

Procedure:
3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1,2-diamine (See Example 1.G) (500 mg, 2.015 mmol) and cyanic bromide (0.484 mL, 2.418 mmol) were added to a round bottom flask at room temperature, suspended in methanol (10.0 mL) and allowed to stir for 1.5 h. Volatiles were removed under reduced pressure followed by the addition of saturated sodium bicarbonate. The precipitate was collected via filtration, washed with ethyl acetate and dried under reduced pressure to afford the title compound (557 mg, 2.039 mmol, quant. yield). Compound was carried forward without further purification or characterization. MS (ESI) m/z 273.8 [M+1]+.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([NH:10][NH2:11])[CH:7]=[CH:8][CH:9]=1)#[N:3].ClC1C=C(N2[C:24]([C:25]3[CH:30]=[C:29](F)[CH:28]=[C:27]([Cl:32])[CH:26]=3)=[CH:23][C:22]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=N2)C=CC=1F>>[Cl:32][C:27]1[CH:26]=[C:25]([C:24]2[N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([C:2]#[N:3])[CH:5]=3)[N:11]=[C:22]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:23]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: N#Cc1cccc(NN)c1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Agent: Cl
Product: CCOC(=O)c1cc(-c2cccc(Cl)c2)n(-c2cccc(C#N)c2)n1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 3A and 3-cyanophenylhydrazine hydrochloride in analogy to the synthesis of the compound of Example 21A. 540 mg of the title compound with 69% purity (25% of theory) are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]([CH3:11])=[C:5]2[CH2:12][CH2:13][OH:14].[CH3:15][S:16]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)(=[O:18])=[O:17].C[O-].[Na+].Cl>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:23]\[C:22]1[CH:21]=[CH:20][C:19]([S:16]([CH3:15])(=[O:18])=[O:17])=[CH:26][CH:25]=1)/[C:6]([CH3:11])=[C:5]2[CH2:12][CH2:13][OH:14]
Reactant: CC1=C(CCO)c2cc(F)ccc2C1
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC1=C(CCO)c2cc(F)ccc2/C1=C\c1ccc(S(C)(=O)=O)cc1
Reaction time: 6 h

Procedure:
5-Fluoro-2-methyl-1H-3-indenyl-(2-hydroxy) ethane (15 g, 0.072 mol), p-methylsulfonylbenzaldehyde (14.0 g, 0.091 mol) and sodium methoxide (13.0 g, 0.24 mol) are heated in methanol (200 ml) at 60° C. under nitrogen with stirring for 6 hours. The reaction mixture is poured onto ice-water (750 g), and is acidified with 2.5N hydrochloric acid. The collected solid is triturated with a little ether to produce (Z)-5-fluoro-2-methyl-1-(p-methylsulfonylbenzylidene)-1H-3-indenyl-(2-hydroxy) ethane. Recrystallization of the crude reaction product results in the separation of the mixture of geometrical isomers (Z/E) and gives the title compound (R1 =5-fluror, R2 =CH3, R3 =H, R4 =CH2OH, n=1, R5 =CH3SO2).
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1>C(O)C>[O:11]=[C:4]1[CH:5]([C:8]([OH:9])=[O:10])[CH2:7][CH2:6][N:13]1[C:14]1[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=1
Reactant: Cc1cccc(N)c1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Solvent: CCO
Product: Cc1cccc(N2CCC(C(=O)O)C2=O)c1
Yield: 83.8 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.250 g, 1.47 mmol) and m-toluidine (0.470 mL; 4.41 mmol) in ethanol (3 mL). 2-oxo-1-m-tolylpyrrolidine-3-carboxylic acid 0.270 g (84%) was obtained as a pink film.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:20]1([C:26]2[N:27]=[C:28]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12]([N:34]2[CH2:35][CH2:36][N:31]([C:28]3[S:29][CH:30]=[C:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:27]=3)[CH2:32][CH2:33]2)=[O:19])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Reactant: CC(=O)Nc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(=O)Nc1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)cs3)CC2)cn1
Temperature: 70 °C
Reaction time: 15 h
Yield: 13.7 %

Procedure:
A mixture of 2,2,2-trichloroethyl [6-(acetylamino)pyridin-3-yl]carbamate (293 mg, 0.897 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (200 mg, 0.815 mmol) and diisopropylethylamine (0.156 ml, 0.897 mmol) in dimethylsulfoxide (2.7 ml) was stirred at 70° C. for 15 hours. Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to obtain the desired product (47.3 mg, 13.7%) as a solid.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([S:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14]/[C:13]/1=[CH:18]\[C:19]1[N:23]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[N:22]=[N:21][CH:20]=1)(=[O:10])[CH3:9].Br[CH:30]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[F:42])[C:31]([CH:33]1[CH2:35][CH2:34]1)=[O:32].[ClH:43]>C(N(CC)CC)C>[ClH:43].[C:8]([S:11][CH:12]1[CH2:17][CH2:16][N:15]([CH:30]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[F:42])[C:31]([CH:33]2[CH2:34][CH2:35]2)=[O:32])[CH2:14]/[C:13]/1=[CH:18]\[C:19]1[N:23]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[N:22]=[N:21][CH:20]=1)(=[O:10])[CH3:9]
Reactant: O=C(C1CC1)C(Br)c1ccccc1F
Reactant: COC(=O)Cn1nncc1/C=C1\CNCCC1SC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cn1nncc1/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1SC(C)=O
Yield: 50 %

Procedure:
Following a procedure similar to that described in Example 150-(g), (E)-4-(acetylsulfanyl)-3-{[1-(methoxycarbonylmethyl)-1H-1,2,3-triazol-5-yl]methylidene}piperidine hydrogen trifluoroacetate (1.06 g) was subjected to the reaction with 2-bromo-2-(2-fluorophenyl)-1-cyclopropylethanone and triethylamine and the free base that was obtained by silica gel chromatography was similarly treated with hydrogen chloride to yield the title compound (650 mg, yield: 50%) as a pale yellow amorphous solid.