Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[O:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[O:31]1C[CH:32]1[CH2:34][N:35]1[C:43]2[CH2:42][CH2:41][N:40]([C:44](=[O:46])[CH3:45])[CH2:39][C:38]=2[C:37]([C:47]2[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][CH:48]=2)=[N:36]1>C(Cl)Cl>[O:17]1[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:15]([O:14][CH:11]2[CH2:10][CH2:9][N:8]([CH2:6][CH:32]([OH:31])[CH2:34][N:35]3[C:43]4[CH2:42][CH2:41][N:40]([C:44](=[O:46])[CH3:45])[CH2:39][C:38]=4[C:37]([C:47]4[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][CH:48]=4)=[N:36]3)[CH2:13][CH2:12]2)=[N:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2noc3ccccc23)CC1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC2CO2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC(O)CN2CCC(Oc3noc4ccccc34)CC2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
A solution of 176 mg (0.55 mmol) of 4-(benzo[d]isoxazol-3-yloxy)-piperidine-1-carboxylic acid tert-butyl ester in CH2Cl2(2 mL) was treated with trifluoroacetic acid (0.5 mL) at room temperature overnight. The solvent was then removed and the crude product dissolved in methanol and stirred over 100 mg of sodium bicarbonate for 1 h, the solid was then filtered off and the filtrate concentrated. The crude piperidine was then dissolved in 4 mL EtOH and treated with 202 mg (0.55 mmol) of 1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone The solution was heated to 60° C. overnight. The solvent was then removed by rotary evaporation and the crude product was purified by column chromatography (silica, 0-10% MeOH/EtOAc) to afford 220 mg (68%) of a white solid. MS (electrospray): exact mass calculated for C30H32F3N5O4, 583.24; m/z found, 584.2 [M+H]+. 1H NMR (CDCl3, 400 MHz, a mixture of amide rotamers): 7.77 (d, J=8.22 Hz, 1H), 7.69 (m, 2H), 7.66-7.61 (m, 2H), 7.54-7.49 (m, 1H), 7.41 (d, J=8.41 Hz, 1H), 7.28-7.23 (m, 1H), 4.93 (br m, 1H), 4.88 and 4.75 (A and B of AB quartet, J=15.65 Hz, 1H), 4.65 (br s, 1H), 4.24-4.18 (m, 0.75H), 4.18-4.09 (m, 1.25H), 4.07-3.98 (m, 1.5H), 3.91-3.79 (m, 0.5H), 3.79-3.67 (m, 1H), 3.02-2.85 (m, 2.4H), 2.85-2.70 (m, 1.6H), 2.61-2.52 (m, 1H), 2.51-2.40 (m, 2H), 2.39-2.30 (m, 1H), 2.24-2.12 (br m, 2H), 2.20 (s, 1.5H), 2.16 (s, 1.5H), 2.02-1.86 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)([CH3:5])[CH2:3][NH2:4].[CH2:11]=O>>[CH2:11]=[N:4][CH2:3][C:2]([CH3:5])([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)[CH3:1]
Reactant: CC(C)(CN)c1ccsc1
Reactant: C=O
Product: C=NCC(C)(C)c1ccsc1

Procedure:
5.8 g (37 mmol) 2-methyl-2-thiophene-3-yl-propylamine and 3.6 mL (44 mmol) formaldehyde were stirred together with 2.0 g molecular sieve (4A powders) overnight at RT. The reaction mixture was filtered and the filtrate was concentrated to dryness by rotary evaporation.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]2[N:5]([CH2:6][CH2:7][CH2:8]2)[C:4](=[O:15])[CH:3]=1.[B-](F)(F)(F)[F:17].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CN(C=O)C>[Cl:1][C:2]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]2[N:5]([CH2:6][CH2:7][CH2:8]2)[C:4](=[O:15])[C:3]=1[F:17]
Reactant: COC(=O)c1c(Cl)cc(=O)n2c1CCC2
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CN(C)C=O
Product: COC(=O)c1c(Cl)c(F)c(=O)n2c1CCC2
Reaction time: 1 h
Yield: 31 %

Procedure:
Compound 1b (1.36 g, 5.98 mmol) was stirred in DMF (10 mL) at 88° C. Selectfluor® (2.54 g, 7.17 mmol) in DMF (8 ml) was added dropwise, and the reaction stirred for 1 h. Additional Selectfluor® (1.2 g, 3.39 mmol) in DMF (5 mL) was added, and the reaction stirred 1 h longer. The solution was concentrated in vacuo and purified by silica gel chromatography (75% EtOAc/CH2Cl2) to give 460 mg (31%) of compound 1c as a white solid. 1H NMR (400 MHz, CDCl3): δ 4.18 (t, 2H, J=7.6 Hz), 3.86 (s, 3H), 3.37 (t, 2H, J=7.6 Hz), 2.20-2.28 (m, 2H). MS (ES) [m+H] calc'd for C10H9ClFNO3, 246, 248. found 246, 248.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[N:17]([CH3:21])[CH:18]=[N:19][CH:20]=3)[S:15][C:8]=12.[CH3:22][C:23]([CH3:25])=[O:24]>O1CCCC1.O>[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[N:17]([CH3:21])[C:18]([C:23]([OH:24])([CH3:25])[CH3:22])=[N:19][CH:20]=3)[S:15][C:8]=12
Reactant: CC(C)=O
Reactant: Cn1cncc1-c1cc2nccc(Cl)c2s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(-c2cc3nccc(Cl)c3s2)cnc1C(C)(C)O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 31 %

Procedure:
In a 50 mL round-bottomed flask 7 mL of tetrahydrofuran and n-butyllithium (0.88 mL, 2.5M in hexane) were cooled to −40° C. A suspension of 7-chloro-2-(3-methyl-3H-imidazol-4-yl)-thieno[3,2-b]pyridine (500 mg, 2.00 mmol) in 9 mL of tetrahydrofuran was added dropwise to the solution and stirred for 40 minutes. Acetone (0.79 mL, 3.00 mmol) was added to the anion and the reaction mixture was allowed to warm to room temperature overnight. The mixture was diluted with water and extracted with chloroform (3×50 mL). The combined extracts were dried over NaSO4, filtered, and concentrated. Chromatography on 50 g of silica gel with 5% methanol:methylene chloride afforded 191 mg (31%) of 2-[5-(7-chloro-thieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazol-2-yl]-propan-2-ol. 1H NMR (400 MHz, CDCl3) δ8.58 (d, 1H), 7.51 (s, 1H), 7.28 (d, 1H), 7.24 (s, 1H), 4.02 (s, 3H), 1.77 (s, 6H). LC-MS: 308.1, 310.1 (MH+); HPLC RT: 4.18 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])(O)[CH2:10][CH3:11])[CH:6]=[CH:7][CH:8]=1.S(=O)(=O)(O)O.[OH-].[Na+]>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[CH:10][CH3:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CCC(O)(c1cccc(OC)c1)c1ccccc1C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC=C(c1cccc(OC)c1)c1ccccc1C
Yield: 77.2 %

Procedure:
To a solution of 2-methylphenyl magnesium bromide (prepared from 4.9 g magnesium turnings and 24 ml of 2-bromotoluene) in dry THF (300 ml) was added dropwise a solution of 3'-methoxypropiophenone (25.9 g, 0.16 mol) in dry THF (200 ml). When addition was complete the mixture was heated at reflux temperature for 2 h. Water (250 ml) was added followed by a saturated ammonium chloride solution (250 ml) and the mixture was left overnight. A 4 N hydrochloric acid solution was added until a clear solution was obtained and the phases was separated. The organic phase was dried over magnesium sulphate and the solvent evaporated in vacuo. The residue was submitted to flash chromatography on silica gel (690 g) using a gradient of n-heptane in ethyl acetate to give 28.2 g (55%) of 1-(3-methoxyphenyl)-1-(2-methylphenyl)-1-propanol. A mixture of 1-(3-methoxyphenyl)-1-(2-methylphenyl)-1-propanol (26.2 g, 0.10 mol), isopropanol (300 ml) and a 6 N solution of sulphuric acid (150 ml) was stirred at room temperature for 2 h. The reaction mixture was neutralised with a 4 N sodium hydroxide solution and extracted with ethyl acetate (2×200 ml). The combined organic phases was dried over magnesium sulphate and the solvent was evaporated in vacuo. The residue was submitted to flash chromatography on silica gel (800 g) using n-heptane as eluent to give 18.4 g (76%) of 1-(3-methoxyphenyl)-1-(2-methylphenyl)-1-propene.
Reaction SMILES: C(O[CH:4](OCC)[N:5]([CH3:7])[CH3:6])C.[N:11]1([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=[CH:14][N:13]=[N:12]1>>[CH3:4][N:5]([CH3:7])[CH:6]=[C:16]([N:11]1[CH:15]=[CH:14][N:13]=[N:12]1)[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(OCC)N(C)C
Reactant: CCOC(=O)Cn1ccnn1
Product: CCOC(=O)C(=CN(C)C)n1ccnn1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
44.2 ml (38.0 g, 257.8 mmol) of N,N-dimethylformamide diethyl acetal are added to 20.0 g (128.9 mmol) of the compound from Example 2A, and the mixture is stirred at 100° C. for 16 h. After cooling to RT, the reaction mixture is concentrated under reduced pressure. The residue is triturated with diethyl ether, filtered off and washed with diethyl ether. Yield: 18.0 g (67% of theory)
Reaction SMILES: N1C2C=CC=CC=2N[CH:2]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[NH:18][C:19]1[N:27]=[C:26]2[C:22]([NH:23][C:24](=[O:34])[N:25]2[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[C:21]([Cl:35])[N:20]=1>>[Cl:35][C:21]1[N:20]=[C:19]([N:18]2[C:12]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=3[N:10]=[CH:2]2)[N:27]=[C:26]2[C:22]=1[NH:23][C:24](=[O:34])[N:25]2[CH:28]1[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1
Reactant: Nc1ccc(Cl)cc1Nc1nc(Cl)c2[nH]c(=O)n(C3CCOCC3)c2n1
Reactant: c1ccc2[nH]cnc2c1
Product: O=c1[nH]c2c(Cl)nc(-n3cnc4ccc(Cl)cc43)nc2n1C1CCOCC1
Yield: 46 %

Procedure:
Pale yellow solid. 46% yield on 2 steps (reduction and benzimidazole closing), on 2.47 mmol scale. Synthesized from 2-(2-amino-5-chlorophenylamino)-6-chloro-9-(tetrahydro-2H-pyran-4-yl)-7H-purin-8(9H)-one. 1H NMR (300 MHz, CDCl3+CD3OD) δ, ppm: 9.08 (s, 1H), 8.61 (s, 1H), 7.74 (d, 1H), 7.40 (d, 1H), 4.65-4.58 (m, 1H), 4.23-4.19 (m, 2H), 3.62 (appt, 2H), 2.82-2.76 (m, 2H), 1.93 (br d, 2H); MS (EI) m/z 405.2 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([C:16]#[C:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3([C:27]([NH2:29])=[O:28])[CH2:26][CH2:25]3)[C:13]([C:30]([F:33])([F:32])[F:31])=[CH:12][N:11]=2)=[CH:5][CH:4]=1.CO>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3([C:27]([NH2:29])=[O:28])[CH2:26][CH2:25]3)[C:13]([C:30]([F:32])([F:33])[F:31])=[CH:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2ncc(C(F)(F)F)c(C#Cc3ccccc3C3(C(N)=O)CC3)n2)cn1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3C3(C(N)=O)CC3)n2)cn1
Yield: 56 %

Procedure:
A solution of 1-(2-((2-((6-methoxypyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethynyl)phenyl)cyclopropanecarboxamide A73 (0.229 g, 0.505 mmol) in EtOAc (20 mL) was stirred over 10% Pd/C (wetted with ca. 53% water, 0.150 g) under an atmosphere of hydrogen for 16 hours. The mixture was filtered through Celite and the solvent was removed in vacuo. Purification by column chromatography (Biotage Isolera, 40 g SiO2, 0-80% EtOAc in petroleum benzine 40-60° C.) gave an off-white solid contaminated with alkyne starting material. The solid was dissolved in EtOAc (20 mL) and MeOH (10 mL) and stirred over 10% Pd/C (wetted with ca. 53% water, 0.130 g) for 16 hours under an atmosphere of hydrogen. The mixture was filtered through Celite and the solvent was removed in vacuo to give the title compound 64 as a white solid (0.130 g, 56%). LCMS-D: rt 3.51 min; m/z 458 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1[NH:15][C:14](=[O:16])[N:13]2[N:17]=[C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:19]=[C:12]2[CH:11]=1.Br[CH2:27][CH:28]1[CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:2].[CH:28]1([CH2:27][N:23]2[CH2:24][CH2:25][CH:20]([C:18]3[N:19]=[C:12]4[N:13]([C:14](=[O:16])[NH:15][C:10]([C:4]5[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:3]=5[Cl:2])=[CH:11]4)[N:17]=3)[CH2:21][CH2:22]2)[CH2:30][CH2:29]1
Reactant: BrCC1CC1
Reactant: O=c1[nH]c(-c2ccc(Cl)cc2Cl)cc2nc(C3CCNCC3)nn12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1[nH]c(-c2ccc(Cl)cc2Cl)cc2nc(C3CCN(CC4CC4)CC3)nn12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
1.00 g (2.50 mmol) of 7-(2,4-dichlorophenyl)-2-(piperidin-4-yl)[1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one hydrochloride were initially charged in DMF (6 ml), and 268 μl (2.75 mmol) of 1-bromomethylcyclopropane and 759 mg (5.49 mmol) of potassium carbonate were added. The reaction mixture was stirred at 80° C. for 16 h, the solution was then filtered and ethyl acetate (100 ml) and water (75 ml) were added. The phases were separated and the aqueous phase was extracted with ethyl acetate (two times 15 ml). The combined organic phases were washed with saturated aqueous sodium chloride solution, dried (magnesium sulfate) and concentrated. The product was taken up in acetonitrile and purified by preparative RP-HPLC (Method 11). This gave 413 mg (39% of theory) of the product.
Reaction SMILES: [Na].[C:2]([O:5][CH2:6][C:7]1[CH2:14][S:13][CH:12]2[N:9]([C:10](=[O:16])[CH:11]2[NH2:15])[C:8]=1[C:17]([OH:19])=[O:18])(=[O:4])[CH3:3].Cl[CH2:21][N:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C)C=O>[CH2:26]([O:25][C:23]([N:22]([CH2:28][O:18][C:17]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][C:7]=1[CH2:6][O:5][C:2](=[O:4])[CH3:3])[CH:11]([NH2:15])[C:10]2=[O:16])=[O:19])[CH3:21])=[O:24])[CH3:27]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Reactant: CCOC(=O)N(C)CCl
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)N(C)COC(=O)C1=C(COC(C)=O)CSC2C(N)C(=O)N12
Temperature: 0 °C

Procedure:
725 mg (2.5 mM) of the sodium salt of 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid in 50 of dimethyl formamide is treated at room temperature with 375 mg (2.5 mM) of N-chloromethyl-N-methylurethane for one hour. The mixture is carefully poured into ice water and the precipitated solid is removed by filtration and washed with water. The solid is dissolved in ethylacetate and washed with aqueous sodium bicarbonate and then with water. The organic layer is dried over magnesium sulfate filtered and evaporated to dryness in vacuo to give 3-[(acetyloxy)methyl]-7-amino-8oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid N-ethoxycarbonyl-N-methylaminomethyl ester.
Reaction SMILES: [C:1]([C:3]1[CH:17]=[CH:16][C:6]([CH2:7]P(=O)(OCC)OCC)=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].[CH:20]([C:22]1[C:31]([CH3:32])=[CH:30][C:29]2[C:28]([CH3:34])([CH3:33])[CH2:27][CH2:26][C:25]([CH3:36])([CH3:35])[C:24]=2[C:23]=1[O:37][CH3:38])=O.Cl>CS(C)=O.O>[CH3:38][O:37][C:23]1[C:24]2[C:25]([CH3:35])([CH3:36])[CH2:26][CH2:27][C:28]([CH3:34])([CH3:33])[C:29]=2[CH:30]=[C:31]([CH3:32])[C:22]=1/[CH:20]=[CH:7]/[C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:17][CH:16]=1
Reactant: COc1c(C=O)c(C)cc2c1C(C)(C)CCC2(C)C
Reactant: CCOP(=O)(Cc1ccc(C#N)cc1)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1c(/C=C/c2ccc(C#N)cc2)c(C)cc2c1C(C)(C)CCC2(C)C
Yield: 76.8 %

Procedure:
A solution of 25.2 g (0.1 mole) of diethyl 4-cyanobenzylphosphonate in 50 ml of dimethyl sulfoxide was added dropwise to a suspension of 3 g (0.1 mole) of sodium hydride (80% strength, freed beforehand from the 20% of paraffin using petroleum ether) in 100 ml of absolute dimethyl sulfoxide at from 25° to 40° C. The mixture was stirred for a further hour, after which a solution of 12 g (50 millimoles) of 2-formyl-5,6,7,8-tetrahydro-1-methoxy-3,5,5,8,8-pentamethylnaphthalene in 100 ml of dimethyl sulfoxide was added dropwise, and the mixture was stirred overnight at room temperature. Thereafter, the reaction mixture was poured onto 1.2 l of water and acidified with 2N hydrochloric acid, the resulting oily product was separated off and stirred with a little methanol, the crystals obtained were filtered off and the solid was washed on the filter with methanol and dried to give 13.8 g of the title compound of melting point 120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[C:16]([Cl:17])=[C:15]([O:18][CH:19]([F:21])[F:20])[N:14]([CH3:22])[N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:26])=O>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[C:16]([Cl:17])=[C:15]([O:18][CH:19]([F:21])[F:20])[N:14]([CH3:22])[N:13]=2)=[CH:7][C:3]=1[C:4]([Cl:26])=[O:5]
Reactant: Cn1nc(-c2cc(C(=O)O)c(Cl)cc2F)c(Cl)c1OC(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cn1nc(-c2cc(C(=O)Cl)c(Cl)cc2F)c(Cl)c1OC(F)F
Reaction time: 0.5 h

Procedure:
A solution of 8 g (22 mmol) of 2-chloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-4-fluorobenzoic acid in 100 ml of toluene was treated with 1 drop of dimethylformamide and 8.6 g (67 mmol) of oxalyl chloride. After the mixture had been stirred for 30 minutes at reflux temperature, it was cooled and concentrated. Yield: quantitative.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1.[Mn]([O-])(=O)(=O)=[O:12].[K+]>ClCCl.[O-2].[O-2].[Mn+4]>[C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: c1ccc2c(c1)CCOC2
Agent: [Mn+4]
Agent: [K+]
Agent: [O-2]
Solvent: ClCCl
Product: O=C1OCCc2ccccc21
Reaction time: 18 h
Yield: 80 %

Procedure:
To a solution of isochroman (5.0 g; 37.3 mmol) in dichloromethane (465 ml) stirred at room temperature was added, over 15 minutes, a homogeneous mixture of potassium permanganate and manganese dioxide (74.60 g) in a 1:3 ratio. The suspension obtained was left for 18 hours at room temperature. The suspension was filtered through a Büchner filter. The solvent was evaporated off under reduced pressure to give 4.42 g of crude product (80%), which was used for the following reaction without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)#[N:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH:55]1[CH2:60][CH2:59][CH:58]([C:61]2[C:69]3[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=3)[NH:63][CH:62]=2)[CH2:57][CH2:56]1>CN(C=O)C>[NH:63]1[C:64]2[C:69](=[CH:68][CH:67]=[CH:66][CH:65]=2)[C:61]([CH:58]2[CH2:59][CH2:60][N:55]([C:6]([C:5]3[CH:4]=[C:3]([CH:11]=[CH:10][CH:9]=3)[C:1]#[N:2])=[O:8])[CH2:56][CH2:57]2)=[CH:62]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: N#Cc1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccc(C(=O)N2CCC(c3c[nH]c4ccccc34)CC2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
3-Cyano-benzoic acid (0.09 g, 0.6 mmol) is dissolved in 3 ml of DMF, then HBTU (0.28 g, 0.75 mmol), HOBt (0.10 g, 0.75 mmol) and DIPEA (0.26 g, 2.0 mmol) are added. The mixture is stirred at RT for 20 min before adding the 3-piperidin-4-yl-1H-indole (0.09 g, 0.6 mmol). The reaction was stirred at RT for 3 hours, monitored with LC/MS. The organic solvent is removed under the reduced pressure and the residue is purified by a silica gel flash column using heptane and ethyl acetate as the elutes.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[CH:6][CH:7]=1.[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([S:16](Cl)(=[O:18])=[O:17])=[N:14][CH:15]=1>>[C:2]1([CH3:1])[CH:7]=[CH:6][C:5]([NH:8][S:16]([C:13]2[CH:12]=[CH:11][C:10]([CH3:9])=[CH:15][N:14]=2)(=[O:18])=[O:17])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)nc1
Reactant: Cc1ccc(N)cc1
Product: Cc1ccc(NS(=O)(=O)c2ccc(C)cn2)cc1

Procedure:
prepared by reaction of p-tolylamine with 5-methyl-pyridine-2-sulfonyl chloride
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[CH2:8][CH2:9][C:10]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[CH2:17][CH2:16][CH2:15]2)=[O:11].[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=1)=[O:24]>>[CH2:17]1[C:18]2[C:14](=[CH:13][C:12]([C:10](=[O:11])[CH2:9][CH2:8][N:35]3[CH2:36][CH2:37][CH:32]([C:28]4[CH:27]=[C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:38])[CH:31]=[CH:30][CH:29]=4)[CH2:33][CH2:34]3)=[CH:20][CH:19]=2)[CH2:15][CH2:16]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCl)c1ccc2c(c1)CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(=O)c3ccc4c(c3)CCC4)CC2)c1

Procedure:
Procedure K (KI) and Scheme E (K2CO3) using 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)-1-propanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 419.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH3:12][N:13]1[CH:17]=[CH:16][N:15]=[C:14]1[SH:18]>>[CH3:12][N:13]1[CH:17]=[CH:16][N:15]=[C:14]1[S:18][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[Cl:1]
Reactant: Cn1ccnc1S
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Product: Cn1ccnc1Sc1ccc([N+](=O)[O-])cc1Cl
Yield: 87 %

Procedure:
Using an analogous procedure to that described in the first paragraph of the portion of Example 8 which is concerned with the preparation of starting materials, 3-chloro-4-fluoronitrobenzene was reacted with 1-methyl-2-imidazolethiol to give 2-chloro-4-nitrophenyl 1-methylimidazol-2-yl sulphide in 87% yield.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:22]([C:26]1[N:27]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=3[S:55](=[O:58])(=[O:57])[NH2:56])=[CH:45][CH:44]=2)[C:28](=[O:41])[N:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]([F:40])([F:39])[F:38])[N:30]=1)[CH2:23][CH2:24][CH3:25].N12CCCN=C1CCCCC2>C1COCC1>[C:1]([NH:56][S:55]([C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=1[C:46]1[CH:47]=[CH:48][C:43]([CH2:42][N:27]2[C:26]([CH2:22][CH2:23][CH2:24][CH3:25])=[N:30][N:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]([F:40])([F:38])[F:39])[C:28]2=[O:41])=[CH:44][CH:45]=1)(=[O:58])=[O:57])(=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1
Reactant: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2)cc1
Temperature: 55 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
A solution of 145 mg (1.18 mmole) of benzoic acid and 192 mg (1.18 mmole) of 1,1'-carbonyldiimidazole in 1 mL of THF was stirred under N2 at 55° C. for 2 hours. Then a solution of 157 mg (0.296 mmole) of 5-n-butyl-2,4-dihydro-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Example 16, Step C) and 133 mL (135 mg, 0.888 mmole) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in 1 mL of THF was added dropwise. After being stirred overnight at 55° C., the mixture was partitioned between ethyl acetate and 5% citric acid (aqueous). The organic layer was washed with H2O and then with saturated NaCl solution. The ethyl acetate phase was then dried over Na2SO4, filtered, and concentrated in vacuo. Flash chromatography of the residue as in Example 16, Step D, gave 159 mg (85%) of the title compound, homogeneous by TLC in 98:2 CH2Cl2 --MeOH and comparable in physical properties to the product made according to Example 16, Step D.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12](F)[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([NH:25][CH3:26])[CH:22]([CH3:24])[CH3:23]>CS(C)=O>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([N:25]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH3:26])[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(C#N)cc1[N+](=O)[O-]
Reactant: CNCC(C)C
Solvent: CS(C)=O
Product: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C#N

Procedure:
The title compound was prepared from (4-cyano-5-fluoro-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example B9) (1.95 g, 6.93 mmol) and N-isobutyl-N-methylamine (3.02 g, 34.7 mmol) in DMSO (20 mL) at RT according to the general procedure C. Obtained as a yellow solid (1.87 g, 77%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[C:15]([O-])(O)=O.[Na+]>CO>[OH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([O:9][CH3:15])=[O:8]
Reactant: O=C(O)c1cncc(O)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cncc(O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 5-hydroxynicotinic acid (10 g, 71.9 mmol) in MeOH (100 mL) was added sulfurous dichloride (1 mL) drop wise over 5 min. The resulting mixture was stirred at room temperature overnight. The resulted solution was added 100 mL of NaHCO3. The precipitate was filtrated and washed with MeOH for several cycles to give 8.5 g of A031-2 (75% yields), which was used for the nest step without further purification.