Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:12][NH2:13])=[N:9]2)=[CH:4][CH:3]=1.[CH:14](OCC)(OCC)OCC>C(OCC)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]3[N:9]2[CH:14]=[N:13][N:12]=3)=[CH:4][CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: NNc1cnc2ccc(Br)cc2n1
Solvent: CCOCC
Product: Brc1ccc2ncc3nncn3c2c1
Temperature: 25 °C

Procedure:
The solution of 7-bromo-2-hydrazinylquinoxaline (200 mg, 0.83 mmol) in triethyl orthoformate (3 mL) was heated to 100° C. for 4 h; after cooling to r.t., the mixture was diluted with ethyl ether, and the precipitate was collected by filtration and dried in vacuo to afford the title product 8-bromo-[1,2,4]triazolo[4,3-a]quinoxaline as yellow solid in 87% yield (180 mg). m/z 251 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][C:7]1[CH:8]=[C:9]([CH2:19][C@H:20]([NH:36]C(OC(C)(C)C)=O)[C:21]([O:23][C@H:24]([CH3:35])[CH2:25][O:26][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:28])=[O:22])[CH:10]=[CH:11][C:12]=1[O:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:5])[CH3:2].[ClH:44]>O1CCOCC1>[ClH:44].[NH2:36][C@@H:20]([CH2:19][C:9]1[CH:10]=[CH:11][C:12]([O:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:7]([O:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:8]=1)[C:21]([O:23][C@H:24]([CH3:35])[CH2:25][O:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28])=[O:22]
Reactant: CCOC(=O)Oc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@H](C)COC(=O)c2ccccc2)cc1OC(=O)OCC
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)Oc1ccc(C[C@H](N)C(=O)O[C@H](C)COC(=O)c2ccccc2)cc1OC(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
(1R)-1-Methyl-2-phenylcarbonyloxyethyl (2S)-3-[3,4-bis(ethoxycarbonyloxy)phenyl]-2-[(tert-butoxy)carbonylamino]propanoate (7) (1.6 g, 2.65 mmol) was dissolved in 10 mL of 4M HCl in dioxane. The reaction mixture was stirred at room temperature for 60 min. Dioxane was completely evaporated under reduced pressure. The resulting white solid was dissolved in water (15 mL) and washed with methyl tert-butyl ether. The aqueous phase was collected and mixed with acetonitrile (10 mL). Lyophilization gave the title compound (6) (1.4 g, 100% yield) as a white solid. 1H NMR (400 MHz, CD3OD): δ 1.31 (3H, d, J=6.8 Hz), 1.35 (6H, t, J=6.8 Hz), 3.23 (1H, d, J=3.2 Hz), 3.25 (1H, d, J=4 Hz), 4.28 (4H, q, 6.8 Hz), 4.31 (1H, dd, J=14, 5.6 Hz), 4.38 (1H, t, J=7.2 Hz), 4.49 (1H, dd, J=12, 3.2 Hz), 5.35 (1H, m), 7.24 (1H, d, J=2 Hz), 7.27 (1H, d, J=8 Hz), 7.28 (1H, d, J=2 Hz), 7.48 (2H, t, J=7.2 Hz), 7.61 (1H, t, J=7.2 Hz), 8.02 (2H, d, J=7.6 Hz). MS (ESI) m/z 504.16 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1C=O.[C:17]([OH:22])(=[O:21])[C:18]([CH3:20])=O.[OH-].[Na+].[CH3:25]O>>[CH3:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]2[C:9]3[C:2](=[CH:3][CH:6]=[CH:7][CH:25]=3)[N:1]=[C:18]([C:17]([OH:22])=[O:21])[CH:20]=2)=[CH:15][CH:14]=1
Reactant: Cc1ccc(-c2ccc(C=O)c(N)c2)cc1
Reactant: CC(=O)C(=O)O
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(-c2cc(C(=O)O)nc3ccccc23)cc1
Temperature: 55 °C
Reaction time: 9 h

Procedure:
Into a solution of 2-amino-4-(4-methylphenyl)benzaldehyde (0.23 g) and pyruvic acid (192 mg) in methanol (20 ml) was added a solution of sodium hydroxide (349 mg)/methanol (20 ml), and the resulting mixture was stirred at 50-60° C. for 9 hours and was then concentrated. The concentrate was extracted with water, and the aqueous layer was washed twice with diethyl ether and was then mixed with 1 N hydrochloric acid to adjust the pH to 1-2. The resulting mixture was extracted with ethyl acetate, and the extract was washed with an aqueous solution of sodium chloride. The extract was dried (anhydrous magnesium sulfate) and was then concentrated. The residue was subjected to purification using silica gel column chromatography (ethyl acetate/methanol=4/1) to obtain 4-(4-methylphenyl)quinoline-2-carboxylic acid (117 mg) as an orange powder.
Reaction SMILES: CO[C:3](=O)[CH2:4][S:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[CH:11][CH:10]=1)=[O:8]>C(O)CC>[CH2:4]([S:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[CH:11][CH:10]=1)=[O:8])[CH3:3]
Reactant: COC(=O)CSCC(=O)c1ccc(-c2ccccc2F)cc1
Solvent: CCCO
Product: CCSCC(=O)c1ccc(-c2ccccc2F)cc1

Procedure:
[2-(2'-Fluoro-4-biphenylyl)-2-oxo-ethylthio]acetic acid methyl ester, m.p. 80°-82° C (from n-propanol).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:37])[C@H:6]([CH2:33][CH:34]([CH3:36])[CH3:35])[NH:7][C:8]1[O:12][N:11]=[C:10]([CH3:13])[C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)=[CH:16][CH:15]=1)#[N:2].C([O-])(O)=O.[Na+]>C1COCC1>[C:1]([CH2:3][NH:4][C:5](=[O:37])[C@H:6]([CH2:33][CH:34]([CH3:35])[CH3:36])[NH:7][C:8]1[O:12][N:11]=[C:10]([CH3:13])[C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:18][CH:19]=1)#[N:2]
Reactant: Cc1noc(N[C@@H](CC(C)C)C(=O)NCC#N)c1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(N[C@@H](CC(C)C)C(=O)NCC#N)c1-c1ccc(N2CCNCC2)cc1
Reaction time: 8 h

Procedure:
To N1-(cyanomethyl)-N2-(4-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}-3-methylisoxazol-5-yl)leucinamide (210 mg, 0.411 mmol) in dry THF (0.5 mL) under dry nitrogen was gradually added a total of 5 equivalents of MesO3H (100 μL, 1.37 mmol) over a period of 3 hours in portions of 1–2 equivalents at a time and the reaction mixture was stirred overnight. Aqueous sat. NaHCO3 was added carefully and the product was extracted with EtOAc (2×), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (NH4OH/MeOH/CH2Cl2, 1/9/90) to afford N-(cyanomethyl)-N2-[3-methyl-4-(4-piperazin-1-ylphenyl)isoxazol-5-yl]leucinamide. MS (−ESI): 409.7 [M−1]−.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:10])=[C:4]([C:7]([O-:9])=[O:8])[S:5][CH:6]=1.[CH3:11][N-:12][CH3:13].[CH3:14][O:15][C:16]1[C:17](=O)[C:18](=[O:22])[C:19]=1[O:20]C>CO>[OH:10][C:3]1[C:2]([NH:1][C:17]2[C:18](=[O:22])[C:19](=[O:20])[C:16]=2[O:15][CH3:14])=[CH:6][S:5][C:4]=1[C:7]([O-:9])=[O:8].[CH3:11][N-:12][CH3:13]
Reactant: COc1c(OC)c(=O)c1=O
Reactant: Nc1csc(C(=O)[O-])c1O
Agent: C[N-]C
Solvent: CO
Product: COc1c(Nc2csc(C(=O)[O-])c2O)c(=O)c1=O
Temperature: 50 °C
Yield: 84.6 %

Procedure:
A mixture of 5.20 g (27.92 mmol, 1.0 eq) of dimethylamide 4-amino-3-hydroxythiophene-2-carboxylate and 5.95 g (41.88 mmol, 1.5 eq) of 3,4-dimethoxy-3-cyclobutene-1,2-dione in 52 ml of methanol was heated at 50° C. for 16 hours. The insoluble material was filtered off and oven-dried under vacuum at 45° C. 7.38 g of dimethylamide 3-hydroxy-4-(2-methoxy-3,4-dioxocyclobut-1-enylamino)thiophene-2-carboxylate were obtained. Yield=89%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([N:15]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:16]4=[O:23])[S:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:24]=1.C(N(CC)CC)C>C(O)C.[Pd]>[N:12]1[C:11]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:24][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[S:14][C:13]=1[N:15]1[C:19]([CH3:20])([CH3:21])[C:18](=[O:22])[NH:17][C:16]1=[O:23]
Reactant: CC1(C)C(=O)NC(=O)N1c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC1(C)C(=O)NC(=O)N1c1nc2c(s1)CCOc1ccccc1-2

Procedure:
A mixture of 49 mg (0.12 mmol) of 1-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-5,5-dimethylimidazolidin-2,4-dione from Example 485, and 0.0334 ml (0.24 mmol) of triethylamine in 5 ml of ethanol was hydrogenated over 120 mg of 10% palladium on charcoal at 1 atm for 3 hours. The mixture was filtered through celite and concentrated in vacuum. The residue was purified on 4 g siligal column eluting the product with ethyl acetate gradient in heptane to give 493. Yield 20 mg (51%). MS(ESI+): 330.1
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:23][CH2:24][P:25]([O:35][CH3:36])([O:27][C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)=[O:26])[C:13]([O:15]CC1C=CC=CC=1)=[O:14])=O)C1C=CC=CC=1.[H][H]>CO.O.[C].[Pd]>[NH2:11][CH:12]([CH2:23][CH2:24][P:25]([O:35][CH3:36])([O:27][C:28]1[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=1)=[O:26])[C:13]([OH:15])=[O:14]
Reactant: COP(=O)(CCC(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)Oc1ccc(C)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COP(=O)(CCC(N)C(=O)O)Oc1ccc(C)cc1
Yield: 50.8 %

Procedure:
Next, 0.70 g (1.37 mmol) of benzyl 2-(N-benzyloxycarbonylamino)-4-[methyl(4-methylphenyl)phosphono]butanoate was dissolved in 30 mL of a solvent mixture of methanol and water at 2:1 and mixed with 270 mg of 5% palladium-carbon and hydrogen gas was introduced for 2 hours. The palladium-carbon was removed by Celite filtration and the filtrate was concentrated under a reduced pressure. The residue was purified by medium pressure reversed-phase column chromatography ODS-S-50B (Yamazen Co., Ltd., Osaka). The column was eluted with a linear gradient of 30 to 60% methanol (6 mL/min flow rate) and the fractions of the compound eluted with 60% methanol were collected. After the elution and purity of the compound were confirmed by TLC (BuOH/AcOH/H2O=5:2:2, ninhydrin coloration), vacuum concentration and freeze drying were carried out to obtain 2-amino-4-[methyl(4-methylphenyl)phosphono]butanoic acid (0.20 g, yield 51%) as a colorless solid.
Reaction SMILES: [H][H].[CH3:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C:12]3[C:24]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[C:17](=[N:25]O)[C:16]=4[CH:15]=[CH:14][CH:13]=3)[NH:9][C:8]=2[CH:27]=1>C(O)C.O1CCCC1.[Ni]>[CH3:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C:12]3[C:24]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[CH:17]([NH2:25])[C:16]=4[CH:15]=[CH:14][CH:13]=3)[NH:9][C:8]=2[CH:27]=1
Reactant: [H][H]
Reactant: Cc1ccc2nc(-c3cccc4c3-c3ccccc3C4=NO)[nH]c2c1
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc2nc(-c3cccc4c3-c3ccccc3C4N)[nH]c2c1
Temperature: 60 °C
Yield: 75.2 %

Procedure:
The procedure used in Example 6 is followed. In a 100 ml autoclave, dissolve 1 g of 4-(6-methyl-1H-benzimidazol-2-yl)-9H-fluoren -9-one oxime (Z,E), obtained in the previous stage, in a mixture of 40 ml of ethanol and 40 ml of tetrahydrofuran, add a spatula of Raney activated nickel and then subject to an initial hydrogen pressure of 1 bar and heat the autoclave at 60° C. for 3 hours. After cooling, the volume of hydrogen absorbed is 142 ml. After filtration of the catalyst over Celite, the filtrate is concentrated under reduced pressure and then taken up in petroleum ether and filtered. In this way, we obtain 720 mg of 4-(6-methyl-1H-benzimidazol-2-yl)-9H-fluorene-9(R,S)-amine, in the form of a beige solid, which is used as it is in the following stage, with the following characteristic:
Reaction SMILES: [H][H].[C:3]1([C:9]#[C:10][CH2:11][OH:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1COCC1>[C:3]1([CH2:9][CH2:10][CH2:11][OH:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: OCC#Cc1ccccc1
Solvent: C1CCOC1
Product: OCCCc1ccccc1
Reaction time: 0.08 h
Yield: 100 %

Procedure:
In Example 6, hydrogenation reaction was conducted under the same condition as Example 1 for THF diluted solution concentration of the substance to be reduced, its flow rate, and hydrogen 9 flow rate, using 3-phenyl-2-propin-1-ol as the substance to be reduced. The reaction time was within five minutes. The analytical result of the reaction product by 1H-NMR showed almost complete hydrogenation of 3-phenyl-2-propin-1-ol, and 3-phenyl-1-propanol was obtained at about 100% yield (See FIG. 6.).
Reaction SMILES: C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[CH:28]1([C:31]2[C:32]([O:41][CH:42]3[CH2:47][CH2:46][C:45]([F:49])([F:48])[CH2:44][CH2:43]3)=[CH:33][C:34]([F:40])=[C:35]([CH:39]=2)[C:36](O)=[O:37])[CH2:30][CH2:29]1.CS(N)(=O)=O.[CH:55]1([S:58]([NH2:61])(=[O:60])=[O:59])[CH2:57][CH2:56]1>>[CH:28]1([C:31]2[C:32]([O:41][CH:42]3[CH2:47][CH2:46][C:45]([F:49])([F:48])[CH2:44][CH2:43]3)=[CH:33][C:34]([F:40])=[C:35]([CH:39]=2)[C:36]([NH:61][S:58]([CH:55]2[CH2:57][CH2:56]2)(=[O:60])=[O:59])=[O:37])[CH2:30][CH2:29]1
Reactant: NS(=O)(=O)C1CC1
Reactant: O=C(O)c1cc(C2CC2)c(OC2CCC(F)(F)CC2)cc1F
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: O=C(NS(=O)(=O)C1CC1)c1cc(C2CC2)c(OC2CCC(F)(F)CC2)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-cyclopropyl-4-((4,4-difluorocyclohexyl)oxy)-2-fluorobenzoic acid and to replace methanesulfonamide with cyclopropanesulfonamide, the title compound was obtained as a colorless solid (0.093 g, 48%): 1H NMR (300 MHz, DMSO-d6) δ 11.79 (br s, 1H), 7.13-7.06 (m, 2H), 4.78 (br s, 1H), 3.08-2.99 (m, 1H), 2.08-1.86 (m, 9H), 1.09-1.06 (m, 4H), 0.88-0.82 (m, 2H), 0.66-0.60 (m, 2H); 19F NMR (282 MHz, DMSO-d6) δ −92.1 (d, J=231 Hz, 1F), −98.5 (d, J=231 Hz, 1F), −112.5 (s, 1F); MS (ES−) m/z 416.10 (M−1).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.Cl.[NH2:15][OH:16].C(=O)(O)[O-].[Na+]>CO>[OH:16][N:15]=[C:6]([NH2:7])[C:5]1[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][C:4]=1[C:10]([F:13])([F:11])[F:12]
Reactant: Cc1ccc(C#N)c(C(F)(F)F)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(C(N)=NO)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
An oven-dried 20 mL reaction vial containing a stir bar was cooled under a stream of dry nitrogen. The vial was charged with 4-methyl-2-(trifluoromethyl)benzonitrile (1000 mg, 5.40 mmol), hydroxylamine hydrochloride (469 mg, 6.75 mmol), sodium bicarbonate (681 mg, 8.10 mmol), and methanol (6 mL). The vial was flushed with nitrogen, sealed, stirred at room temperature for 30 minutes, and then placed in a sand bath set to 75° C. and stirred overnight. The crude reaction material was purified by reverse phase preparative HPLC. The collected product fractions were evaporated under vacuum to afford N′-hydroxy-4-methyl-2-(trifluoromethyl)benzimidamide (0.54 g, 2.45 mmol, 45% yield). MS M+1=219.0.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1.Cl[CH2:14][C:15]([OH:17])=[O:16]>CN(C=O)C>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][O:12][CH2:14][C:15]([OH:17])=[O:16])=[CH:6][CH:5]=1
Reactant: O=C(O)CCl
Reactant: OCCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)COCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a suspension of NaH (9.6 g, 0.4 mol) in DMF (100 mL), a solution of 2-(4-bromophenyl)ethanol (20.1 g, 0.1 mol; see step (i) above) in DMF (100 mL) was added, at 0° C. The resulting mixture was then stirred for 45 minutes at room temperature. After cooling the reaction mixture to 0° C., a solution of chloroacetic acid (9.4 g, 0.1 mol) in DMF (50 mL) was added, and the resulting mixture was stirred at 55 to 60° C. for 3 h. The reaction was quenched by adding cold (about 0° C.) water and then acidification to pH 2.0 (by addition of 1.5 N HCl). The mixture was extracted with ethyl acetate (5×200 mL) and the combined organic layers were washed with water and brine. The sub-title compound was isolated as pale brown solid after evaporation (yield: 14 g, 54%).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[O:38][C:39]2[C:45]([CH2:46][CH2:47][NH:48][C:49](=[O:51])[CH3:50])=[CH:44][CH:43]=[CH:42][C:40]=2[CH:41]=1>>[C:49]([NH:48][CH2:47][CH2:46][C:45]1[C:39]2[O:38][C:37]([CH2:36][O:1][CH:2]3[CH:7]([C:8]4[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[O:26][CH3:27])=[CH:10][CH:9]=4)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]3)=[CH:41][C:40]=2[CH:42]=[CH:43][CH:44]=1)(=[O:51])[CH3:50]
Reactant: CC(=O)NCCc1cccc2cc(CCl)oc12
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cc3cccc(CCNC(C)=O)c3o2)cc1

Procedure:
Analogously to Method D, 1.18 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 0.64 g of N-[2-(2-chloromethylbenzofuran-7-yl)ethyl]acetamide are reacted. The title compound is obtained as a yellow oil. Rf=0.12 (3:1 EtOAc-heptane); Rt=5.65.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:43])/[CH:4]=[CH:5]/[C:6]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:13]=2[N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[N:8](CC2C=CC(OC)=CC=2)[N:7]=1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:52]>>[ClH:52].[C:28]1([C:12]2[C:13]([N:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]3)=[C:14]3[C:6](/[CH:5]=[CH:4]/[C:3]([O:2][CH3:1])=[O:43])=[N:7][NH:8][C:9]3=[N:10][CH:11]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: ClCCl
Reactant: COC(=O)/C=C/c1nn(Cc2ccc(OC)cc2)c2ncc(-c3ccccc3)c(N3CCN(C(=O)OC(C)(C)C)CC3)c12
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)/C=C/c1n[nH]c2ncc(-c3ccccc3)c(N3CCNCC3)c12
Product: Cl
Temperature: 60 °C
Yield: 106 %

Procedure:
A solution of (E)-tert-butyl 4-(3-(3-methoxy-3-oxoprop-1-enyl)-1-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (380 mg, 0.65 mmol) in 25% TFA/CH2Cl2 was stirred at room temperature. Next, the solvent was removed, and the residue was evaporated from toluene (2×30 mL). Neat TFA (10 mL) was added to the resulting residue and heated at 60° C. for 4 hours. TFA was removed in vacuo, and the residue was evaporated from toluene (2×10 mL). 2M HCl in ether (5 mL) was added to the residue, and the mixture was sonicated for a few minutes. The solid formed was filtered, washed with ether (3×10 mL) and dried under high vacuum for 6 hours to provide (E)-methyl 3-(5-phenyl-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acrylate hydrochloride salt (300 mg, 106% yield) as a solid. LCMS (APCI+) m/z 364.1 (M+H)+, Retention time=2.61 minutes.
Reaction SMILES: C[O:2][C:3](=[O:42])[CH:4]=[C:5]([C:7]1[N:8]([S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)(=[O:35])=[O:34])[C:9]2[C:14]([CH:15]=1)=[C:13]([C:16]1[CH:21]=[C:20]([CH:22]([CH3:24])[CH3:23])[CH:19]=[C:18]([CH:25]([CH3:27])[CH3:26])[C:17]=1[O:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:12]=[CH:11][CH:10]=2)[CH3:6].[OH-].[Na+]>CO.O1CCOCC1.Cl.O>[C:36]1([S:33]([N:8]2[C:9]3[C:14](=[C:13]([C:16]4[CH:21]=[C:20]([CH:22]([CH3:23])[CH3:24])[CH:19]=[C:18]([CH:25]([CH3:26])[CH3:27])[C:17]=4[O:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:12]=[CH:11][CH:10]=3)[CH:15]=[C:7]2[C:5]([CH3:6])=[CH:4][C:3]([OH:42])=[O:2])(=[O:34])=[O:35])[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CCCCOc1c(-c2cccc3c2cc(C(C)=CC(=O)OC)n3S(=O)(=O)c2ccccc2)cc(C(C)C)cc1C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: CCCCOc1c(-c2cccc3c2cc(C(C)=CC(=O)O)n3S(=O)(=O)c2ccccc2)cc(C(C)C)cc1C(C)C
Yield: 107.9 %

Procedure:
3-[1-Benzenesulfonyl-4-(2-butoxy-3,5-diisopropyl-phenyl)-1H-indol-2-yl]-but-2-enoic acid methyl ester (74 mg, 0.126 mmol) was dissolved in methanol (1 mL)/dioxane (1 mL) and treated with 1N NaOH (1 mL, 1 mmol) at 60° C. for 2 h. The reaction was diluted with 1N HCl (3 mL)/water (10 mL) and extracted with ethyl acetate (3×10 mL). The organic portions were washed with water (10 mL), brine (10 mL), dried (MgSO4), filtered and evaporated in vacuo to provide 78 mg of a yellow oil. The material was purified using radial chromotagraphy with a gradient of hexane/ethyl acetate to provide 42 mg (58%) of a yellow amorphous foam. 1H NMR (250 MHz, CDCl3): δ 8.08 (d, 1H, 8.2),7.58 (m, 2H), 7.42-7.21 (m, 5H), 7.03 (d, 1H, J=2.2), 6.82 (d, 1H, J=2.2), 6.49 (s, 1H), 6.00 (bs, 1H), 3.28 (sep, 1H, J=6.9), 2.96 (t, 2H, J=6.0), 2.81 (sep, 1H, J=6.9), 1.18 (d 6H, J=6.9), 1.17 (d, 6H, J=6.9). MS [EI+] 574, (M+H)+, [EI−] 572 (M−H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[NH2:12][C:13](N)=[O:14]>O>[Br:8][C:6]1[CH:5]=[N:4][C:3]2[C:9]([OH:11])=[N:12][C:13]([OH:14])=[N:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Br)cnc1C(=O)O
Reactant: NC(N)=O
Solvent: O
Product: Oc1nc(O)c2ncc(Br)cc2n1
Temperature: 200 °C
Reaction time: 2.5 h
Yield: 89.8 %

Procedure:
To a 100 mL round bottom flask, 3-amino-5-bromo-pyridine-2-carboxylic acid (1 g, 0.0046 mol) and urea (2.768 g, 0.4629 mol) were added. The reaction mixture was stirred at 200° C. for 2.5 h. The reaction mixture was cooled, water was added and stirred to provide a precipitate. The precipitate was filtered and dried to provide the title compound [1 g, 91%]. This material was taken to the next step without any further purification.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([F:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[CH:3]=1.S(C1C=CC(C)=CC=1)(O)(=O)=O.CNC.[C:35]([S:39](Cl)=[O:40])([F:38])([F:37])[F:36]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([F:13])=[CH:11][C:10]([C:14]([F:16])([F:15])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:39]([C:35]([F:38])([F:37])[F:36])=[O:40]
Reactant: O=S(Cl)C(F)(F)F
Reactant: N#Cc1cc(N)n(-c2c(F)cc(C(F)(F)F)cc2Cl)n1
Agent: CNC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: N#Cc1nn(-c2c(F)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)C(F)(F)F
Temperature: 40 °C
Reaction time: 16 h
Yield: 64.6 %

Procedure:
To a solution of 5-amino-1-(2-chloro-6-fluoro-4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carbonitrile (140 g, 459.6 mmol, 1.00 eq.) and dimethylamine tosylate (151.8 g, 698.6 mmol, 1.52 eq.) in toluene (840 mL) was added CF3SOCl (89.7 g, 588.3 mmol, 1.28 eq.). After the mixture was stirred at 40° C. for 16 h, nitrogen was bubbled through the solution and the solution was cooled to rt. Then the mixture was poured into 2 L ice/water and stirred at 0° C. for 1 h. The precipitated solid was isolated by filtration and dried under vacuum. The solid was recrystallized with toluene to give 5-amino-1-(2-chloro-6-fluoro-4-(trifluoromethyl)phenyl)-4-(trifluoromethylsulfinyl)-1H-pyrazole-3-carbonitrile (125 g, 64%) as yellow solid.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([NH2:13])=[O:12])=[CH:4][C:3]=2[O:2]1.[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1>C(=O)([O-])[O-].[Na+].[Na+]>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]2[C:6]3[C:5](=[CH:4][C:3]4[O:2][CH2:1][O:9][C:8]=4[CH:7]=3)[CH2:10][C:11](=[O:12])[NH:13]2)=[CH:17][CH:16]=1
Reactant: NC(=O)Cc1ccc2c(c1)OCO2
Reactant: O=Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C1Cc2cc3c(cc2C(c2ccc(Cl)cc2)N1)OCO3
Temperature: 100 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
A flask containing polyphosphoric ester (90 g) was held at 100° C. (oil bath temperature). A mixture of 3,4-methylenedioxyphenylacetamide (22 g, 123 mmol) and parachlorobenzaldehyde (17.1 g, 122 mmol) was added in three portions over half an hour, with stirring. The solution (dark red) was heated at 100° C. for 5 h and poured onto ice (400 ml). A 10% solution (aqueous) of sodium carbonate (2 liters) was added and the mixture was left overnight. The resulting oily gum was extracted with chloroform (2×500 ml) and the chloroform extracts washed with brine (50 ml) and dried over sodium sulphate. The chloroform solution was filtered and the solvent was removed under reduced pressure. The solid so formed was triturated with ethanol (2×30 ml) to give 1-(4-chlorophenyl)-6,7-methylenedioxy-1,4-dihydroisoquinol-3-one (7 g). The combined ethanol layers were evaporated under reduced pressure and the residue chromatographed (Silica gel (300 g), chloroform as eluent) to give a further 8 g of product. Total yield (15 g, 41%), m.p. 200°-202° C. (ethanol).