Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC(S[CH:8]2[S:14][C:12](=[O:13])[NH:11][C:9]2=[O:10])=CC=1.C[C:16]1[CH:21]=[CH:20][CH:19]=[C:18](SC2SC(=O)NC2=O)[CH:17]=1.O[O:31][S:32]([O-:34])=O.[K+]>CO.O>[C:16]1([S:32]([CH:8]2[S:14][C:12](=[O:13])[NH:11][C:9]2=[O:10])(=[O:34])=[O:31])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1NC(=O)C(Sc2ccccc2)S1
Reactant: Cc1cccc(SC2SC(=O)NC2=O)c1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C1NC(=O)C(S(=O)(=O)c2ccccc2)S1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 73 %

Procedure:
A solution of 5-(benzenesulfanyl)-thiazolidine-2,4-dione, [(III), Example 6, 10.0 g, 41.8 mmol] in methanol (105 mL) was added to a mechanically stirred suspension of oxone (51.4 g, 83.6 mmol) in water (210 mL) at 0° C. The suspension was immediately warmed to room temperature. After 3.5 h, the reaction was diluted with water (1.5 L) and the solid was filtered. The solid was washed with water and dried in vacuo to provide the title compound as a white solid (8.31 g, 73%): mp 130°-133° C.: NMR (CDCL3): δ8.07 (s, 1H, NH), 7.98 (d, J=7.2 Hz, 2H, ArH) 7.78 (t, J=7.5 Hz, 1H, ArH), 7.67 (t, J=8.1 Hz, 2H, ArH), 5.44 (s, 1H CH); MS(EI): 225 (MI, 24%), 182 (18%), 153 (12%), 110 (100%).
Reaction SMILES: COP([O-])(OC)=O.[C:8]1([I+][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)C=CC=CC=1.[C:21]1(C)[CH:26]=[CH:25][C:24]([S:27]([OH:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1.N>C(Cl)Cl>[C:23]1([CH3:8])[C:24]([S:27]([O-:30])(=[O:28])=[O:29])=[CH:25][CH:26]=[CH:21][CH:22]=1.[C:15]1([S+:27]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:24]2[CH:23]=[CH:22][CH:21]=[CH:26][CH:25]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: c1ccc([I+]c2ccccc2)cc1
Agent: COP(=O)([O-])OC
Agent: N
Solvent: ClCCl
Product: Cc1ccccc1S(=O)(=O)[O-]
Product: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Yield: 98.5 %

Procedure:
Diphenyliodonium dimethylphosphate (315 mg; 1 mmol) and p-toluenesulfonic acid (189 mg; 1.1 mmol) were dissolved in methylene chloride (10 ml), and the mixture was stirred, followed by addition of 1% aqueous ammonia (10 ml). After the alkalinity of the solution was confirmed, the solution was stirred vigorously. The thus-obtained mixture was allowed to stand, and the aqueous layer was separated. The aqueous layer was washed with water successively until the aqueous layer exhibited neutral pH. The methylene chloride solution was dried, and the solvent was removed through distillation. The residue was washed in ether by stirring, to thereby precipitate 214 mg of the target compound as white crystals (yield: 84%).
Reaction SMILES: [CH:1]1CC[CH2:5][CH2:4][CH2:3][CH:2]=1.C[N+]1([O-])[CH2:14][CH2:13][O:12]CC1.[OH2:16]>C(#N)C.[Os](=O)(=O)(=O)=O>[C@@H:13]1([OH:12])[CH2:14][CH2:5][CH2:4][CH2:3][CH2:2][C@@H:1]1[OH:16]
Reactant: C1=CCCCCC1
Reactant: C[N+]1([O-])CCOCC1
Reactant: O
Agent: O=[Os](=O)(=O)=O
Solvent: CC#N
Product: O[C@@H]1CCCCC[C@@H]1O
Temperature: 45 °C
Reaction time: 21 h

Procedure:
Cycloheptene (3.85 g) was dissolved in acetonitrile (45 ml) and water (15 ml), and to the solution N-methylmorpholine N-oxide (5.15 g), microcapsulated osmium tetroxide (1 g, containing 10% osmium tetroxide) was added, and the mixture was stirred at 40 to 50° C. for 21 hours. Insoluble microcapsulated osmium tetroxide was removed by filtration, and the insoluble substance was washed with acetonitrile and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hexane:ethyl acetate=1:1) to obtain the title compound (4.77 g) as a colorless solid.
Reaction SMILES: C1(=O)[N:5]([C:6]#[C:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)C(=O)C2=CC=CC=C12.[H][H].O.NN>CO.[Pt]=O>[Cl:18][C:14]1[CH:13]=[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH2:5])[CH:17]=[CH:16][CH:15]=1
Reactant: [H][H]
Reactant: O=C1c2ccccc2C(=O)N1C#CCCCCc1cccc(Cl)c1
Agent: O=[Pt]
Agent: NN
Solvent: O
Solvent: CO
Product: NCCCCCCc1cccc(Cl)c1
Reaction time: 72 h

Procedure:
A suspension of 1-(phthalimido)-6-(3-chlorophenyl)hex-1-yne (10 g, 30 mmol) in methanol (100 ml) was treated with platinum oxide (250 mg) and the mixture hydrogenated at 50 psi for 72 h. Further quantities of catalyst were added at intervals and when the theoretical uptake of hydrogen was complete, the mixture was filtered and the filtrate evaporated to a brown oil (9.5 g, 96%). This was dissolved in ethanol (100 ml) and treated with hydrazine hydrate (2.8 g, 56 mmol) under reflux for 16 h. The mixture was cooled to 5°
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([CH:21]=O)=[CH:20][C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CO>C1COCC1.CCOC(C)=O>[F:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([CH2:21][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:20][C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5]
Reactant: C1COCCN1
Reactant: O=Cc1ccc2[nH]c(-c3n[nH]cc3NC(=O)c3c(F)cccc3F)nc2c1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)c1c(F)cccc1F
Temperature: 25 °C
Yield: 10.3 %

Procedure:
To a mixture of 2,6-difluoro-N-[3-(5-formyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (75.0 mg, 0.20 mmol) in anhydrous THF (5 ml) stirring at ambient temperature was successively added 3 Å molecular sieves, morpholine (35 μL, 0.40 mmol) and triacetoxy sodiumborohydride (127 mg, 0.60 mmol). The mixture was stirred for 4 h, MeOH (3 ml) added and then the mixture reduced in vacuo. The residue was taken up in EtOAc, washed with water and brine, dried (MgSO4), reduced in vacuo and then purified through preparative LC/MS to give 2,6-difluoro-N-[3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (9 mg, 10%) as a white solid. (LC/MS: Rt 1.90, [M+H]+ 439.09).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](/[N:8]=[CH:9]/N(C)C)=[N:6][CH:7]=1.Cl[CH2:14][C:15](=[O:17])[CH3:16].C([O-])(O)=O.[Na+]>CC(O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:14]([C:15](=[O:17])[CH3:16])=[CH:9][N:8]=2)[CH:7]=1
Reactant: CN(C)/C=N/c1ccc(Br)cn1
Reactant: CC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC(=O)c1cnc2ccc(Br)cn12
Yield: 47.5 %

Procedure:
(E)-N′-(5-Bromopyridin-2-yl)-N,N-dimethylformimidamide (2.0 g, 8.8 mmol), 1-chloropropan-2-one (1.2 mL, 1.4 g, 15 mmol), NaHCO3 (1.3 g, 15.5 mmol) in 2-propanol (30 mL) were heated at 90° C. under nitrogen for 12 h. The dark reaction mixture was cooled and the dense heterogeneous suspension was diluted with water. The solid was collected by filtration, washed with water and dried to obtain 1.0 g of 1-(6-bromoimidazo[1,2-a]pyridin-3-yl)ethan-1-one. 1H NMR (300 MHz, DMSO-d6) δ 9.62 (d, J=1.9 Hz, 1H), 8.61 (s, 1H), 7.81 (d, J=9.5 Hz, 1H), 7.75 (dd, J=9.5, 1.9 Hz, 1H), 2.55 (s, 3H). See Bioorg. Med. Chem. Lett. 15(1), 403-412 (2007); Int'l Pat. App. Pub, no. 2009/158011.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[C:11]=1[O:20]COC)=[O:9])([CH3:6])[CH3:5]>C(O)(C)C.O1CCCC1.Cl>[CH3:1][O:2][C:3](=[O:24])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[C:11]=1[OH:20])=[O:9])([CH3:6])[CH3:5]
Reactant: COCOc1c(C(=O)NC(C)(C)C(=O)OC)ccc2c1CCCC2
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)O
Product: COC(=O)C(C)(C)NC(=O)c1ccc2c(c1O)CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
1.023 g 2-[(1-methoxymethoxy-5,6,7,8-tetrahydro-naphthalene-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester was dissolved in a mixture of isopropanol (8 ml), tetrahydrofurane (8 ml) and HCl conc. (4 ml). It was stirred at room temperature for one hour. The mixture was concentrated in vacuo, then 20 ml of ethyl acetate and 30 ml of water were added to the residue. The organic layer was separated, dried over magnesium sulphate and concentrated in vacuo to afford 0.857 g of 2-[(1-hydroxy-5,6,7,8-tetrahydro-naphthalene-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:22]=[CH:21][C:8]2[N:9]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[S:11][C:7]=2[CH:6]=1)=[NH:4].[C:23](Cl)(=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)(=O)C>[CH:18]([N:15]1[CH2:14][CH2:13][N:12]([C:10]2[S:11][C:7]3[CH:6]=[C:5]([C:3]4[N:4]=[C:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[O:1][N:2]=4)[CH:22]=[CH:21][C:8]=3[N:9]=2)[CH2:17][CH2:16]1)([CH3:19])[CH3:20]
Reactant: CC(C)N1CCN(c2nc3ccc(C(=N)NO)cc3s2)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: CC(=O)O
Product: CC(C)N1CCN(c2nc3ccc(-c4noc(-c5ccccc5)n4)cc3s2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
To a solution of N-hydroxy-2-(4-isopropylpiperazin-1-yl)benzothiazole-6-carboxamidine (650 mg, 2.04 mmol) in acetic acid (40 mL) was added benzoylchloride (3 mL). The reaction mixture was stirred overnight at room temperature and then refluxed for 2 h. The reaction mixture was concentrated in vacuo and the residue was dissolved into 0.5 N hydrochloric acid (30 mL). The aqueous solution was extracted with diethyl ether (3×15 mL). The organic layer was discarded and the aqueous phase was basified to pH 13 with 4 N sodium hydroxide and then extracted with ethyl acetate (4×10 mL). The combined organic extracts were evaporated and the residue was recrystallized three times from a mixture of CH2Cl2 and MeOH to give 189 mg (26%) of 2-(4-isopropylpiperazin-1-yl)-6-(5-phenyl-[1,2,4]oxadiazol-3-yl)benzothiazole.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][NH:18][CH2:19][CH2:20][CH:21]=2)=[C:12]([OH:22])[CH:11]=1)([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:23](#N)C.C=O.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH3:9][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][N:18]([CH3:23])[CH2:19][CH2:20][CH:21]=2)=[C:12]([OH:22])[CH:11]=1)([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC#N
Reactant: CCCCCCC(C)(C)c1ccc(C2=CCCNC2)c(O)c1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCCCCC(C)(C)c1ccc(C2=CCCN(C)C2)c(O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 25° C. solution of 1.0 g. (3.32 mmoles) of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-1,2,5,6-tetrahydropyridine in 15 ml. of acetonitrile is added 1.32 ml. (17.6 mmoles) of 37% formaldehyde solution. After stirring for one hour the reaction is cooled to 0° C. and 332 mg. (5.3 mmole) of sodium cyanoborohydride added. The reaction mixture is allowed to warm to 25° C. over a one hour period while the pH is maintained at 7 by the addition of acetic acid. The reaction mixture is evaporated, made basic with 2N potassium hydroxide and extracted with 200 ml. of dichloromethane. The organic extract is dried over magnesium sulfate and evaporated. The residue is crystallized from ether-pentane to yield 350 mg. of the title compound.
Reaction SMILES: C(O)(=O)C.[CH3:5][CH2:6][CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:25]([C:26]4[N:30](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:29]=[N:28][N:27]=4)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[C:11]([C:50]([O:52][CH2:53][C:54]2[O:59][C:57](=[O:58])[O:56][C:55]=2[CH3:60])=[O:51])=[C:10]([C:61]([OH:64])([CH3:63])[CH3:62])[N:9]=1>CC(C)=O>[CH3:5][CH2:6][CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:18][CH:19]=2)[C:11]([C:50]([O:52][CH2:53][C:54]2[O:59][C:57](=[O:58])[O:56][C:55]=2[CH3:60])=[O:51])=[C:10]([C:61]([OH:64])([CH3:63])[CH3:62])[N:9]=1
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCc2oc(=O)oc2C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCc2oc(=O)oc2C)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
To 75% aqueous acetic acid (1000 ml) was slowly added trityl olmesartan medoxomil (110 gms) [prepared as described in example 5] at 25-30° C. The contents were stirred at 60° C. for 1 hour. The reaction mass was chilled to 0-5° C. and filtered to remove tritanol. The reaction mass was concentrated under reduced pressure. The residue was quenched with water (500 ml), neutralized with a base and extracted in dichloromethane (500 ml). The clear dichloromethane extract was then concentrated under reduced pressure and stripped off with acetone. The residue thus obtained was isolated from the acetone (250 ml) to give 55 gms of the title compound. Chromatographic purity->99%.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:43][CH3:44])=[C:10]([CH2:19][NH:20][C:21](=[O:42])[CH2:22][C:23]([NH:25][CH2:26][C:27]3[CH:28]=[C:29]([C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([CH:40]=O)[CH:35]=4)[C:30]([F:33])=[CH:31][CH:32]=3)=[O:24])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:45][C@H:46]1[CH2:51][NH:50][CH2:49][CH2:48][N:47]1C(OC(C)(C)C)=O.C(O)(=O)C>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:43][CH3:44])=[C:10]([CH2:19][NH:20][C:21](=[O:42])[CH2:22][C:23]([NH:25][CH2:26][C:27]3[CH:28]=[C:29]([C:34]4[CH:35]=[CH:36][CH:40]=[C:38]([CH2:37][N:50]5[CH2:49][CH2:48][NH:47][C@@H:46]([CH3:45])[CH2:51]5)[CH:39]=4)[C:30]([F:33])=[CH:31][CH:32]=3)=[O:24])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1ccc(F)c(-c2cccc(C=O)c2)c1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1ccc(F)c(-c2cccc(CN3CCN[C@@H](C)C3)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.7 %

Procedure:
N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-formyl-3-biphenylyl)methyl]propanediamide (36.0 mg, 0.06 mmol) was diluted in DMSO (1.5 mL) and dispensed into a 1 dram vial containing 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (0.18 mmol) and acetic acid (3.6 mg, 0.6 mmol) and fitted with a magnetic stir bar. The resulting solution was stirred at room temperature for 4 h. MP-B(OAc)3H (0.6 mmol, 140 mg) was added and the solution was stirred for another 12 h. The polymer reagent was filtered and to the filtrate was added MeOH (2.0 mL) and 1 drop of concentrated HCl. The solution was heated at 60° C. for 12 h. Purification was completed via reverse phase HPLC (acidic conditions) using a Gilson. The product was dissolved in 3 mL MeOH and went through a 0.5 g amine column (washed with 8 mL MeOH) to afford 16.3 mg of the title compound (38.9%). LC-MS m/z 700 (M+H)+, 0.66 min (ret time).
Reaction SMILES: FC(F)(F)[C:3]([OH:5])=[O:4].[CH3:8][CH:9]([CH3:40])[CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[N:14][CH:13]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[CH:33]=2)=[O:30])[C:12]1=[O:39].[CH3:41][C:42]1[CH:43]=C(N=C=O)C=C[CH:47]=1.CCOCC>O1CCCC1>[C:42]([O:5][C:3]([N:25]1[CH2:24][CH2:23][CH:22]([C:15]2[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:11]([CH2:10][CH:9]([CH3:40])[CH3:8])[C:12](=[O:39])[CH:13]([NH:28][C:29]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[CH:33]=3)=[O:30])[N:14]=2)[CH2:27][CH2:26]1)=[O:4])([CH3:43])([CH3:47])[CH3:41]
Reactant: Cc1cccc(N=C=O)c1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cccc(NC(=O)NC2N=C(C3CCNCC3)c3ccccc3N(CC(C)C)C2=O)c1
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)NC2N=C(C3CCN(C(=O)OC(C)(C)C)CC3)c3ccccc3N(CC(C)C)C2=O)c1
Reaction time: 1 h
Yield: 62.3 %

Procedure:
To a solution of the previous amino (0.35 g, 0.85 mmol) [Step 7] in anhydrous tetrahydrofuran (5 ml) was added 3-methylphenyl isocyanate (110 μl, 0.85 mmol) dropwise, under nitrogen. The resultant suspension was left to stand at room temperature for 1 h, after which time ether (20 ml) was added The solid was filtered off, washed with more ether and recrystallized from methanol to afford the title urea (290 mg, 62%) as a white solid. The mother liquors were evaporated and the residue chromatographed on silica gel, using 3:1 petrol-ethyl acetate followed by 1:1 petrol-ethyl acetate as the eluant. The product (103 mg, 22%) was isolated as a white solid; mp 202°-204° C. (MeOH); δH (360 MHz, CDCl3) 0.71 (3H, d, J=6.6 Hz), 0.78 (3H, d, J=6.6 Hz), 1.25-1.31 (1H, m), 1.43 (9H, s), 1.58-1.64 (2H, m), 1.73-1.77 (1H, m), 1.98-2.04 (1H, m), 2.31 (3H, m), 2.68-2.80 (2H, m), 2.91-2.98 (1H, m), 3.43 (1H, dd, J=13.8 and 5.1 Hz), 4.04-4.24 (2H, m), 4.29 (1H, dd, J=13.8 and 9.2 Hz), 5.33 (1H, d, J=6.5 Hz), 6.63 (1H, d, J=7.8 Hz), 6.70 (1H, s), 6.87 (1H, d, J=7.3 Hz), 7.08 (1H, d, J=8.1 Hz), 7.17 (1H, t, J=7.7 Hz), 7.20 (1H, s), 7.28 (1H, d, J=7.9 Hz), 7.36 (1H, d, J=8.0 Hz), 7.51 (1H, t, J=7.1 Hz), 7.56 (1H, d, J=7.9 Hz); m/z (CI, NH3) 547 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][CH:17]([C:21]([OH:23])=O)[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][CH:17]([C:21]([NH:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[O:23])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CC(C(=O)O)CC4)cc1
Reactant: Nc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ncc3c4c(cnc32)CC(C(=O)Nc2ccccc2)CC4)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinoline-7-carboxylic acid (0.072 g, 0.21 mmol), diisopropylethylamine (0.1 mL), aniline (23 μl, 0.21 mmol) in dimethylformamide (5 mL) was added HBTU (0.121 g). The mixture was stirred at room temperature for 24 hours, poured into ethyl acetate (100 mL) and washed with water (200 mL). The organic layer was dried with anhydrous magnesium sulfate and evaporated to dryness to give crude 3-(4-methoxybenzyl)-N-phenyl-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinoline-7-carboxamide as a brown oil, which was used in the next step without any further purification. LCMS [M+H]: 413.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][OH:15])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Br[CH2:24][CH2:25][CH:26]1CC[CH2:29][CH2:28][CH2:27]1>CN(C=O)C.O>[CH2:24]([N:7]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][OH:15])[N:9]=1)[C:6](=[O:16])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: BrCCC1CCCCC1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CO)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCN(C(=O)OC(C)(C)C)c1cccc(CO)n1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 69 %

Procedure:
To a stirred solution of tert-butyl[6-(hydroxymethyl)pyridin-2-yl]carbamate (3.79 g, 16.9 mmol) in DMF, cooled to 0° C. with a brine/ice bath, was added potassium tert-butoxide (126 mg, 1.07 mmol). The mixture was stirred 5 minutes at 0° C. then 1-bromo-2cyclohexylethane (205 mg, 1.07 mmol) was added. After stirring at room temperature for 4 h, the reaction mixture was diluted with water (200 mL), extracted with ethyl acetate (150 mL). The organic layer was washed with water, dried (MgSO4) and concentrated in vacuo. Purification on silica gel afforded tert-butyl hexyl[6-(hydroxymethyl)pyridin-2-yl]carbamate as a yellow oil [3.60 g, yield 69%; HPLC/MS: m/z=309 (M+H); log P(HCOOH)=3.94].
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:19][CH2:20][CH3:21])[N:6]2[CH2:13]/[C:14](=[N:17]/[H])/[NH:15][OH:16].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[CH3:40][N:41]1[C:45]([C:46](O)=O)=[CH:44][C:43]([CH3:49])=[N:42]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:19][CH2:20][CH3:21])[N:6]2[CH2:13][C:14]1[N:17]=[C:46]([C:45]2[N:41]([CH3:40])[N:42]=[C:43]([CH3:49])[CH:44]=2)[O:16][N:15]=1
Reactant: [H]/N=C(/Cn1c(CCC)cc2c(Cl)c(C#N)ccc21)NO
Reactant: Cc1cc(C(=O)O)n(C)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc2c(Cl)c(C#N)ccc2n1Cc1noc(-c2cc(C)nn2C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Synthesized as described in Example 32A and Example 33 using (1Z)-2-(4-chloro-5-cyano-2-propyl-1H-indol-1-yl)-N-hydroxyethanimidamide (0.030 g, 0.1 mmol) in anhydrous THF (5 mL) with propanephosphonic acid cyclic anhydride (T3P) (0.034 g, 0.12 mmol), 1,3-dimethyl-1H-pyrazole-5-carboxylic acid (0.014 g, 0.1 mmol) and DIEA (0.016 g, 0.12 mmol) and stirred at rt for 1 h and then heated at 120° C. for 2 h in the microwave: 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.46 (d, J=8.5 Hz, 1H), 6.71 (s, 1H), 5.44 (s, 2H), 4.12 (s, 3H), 2.97 (t, 2H), 2.30 (s, 3H), 1.80-1.72 (m, 2H), 1.04 (t, 3H); MS (ES) m/z 395 (M+1).
Reaction SMILES: CCC.C=CC.CCC.C1N(P([O:21][C:22]2[CH:27]=[CH:26][C:25]([O:28]P(N3CCOCC3)(N3CC3)=O)=[CH:24][CH:23]=2)(N2CCOCC2)=O)C1.C=CC.[O:43]=O>>[CH:22]([CH:23]=[CH2:24])=[O:21].[C:25]([OH:28])(=[O:43])[CH:26]=[CH2:27]
Reactant: O=O
Reactant: O=P(Oc1ccc(OP(=O)(N2CCOCC2)N2CC2)cc1)(N1CCOCC1)N1CC1
Solvent: C=CC
Solvent: CCC
Product: C=CC(=O)O
Product: C=CC=O

Procedure:
If propane is used as a starting material, it can be converted into a propene/propane mixture by: catalytic oxydehydrogenation as described, for example, in Catalysis Today 24 (1995), 307–313 or U.S. Pat. No. 5,510,558; homogeneous oxydehydrogenation as described, for example, in EP-A-0 253 409, EP-A-0 293 224, DE-A-195 08 558 or EP-A-0 117 146. When a propene/propane mixture is used, propane acts as a diluent gas. Suitable propene/propane mixtures include refinery propene (70% of propene and 30% of propane) of cracker propene (95% of propene and 5% of propane) or propene from a conventional propane dehydrogenation (99.5% of propene and 0.5% of propane). In principle, propene/propane mixtures can be oxidized with mixtures of oxygen and nitrogen of any composition to give acrolein and acrylic acid, as well as propene from an upstream propane dehydrogenation without prior propane/propene separation (20% of propene and 80% of propane).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24]Cl)=[C:12]2[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]1(=[O:43])[NH:37][C:36](=[O:38])[C:35]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]12.[K].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24][N:37]1[C:33](=[O:43])[C:34]3[C:35](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:36]1=[O:38])=[C:12]2[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)Cn1c(CCl)c(-c2cccc(F)c2)c2cc(OCc3ccccc3)ccc2c1=O
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cn1c(CN2C(=O)c3ccccc3C2=O)c(-c2cccc(F)c2)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 88.1 %

Procedure:
A solution of 6-benzyloxy-3-chloromethyl-4-(3-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone (3.60 g, 8 mmol) and potassium phthalimide (2.22 g, 12 mmol) in N,N-dimethylformamide (30 ml) was stirred at room temperature for 6 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give 2-[[6-benzyloxy-4-(3-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methyl]-1H-isoindole-1,3(2H)-dione (3.95 g, 88.2%) as crystals.