Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]56[CH2:32][CH:31]5[CH2:30][N:29]([C:33]5[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=5)[C:28]6=[O:40])=[O:26])=[CH:20][C:19]=4[F:41])=[C:11]3[C:10]([N:42]3[CH2:47][CH2:46][N:45](C(OC(C)(C)C)=O)[CH2:44][CH2:43]3)=[N:9]2)=CC=1>C(O)(C(F)(F)F)=O>[F:41][C:19]1[CH:20]=[C:21]([NH:24][C:25]([C:27]23[CH2:32][CH:31]2[CH2:30][N:29]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[C:28]3=[O:40])=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:8][N:9]=[C:10]([N:42]3[CH2:43][CH2:44][NH:45][CH2:46][CH2:47]3)[C:11]=12
Reactant: COc1ccc(Cn2nc(N3CCN(C(=O)OC(C)(C)C)CC3)c3c(Oc4ccc(NC(=O)C56CC5CN(c5ccc(F)cc5)C6=O)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Oc2ccnc3[nH]nc(N4CCNCC4)c23)c(F)c1)C12CC1CN(c1ccc(F)cc1)C2=O
Yield: 44.8 %

Procedure:
A solution of tert-butyl 4-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(3-(4-fluorophenyl)-2-oxo-3-aza-bicyclo[3.1.0]hexane-1-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)piperazine-1-carboxylate (100 mg, 0.131 mmol) was heated in TFA (4 mL) for 12 hours. Excess TFA was removed and the residue was purified by flash column chromatography (20% MeOH in CH2Cl2) to afford the product N-(3-fluoro-4-(3-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-3-(4-fluorophenyl)-2-oxo-3-aza-bicyclo[3.1.0]hexane-1-carboxamide (32 mg, 44.9% yield) as a yellow solid. LRMS (APCI pos) m/e 546.3 (M+1). 1H NMR (DMSO-d6, 400 MHz) δ 12.90 (s, 1H), 10.48 (s, 1H), 8.88 (s, br, 1H), 8.25 (d, 1H), 7.92 (d, 1H), 7.60-7.69 (m, 2H), 7.47-7.53 (m, 2H), 7.22-7.30 (m, 2H), 6.16-6.22 (d, 1H), 4.09-4.17 (m, 1H), 3.77-3.80 (m, 1H), 3.50-3.60 (m, 1H), 3.35-3.40 (m, 1H), 3.22-3.33 (m, 4H), 3.16-3.21 (m, 1H), 2.66-2.74 (m, 1H), 1.80-1.84 (m, 1H), 1.46-1.52 (m, 1H), 1.06-1.12 (m, 1H).
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[NH2:26][N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[N:27]1([NH:26][C:3]([C:5]2[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)=[N:14][O:15][C:16]=3[CH3:17])[CH:9]=2)=[O:4])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NN1CCCCC1
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2C)nn1C
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)NN2CCCCC2)n(C)n1
Yield: 52 %

Procedure:
As described for example 48c, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.29 mmol) was converted, using 1-aminopiperidine instead of N,N-dimethylhydrazine, to the title compound (62 mg, 52%) which was obtained as a colorless oil. MS: m/e=414.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@:9]1([CH2:15][N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[O:12][C:11](=[O:13])[C@@H:10]1[CH3:14].C[N:22](C1C=CC=CN=1)C>N>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@:9]([OH:12])([CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C@@H:10]([CH3:14])[C:11]([NH2:22])=[O:13]
Reactant: CN(C)c1ccccn1
Reactant: C[C@H]1C(=O)O[C@@]1(Cn1cncn1)c1cc(F)ccc1F
Agent: N
Product: C[C@@H](C(N)=O)[C@](O)(Cn1cncn1)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 5096.7 %

Procedure:
7.1 g (25.4 mmol) of (3R,4R)-4-(2,5-difluorophenyl)-3-methyl-4-[1,2,4]triazol-1-ylmethyl-oxetan-2-one were dissolved in 250 ml aqueous ammonia (NH4OH 25%) and, after the addition of 64 mg (0.5 mmol) of dimethylaminopyridine, were stirred for 1 hour at room temperature. Evaporation of the reaction mixture gave crude 7.55 g (100% yield) of (2R,3R)-3-(2,5-difluoro-phenyl)-3-hydroxy-2-methyl-4-[1,2,4]triazol-1-yl-butyramide.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[OH:8])=[CH:3][CH:2]=1.[H][H]>[Pt]=O.C(O)(=O)C>[C:9]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH:4]2[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]2)[OH:8])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccncc1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Temperature: 75 °C
Reaction time: 3 h
Yield: 89.8 %

Procedure:
A 1.4 liter hydrogenation shaker bomb was charged with 4-pyridyl diphenyl carbinol (46.5 grams, 0.18 mole), platinum oxide (2.0 grams) and glacial acetic acid (325 ml). The bomb was sealed, pressurized with hydrogen to 200 psi, and heated with shaking to 75° C. for 3 hours. The bomb was then cooled and the contents filtered and evaporated to remove the acetic acid. After evaporation, the material was neutralized with aqueous sodium hydroxide (120 grams of 50% NaOH and 330 ml water). The solid material was thereafter filtered and washed with cold water to give on drying diphenyl 4-piperidyl carbinol (Azacyclonol) (43.2 grams, 91% yield). To an ethanolic solution of Azacyclonol was added hydrogen chloride, thus giving Azacyclonol hydrochloride salt.
Reaction SMILES: [C:1]([N:9]1[C@H:13]([C:14](=[O:24])[NH:15][C@H:16]([CH3:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][S@@:11](=[O:25])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:34])C=1>C(Cl)Cl>[C:1]([N:9]1[C@H:13]([C:14](=[O:24])[NH:15][C@H:16]([CH3:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][S:11](=[O:34])(=[O:25])[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](NC(=O)[C@@H]1C[S@@](=O)CN1C(=O)c1ccccc1)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C[C@@H](NC(=O)[C@@H]1CS(=O)(=O)CN1C(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.3 %

Procedure:
To a solution of 357 mg of (1R,4R)-3-benzoyl-4-[(R)-α-methylbenzylcarbamoyl]-1-oxothiazolidine (prepared as described in Example 25 or 28 ) in 10 ml of methylene chloride were added 203 mg of 85% m-chloroperbenzoic acid, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was then washed, in turn, with 30 ml of a 4% aqueous solution of sodium bicarbonate and with 30 ml of water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to leave an oil, which was then subjected to column chromatography through 80 g of silica gel, eluted with a 97.5:2.5 by volume mixture of methylene chloride and ethanol, to give an oil. This oil was crystallized by the addition of benzene to give 266 mg of the title compound in the form of crystals. The physical properties of these crystals were identical with those of the compound obtained as described in Example 27.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH:12]([OH:25])[C:13]1[N:17]2[N:18]=[C:19]([C:22](=O)[CH3:23])[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.Cl.[NH2:27][NH:28][C:29]([NH2:31])=[O:30].C(N(CC)CC)C>CO>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH:12]([OH:25])[C:13]1[N:17]2[N:18]=[C:19](/[C:22](=[N:27]/[NH:28][C:29]([NH2:31])=[O:30])/[CH3:23])[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1
Reactant: NNC(N)=O
Reactant: CC(=O)c1ccc2ncc(C(O)c3cc4cccnc4cc3F)n2n1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: C/C(=N\NC(N)=O)c1ccc2ncc(C(O)c3cc4cccnc4cc3F)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.1 %

Procedure:
To a solution of 1-(3-((7-fluoroquinolin-6-yl)(hydroxy)methyl)imidazo[1,2-b]pyridazin-6-yl)ethanone (100 mg, 0.27 mmol) in methanol (15 mL) was added semicarbazide hydrochloride (45 mg, 0.41 mmol). Triethyl amine was added dropwise to adjust the pH to 5-6. The reaction mixture was stirred at room temperature overnight. The precipitate was collected by filtration and dried over vacuum pump to afford 50 mg (yield: 47%) title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.68 (s, 1H), 8.89 (dd, 1H), 8.45 (d, 1H), 8.25 (m, 2H), 7.99 (d, 1H), 7.72 (d, 1H), 7.57 (s, 1H), 7.52 (q, 1H), 6.67 (b, 2H), 6.62 (s, 1H), 6.47 (b, 1H), 2.19 (s, 3H). LCMS (method A): [MH]+=394, tR=3.95 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:12])=[C:4]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[N:6][CH:7]=1.[CH:13](OCC)(OCC)OCC>>[Cl:1][C:2]1[C:3]2[N:12]=[CH:13][N:8]([CH2:9][CH2:10][CH3:11])[C:4]=2[N:5]=[N:6][CH:7]=1
Reactant: CCCNc1nncc(Cl)c1N
Reactant: CCOC(OCC)OCC
Product: CCCn1cnc2c(Cl)cnnc21
Temperature: 140 °C
Yield: 47 %

Procedure:
A mixture of 5-chloro-N3-propylpyridazine-3,4-diamine (Preparation 100, 800 mg, 4.30 mmol) and triethyl orthoformate (10 mL) was heated at 140° C. for 4 hours. After evaporation in vacuo, the crude residue was purified by silica gel column chromatography eluting with CH2Cl2:MeOH 98:2 to afford the title compound as a brown solid in 47% yield, 400 mg.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[CH:2]=1.OS(O)(=O)=O.[OH-].[Na+].[CH3:23]O>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([O:13][CH3:23])=[O:12])=[CH:9][CH:8]=2)[CH:2]=1
Reactant: CO
Reactant: O=C(O)c1ccc(-c2cccnc2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1ccc(-c2cccnc2)cc1
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
To a solution of 4-[pyridin-3-yl]-benzoic acid (2.2 g, 11 mmol) (reference example 17b) in methanol (33 mL) was added conc. H2SO4 (5 mL). The resulting solution was warmed to 60° C. and stirred at this temperature for 45 min. The reaction mixture was then allowed to cool to room temperature then poured into ice. The pH of the resulting solution was adjusted to 7 using a 10 M solution of NaOH. The product was then extracted into ethyl acetate. This solution was washed with brine, dried over MgSO4 and concentrated to give 1.74 g of the title compound as a tan solid. 1H NMR (CDCl3) d 3.96 (s, 3H), 7.40 (dd, J=8, 5 Hz, 1H), 7.66 (m, 2H), 7.93 (m, 1H), 8.15 (m, 2H), 8.65 (bs, 1H), 8.89 (bs, 1H). MS (EI) m/z 213 (M)+.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][C@@H:16]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29](=[O:34])[NH:30][CH:31]([CH3:33])[CH3:32])=[CH:24][CH:23]=1)[C:17]([O:19][CH3:20])=[O:18])=O)(C)(C)C>C(Cl)Cl>[NH2:15][C@@H:16]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([NH:30][CH:31]([CH3:33])[CH3:32])=[O:34])=[CH:24][CH:23]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)[C@H](Cc1ccc(OC(=O)NC(C)C)cc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](N)Cc1ccc(OC(=O)NC(C)C)cc1
Reaction time: 1 h
Yield: 100 %

Procedure:
Trifluoroacetic acid (0.5 mL, 6 mmol) was added to (S)-methyl 2-(tert-butoxycarbonylamino)-3-(4-(isopropylcarbamoyloxy)phenyl)propanoate in methylene chloride (2 mL). The reaction was stirred for 1 h, and was concentrated under reduced pressure to give crude product, methyl (2S)-2-amino-3-(4-{[(isopropylamino)carbonyl]oxy}phenyl)propanoate (50 mg, 100%). Analytical LCMS (M+H)+: m/z=281.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]([O:12]C)=[O:11])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:20]([CH3:29])[C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:22])[CH:15]=1.[OH-].[Li+]>O1CCCC1>[NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:20]([CH3:29])[C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:22])[CH:15]=1
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)O)cc2N)c1
Yield: 253.9 %

Procedure:
A solution of 123.9 mg (0.311 mmol, 1 eq) of methyl 3-[2-amino-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoate in 3 ml of tetrahydrofuran in the presence of 550 μL (0.623 mmol, 2 eq) of 1N lithium hydroxide solution is stirred at room temperature for 4 hours. The reaction medium is concentrated, hydrolyzed with water, acidified with acetic acid and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and evaporated. The residue is taken up in heptane and then recrystallized from acetonitrile. 302.8 mg of 3-[2-amino-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoic acid are obtained in the form of a white powder (m.p.=84.9° C.) Yield=75%
Reaction SMILES: [C:1]12([OH:13])[CH2:10][C:5]3([OH:11])[CH2:6][CH:7]([CH2:9][C:3]([OH:12])([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:14](O)(=[O:18])[C:15]([CH3:17])=[CH2:16].S(=O)(=O)(O)O.COC1C=CC(O)=CC=1.O=O.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[C:14]([O:13][C:1]12[CH2:10][C:5]3([OH:11])[CH2:6][CH:7]([CH2:9][C:3]([OH:12])([CH2:4]3)[CH2:2]1)[CH2:8]2)(=[O:18])[C:15]([CH3:17])=[CH2:16]
Reactant: C=C(C)C(=O)O
Reactant: OC12CC3CC(O)(C1)CC(O)(C3)C2
Agent: COc1ccc(O)cc1
Agent: O=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OC12CC3CC(O)(CC(O)(C3)C1)C2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a 2 L jacket-equipped separable flask provided with a stirrer, a thermometer, a Dean-Stark water separator, a Dimroth condenser and a prepared gas introduction tube, 128.9 g of 1,3,5-adamantanetriol, 361 g of methacrylic acid, 1.7 g of concentrated sulfuric acid as an acid catalyst, 1.1 g of p-methoxyphenol as a polymerization inhibitor, and 750 ml of toluene as a solvent were put. Prepared gas diluted with nitrogen so as to have an oxygen concentration of about 5% by volume was supplied at a rate of 0.2 L/min. The reaction operation was performed as follows. While the solution was heated and water generated as a secondary product was removed by the Dean-Stark water separator, the reflux state was continued for 12 hours. Thus, 3,5-dihydroxy-1-adamantyl methacrylate was synthesized. The obtained reaction solution was cooled down to room temperature, and then a 10% by weight of aqueous solution of sodium hydroxide was added while stirring to neutralize the residual methacrylic acid and sulfuric acid. Then, the neutralized water phase was drawn out from the two-phase solution. The resultant organic phase was washed with 500 ml of ion exchange water twice. After the water phase was all united, extraction was performed with 300 ml of ethyl acetate twice. To the ethyl acetate solution, 0.76 g of p-methoxyphenol was added as a polymerization inhibitor and dissolved completely. Precise filtration was performed by use of a Teflon® filter having a pore diameter of 0.1 μm. Then, the resultant solution was concentrated by use of an evaporator while the temperature of the solution was kept at 40° C., until the weight of the solution became 110 g. After the concentration was finished, cooling crystallization was performed at a temperature of an ice water bath to separate the crystal by filtration. The crystal was rinsed with ion exchange water twice, and then dried at a reduced pressure at 35° C. for 24 hours. During the process from the dehydration esterification reaction to the solid-liquid separation and until the termination of rinsing performed by use of ion exchange water, the prepared gas was kept blown into the solution. Table 1 shows the analysis results of the obtained 3,5-dihydroxy-1-adamantyl methacrylate. Tetrahydrofuran was used as the solvent for measuring the turbidity.
Reaction SMILES: [NH2:1][C@H:2]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH2:7][CH2:6]1)=[O:4].[C:29]([CH:36]([NH2:39])C=O)(OC(C)(C)C)=O.[BH4-].[Na+]>CO>[NH2:39][CH2:36][CH2:29][NH:1][C@H:2]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3ccccc23)CC1
Reactant: CC(C)(C)OC(=O)C(N)C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NCCN[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3ccccc23)CC1
Reaction time: 3 h
Yield: 63.5 %

Procedure:
(2R)-2-Amino-3-(4-chlorophenyl)-1-(4-quinazolin-4-yl-piperazin-1-yl)-propan-1-one (free-base, 41 mg, 0.104 mmol) was stirred at room temperature with Boc-2-aminoacetaldehyde (16 mg, 0.104 mmol) in 0.7 mL methanol for 1 hour, after which NaBH4 (6 mg, 0.160 mmol) was added. The reaction mixture was stirred for 3 hours and then quenched with 1N NaOH. The reaction mixture was extracted with DCM, and the combined extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation. The crude residue was purified on silica (15:1 DCM/MeOH). The resulting Boc-amine intermediate was treated with 1.4 mL 4M HCl/dioxane and stirred at room temperature for 14 hours, after which the reaction mixture was diluted with ether. The solids were isolated by filtration with nitrogen pressure and dried under reduced pressure to give the desired product (29 mg, 51%) as the trihydrochloride salt. Rt 1.69. MS (CI+) [M+H]+ 439.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.[CH3:12][O:13]C1C(N)=CC=CC=1>[O-2].[V+5].[O-2].[O-2].[O-2].[O-2].[V+5]>[CH:12]([NH:9][C:8]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:2][CH3:1])=[O:13]
Reactant: COc1ccccc1[N+](=O)[O-]
Reactant: COc1ccccc1N
Agent: [V+5]
Agent: [O-2]
Product: COc1ccccc1NC=O
Yield: 24.8 %

Procedure:
The procedure of Example 4 was repeated using o-nitroanisole (4 mmol, 0.55 g) as starting material and vanadium(v) oxide (2.3 mg) instead of sodium molybdate dihydrate. After 2.5 h at 90-95° C. a yield of 24.8% of o-formoanisidide was obtained. o-Anisidine (62.8%) was found to be the main product.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[N:6]([C:9]3[CH:10]=[C:11]([NH:15][C:16]([NH:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[O:17])[CH:12]=[CH:13][CH:14]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][N:37]([CH:39]3[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]3)[CH:38]=2)O1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:21][C:20]([F:23])([F:22])[CH2:19][NH:18][C:16]([NH:15][C:11]1[CH:10]=[C:9]([N:6]2[C:5]3[CH:24]=[CH:25][C:2]([C:34]4[CH:35]=[N:36][N:37]([CH:39]5[CH2:40][CH2:41][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:43][CH2:44]5)[CH:38]=4)=[CH:3][C:4]=3[N:8]=[CH:7]2)[CH:14]=[CH:13][CH:12]=1)=[O:17]
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(Br)ccc32)c1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc4c(c3)ncn4-c3cccc(NC(=O)NCC(F)(F)F)c3)cn2)CC1
Yield: 34 %

Procedure:
The mixture of N-[3-(5-bromo-1H-benzimidazol-1-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (1.0000 g, 2.4202 mmol) (prepared from the procedure of Example 1, step 4), tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (1.1 g, 2.8 mmol), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complex with dichloromethane (1:1) (0.1 g, 0.1 mmol, Aldrich, Cat. No. 697360) and sodium carbonate (510 mg, 4.8 mmol) in 1,4-dioxane (10 mL) and a few drops of water was heated at 120° C. under nitrogen overnight. After the reaction mixture was cooled to r.t, it was filtered, and the solid was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on a silica gel column using 6% MeOH CH2Cl2 as eluent to afford the desired compound (0.48 g, 34%). LCMS (M+H)+: m/z=584.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=1)[CH2:10][C:9]2([CH3:24])[CH3:23])=[O:5])[CH3:2].[CH:25]([O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)([CH3:27])[CH3:26].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[C:18]([C:32]3[CH:33]=[CH:34][C:29]([O:28][CH:25]([CH3:27])[CH3:26])=[CH:30][CH:31]=3)[CH:19]=[CH:20][CH:21]=1)[CH2:10][C:9]2([CH3:24])[CH3:23])=[O:5])[CH3:2]
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(Br)c1)N2
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(-c3ccc(OC(C)C)cc3)c1)N2
Temperature: 120 °C
Yield: 90.2 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.43 g, 1.1 mmol), 4-isopropoxy benzeneboronic acid (0.40 g, 2.2 mmol), bis(triphenylphosphine)palladium (II) chloride (77.2 mg, 0.11 mmol) and 2 M sodium carbonate (1.6 mL, 3.2 mmol) in dioxane (5 mL) was heated for 3 h at 120° C. After coiling to room temperature, the mixture was treated with ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (10% ethyl acetate/hexanes) to afford 2-(4′-isopropoxy-biphenyl-3-yl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.44 g, 90%) as a white solid: MS (ESI) M+1=444.1.
Reaction SMILES: C[N:2]([CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][C@H:16]3[CH2:20][O:19][C:18](=[O:21])[NH:17]3)[CH:13]=2)[NH:8][CH:7]=1)C>C(Cl)(Cl)Cl>[C:4]([CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][C@H:16]3[CH2:20][O:19][C:18](=[O:21])[NH:17]3)[CH:13]=2)[NH:8][CH:7]=1)#[N:2]
Reactant: CN(C)CCc1c[nH]c2ccc(C[C@H]3COC(=O)N3)cc12
Solvent: ClC(Cl)Cl
Product: N#CCc1c[nH]c2ccc(C[C@H]3COC(=O)N3)cc12
Yield: 81 %

Procedure:
A solution of the product from step (b) (2.5 g) and polyphosphate ester (20.0 g) in chloroform (40 ml) was refluxed for 20 minutes. Ice was added to the cooled mixture and the chloroform evaporated in vacuo. The remaining aqueous phase was extracted with ethyl acetate and the combined extracts evaporated in vacuo to give the desired product as a pale yellow oil (1.8 g).