Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[O:7][C:6]1([C:8]1[N:13]=[CH:12][C:11]([C:14]3[CH:15]=[C:16]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[C:17]4[S:21][C:20]([NH:22][C:23]([NH:25][CH2:26][CH3:27])=[O:24])=[N:19][C:18]=4[CH:28]=3)=[CH:10][N:9]=1)[CH2:5][CH2:4][O:3][CH2:2]2.S(=O)(=O)(O)[OH:36].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.O>[OH:7][CH:1]1[C:6]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH:15]=[C:16]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[C:17]4[S:21][C:20]([NH:22][C:23]([NH:25][CH2:26][CH3:27])=[O:24])=[N:19][C:18]=4[CH:28]=3)=[CH:10][N:9]=2)([OH:36])[CH2:5][CH2:4][O:3][CH2:2]1
Reactant: O=S(=O)(O)O
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(C45CCOCC4O5)nc3)cc(-c3ccccn3)c2s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2cc(-c3cnc(C4(O)CCOCC4O)nc3)cc(-c3ccccn3)c2s1
Temperature: 25 °C
Yield: 42 %

Procedure:
Compound iii (20 mg; 0.042 mmol) was dissolved in THF-H2O (10:1, 11 mL). Conc. sulfuric acid (20 μL) and p-toluenesulphonic acid (0.7 mg, 4 mmol) were added and the mixture stirred at RT. The mixture was concentrated in vacuo and purified over silica (0-100% 0.1% FA (aq)-MeCN) yielding Compound 8 (8.8 mg, 42%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:12]([N:13]=[C:14]=[O:15])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[C@@:16]12([OH:25])[N:23]([CH3:24])[C@@H:20]([CH2:21][CH2:22]1)[CH2:19][CH:18]=[CH:17]2>C(#N)C>[C:12]1([NH:13][C:14]([O:25][C@@:16]23[N:23]([CH3:24])[C@@H:20]([CH2:21][CH2:22]2)[CH2:19][CH:18]=[CH:17]3)=[O:15])[C:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CN1[C@@H]2CC=C[C@@]1(O)CC2
Reactant: O=C=Nc1ccccc1-c1ccccc1
Solvent: CC#N
Product: CN1[C@@H]2CC=C[C@@]1(OC(=O)Nc1ccccc1-c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5.0 g (0.026 mol) of 2-biphenylisocyanate is placed in 10 mL acetonitrile, and a solution of 3.619 g (0.026 mol) tropenol in 5 mL acetonitrile is added dropwise, then stirred for 24 hours at ambient temperature. The solution is concentrated by evaporation and the residue is distributed between dichloromethane and water. The organic phase is dried over sodium sulfate and evaporated to dryness. Yield: 7.4 g yellowish-orange oil (85% of theory).
Reaction SMILES: C([O:3][C:4](=[O:27])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)C.[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[C:23]([O:22][C:20]([NH:19][CH:16]1[CH2:15][CH2:14][N:13]([C:10]2[CH:9]=[CH:8][C:7]([CH:6]=[CH:5][C:4]([OH:27])=[O:3])=[CH:12][CH:11]=2)[CH2:18][CH2:17]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CCOC(=O)C=Cc1ccc(N2CCC(NC(=O)OC(C)(C)C)CC2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(C=CC(=O)O)cc2)CC1
Temperature: 25 °C

Procedure:
The 4-(4-tert-butoxycarbonylaminopiperidin-1-yl)-cinnamic acid ethyl ester (2.7 g, 7.2 mmol) obtained in Example 8(1) was dissolved in ethanol (40 ml), and a 4M sodium hydroxide aqueous solution (3.6 ml) was added thereto. The mixture was refluxed under heat for 12 hours. The reaction mixture was cooled to room temperature, and water (40 ml) was added thereto. The mixture was neutralized with 10% citric acid aqueous solution, and the precipitate was collected by filtration, thereby obtaining 4-(4-tert-butoxycarbonylaminopiperidin-1-yl)-cinnamic acid (1.9 g, 77%) as a white solid.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[CH:17]([N:20]([CH2:23][CH2:24][C:25]#[N:26])[S:21]Cl)([CH3:19])[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[CH:17]([N:20]([CH2:23][CH2:24][C:25]#[N:26])[S:21][N:2]([CH3:1])[C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)([CH3:19])[CH3:18]
Reactant: CC(C)N(CCC#N)SCl
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N(CCC#N)SN(C)C(=O)Oc1cccc2c1OC(C)(C)C2
Temperature: 0 °C

Procedure:
2.2 g (0.01 mole) of 2,3-dihydro-2,2-dimethylbenzofuran-7-yl N-methyl-carbamate and 1.8 g (0.01 mole) of N-isopropyl-N-cyanoethylaminosulfenyl chloride were dissolved in 30 ml of methylene chloride, and the solution was cooled to 0° C. 1.2 g (0.012 mole) of triethylamine was dropwise added thereto with stirring, and allowed to react for 2 hours at the same temperature. After completion of the reaction, the reaction solution was washed successively with water, diluted hydrochloric acid and water. The methylene chloride layer was dried and concentrated under reduced pressure to obtain an oily product which was almost entirely composed of the desired product although containing small amounts of the starting materials and impurities.
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:11]([O-])([O-:13])=[O:12].[Na+]>S(=O)(=O)(O)O>[OH:1][C:2]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cccnc1O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)c1cc([N+](=O)[O-])cnc1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 45 %

Procedure:
To 2-hydroxy-nicotinic acid (3.6 mmol) in sulfuric acid (30% free SO3, 2 ml) was added sodium nitrate (7.2 mmol) portionwise over 20 min. The solution was allowed to stir for 20 h at room temperature. The solution was then poured onto ice-water and the precipitate that formed was filtered off, washed with water and dried in a vacuum oven to afford a pale yellow solid (45%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[O:18][C:19]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])=[C:20]([CH2:22][OH:23])[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(OS(C)(=O)=O)(=O)=O.C(N(C(C)C)CC)(C)C.[I-].[Na+].[F:52][C:53]([F:57])([F:56])[CH2:54][O-].[Na+]>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[O:18][C:19]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])=[C:20]([CH2:22][O:23][CH2:54][C:53]([F:57])([F:56])[F:52])[N:21]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [O-]CC(F)(F)F
Reactant: O=C(OCc1ccccc1)N1CCC(c2nc(CO)c(-c3ccc(F)cc3F)o2)CC1
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1CCC(c2nc(COCC(F)(F)F)c(-c3ccc(F)cc3F)o2)CC1
Temperature: 0 °C

Procedure:
To a three neck 0.5 liter round bottom flask fitted with mechanical stirrer, nitrogen inlet and dropping funnel is added 4-[5-(2,4-Difluoro-phenyl)-4-hydroxymethyl-oxazol-2-yl]-piperidine-1-carboxylic acid benzyl ester, methane sulfonic anhydride (5.87 g, 33.7 mmol), and 150 mL of dry tetrahydrofuran. The mixture is stirred and cooled to 0° C., followed by dropwise addition of diisopropyl ethylamine (8.4 mL, 48 mmol). The mixture is stirred for 1 hour at 0° C. and then allowed to warm to room temperature. To the resultant mixture is then added sodium iodide (7.75 g, 51.7 mmol), and the mixture is stirred for an additional three hours. The sodium 2,2,2-trifluoroethoxide (0.151 mmol in 80 mL of dry tetrahydrofuran) is added dropwise over a 15 minute period and the resulting mixture is stirred for an additional 1 hour. The mixture is cooled to 0° C. and carefully quenched with 125 mL of water. After the addition was complete, the mixture is extracted with water and methylene chloride. The aqueous is washed with an additional three portions of methylene chloride, using 300 mL volumes. The organics are combined, washed with brine, dried over magnesium sulfate and concentrated to a thick residue. The residue is purified by preparative medium performance liquid chromatography to give upon concentration the desired fractions of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][CH2:10][C:11](=[O:18])[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:4][CH2:3]1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][N:26]=2)[C:21]([CH:28]=O)=[CH:20]1.CO.[ClH:32]>C(O)C>[ClH:32].[NH:19]1[C:27]2=[N:26][CH:25]=[CH:24][CH:23]=[C:22]2[C:21]([CH:28]=[C:10]2[O:9][C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11]2=[O:18])=[CH:20]1
Reactant: CCOC(=O)C1=C(N2CCN(C)CC2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CCOC(=O)C1=C(N2CCN(C)CC2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 9 %

Procedure:
To a solution of ethyl 2-(4-methylpiperazinyl)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.038 g, 0.15 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.022 g, 0.15 mmol) in ethanol (1.0 mL), 2M hydrochloric acid in methanol (0.17 mL, 0.34 mmol) was added at ambient temperature. The mixture was refluxed for 40 min. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound as solid (0.0069 g, y. 9%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:13][CH3:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([Cl:12])=[CH:7][CH:6]=2.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].N1C=CC=CC=1>ClCCl>[Cl:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]=[C:3]([O:13][CH3:14])[C:2]([NH:1][C:16](=[O:17])[O:18][CH2:19][CH3:20])=[N:11]2
Reactant: COc1nc2ccc(Cl)cc2nc1N
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1nc2cc(Cl)ccc2nc1OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 95 %

Procedure:
3-Amino-6-chloro-2-methoxyquinoxaline (629 mg, 3.00 mmol) and ethyl chloroformate (391 mg, 3.60 mmol) were dissolved in dichloromethane (50 ml) at room temperature and thereto pyridine (285 mg, 3.60 mmol) was added. The resulting mixture was stirred at room temperature for 10 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (3:1) mixture and concentration gave 803 mg of the titled compound (yield, 95%).
Reaction SMILES: O=[C:2]([CH2:7][CH2:8][CH:9]=[CH2:10])[C:3]([O:5][CH3:6])=[O:4].[C:11]1([NH:17]N)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:6][O:5][C:3]([C:2]1[NH:17][C:11]2[C:16]([C:7]=1[CH2:8][CH:9]=[CH2:10])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:4]
Reactant: C=CCCC(=O)C(=O)OC
Reactant: NNc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: C=CCc1c(C(=O)OC)[nH]c2ccccc12
Reaction time: 1 h
Yield: 46.2 %

Procedure:
The solution of methyl 2-oxo-5-hexenoate (19.5 g), phenylhydrazine (14.8 g) and anhydrous p-toluenesulfonic acid (0.5 g) in dry benzene was refluxed for 0.5 hour. The solution of anhydrous p-toluenesulfonic acid (35.3 g) in dry-benzene (150 ml) was added to the solution at 50° C. over five minutes. After being stirred at 50°-60° C. for 1 hour, the mixture was refluxed for 2 hours. After cooling, the reaction mixture was diluted with chilled water and extracted twice with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (10% ethyl acetate-toluene) to give 3-allyl-2-indolecarboxylic acid methyl ester (13.6 g) as crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[CH2:9][CH2:10]Cl)=[CH:4][CH:3]=1.[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[CH2:9][CH2:10][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[CH:4][CH:3]=1
Reactant: c1c[nH]cn1
Reactant: OC(CCCl)c1ccc(Br)cc1
Solvent: CN(C)C=O
Product: OC(CCn1ccnc1)c1ccc(Br)cc1
Yield: 44 %

Procedure:
A solution of 1-(4-Bromo-phenyl)-3-chloro-propan-1-ol* (1.5 g, 6.01 mmol) and imidazole (1.23 g, 18.03 mmol) in dimethylformamide (18 ml) was heated at 100° C. for 18 hrs then partitioned between water and ethyl acetate. The organic extracts were combined, dried (MgSO4), filtered, concentrated and purified by column chromatography (SiO2), eluting with methanol:dichloromethane (2:98) to methanol:dichloromethane (6:94) to afford the title compound (0.75 g, 44% yield). LC/MS: (PS-B3) Rt 2.48 [M+H]+ 281.14, 283.11.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1.[CH3:31][NH2:32].[BH4-].[Na+]>CO>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:32][CH3:31])=[CH:25][CH:24]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1
Reactant: O=Cc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
Using General Procedure B: To a solution of 4-{[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzaldehyde (AMD9882) (120 mg, 0.30 mmol) in MeOH (2 mL) was added methylamine (2.0 M solution in methanol, 1 mL, 2.00 mmol) and the resultant solution was stirred at room temperature for 5 hours. Solid NaBH4 (18 mg, 0.48 mmol) was added to the solution and the mixture was stirred at room temperature for an additional 30 minutes. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 50:1:1 CH2Cl2/CH3OH/NH4OH) provided the free base of the title compound (74 mg, 59%) as a white solid.
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[N:12]=2)[C:7](=[O:15])[C:6]([C:16]([OH:18])=O)=[CH:5]1)([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[NH2:32][C:33]1[NH:37][N:36]=[N:35][N:34]=1>CN(C)C=O>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[N:12]=2)[C:7](=[O:15])[C:6]([C:16]([NH:32][C:33]2[NH:37][N:36]=[N:35][N:34]=2)=[O:18])=[CH:5]1)([CH3:2])[CH3:3]
Reactant: Cc1ccc2c(=O)c(C(=O)O)cn(C(C)C)c2n1
Reactant: Nc1nnn[nH]1
Agent: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc2c(=O)c(C(=O)Nc3nnn[nH]3)cn(C(C)C)c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1,4-Dihydro-1-isopropyl-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid (Example 3b, 0.9 g) was warmed in dimethylformamide (70 ml) and triethylamine (0.7 ml) was added. The solution was cooled to 0° and ethyl chloroformate (0.4 ml) was added and the mixture was kept for 30 minutes. 5-Amino-1H-tetrazol (3.6 g) was added and the mixture was stirred at room temperature for 18 hours and filtered. The filtrate was evaporated and the residue was crystallised from a mixture of dimethylforamido and isopropanol. The product had m.p. >300° (d) (36%).
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=2)=[O:8])[CH:2]=1.[C:22]1([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>C1(C)C=CC=CC=1.[Pd].[Pd].CC(C)=O>[C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N:28]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:11][CH:10]=2)=[O:8])[CH:2]=1
Reactant: O=C(c1ccc(Br)cc1)c1cccc(-c2ccccc2)c1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: O=C(c1ccc(N(c2ccccc2)c2ccccc2)cc1)c1cccc(-c2ccccc2)c1
Reaction time: 24 h
Yield: 80.8 %

Procedure:
Biphenyl-3-yl(4-bromophenyl)methanone (5.0 g, 14.83 mmol) and diphenylamine (3.8 g, 22.2 mmol) were dissolved in toluene (150 mL) under a nitrogen atmosphere, and then tris(benzylidine acetone dipalladium) (0.3 g, 0.3 mmol) was added thereto under nitrogen. Also, P(t-Bu)3 (0.3 g, 1.5 mmol) was added to the reaction mixture solution, followed by addition of NaOBut (4.3 g, 44.5 mmol). The reaction mixture solution was refluxed and stirred for 24 hours. After the reaction was over, the reaction mixture solution was filtered through a thin silica pad at a high temperature to thereby remove palladium. The filtrate was concentrated, and was passed through a silica gel column by using hexane-dichloromethane 7:3 as an eluant. After the solvent was removed, the residue material was dried in vacuum to thereby obtain a white solid (5.1 g, yield: 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:31])=[C:6]([C:8]2[CH:13]=[C:12]([NH:14][C:15]3[C:16]4[C:17](=[CH:21][N:22]([CH2:24][CH:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)[N:23]=4)[N:18]=[CH:19][CH:20]=3)[CH:11]=[CH:10][N:9]=2)[CH:7]=1.C(N(CC)C(C)C)(C)C.[CH2:41]([N:43]=[C:44]=[O:45])[CH3:42]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:31])=[C:6]([C:8]2[CH:13]=[C:12]([NH:14][C:15]3[C:16]4[C:17](=[CH:21][N:22]([CH2:24][CH:25]5[CH2:30][CH2:29][N:28]([C:44]([NH:43][CH2:41][CH3:42])=[O:45])[CH2:27][CH2:26]5)[N:23]=4)[N:18]=[CH:19][CH:20]=3)[CH:11]=[CH:10][N:9]=2)[CH:7]=1
Reactant: CCN=C=O
Reactant: Fc1ccc(Cl)cc1-c1cc(Nc2ccnc3cn(CC4CCNCC4)nc23)ccn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)N1CCC(Cn2cc3nccc(Nc4ccnc(-c5cc(Cl)ccc5F)c4)c3n2)CC1
Temperature: 25 °C

Procedure:
N-(2-(5-Chloro-2-fluorophenyl)pyridin-4-yl)-2-(piperidin-4-ylmethyl)-2H-pyrazolo[4,3-b]pyridin-7-amine (20 mg, 0.046 mmol) and N,N-diisopropylethylamine (7.97 μl, 0.046 mmol) were combined in dichloromethane (1.5 mL) followed by ethyl isocyanate (3.62 μl, 0.046 mmol). The reaction was then stirred at room temperature over night. The solvent was then evaporated to give a residue which was partitioned between EtOAc and 1N NaOH. The organic layer was washed with water and then brine, dried over Na2SO4, filtered, concentrated, and evaporated in-vacuo to give the title compound as a light yellow solid. MS [M+H] found 507.0.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[C:21]1([CH3:30])[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][NH2:29])=[CH:23][CH:22]=1.[BH4-].[Na+]>CO>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:29][CH2:28][CH2:27][C:24]2[CH:25]=[CH:26][C:21]([CH3:30])=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=1
Reactant: Cc1ccc(CCN)cc1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CNCCc2ccc(C)cc2)ccc1Oc1ccc(C(N)=O)cn1
Reaction time: 8 h
Yield: 99.5 %

Procedure:
Place 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.100 g 0.367 mmol), 2-p-tolylethylamine (0.0546 g, 0.404 mmol) and 3 Å molecular sieves in a vial. Add methanol (3.6 mL), cap and stir overnight. Add NaBH4 (in excess over two portions) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 5 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 10 g ISCO® column with (2.0 M NH3 in methanol) in ethyl acetate to give 6-{2-methoxy-4-[(2-p-tolylethylamino)methyl]phenoxy}nicotinamide (0.143 g, 97.8%). Dissolve the compound in dichloromethane (2.5 mL) and add 1 equivalent of 0.50 M methanesulfonic acid in dichloromethane. Stir the solution for a short time before concentrating to give the title compound (0.168 g, ˜100%): TOF MS ES+ 392.1 (M+H)+, HRMS calcd for C23H26N3O3 392.1974 (M+H)+, found 392.1966, time 0.39 min; HPLC [Waters XTerra™ MS C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 15 min], tR=8.4 min, 100% purity.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[Na].[C:6](OC)(=[O:13])[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1>N>[C:6]([NH:1][C:2]([NH2:4])=[O:3])(=[O:13])[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccncc1
Reactant: NC(N)=O
Agent: N
Agent: [Na]
Product: NC(=O)NC(=O)c1ccncc1

Procedure:
Urea (7.5 g., 0.125 mole) is suspended in liquid ammonia (250 ml.) in a round bottom flask fitted with an acetone/dry-ice condenser. Sodium pellets (2.9 g., 0.125 mole) are added and, after they have dissolved, methyl isonicotinate (12 g., 0.089 mole) is added to the mixture. The ammonia is allowed to evaporate from the mixture overnight. The yellow-tan residue is dissolved in water (150 ml.), the pH of the mixture adjusted to 5.5 with glacial acetic acid, and the precipitate which forms filtered, washed with water and air dired. It is then washed with hexane and triturated with boiling methanol. The white solid (isonicotinic acid) is removed by filtration and the filtrate evaporated to dryness to give the title product as a yellowish solid: m.p. 245°-247° C. Quantitative analysis and infra-red data are consistent with the values expected for the product.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][C:48]([F:51])([F:50])[F:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([C:52]([OH:54])=[O:53])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.S(=O)(=O)(O)O.[C:62](=O)(O)[O-].[Na+]>O1CCCC1>[CH3:62][O:53][C:52]([C@:10]12[O:32][C@:13]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][C:48]([F:49])([F:50])[F:51])=[CH:43][CH:42]=4)[CH:34]=3)([O:12][CH2:11]1)[C@H:14]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@@H:15]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@@H:9]2[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:54]
Reactant: O=C(O)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OC(F)(F)F)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OC(F)(F)F)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Temperature: 45 °C
Reaction time: 20 h
Yield: 66.5 %

Procedure:
To a solution of (1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[[4-(trifluoromethoxy) phenyl]methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-carboxylic acid 16a (0.49 g, 0.64 mmol) in tetrahydrofuran (2 mL) were added methanol (8 mL) and concentrated sulphuric acid (0.24 mL) at room temperature. The mixture was stirred at 45° C. for 20 hours. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate till pH becomes 7 and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with saturated aqueous sodium chloride (10 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=20/1 to give the title compound 16b as a white solid (322 mg, 66.5%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ(ppm): 7.48 (d, 1H), 7.44-7.38 (m, 2H), 7.32 (m, 7H), 7.26 (m, 3H), 7.21 (d, 1H), 7.16 (m, 4H), 7.05 (d, 2H), 6.87 (d, 2H), 4.90-4.81 (m, 2H), 4.79 (d, 1H), 4.63 (d, 1H), 4.53 (d, 1H), 4.32 (d, 1H), 4.20 (dd, 2H), 4.10 (t, 2H), 4.02 (dd, 1H), 3.89 (d, 1H), 3.74 (d, 1H), 3.71 (s, 3H).
Reaction SMILES: C(N)C#C.ClC=CC(Cl)Cl.[CH2:11]([NH:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[C:12]#[CH:13].[Cl:20][CH:21]([Cl:25])[C:22](Cl)=[O:23]>>[CH2:11]([N:14]([CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[C:22](=[O:23])[CH:21]([Cl:25])[Cl:20])[C:12]#[CH:13]
Reactant: C#CCNCC=C(Cl)Cl
Reactant: O=C(Cl)C(Cl)Cl
Agent: C#CCN
Agent: ClC=CC(Cl)Cl
Product: C#CCN(CC=C(Cl)Cl)C(=O)C(Cl)Cl

Procedure:
From propargylamine and 1,3,3-trichloropropene, proceeding as in Example 1, there was prepared N-propargyl-N-(3,3,-dichloroallyl) amine: b.p.15 mm =88°-91° C., from which, by reaction with dichloroacetyl chloride, there was obtained N-propargyl-N-(3,3-dichloroallyl)dichloroacetamide, (Applicants' Mark 834l), a yellowish oil.