Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]([CH:12]=[C:13](Cl)Cl)=[O:11].[Na].S(=O)(=O)(O)[OH:18].[CH2:22]([OH:24])[CH3:23]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]([CH2:12][C:13]([O:24][CH2:22][CH3:23])=[O:18])=[O:11]
Reactant: CCO
Reactant: O=C(C=C(Cl)Cl)c1cc(F)c(Cl)cc1Cl
Reactant: O=S(=O)(O)O
Agent: [Na]
Solvent: ClCCl
Product: CCOC(=O)CC(=O)c1cc(F)c(Cl)cc1Cl
Yield: 79.9 %

Procedure:
28.8 g (0.1 mole) of 2,2-dichlorovinyl 2,4-dichloro-5-fluoro-phenyl ketone are added in portions to a solution of 4.6 g of sodium in 80 ml of absolute ethanol at 0°-5° C., while cooling (ice/methanol) and stirring. When the exothermic reaction has subsided, the mixture is stirred at room temperature for a further 30 minutes, the solvent is stripped off in vacuo and the residue is taken up in 100 ml of methylene chloride. The mixture is shaken thoroughly with 100 ml of 2N sulphuric acid, the methylene chloride solution is separated off in a separating funnel and the aqueous phase is extracted another three times with 50 ml of methylene chloride each time. The combined methylene chloride solutions are washed with 100 ml of saturated sodium chloride solution and dried over sodium sulphate. The solvent is then distilled off in vacuo. The brown oily residue crystallizes on standing. Distillation under a fine vacuum gives 22.3 g (79.9%) of ethyl 2,4-dichloro-5-fluoro-benzoylacetate of boiling point 125°-126° C./0.16 mbar. Colorless crystals of melting point 44°-45° C.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([S@@:4]([NH:6][C@:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:12])[CH2:8][C:9]([OH:11])=O)=[O:5])[CH3:3].[C:20]1([CH3:27])[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:19][C:2]([CH3:1])([S@@:4]([NH:6][C@:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:12])[CH2:8][C:9]([NH:26][C:22]1[CH:21]=[C:20]([CH3:27])[CH:25]=[CH:24][CH:23]=1)=[O:11])=[O:5])[CH3:3]
Reactant: Cc1cccc(N)c1
Reactant: CC(C)(C)[S@](=O)N[C@](C)(CC(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1cccc(NC(=O)C[C@@](C)(N[S@@](=O)C(C)(C)C)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.1 %

Procedure:
To a solution of (R)-3-((S)-1,1-dimethylethylsulfinamido)-3-phenylbutanoic acid (266 mg, 0.94 mmol) in CH2Cl2 (5 mL) was added m-tolylamine (111 mg, 1.03 mmol), DCC (212 mg, 1.03 mmol) and DMAP (11.5 mg, 0.094 mmol) at 0° C. Then the reaction mixture was stirred at room temperature overnight. The residue was purified by preparative TLC to give (R)-3-((S)-1,1-dimethylethylsulfinamido)-3-phenyl-N-m-tolylbutanamide (25 mg, 7%). 1H NMR (CDCl3): 1.10-1.20 (m, 12H), 1.51-1.65 (m, 11H), 3.10-3.30 (m, 2H), 4.25 (s, 1H), 6.80-6.90 (m, 1H), 7.06-7.15 (m, 1H), 7.28-7.48 (m, 5H), 7.50-7.60 (m, 2H), 8.95 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.[C:11]([O:16][CH3:17])(=[O:15])[C:12]([CH3:14])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[H][H]>C(O)C.[Pd]>[CH3:17][O:16][C:11](=[O:15])[C@H:12]([CH3:14])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)=O
Reactant: [H][H]
Reactant: CC(=O)c1ccc(N)cc1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCc1ccc(N[C@@H](C)C(=O)OC)cc1

Procedure:
A solution of 0.68 g (5 mmol) of 4′-aminoacetophenone (Aldrich), 0.60 mL of 90% methyl pyruvate (Aldrich) and 0.05 g (0.25 mmol) of p-toluenesulfonic acid in ethanol was hydrogenated in the presence of a catalytic amount of 10% Pd/C at from 30 to 15 psi of hydrogen for 16 hours. The catalyst was removed by filtering the reaction mixture through Celite and the solvent was evaporated to provide the crude product. The product was purified by column chromatography (silica gel using 1:9 EtOAc/hexanes as the eluant) to provide the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][C:7]([CH3:14])([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=O.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)(Cl)Cl>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][CH2:1][C:3]2[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=2)[O:6][C:7]([CH3:14])([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(C)(C)Oc1cccc(C=O)c1
Reactant: NCc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(C)(C)Oc1cccc(CNCc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Ethyl 2-(3-formylphenoxy)-2-methylpropionate (25 g, 105.8 mmol) was dissolved in 1,2-dichloroethane (300 mL). Subsequently, 4-chlorobenzylamine (15.44 mL, 127.0 mmol) and acetic acid (7.26 mL, 127.0 mmol) were added thereto, and the resultant mixture was stirred for 20 minutes at 0° C. Subsequently, sodium (triacetoxy)borohydride [NaBH(OAc)3 (26.91 g, 127.0 mmol)] was added thereto, and the mixture was stirred for five hours at room temperature. After completion of reaction, chloroform was added. Washing was performed sequentially with aqueous saturated sodium bicarbonate, water, and saturated brine, followed by drying over magnesium sulfate. The reaction mixture was subjected to filtration, concentration under reduced pressure, and purification by silica gel column chromatography (chloroform/methanol=10/1), whereby a yellow oil was obtained (35.27 g, 92%).
Reaction SMILES: [CH:1](=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].O.C(OCC)(=O)C.[CH3:20][C:21]([CH3:23])=[O:22]>>[C:4]1([CH:3]=[CH:2][CH:1]=[CH:20][C:21](=[O:22])[CH3:23])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=CC=Cc1ccccc1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)C=CC=Cc1ccccc1
Reaction time: 0.5 h
Yield: 91 %

Procedure:
In a 250 ml single neck flask was charged 13.2 g (100 mmoles,1.0 eq) of cinnamaldehyde dissolved in 30 ml of acetone. To this was added 5 g of 10% aqueous sodium hydroxide solution (12.5 mmoles, 0.125 eq), dropwise and during the course of addition, temperature was kept no higher than 25° C., while the mixture was agitated continuously for 30 minutes. To the mixture was added 50 ml of water, followed by 100 ml of ethyl acetate, the phases were separated and the organic phase was washed with water three times and then dried, and concentrated to obtain 15.7 g of 4-(2-phenylethenyl)-3-buten-2-one as a faintly yellow oil in 91% yield.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13](=[O:16])[N:12]([CH2:17][C:18]3[CH:19]=[C:20]([C:24]4[N:29]=[CH:28][C:27]([O:30][CH2:31][CH:32]5[CH2:37][CH2:36][N:35]([C:38](OC(C)(C)C)=O)[CH2:34][CH2:33]5)=[CH:26][N:25]=4)[CH:21]=[CH:22][CH:23]=3)[N:11]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[NH2:2].C=O>C(O)=O.O>[CH3:38][N:35]1[CH2:34][CH2:33][CH:32]([CH2:31][O:30][C:27]2[CH:26]=[N:25][C:24]([C:20]3[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=3)[CH2:17][N:12]3[C:13](=[O:16])[CH:14]=[CH:15][C:10]([C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[C:1]([NH2:2])=[O:3])=[N:11]3)=[N:29][CH:28]=2)[CH2:37][CH2:36]1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cnc(-c3cccc(Cn4nc(-c5cccc(C(N)=O)c5)ccc4=O)c3)nc2)CC1
Agent: C=O
Solvent: O=CO
Solvent: O
Product: CN1CCC(COc2cnc(-c3cccc(Cn4nc(-c5cccc(C(N)=O)c5)ccc4=O)c3)nc2)CC1
Temperature: 110 °C
Reaction time: 48 h

Procedure:
1.25 g (2.1 mmol) of tert-butyl 4-(2-{3-[3-(3-carbamoylphenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yloxymethyl)piperidine-1-carboxyl-ate are dissolved in 6 ml of formic acid, and 500 μl (6.3 mmol) of 35% formaldehyde solution in water are added. The reaction mixture is stirred at 110° C. for 48 h. The reaction mixture is evaporated, taken up in dichloro-methane, washed with saturated sodium hydrogencarbonate solution, dried over sodium sulfate and purified by means of column chromatography on silica gel. ESI: 511 (M+H);
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:10].[OH:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(#N)C>[CH2:12]([NH:11][C:9](=[O:10])[CH2:8][N:26]1[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][CH2:20][OH:19])[CH2:24][CH2:25]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCNC(=O)CBr
Reactant: OCCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCNC(=O)CN1CCN(CCCO)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.5 %

Procedure:
Potassium carbonate (2.49 g, 18 mmol) was added to a solution of 2-bromo-N-heptylacetamide (3.30 g, 15 mmol) obtained in Example 16 and 1-(3-hydroxypropyl)piperazine (2.16 g, 15 mmol) in acetonitrile (60 ml) and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated and the residue was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution successively and dried over anhydrous sodium carbonate and the residue obtained after evaporation of the solvent was purified by a silica gel column chromatography (75 g of silica gel; developing solvent, ammonia-saturated methanol:chloroform=1:20) to provide 4.38 g (yield 97%) of N-heptyl-2-[4-[3-hydroxypropyl]piperazin-1-yl]acetamide as colorless oil.
Reaction SMILES: [CH:1]([C:3]1[CH:21]=[CH:20][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1)=[O:2].[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[C@:30]([OH:45])([C@H:37]([S:39][CH:40]([CH2:43]O)[CH2:41][OH:42])[CH3:38])[CH2:31][N:32]1[CH:36]=[N:35][CH:34]=[N:33]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[C@@:30]([OH:45])([CH2:31][N:32]1[CH:36]=[N:35][CH:34]=[N:33]1)[C@H:37]([S:39][C@@H:40]1[CH2:41][O:42][C@@H:1]([C:3]2[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:17])[F:19])=[CH:12][CH:11]=3)=[O:8])=[CH:20][CH:21]=2)[O:2][CH2:43]1)[CH3:38]
Reactant: O=Cc1ccc(C(=O)Nc2ccc(C(F)(F)F)cc2)cc1
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: C[C@@H](S[C@H]1CO[C@H](c2ccc(C(=O)Nc3ccc(C(F)(F)F)cc3)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In the same manner as that described in Example 3(3), a reaction was carried out using 4-formyl-4′-(trifluoromethyl)benzanilide (300 mg, 1.0 mmol), (2R,3R)-2-(2,4-difluorophenyl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol (334 mg, 0.93 mmol) and p-toluenesulfonic acid monohydrate (318 mg, 1.7 mmol) and the reaction mixture was treated according to a similar procedure to that described in Example 3(3) to give the trans isomer of the title compound (275 mg, yield 47%) as a white solid and the cis isomer (58 mg, yield 10%) as a colorless oil. The trans isomer was recrystallized from ethyl acetate-hexane to give white powdery crystals.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH2:21]([NH2:26])[CH2:22][CH2:23][CH2:24][CH3:25].[BH4-].[Na+]>CO>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:26][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=1
Reactant: COc1cc(C=O)ccc1Oc1cnc(C(N)=O)cn1
Reactant: CCCCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCCNCc1ccc(Oc2cnc(C(N)=O)cn2)c(OC)c1
Reaction time: 8 h
Yield: 71.4 %

Procedure:
Place 5-(4-formyl-2-methoxyphenoxy)pyrazine-2-carboxamide (Example 719, Part A) (0.200 g, 0.732 mmol), amylamine (0.0670 g, 0.769 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (3.6 mL), cap and stir overnight. Add NaBH4 (ca. 3-5 eq in two portions) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 60% to 90% (5% (2.0 M NH3 in methanol) in ethyl acetate) in hexanes. Concentrate the fractions containing the product. Take the solid up in ethyl acetate (50 mL) and wash with 1.0 N NaOH to give the title compound (0.180 g, 71.7%): TOF MS ES+ 345.2 (M+H)+, HRMS calcd for C18H25N4O3 345.1927 (M+H)+, found 345.1926, time 0.52 min; HPLC [Waters XTerra™ 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 23 min], tR=10.4 min, 100% purity.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C=O>[CH2:15]([O:7][C:6]1[CH:5]=[CH:4][C:3]([Br:8])=[CH:2][CH:1]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccc(Br)cc1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(OCc2ccccc2)cc1
Temperature: 97.5 °C
Yield: 90.2 %

Procedure:
p-Bromophenol (25.0 g) and anhydrous potassium carbonate (20.0 g) were suspended in N,N-dimethylformamide (250 mL). To the suspension was added dropwise benzyl chloride (20.2 g) at room temperature. After heating at 95 to 100° C. for one hour, the reaction mixture was cooled to room temperature and water (400 mL) was added. After extraction with ethyl acetate, the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give the title compound (34.3 g) as milk-white crystals in a yield of 90%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[CH:22]=[N:23][NH:24][C:17]=23)[C:12]([CH3:25])=[CH:11][N:10]=1.[N:26]([CH2:29][CH3:30])=[C:27]=[O:28]>C(#N)C.N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[CH:22]=[N:23][N:24]([C:27]([NH:26][CH2:29][CH3:30])=[O:28])[C:17]=23)[C:12]([CH3:25])=[CH:11][N:10]=1
Reactant: Cc1cnc(-c2cc(F)ccc2F)nc1Nc1ccnc2cn[nH]c12
Reactant: CCN=C=O
Solvent: CC#N
Solvent: c1ccncc1
Product: CCNC(=O)n1ncc2nccc(Nc3nc(-c4cc(F)ccc4F)ncc3C)c21
Temperature: 70 °C

Procedure:
To N-(2-(2,5-Difluorophenyl)-5-methylpyrimidin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine (108 mg, 0.319 mmol) suspended in acetonitrile (3.2 mL) was added isocyanatoethane (125.3 μl, 1.60 mmol), 15 drops of pyridine and the mixture was heated at 70° C. overnight. The reaction was cooled to give a solid which was collected by filtration, rinsed with a acetonitrile, and dried under high vacuum to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (3H, t, J=7.20 Hz) 2.43 (3H, s) 3.37-3.48 (2H, m) 7.36-7.51 (2H, m) 7.85 (1H, ddd, J=9.22, 5.94, 3.03 Hz) 8.47-8.57 (1H, m) 8.65 (1H, s) 9.06 (1H, d, J=5.30 Hz) 9.13 (1H, t, J=5.94 Hz) 12.07 (1H, s). MS [M+H] found 410.4.
Reaction SMILES: [C:1]([N:20]1[C:28]2[CH:27]=[C:26]([NH:29]C(=O)OC)[N:25]=[CH:24][C:23]=2[C:22]([NH:34][C:35](=[O:44])[O:36][CH2:37]C2C=CC=CC=2)=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.CO.[Pd]>[NH2:29][C:26]1[N:25]=[CH:24][C:23]2[C:22]([NH:34][C:35](=[O:44])[O:36][CH3:37])=[N:21][N:20]([C:1]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:28]=2[CH:27]=1
Reactant: COC(=O)Nc1cc2c(cn1)c(NC(=O)OCc1ccccc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(N)ncc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.7 %

Procedure:
To a 50 mL round bottom flask charged with benzyl methyl (1-trityl-1H-pyrazolo[4,3-c]pyridine-3,6-diyl)dicarbamate (126 mg, 0.216 mmol) in ethyl acetate (4 ml) and methanol (4 ml) was added palladium on carbon (45.9 mg, 0.043 mmol). The flask was evacuated and back-filled with hydrogen gas using an attached balloon. This procedure was attempted a further two times. The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 16 h. The palladium was filtered off by passing the reaction mixture through celite and washing through with ethyl acetate (20 mL). The volatiles were removed in vacuo to afford crude methyl (6-amino-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate (95 mg, 0.211 mmol, 98% yield) as a white solid. MS ESI calc'd. For C27H24N5O2 [M+H]+ 450. found 450.
Reaction SMILES: [C:1]([C:3]1[C:8]([CH2:9][C:10]([O:12]C)=O)=[CH:7][CH:6]=[CH:5][N:4]=1)#[CH:2].C([N:16](CC)CC)C.Cl[C:22]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([CH:39]3[CH2:44][CH2:43][N:42](C(OC(C)(C)C)=O)[CH2:41][CH2:40]3)=[CH:35][CH:34]=2)[N:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:42]1[CH2:43][CH2:44][CH:39]([C:36]2[CH:37]=[CH:38][C:33]([NH:32][C:24]3[N:25]=[C:26]([CH2:2][CH2:1][C:3]4[C:8]([CH2:9][C:10]([NH2:16])=[O:12])=[CH:7][CH:6]=[CH:5][N:4]=4)[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:22][N:23]=3)=[CH:34][CH:35]=2)[CH2:40][CH2:41]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Reactant: CCN(CC)CC
Reactant: C#Cc1ncccc1CC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)Cc1cccnc1CCc1nc(Nc2ccc(C3CCNCC3)cc2)ncc1C(F)(F)F
Temperature: 120 °C
Yield: 88.1 %

Procedure:
A solution of methyl 2-(2-ethynylpyridin-3-yl)acetate (I120) (43.6 mg, 0.249 mmol) in dimethylformamide (2 mL) and triethylamine (107 μL, 0.765 mmol) were added to a mixture of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I45) (87.4 mg, 0.191 mmol), Pd(PPh3)2Cl2 (13 mg, 0.019 mmol), Cu(I)I (5.5 mg, 0.029 mmol) and triphenylphosphine (7.5 mg, 0.017 mmol) in dimethylformamide (2 mL). The reaction mixture was heated under microwave irradiation at 120° C. for 10 minutes. The cooled mixture was diluted with EtOAc and passed through a plug of celite, washing with ethyl acetate (100 mL). The solvent was removed under reduced pressure and the residue partitioned between EtOAc (70 mL) and water (50 mL). The layers separated and the aqueous layer extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (70 mL) and dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give a dark brown residue. The residue was purified by column chromatography on silica gel (0-40% EtOAc in petroleum benzine 40-60° C.) to yield the title compound (I121) (81.5 mg, 72%) as a brown viscous oil which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:46])[CH2:13][C:12]2[CH:11]=[C:10]3[N:5]([CH2:6][CH2:7][N:8]([C:15]4[C:20]([CH2:21][OH:22])=[C:19]([C:23]5[CH:24]=[C:25]([NH:31][C:32]6[CH:37]=[CH:36][N:35]=[C:34]([N:38]7[CH2:42][CH2:41][CH:40]([C:43](O)=[O:44])[CH2:39]7)[N:33]=6)[C:26](=[O:30])[N:27]([CH3:29])[CH:28]=5)[CH:18]=[CH:17][N:16]=4)[C:9]3=[O:14])[C:4]=2[CH2:3]1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)O[N:58]1[C:62]2N=CC=C[C:61]=2[N:60]=N1>C(N(CC)CC)C.NCC#N.C1COCC1>[C:62]([CH2:61][NH:60][C:43]([CH:40]1[CH2:41][CH2:42][N:38]([C:34]2[N:33]=[C:32]([NH:31][C:25]3[C:26](=[O:30])[N:27]([CH3:29])[CH:28]=[C:23]([C:19]4[CH:18]=[CH:17][N:16]=[C:15]([N:8]5[CH2:7][CH2:6][N:5]6[C:10](=[CH:11][C:12]7[CH2:13][C:2]([CH3:46])([CH3:1])[CH2:3][C:4]=76)[C:9]5=[O:14])[C:20]=4[CH2:21][OH:22])[CH:24]=3)[CH:37]=[CH:36][N:35]=2)[CH2:39]1)=[O:44])#[N:58]
Reactant: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CC(C)(C)C5)C3=O)c2CO)cc(Nc2ccnc(N3CCC(C(=O)O)C3)n2)c1=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CC(C)(C)C5)C3=O)c2CO)cc(Nc2ccnc(N3CCC(C(=O)NCC#N)C3)n2)c1=O
Temperature: 30 °C
Yield: 28.3 %

Procedure:
A 50 mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 102c (100 mg, 0.16 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU, 152 mg, 0.40 mmol), triethylamine (TEA, 8 drops), THF (10 mL), and 2-aminoacetonitrile (5 drops). The mixture was heated at 30° C. for 5 h. After this time the reaction was cooled to room temperature. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 102 (30 mg, 28%) as a white solid. MS: [M+H]+ 663.2. 1H NMR (500 MHz, DMSO-d6) δ 8.88 (d, J=6.0 Hz, 1H), 8.81 (s, 1H), 8.74 (s, 1H), 8.47 (d, J=5.0 Hz, 1H), 7.95 (d, J=5.5 Hz, 1H), 7.71 (s, 1H), 7.35 (d, J=4.5 Hz, 1H), 6.58-6.55 (m, 2H), 5.02 (s, 1H), 4.53-4.51 (m, 1H), 4.43-4.40 (m, 1H), 4.23-4.15 (m, overlap, 5H), 3.86-3.84 (m, 1H), 3.72-3.69 (m, 1H), 3.62 (s, 3H), 3.60-3.56 (m, 1H), 3.51-3.43 (m, 2H), 3.10-3.08 (m, 1H), 2.62-2.54 (m, 2H), 2.43 (s, 2H), 2.18-2.16 (m, 1H), 2.06-2.04 (m, 1H), 1.22 (s, 6H).
Reaction SMILES: [CH3:1][CH:2]([CH2:13][Cl:14])[CH2:3][Si:4]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)(Cl)Cl.[CH2:15]([OH:18])[CH2:16][CH3:17].Cl>>[CH3:1][CH:2]([CH2:13][Cl:14])[CH2:3][Si:4]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([O:18][CH2:15][CH2:16][CH3:17])[O:18][CH2:15][CH2:16][CH3:17]
Reactant: CC(CCl)C[Si](Cl)(Cl)C1CCCCC1
Reactant: CCCO
Agent: Cl
Product: CCCO[Si](CC(C)CCl)(OCCC)C1CCCCC1

Procedure:
The same apparatus as that described in Example 1 was used. 1367 g (5 mols) of (2-methyl-3-chloropropyl)-cyclohexyl-dichlorosilane were introduced into the flask. At a starting temperature of 60° C., 300 g (5 mols) of n-propanol were added at a uniform rate over a period of 140 minutes. Thereafter the mixture was heated in 120 minutes to 145° C., accompanied by the escape of dissolved hydrogen chloride. The system was from this time forward evacuated to such an extent that it began to boil at a sump temperature of 145° C. An additional 300 g (5 mols) of n-propanol were introduced into the boiling reaction mixture over a period of 140 minutes. The reaction mixture was allowed to react for 35 minutes more, and then the crude product was worked up by vacuum distillation.
Reaction SMILES: [C:1]1(=[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]2=[O:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][O:2]1.[CH2:20]=O.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CCO.O1CCOCC1>[C:1]1(=[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:20][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:11]2=[O:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][O:2]1
Reactant: C=O
Reactant: C1CCNCC1
Reactant: O=C1Nc2ccccc2C1=C1OCc2ccccc21
Solvent: C1COCCO1
Solvent: CCO
Product: O=C1C(=C2OCc3ccccc32)c2ccccc2N1CN1CCCCC1
Temperature: 25 °C
Yield: 62.2 %

Procedure:
A mixture of 3-(3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (4.32 g, 17.3 mmol), paraformaldehyde (0.99 g, 32.9 mmol), and piperidine (2.14 mL, 21.7 mmol) in 192 mL EtOH and 48 mL dioxane was heated at reflux for 18.5 h. The solution was concentrated in vacuo to a volume of 100 mL and then refluxed for 1 h to dissolve the precipitant. The mixture was allowed to cool to room temperature and the precipitate filtered to give the title compound (3.728 g) as a bright yellow solid. An additional 0.52 g of the title compound was obtained by crystallization of the filtrate from ethyl acetate. The two lots were combined to give 4.248 g (71%) of the title compound as a bright yellow solid.