Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH2:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12](=[O:20])[N:13]([CH3:19])[N:14]=[CH:15][C:16]=1[O:17]C)[CH3:4].Cl>C(OCC)(=O)C.O.O1CCOCC1>[CH2:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12](=[O:20])[N:13]([CH3:19])[N:14]=[CH:15][C:16]=1[OH:17])[CH3:4]
Reactant: CCc1ccccc1-c1c(OC)cnn(C)c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CCc1ccccc1-c1c(O)cnn(C)c1=O
Yield: 68.1 %

Procedure:
After 50 mL of water, 4.657 g of potassium hydroxide (content, 85%) and 5 mL of 1,4-dioxane were added to 3.193 g of 4-(2-ethylphenyl)-5-methoxy-2-methyl-3(2H)-pyridazinone (Compound II-1), the mixture was stirred and heated under reflux for 36 hours. After cooling, concentrated hydrochloric acid was added to the reaction mixture to acidify, to which 10 ml of water and 100 ml of ethyl acetate were added. The resulting mixture was filtered to remove insoluble substances and the filtrate was separate to two phase. The organic layer was washed with water and then a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The solid obtained was washed with a mixed solvent of ethyl acetate and hexane (1:2) to yield 2.050 g of the title compound as colorless crystals.
Reaction SMILES: C(OC(N1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[CH3:31][O:32][C:33]1[CH:38]=[CH:37]C(CCN)=[CH:35][CH:34]=1>>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:12]([CH2:11][CH2:10][NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Reactant: COc1ccc(CCN)cc1
Product: COc1ccc(CCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 2-(4-methoxyphenyl)ethylamine instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 393 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (1H, br. s.) 10.24 (1H, s) 8.14 (0H, t) 8.02 (1H, d, J=5.42 Hz) 7.77 (1H, d, J=5.42 Hz) 7.46 (1H, d, J=5.37 Hz) 7.31 (1H, dd, J=3.34, 2.56 Hz) 7.13 (2H, d, J=8.69 Hz) 6.76-6.84 (3H, m) 6.44 (1H, dd, J=3.49, 1.93 Hz) 3.69 (3H, s) 3.37-3.48 (2H, m) 2.75 (2H, t, J=7.37 Hz)
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH:2]=[CH2:3].[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][CH:13]=1)=O.Cl.[NH2:22][OH:23].C(OC)(OC)OC>C1COCC1.N1C=CC=CC=1>[OH:23][N:22]=[C:10]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:7][CH2:6][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:8])=[O:20])=[CH:14][CH:13]=1)[CH3:9]
Reactant: NO
Reactant: CC(=O)c1ccc(N=C=O)cc1
Reactant: C=CCOC(=O)CN
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: COC(OC)OC
Product: C=CCOC(=O)CNC(=O)Nc1ccc(C(C)=NO)cc1
Reaction time: 3 h

Procedure:
A solution of 0.02 mol glycine allyl ester in 40 mL of THF is added dropwise to a solution of 0.02 mol of 4-isocyanatoacetophenone and 5 mL of pyridine in 40 mL of THF and the reaction mixture is stirred for 3 hours. The solvent is then removed by rotary evaporator. The residue is dispersed in 50 mL of CH3OH, and 0.022 mol of hydroxylamine hydrochloride and 0.06 mol of trimethyl orthoformate are added. The reaction mixture is heated to reflux for 1 hour. The solvent is removed by rotary evaporator to give the product, N-[4-(1-hydroxyiminoethyl)phenyl]-N'-allyloxycarbonylmethylurea.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7]C(=O)[C:5]2=[O:12].[OH:13]O.Cl>[OH-].[Na+]>[NH2:7][C:8]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=1[C:5]([OH:12])=[O:13]
Reactant: OO
Reactant: O=C1Nc2ccc(F)cc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(F)cc1C(=O)O
Reaction time: 0.33 h
Yield: 80.9 %

Procedure:
A stirred solution of 5-fluoroisatin (39 g, 0.236 mol) in NaOH (5%, 500 mL) was treated dropwise over 10 min with 30% H2O2 (57 g, calculated to contain 17 g, 0.5 mol). After another 20 min of being stirred, during which became warm and effervesced, the solution was cooled in an ice-bath and acidified to pH=4 with 3 M HCl. The precipitated solid was collected and dried in air to obtain 2-amino-5-fluoro-benzoic acid 1 as a beige powder (29.6 g, 80%). 1H NMR (DMSO-d6) δ 7.3-8.2 (m, 2H), 7.08 (d, J=9 Hz, 1H), 6.63 (d, J=9 Hz, 2H), 2.13 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].C(N(CC)CC)C.[CH3:17][Si:18](Br)([CH3:20])[CH3:19]>C1C=CC=CC=1>[CH3:17][Si:18]([CH3:20])([CH3:19])[NH:4][C:3]1[C:2]([Cl:1])=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:9]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: C[Si](C)(C)Br
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C[Si](C)(C)Nc1c(Cl)cccc1Cl
Yield: 75.1 %

Procedure:
A solution of 60 ml of benzene, 5.0 g (30.9 mmole) of 2,6-dichloroaniline, 10.6 ml (76.0 mmole) of triethylamine, and 8.08 ml (61.1 mmole) of trimethylsilyl bromide was heated at reflux for 54 hours, cooled, filtered, and the solvent was removed from the filtrate in vacuo. The residue was evacuated at 1 mm to remove any excess trimethylsilyl bromide. The residual mixture was filtered into a round-bottomed flask and distilled using a short Vigreaux column to provide 5.43 g (23.2 mmole, 75.0 percent yield) of the N-trimethylsilyl-2,6-dichloroaniline as a 97 percent pure amber oil, bp 74° C.-75° C. at 0.4 mm.
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]([C:15]1([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.CO>[NH:12]1[C:11]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:5]=[C:13]1[C:15]1([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16]1
Reactant: Nc1cnccc1NC(=O)C1(NC(=O)OCc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: O=C(NC1(c2nc3cnccc3[nH]2)CC1)OCc1ccccc1
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To a medium size microwave vial was added 5 mL of acetic acid and 850 mgs of the crude reaction mixture prepared in the previous step (benzyl 1-(4-aminopyridin-3-lcarbamoyl)cyclopropylcarbamate and benzyl 1-(3-aminopyridin-4-ylcarbamoyl)cyclopropylcarbamate). The vial was sealed and the mixture heated at 120° C. for 70 minutes in the microwave. The vessel was cooled to near 0° C. and 50 mL of cold saturated sodium carbonate was added along with 100 mL of 10:1 DCM/methanol. The product was extracted; the organics washed with brine, dried over magnesium sulfate and evaporated. The product mixture was taken up in 15 mL of methanol and purified using a Shimadzu preparative HPLC employing methanol/water/trifluoroacetic acid where solvent A was 10% methanol/90% water/0.1% trifluoroacetic acid and solvent B was 10% water/90% methanol/0.1% trifluoroacetic acid with a Phenomenex-Luna 10 μm C18 30×100 mm column at a gradient of 0-100% B and a flow rate of 40 mL/min. over 15 minutes with a 10 minute hold. Solvent was removed giving a 70% yield of benzyl 1-(1H-imidazo[4,5-c]pyridin-2-yl)cyclopropylcarbamate as a light yellow solid. 1H NMR (400 MHz, CD3OD) δ ppm 1.44-1.59 (m, 2 H), 1.68-1.83 (m, 2 H), 5.05-5.14 (m, 2 H), 6.99-7.14 (m, 1 H), 7.19-7.41 (m, 4 H), 7.88-7.97 (m, 1 H), 8.40 (d, J=6.5 Hz, 1 H), 8.97 (s, 1H). LCMS rt=1.483 min., m/z 309.2 (M+H), 94.5% purity.
Reaction SMILES: C(OC([N:7]1[CH2:11][C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:9][C@H:8]1[CH2:20][CH2:21]OS(C)(=O)=O)=O)C=C.[Na].[NH:28]1[CH:32]=[N:31][CH:30]=[N:29]1.CN(C)[CH:35]=[O:36]>>[CH2:10]([O:12][N:7]1[CH2:11][C@H:10]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])[C:9](=[C:35]=[O:36])[C@H:8]1[CH2:20][CH2:21][N:28]1[CH:32]=[N:31][CH:30]=[N:29]1)[CH:9]=[CH2:8]
Reactant: c1nc[nH]n1
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCOS(C)(=O)=O
Reactant: CN(C)C=O
Agent: [Na]
Product: C=CCON1C[C@H](O[Si](C)(C)C(C)(C)C)C(=C=O)[C@H]1CCn1cncn1
Temperature: 60 °C
Reaction time: 3.5 h

Procedure:
A mixture of (2R,4R)-1-allyloxycarbonyl-4-(t-butyldimethylsilyloxy)-2-(2-methanesulfonyloxyethyl)pyrrolidine (10.0 g) and 1,2,4-triazole sodium salt (2.45 g) in dimethylformamide (50 ml) was stirred at 60° C. for 3.5 hours. After cooling to room temperature, the mixture was quenched by the addition of water (100 ml) and extracted with a mixture of hexane and ethyl acetate (2:1, 50 ml×4). The combined extract was washed with water (400 ml), brine (100 ml) and dried over magnesium sulfate. Evaporation of the solvent gave (2R,4R)-1-allyloxy-carbonyl-4-(t-butyldimethylsilyloxy)-2-[2-(1,2, 4-triazol-1-yl)ethyl]pyrrolidine (8.82 g) as a light brown paste.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[N:9][C:8]([C@@H:20]([NH2:22])[CH3:21])=[CH:7]2.Cl[C:24]1[C:25]2[N:32]=[CH:31][S:30][C:26]=2[N:27]=[CH:28][N:29]=1.C(N(CC)CC)C>CCCCO>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[N:9][C:8]([C@@H:20]([NH:22][C:24]1[C:25]3[N:32]=[CH:31][S:30][C:26]=3[N:27]=[CH:28][N:29]=1)[CH3:21])=[CH:7]2
Reactant: C[C@H](N)c1cc2cccc(Cl)c2c(CCN2CCOCC2)n1
Reactant: Clc1ncnc2scnc12
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: C[C@H](Nc1ncnc2scnc12)c1cc2cccc(Cl)c2c(CCN2CCOCC2)n1
Temperature: 25 °C

Procedure:
A mixture of (S)-1-(8-chloro-1-(2-morpholinoethyl)isoquinolin-3-yl)ethanamine 71 (100 mg, 0.31 mmol, 1 eq), 7-chlorothiazolo[5,4-d]pyrimidine (E-4) (108 mg, 0.63 mmol, 2 eq) and triethylamine (130 mg, 1.25 mmol, 4.0 eq) in n-BuOH (40 mL) was stirred at reflux for 16 h. The reaction mixture was cooled to RT and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (1-5% MeOH-DCM) to afford the product (S)—N-(1-(8-chloro-1-(2-morpholinoethyl)isoquinolin-3-yl)ethyl)thiazolo[5,4-d]pyrimidin-7-amine 72. ESI-MS m/z: 455.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][OH:14])=[N:10][CH:11]=1.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.[H-].[Na+].O>CN(C)C=O>[CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][O:14][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:10][CH:11]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COCOCc1ccc(CCO)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOCc1ccc(CCOc2ccc([N+](=O)[O-])cc2)nc1
Yield: 78.5 %

Procedure:
To a solution of 2-(5-methoxymethoxymethyl-2-pyridyl)ethanol (11.6 g) and 4-fluoronitrobenzene (8.5 g) in N,N-dimethylformamide (100 ml) was added by portions sodium hydride in oil (60%, 2.8 g) with ice-cooling. The reaction mixture was stirred with ice-cooling for additional 1 hour, poured into water and then extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The oily residue was subjected to silica gel column chromatography. A fraction eluted with chloroform-methanol (40:1, v/v) gave 5-methoxymethoxymethyl-2-[2-(4-nitrophenoxy)ethyl]pyridine (14.7 g, yield: 79%) as oil.
Reaction SMILES: S(=O)(=O)(O)O.[CH:6]([O:11][CH3:12])(OC)OC.[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])C[CH2:17]2.CC1C=CC(S(OI(O)C2C=CC=CC=2)(=O)=O)=CC=1>CO>[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[CH:6]([O:11][CH3:12])[CH2:17]2
Reactant: COC(OC)OC
Reactant: O=C1CCc2cc(Cl)ccc21
Agent: Cc1ccc(S(=O)(=O)OI(O)c2ccccc2)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC1Cc2cc(Cl)ccc2C1=O
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
A 22 L multi-neck reactor equipped with a temperature probe, a nitrogen inlet, a cooling bath and an overhead mechanical stirrer was charged with methanol (2400 mL) and cooled to −20° C. Sulfuric acid (384 mL, 7.22 mol) was charged via an addition funnel over 1 hour. The temperature was maintained at about −25° C. and peaked at −18° C. for ˜5 minutes. Trimethyl orthoformate (906 mL, 8.3 mol) was added over 10 minutes followed by 5-chloro-2,3-dihydro-1H-inden-1-one (17) (600.00 g, 3.61 mol) as a solid. The internal temperature slightly increased by 2° C. Koser's reagent (1553 g, 3.97 mol) was dissolved in methanol (2400 mL) over 20 minutes which was added to the reaction vessel over 1 hour and 15 minutes. The addition was exothermic and the internal temperature was maintained at about −20° C. Upon completion of addition, the dark red solution was stirred at −20° C. for 1 hour, at which point HPLC analysis indicated complete conversion to the desired product. Water (7200 mL) was added in small portions. After the addition of a small amount of water (˜50 mL), the product suddenly precipitated. The agitation became slow and difficult. The mixture was stirred at 0˜10° C. for 1 hour and was filtered through a 3000 mL coarse fritted funnel. The filtration was complete in 2 hours and the cake was rinsed with water (7200 mL) until the pH of the filtrate reached about 5. The wet cake was added back to the reactor and heptane (3000 mL) was added. The mixture was stirred at −20° C. for 1 h and filtered. The cake was rinsed with heptanes (1200 mL) and conditioned for 30 minutes. The wet cake was dried under high vacuum for 3 days to completely remove heptane and reduce the water content to <2%. The material had purities of 99% (AUC by HPLC) and 93 wt % by wt % assay (622.88 g, 88%). 1H NMR (300 MHz, CDCl3, δ): 7.69 (m, 1H), 7.43 (s, 1H), 7.38 (m, 1H), 4.18 (m, 1H), 3.63 (s, 3H), 3.47 (m, 1H) and 2.99 (m, 1H).
Reaction SMILES: Br[C:2]([CH:16]([CH3:18])[CH3:17])=[C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1COCC1.C([Li])CCC.Cl[P:30]([CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)[CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>O>[C:4]1([C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:2]([P:30]([CH:37]2[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]2)[CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH:16]([CH3:18])[CH3:17])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)C(Br)=C(c1ccccc1)c1ccccc1
Reactant: ClP(C1CCCCC1)C1CCCCC1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(=C(c1ccccc1)c1ccccc1)P(C1CCCCC1)C1CCCCC1
Temperature: -70 °C
Reaction time: 3 h
Yield: 43 %

Procedure:
Into a reactor were introduced 1.20 g (4.00 mmol) of the 2-bromo-1,1-diphenyl-3-methylbutene and 12 mL of THF under a nitrogen atmosphere. The contents were cooled to −70° C., and 2.8 mL (4.4 mmol; 1.6 M hexane solution) of butyllithium was gradually added dropwise thereto. The resultant mixture was stirred at that temperature for 30 minutes. Thereafter, 1.1 mL (4.8 mmol) of chlorodicyclohexylphosphine was added thereto, and this mixture was stirred at that temperature for 3 hours and then heated to room temperature over 13 hours. Water was added to the reaction mixture. The organic layer was extracted with ethyl acetate, and the extract was dried with anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure. The concentrate was recrystallized from ethanol and toluene to obtain 0.72 g (43%) of the target compound as white crystals.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:14]2[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][CH:15]=2)[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[C:30]([O:29][C:27]([N:13]([C@@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[C:14]1[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][CH:15]=1)=[O:28])([CH3:31])([CH3:32])[CH3:33]
Reactant: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCN(Cc3ccccc3)C2)nc1
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCNC2)nc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
To a solution of ethyl (2E)-3-{6-[[(3R)-1-benzyl-3-pyrrolidinyl](tert-butoxycarbonyl) amino]-3-pyridyl}acrylate (5.45 g) in toluene (55 ml) was added 1-chloroethyl chloroformate (2.59 g) at room temperature and stirred at 20° C. for 1 hour. 1-Chloroethyl chloroformate (795 mg) and N,N-diisopropylethylamine (0.736 ml) was added to the mixture, and the solution was stirred at 20° C. for 15 minutes. After it was concentrated under reduced pressure, the resulting residue was dissolved in EtOH (70 ml). The mixture was stirred at 65° C. for 30 minutes, and concentrated under reduced pressure. The residue was poured into a mixture of aq NaHCO3 solution (80 ml) and dichloromethane (100 ml). The organic layer was separated and dried over sodium sulfate, and evaporated under reduced pressure to give crude oil. The oil was purified by column chromatography (silica gel 125 g, dichloromethane/MeOH (60/1 to 15/1) to give ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate as oil (2.0 g).
Reaction SMILES: C([BH3-])#N.[NH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C(O)(=O)C.O=[CH:15][CH2:16][CH2:17][C:18]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[N:21]=[C:20]([C:34]#[N:35])[N:19]=1>C(#N)C>[N:4]1([CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[N:21]=[C:20]([C:34]#[N:35])[N:19]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: N#Cc1nc(CCC=O)cc(-c2cccc(C(F)(F)F)c2)n1
Reactant: C1CCNCC1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CC#N
Product: N#Cc1nc(CCCN2CCCCC2)cc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 150 °C

Procedure:
To a suspension of macroporous cyanoborohydride (102 mg, 2.35 mmol/g) in acetonitrile (0.5 mL), was added piperidine (19 μL), acetic acid (0.1 mL), and a solution of 4-(3-oxo-propyl)-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile (49 mg) in acetonitrile (0.5 mL). The mixture was heated in the microwave at 150° C. for 10 min, filtered in a fritted tube using a Vacmaster multi-filtration apparatus, and purified by preparative-HPLC. 4-(3-Piperidin-1-yl-propyl)-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile was isolated as a clear gum (12 mg).
Reaction SMILES: C([N:3]=[C:4]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH:5][C@@H:6]1[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH3:19])([CH3:18])[C@H:7]1[OH:20])#N.[C:28](OC(=O)C)(=[O:30])[CH3:29]>N1C=CC=CC=1>[C:28]([O:20][C@H:7]1[C@H:6]([NH:5][C:4]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[NH:3])[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]1([CH3:18])[CH3:19])(=[O:30])[CH3:29]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=NC#N)Nc2ccccc2)[C@@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1[C@H](NC(=N)Nc2ccccc2)c2cc(C#N)ccc2OC1(C)C
Yield: 112.4 %

Procedure:
The solution of the title compound from Example 3 (2.52 g, 6.98 mmoles) and acetic anhydride (1.0 g, 9.8 mmoles) in pyridine (25 ml) was stirred for 60 hours at room temperature. The crude reaction mixture was partitioned between ethyl acetate and 5% aqueous hydrogen chloride. The organic layer was washed with distilled water, saturated sodium hydrogen carbonate solution, saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was recovered under vacuum to obtain 2.97 g of a white solid. The crude reaction product was recrystallized from ethanol in two crops to obtain 2.24 g of the title compound as a pure white solid, m.p. 239°-240° C. 1H NMR (DMSO-d6) δ 9.36 (s, 1H), 7.63 (m, 3H), 7.35 (m, 2H), 7.20 (m, 3H), 6.97 (d, J=8.80 Hz, 1H), 5.23 (m, 2H), 2.17 (s, 3H), 1.34 (s, 3H), 1.25 (s, 3H). 13C NMR (DMSO-d6) δ 169.69, 158.69, 155.75, 136.95, 132.94, 132.66, 129.03, 125.28, 124.25, 123.79, 118.86, 118.09, 116.62, 103.31, 78.43, 72.07, 49.49, 25.85, 20.67, 19.54.