Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:18]=[C:5]2[N:6]=[C:7]([CH3:17])[C:8]([CH:11]([OH:16])[C:12]([O:14][CH3:15])=[O:13])=[C:9]([Cl:10])[N:4]2[N:3]=1.C(Cl)Cl.Cl(O)(=O)(=O)=O>C(OC(C)(C)C)(=O)C>[Br:1][C:2]1[CH:18]=[C:5]2[N:6]=[C:7]([CH3:17])[C:8]([CH:11]([O:16][C:8]([CH3:11])([CH3:9])[CH3:7])[C:12]([O:14][CH3:15])=[O:13])=[C:9]([Cl:10])[N:4]2[N:3]=1
Reactant: COC(=O)C(O)c1c(C)nc2cc(Br)nn2c1Cl
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Solvent: CC(=O)OC(C)(C)C
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2cc(Br)nn2c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 120 %

Procedure:
To a suspension of methyl 2-(2-bromo-7-chloro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (80 mg, 0.239 mmol) in tert-butyl acetate (2 mL) at room temperature was added CH2Cl2 (2 mL) followed by perchloric acid (0.022 mL, 0.359 mmol). The reaction mixture was stirred for 4 h at room temperature. The reaction mixture was quenched with water and diluted with ethyl acetate. The organic phase was washed with saturated NaHCO3 and dried over sodium sulfate. The solvent was evaporated. Purification by silica gel chromatography provided the title compound (56 mg, 59.9%). 1H NMR (500 MHz, MeOD) δ 1.27 (9 H, s), 2.62 (3 H, s), 3.74 (3 H, s), 5.75 (1 H, s), 6.75 (1 H, s).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Br[CH2:30][CH2:31][C:32]#[N:33]>C(Cl)Cl>[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]([N:23]1[CH2:28][CH2:27][N:26]([CH2:30][CH2:31][C:32]#[N:33])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N#CCCBr
Reactant: c1ccc(C(c2ccccn2)N2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#CCCN1CCN(C(c2ccccc2)c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.7 %

Procedure:
1.05 g of N,N-diisopropyl-N-ethylamine was added, with stirring, to a solution of 2.0 g of 4-[α-(2-pyridyl)benzyl]piperazine and 1.0 g of 3-bromopropionitrile in 20 ml of methylene chloride, whilst ice-cooling, and the mixture was stirred at room temperature for 16 hours. At the end of this time, the mixture was poured into ice-water and extracted with chloroform. The extracts were combined and dried over anhydrous sodium sulfate, after which the solvent as removed by evaporation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 20:1 by volume mixture of ethyl acetate and ethanol as the eluent, to give 2:1 g (yield 88%) of the title compound as crystals, melting at 114°-116° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[CH2:26][CH2:25]3)=[CH:19][CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.C(O)C>Cl>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[CH2:26][CH2:25]3)=[CH:21][CH:22]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OC3CCN(c4ccccn4)CC3)cc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1nn(Cc2ccc(OC3CCN(c4ccccn4)CC3)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.5 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-[4-[1-(2-pyridyl)piperidine-4-yloxy]benzyl]-1H-pyrazole-4-yl]propionate (598 mg), 1 N aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for 3 hours, diluted with 1 N hydrochloric acid (2.5 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained crystals were collected by filtration, and 3-[3-ethoxy-1-[4-[1-(2-pyridyl)piperidine-4-yloxy]benzyl]-1H-pyrazol-4-yl]propionic acid (408 mg, yield: 72%) was obtained. This was recrystallized from ethanol-hexane. Melting point: 142–143° C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][NH:4][C:5](=[O:22])[C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][O:16][C:17](=[O:19])[CH3:18])[C:7]=1[OH:21].C[O-].[Na+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[F:24][C:2]([F:1])([F:23])[CH2:3][NH:4][C:5](=[O:22])[C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][O:16][C:17](=[O:19])[CH3:18])[C:7]=1[O:21][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)OCC(=O)Nc1cc(F)cc(C(=O)NCC(F)(F)F)c1O
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)OCC(=O)Nc1cc(F)cc(C(=O)NCC(F)(F)F)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
7.75 g (22 mmol) of 3-acetoxyacetamido-5-fluoro-2-hydroxy-benzoic acid-(2,2,2,-trifluoro-ethyl)amide (Example 37d) is dissolved in 50 ml of dry THF. 1.35 g (25 mmol) of sodium methylate is added, stirred for 15 minutes at room temperature, 4.27 g (25 mmol) of benzylbromide is added and refluxed for 1 hour. The reaction solution is then cooled to room temperature, NaBr is filtered off, the filtrate is concentrated by evaporation in a vacuum and the residue is chromatographed on silica gel 60 with ethyl acetate/hexane. 5.2 g=53.4% of the theoretical yield is obtained as an amorphous solid.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:48])[CH:5]([NH:15][C:16]([C:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[C:27]([O:29][C:30]3[CH:35]=[C:34]([C:36]([NH:38][C:39]4[CH:44]=[C:43]([CH3:45])[CH:42]=[CH:41][C:40]=4[F:46])=[O:37])[CH:33]=[CH:32][C:31]=3[F:47])[CH:26]=[CH:25][N:24]=2)[NH:20][CH:19]=1)=[O:17])[CH2:6][CH2:7][C:8]([O:10]C(C)(C)C)=[O:9])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([NH:3][C:4](=[O:48])[CH:5]([NH:15][C:16]([C:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[C:27]([O:29][C:30]3[CH:35]=[C:34]([C:36]([NH:38][C:39]4[CH:44]=[C:43]([CH3:45])[CH:42]=[CH:41][C:40]=4[F:46])=[O:37])[CH:33]=[CH:32][C:31]=3[F:47])[CH:26]=[CH:25][N:24]=2)[NH:20][CH:19]=1)=[O:17])[CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH3:2]
Reactant: CCNC(=O)C(CCC(=O)OC(C)(C)C)NC(=O)c1c[nH]c(-c2cc(Oc3cc(C(=O)Nc4cc(C)ccc4F)ccc3F)ccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)C(CCC(=O)O)NC(=O)c1c[nH]c(-c2cc(Oc3cc(C(=O)Nc4cc(C)ccc4F)ccc3F)ccn2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of tert-butyl 5-(ethylamino)-4-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]-5-oxopentanoate (75 mg, 0.11 mmol) in 5 ml of methylene chloride was added 1 ml of TFA. The mixture was stirred at room temperature for 90 minutes, and evaporated to dryness under reduced pressure. The residue was re-dissolved in 5 ml of methanol and poured into 100 ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried in vacuo to give 5-(ethylamino)-4-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]-5-oxopentanoic acid as white solid. Yield: 60 mg, 87%.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:9]=[CH:8][C:7]=1[CH:17]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[C:18]1[CH:19]=[CH:20][C:21]([O:31][CH2:32][CH:33]([CH3:35])[CH3:34])=[C:22]([CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])[CH:23]=1)[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].O.Cl>C(O)C.C(Cl)(Cl)Cl>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:9]=[CH:8][C:7]=1[CH:17]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[C:18]1[CH:19]=[CH:20][C:21]([O:31][CH2:32][CH:33]([CH3:34])[CH3:35])=[C:22]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH:23]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: CCOC(=O)CCc1cc(C(NS(C)(=O)=O)c2ccc(OCC(C)C)cc2OCC(C)C)ccc1OCC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: O
Product: CC(C)COc1ccc(C(NS(C)(=O)=O)c2ccc(OCC(C)C)c(CCC(=O)O)c2)c(OCC(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
In 7 ml of ethanol is dissolved 1.26 g of ethyl 3-(5-{(2,4-diisobutoxyphenyl)[(methylsulfonyl)-amino]methyl}-2-isobutoxyphenyl)propanoate, to which is added 1.3 ml of 5 mol/L solution of sodium hydroxide. The mixture is stirred at ambient temperature for one hour. Water and chloroform are added to the reaction mixture, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1) to obtain 0.92 g of 3-(5-{(2,4-diisobutoxyphenyl)[(methylsulfonyl)amino]methyl}-2-isobutoxyphenyl)propanoic acid as a light yellow oily product.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][C@H:3]1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[CH:21]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]CC=1.C(OCC)(=O)C>C1(=O)CCCCC1.[C].[Pd]>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:21]=2)[CH2:4][C@H:3]1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNc2ccccc2NC1=O
Reactant: C1=CCCCCCC1
Agent: [Pd]
Solvent: O=C1CCCCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccccc2)c2ccccc2NC1=O
Temperature: 145 °C
Reaction time: 2.5 h
Yield: 50.2 %

Procedure:
To a solution of 5 g of (R)-(+)-2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine in 25 ml of cyclohexanone were added 5.96 g of cyclooctene and 0.5 g of 10% palladium carbon. The mixture was stirred at the internal temperature of 145° C. for 2.5 hours. After the reaction mixture was cooled to room temperature, 20 ml of ethyl acetate was added. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was crystallized by adding thereto diisopropyl ether and n-hexane and the resulting crystals were collected by filtration, whereby 3.2 g of the title compound was obtained.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[C:24]([C:32]1[CH:50]=[CH:49][C:35]2[N:36]=[C:37]([C:39]3[C:40]([CH3:48])=[C:41]([C:45]([OH:47])=O)[NH:42][C:43]=3[CH3:44])[NH:38][C:34]=2[CH:33]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[CH3:51][N:52]([CH3:57])[CH2:53][CH2:54][NH:55]C>N1C=CC=CC=1>[CH3:51][N:52]([CH3:57])[CH2:53][CH2:54][NH:55][C:45]([C:41]1[NH:42][C:43]([CH3:44])=[C:39]([C:37]2[NH:38][C:34]3[CH:33]=[C:32]([C:24](=[O:31])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:50]=[CH:49][C:35]=3[N:36]=2)[C:40]=1[CH3:48])=[O:47]
Reactant: Cc1[nH]c(C(=O)O)c(C)c1-c1nc2ccc(C(=O)c3ccccc3)cc2[nH]1
Reactant: CNCCN(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: c1ccncc1
Product: Cc1[nH]c(C(=O)NCCN(C)C)c(C)c1-c1nc2ccc(C(=O)c3ccccc3)cc2[nH]1
Temperature: 60 °C
Reaction time: 5 h
Yield: 62.1 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (88 mg, 0.46 mmol) and 1-hydroxybenzotriazole monohydrate (70 mg, 0.46 mmol) were added to a pyridine (2 ml) solution of the 4-(5-benzoylbenzimidazol-2-yl)-3,5-dimethylpyrrole-2-carboxylic acid (150 mg, 0.42 mmol) obtained in Example 10. N,N,N′-Trimethyl ethylenediamine (43 mg, 0.42 mmol) was added to the resultant solution and heated. The reaction mixture was stirred for 5 hours at 60° C. (internal temperature), and then allowed to cool to room temperature. The solvent was evaporated, and the residue was purified using medium pressure silica gel flash column chromatography (NH silica gel, chloroform:methanol=98:2) to afford N-methyl-N-(2-dimethylaminoethyl-4-(5-benzoylbenzimidazol-2-yl)-3,5-dimethylpyrrole-2-carboxamide (112 mg, 61%) as a light yellow amorphous.
Reaction SMILES: [CH3:1][O:2]/[C:3](=[CH:8]\[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:34])[C:22](OC3C=CC([N+]([O-])=O)=CC=3)=[O:23])[CH:16]=2)=[CH:11][CH:10]=1)/[C:4]([O:6][CH3:7])=[O:5].[CH2:35]([NH2:39])[CH2:36][CH2:37][CH3:38]>>[CH2:35]([NH:39][C:22](=[O:23])[N:21]([C:17]1[CH:16]=[C:15]([C:12]2[CH:11]=[CH:10][C:9](/[CH:8]=[C:3](\[O:2][CH3:1])/[C:4]([O:6][CH3:7])=[O:5])=[CH:14][CH:13]=2)[CH:20]=[CH:19][CH:18]=1)[CH3:34])[CH2:36][CH2:37][CH3:38]
Reactant: CCCCN
Reactant: COC(=O)/C(=C/c1ccc(-c2cccc(N(C)C(=O)Oc3ccc([N+](=O)[O-])cc3)c2)cc1)OC
Product: CCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OC)C(=O)OC)cc2)c1
Yield: 64 %

Procedure:
In a manner similar to that of Example 10d, starting with 1.7 g (3.2 mmol) of methyl (Z)-2-methoxy-3-{3′-[methyl-(4-nitrophenoxycarbonyl)amino]biphenyl-4-yl}acrylate and 0.4 mL (3.9 mL) of n-butylamine, 0.8 g (64%) of methyl (Z)-3-[3′-(3-butyl-1-methylureido)biphenyl-4-yl]-2-methoxyacrylate is obtained in the form of a white solid with a melting point of 89° C.
Reaction SMILES: [C:1]12([CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]1)[C:10]1[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:4][CH2:3][CH2:2]2.[BH4-].[Na+]>C(O)C>[C:1]12([CH2:11][CH2:12][CH:13]([OH:16])[CH2:14][CH2:15]1)[C:10]1[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:4][CH2:3][CH2:2]2
Reactant: O=C1CCC2(CCCc3ccccc32)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC1CCC2(CCCc3ccccc32)CC1

Procedure:
A 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-one (r) produced in step (10) has its 4-keto function reduced, e.g., by mixing said compound in a solvent such as ethanol with sodium borohydride at moderate (room) temperature for from about 3 to about 8 hours, to produce a corresponding 3',4'-dihydrospiro[cyclohexane-1,1'(2H)naphthalen]-4-ol (s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15](OCC)=[O:16])[N:14]=2)=[CH:5][C:4]=1[O:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[S:11][CH:12]=[C:13]([CH2:15][OH:16])[N:14]=2)=[CH:5][C:4]=1[O:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24]
Reactant: CCOC(=O)c1csc(Nc2ccc(OC)c(OCC=C(C)C)c2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Nc2nc(CO)cs2)cc1OCC=C(C)C
Reaction time: 3 h
Yield: 52 %

Procedure:
A solution of ethyl 2-(4-methoxy-3-(3-methylbut-2-enyloxy)phenylamino)thiazole-4-carboxylate (67 mg, 0.18 mmol) in anhydrous THF (1 mL) was added to a suspension of LiAlH4 (14 mg, 0.37 mmol) in dry THF (1 mL) at 0° C. under nitrogen atmosphere. After 3 h, the reaction mixture was quenched with H2O, filtrated, dried over MgSO4 and concentrated. The crude product was purified by flash chromatography on silica gel (hexane:EtOAc 1/1) to give the title compound (30 mg, 50% yield).
Reaction SMILES: [CH2:1]([CH:7]([CH2:9][NH2:10])O)[CH2:2][CH2:3][CH2:4]CC.C(N)CCCCC.[CH2:18]1[O:20][CH2:19]1>>[CH2:9]([NH:10][CH2:18][CH2:19][OH:20])[CH2:7][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: C1CO1
Reactant: CCCCCCC(O)CN
Solvent: CCCCCCN
Product: CCCCCCNCCO

Procedure:
In an alternate synthesis scheme for n-hexyl ethanolamine, the ethoxylation steps remained the same as above in sequence, temperature and pressure. However, the preferred weight fraction of n-hexyl amine to ethylene oxide was lowered to approximately 88 pounds n-hexyl amine to 12 pounds ethylene oxide to yield 100 pounds of reaction mass. The weight ratio of mono to di ethoxylates in the reaction mass was approximately 4.0-4.2 mono to 1.0 di. The purification section was also the same except the process was stopped after removal of n-hexyl amine overhead. The final bottoms fraction contained n-hexyl ethanolamine and some diethoxylates byproducts (less than 20% by weight).
Reaction SMILES: [C:1]([CH:3]1[CH2:5][CH:4]1[C@H:6]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=4)[N:22]([CH3:30])[N:21]=3)[N:18]=2)[N:13](COCC[Si](C)(C)C)[CH:12]=1)=[O:10])[CH3:7])#[N:2].C(Cl)Cl.C(N)CN.O>C(O)(C(F)(F)F)=O>[C:1]([CH:3]1[CH2:5][CH:4]1[C@H:6]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=4)[N:22]([CH3:30])[N:21]=3)[N:18]=2)[NH:13][CH:12]=1)=[O:10])[CH3:7])#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C1CC1C#N
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C1CC1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
2-(6-Chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(2-cyano-cyclopropyl)-ethyl]-amide, diastereomer A (210 mg, 0.382 mmol) was dissolved in a 4:6 solution of TFA:DCM (57 mL). After stirring at room temperature overnight, the volatiles were removed under reduced pressure. The crude material was then dissolved in dichloromethane and treated with ethylenediamine (229 mg, 3.82 mmol). After stirring at room temperature overnight, water was added and the resulting precipitate was collected by filtration to give 140 mg (87%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(2-cyano-cyclopropyl)-ethyl]-amide (diastereomer A) as a light yellow solid. MS: (M+H)+=420. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.70 (bs, 1H) 9.08 (s, 4H) 8.32-8.58 (m, 2H) 8.13 (dd, J=12.27, 8.12 Hz, 1H) 7.98 (s, 1H) 7.24-7.44 (m, 1H) 4.16 (s, 3H) 3.80 (d, J=5.29 Hz, 1H) 1.61-1.96 (m, 2H) 1.40 (m, 3H) 0.98-1.30 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([NH2:16])[C:12]([NH2:15])=[CH:13][CH:14]=2)[O:3]1.[C:18](N1C=CN=C1)(N1C=CN=C1)=[O:19].Cl>C1COCC1>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:17])([CH3:1])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]3[NH:15][C:18](=[O:19])[NH:16][C:11]=3[CH:10]=2)[O:5]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC1(C)OB(c2ccc(N)c(N)c2)OC1(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc3[nH]c(=O)[nH]c3c2)OC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1,2-diamine (1.20 g, 5.1 mmol) in anhydrous THF (20 mL) was added 1,1′-carbonyldiimidazole (910 mg, 5.6 mmol). The reaction mixture was stirred at room temperature for 2 hours. The resulting solution was acidified with 1 N HCl (10 mL) and extracted twice with 50 mL portions of Et2O. The combined organic layers were washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 1.0 g (79%) of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one. 1H NMR (400 MHz, CDCl3): δ 7.46 (dd, 1H), 7.40 (s, 1H), 7.35 (dd, 1H), 1.35 (s, 12H). MS (EI) for C13H17BN2O3: 261 (MH+).
Reaction SMILES: Br[C:2]1[C:17]([F:18])=[CH:16][C:5]([O:6][CH2:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[N:12][CH:13]=2)=[C:4]([O:19][CH3:20])[CH:3]=1.[Cu][C:22]#[N:23]>CN(C)C=O.ClCCl>[F:18][C:17]1[CH:16]=[C:5]([O:6][CH2:7][C:8]2[CH:13]=[N:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:4]([O:19][CH3:20])=[CH:3][C:2]=1[C:22]#[N:23]
Reactant: COc1ccc(COc2cc(F)c(Br)cc2OC)cn1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(COc2cc(F)c(C#N)cc2OC)cn1
Temperature: 150 °C
Reaction time: 16 h
Yield: 84.4 %

Procedure:
To a stirred solution of 5-((4-bromo-5-fluoro-2-methoxyphenoxy)methyl)-2-methoxypyridine (4.57 g, 13.36 mmol) in N,N-dimethylformamide (50 mL) was added copper(I) cyanide (3.59 g, 40.07 mmol). The mixture was heated to 150° C. After 16 h, the mixture was allowed to cool to room temperature and was diluted with dichloromethane. The mixture was filtered through Celite. The filtrate was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. Chromatographic purification (Combi-Flash, 80 g SiO2 column, 1-5% methanol/dichloromethane elute) afforded 3.25 g (84%) of 2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzonitrile as an off-white solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[C:7]([F:10])[N:6]=[C:5]([F:11])[C:4]=1[Cl:12].[C:13]([O-:21])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Na+]>CN(C=O)C>[C:13]([O:21][CH2:2][C:3]1[C:8]([Cl:9])=[C:7]([F:10])[N:6]=[C:5]([F:11])[C:4]=1[Cl:12])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C([O-])c1ccccc1
Reactant: Fc1nc(F)c(Cl)c(CBr)c1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCc1c(Cl)c(F)nc(F)c1Cl)c1ccccc1
Reaction time: 1 h
Yield: 81.2 %

Procedure:
To a stirred DMF (90 ml) in an ice bath, 4-(bromomethyl)-3,5-dichloro-2,6-difluoropyridine (20 g, 72 mmol) and sodium benzoate (15 g, 104 mmol) were added. After 1 hr., the mixture was stirred in a water bath for ca. 20 hr. The product was then extracted with ether, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a light brown oil. The light brown oil was purified by silica gel column chromatography (eluent, ether:hexane (1:15) to afford 18.6 g (81%) of (3,5-dichloro-2,6-difluoropyridin-4-yl)methyl benzoate as a colorless oil. 1H NMR (200 MHz, CDCl3) δ 5.61 (2H, s), 7.40-7.64 (3H, m), 8.00-8.05 (2H, m).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:15]([CH2:17][C:18]1([N:44]2[CH:48]=[C:47]([C:49]3[C:50]4[CH:57]=[CH:56][NH:55][C:51]=4[N:52]=[CH:53][N:54]=3)[CH:46]=[N:45]2)[CH2:21][N:20]([C@@H:22]2[CH2:27][CH2:26][C@H:25]([O:28][C:29]3[N:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[N:32]=[C:31]([C:39]([N:41]([CH3:43])[CH3:42])=[O:40])[CH:30]=3)[CH2:24][CH2:23]2)[CH2:19]1)#[N:16].[CH3:58]NCC>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:15]([CH2:17][C:18]1([N:44]2[CH:48]=[C:47]([C:49]3[C:50]4[CH:57]=[CH:56][NH:55][C:51]=4[N:52]=[CH:53][N:54]=3)[CH:46]=[N:45]2)[CH2:21][N:20]([C@@H:22]2[CH2:27][CH2:26][C@H:25]([O:28][C:29]3[N:34]=[C:33]([C:35]([F:38])([F:36])[F:37])[N:32]=[C:31]([C:39]([N:41]([CH2:43][CH3:58])[CH3:42])=[O:40])[CH:30]=3)[CH2:24][CH2:23]2)[CH2:19]1)#[N:16]
Reactant: CCNC
Reactant: CN(C)C(=O)c1cc(O[C@H]2CC[C@@H](N3CC(CC#N)(n4cc(-c5ncnc6[nH]ccc56)cn4)C3)CC2)nc(C(F)(F)F)n1
Solvent: O=C(O)C(F)(F)F
Product: CCN(C)C(=O)c1cc(O[C@H]2CC[C@@H](N3CC(CC#N)(n4cc(-c5ncnc6[nH]ccc56)cn4)C3)CC2)nc(C(F)(F)F)n1

Procedure:
This compound was prepared by a procedure similar to that of Example 46 using 6-[(cis-4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}cyclohexyl)oxy]-2-(trifluoromethyl)pyrimidine-4-carboxylic acid (20.00 mg, 0.02866 mmol) (Example 46, Step 4) and N-methylethylamine, (4.41 mg, 0.0747 mmol). 1H NMR (300 MHz, CD3OD) δ 9.15 (s, 1H), 8.92 (d, 1H), 8.61 (s, 1H), 7.85 (d, 1H), 7.31 (d, 1H), 7.17 (s, 1H), 5.52 (m, 1H), 5.11 (d, 2H), 4.83 (d, 2H), 3.75 (s, 2H), 3.64-3.47 (m, 3H), 3.08 and 3.00 (2 s, 3H), 2.30 (m, 2H), 2.03 (m, 2H), 1.91-1.58 (m, 4H), 1.24 (t, 3H). MS (ES): 609(M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1)[CH:5]=O.[CH3:21][C:22]1[C:27]([CH3:28])=[CH:26][CH:25]=[C:24]([NH2:29])[C:23]=1[NH2:30]>>[CH3:21][C:22]1[C:23]2[N:30]=[C:5]([C:4]3[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][CH2:13][N:14]4[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]4)=[C:2]([CH3:1])[CH:3]=3)[NH:29][C:24]=2[CH:25]=[CH:26][C:27]=1[CH3:28]
Reactant: Cc1ccc(N)c(N)c1C
Reactant: Cc1cc(C=O)ccc1OCCCN1CCN(C)CC1
Product: Cc1cc(-c2nc3c(C)c(C)ccc3[nH]2)ccc1OCCCN1CCN(C)CC1
Yield: 75.3 %

Procedure:
This compound was prepared by the method described in Example 1, using 3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzaldehyde (180 mg, 0.65 mmol, 1.0 equiv), 3,4-dimethyl-benzene-1,2-diamine (89 mg, 0.65 mmol, 1.0 equiv), and Na2S2O5 (161 mg, 0.85 mmol, 1.3 equiv) in General Procedure 3. Purification by Method 2 afforded 192 mg (75%) of the title compound. MS (electrospray): mass calculated for C24H32N4O, 392.26; m/z found, 393.5 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.95-7.85 (m, 2H), 7.35-7.23 (m, 1H), 7.08-7.00 (m, 2H), 4.12 (t, J=6.0 Hz, 2H), 2.64-2.37 (m, 16H), 2.29 (s, 6H), 2.10-2.00 (m, 2H).