Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([O-:40])([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N+:36]([CH3:39])([CH3:38])[CH3:37])([O:3][CH2:4][CH:5]([OH:26])[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:2].[CH3:41][N:42]=[C:43]=[O:44]>>[P:1]([O-:40])([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N+:36]([CH3:39])([CH3:38])[CH3:37])([O:3][CH2:4][CH:5]([O:26][C:43](=[O:44])[NH:42][CH3:41])[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:2]
Reactant: CN=C=O
Reactant: CCCCCCCCCCCCCCCCCCOCC(O)COP(=O)([O-])OCCCCCCCC[N+](C)(C)C
Product: CCCCCCCCCCCCCCCCCCOCC(COP(=O)([O-])OCCCCCCCC[N+](C)(C)C)OC(=O)NC
Yield: 41 %

Procedure:
By following the procedure of 8, 720 mg of the alcohol derivative obtained in Example 28 was reacted with 2 ml of methyl isocyanate to give 320 mg (yield: 41%) of the desired product.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:8][N:7]=1)=[O:5])C.CO.O.O[Li].O>C1COCC1>[C:11]1([C:9]2[NH:8][N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc(-c2ccccc2)[nH]n1
Temperature: 45 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
A solution of 2,4-dioxo-4-phenyl-butyric acid ethyl ester (1.68 g, 0.0076 mole), acetic acid (10 mL) and hydrazine hydrate (0.42 g, 0.0083 mole) was heated to reflux for 5 hours. The reaction mixture was then poured into iced water, basified with saturated aqueous NaHCO3 solution and the product was extracted with ethyl acetate. The ethyl acetate layer was collected and washed with brine solution, dried over sodium and concentrated under reduced pressure. The resulting residue was purified by column chromatography using basic aluminium oxide (50% ethyl acetate in hexane) to afford 1.442 g (88%) of 5-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester. LCMS: 217.09 (M+1)+, 97.92%. To a stirred solution of 5-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester (1.4 g, 0.00667 mol) in a mixture of THF (30 mL), methanol (15 mL) and H2O (10 mL) was added LiOH.H2O (0.839 g, 0.0199 mol) at ambient temperature. The resulting mixture was stirred at 45° C. overnight. Volatiles were evaporated and the residue was diluted with water, acidified with concentrated HCl solution and the product was extracted with ethyl acetate. The ethyl acetate layer was collected, dried over sodium sulfate and concentrated under reduced pressure to afford 1.26 g (86%) of 5-phenyl-1H-pyrazole-3-carboxylic acid. LCMS: 189.06 (M+1)+, 97.7%.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.[CH3:11][C:12]([CH3:14])=O.C(O)(=O)C.N1CCOCC1>CC(OC)(C)C>[CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[C:6](=[C:12]([CH3:14])[CH3:11])[C:4](=[O:5])[O:3]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(C)=O
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Solvent: C1COCCN1
Product: CC(C)=C1C(=O)OC(C)(C)OC1=O
Reaction time: 0.08 h
Yield: 70.4 %

Procedure:
Meldrum's acid (100.0 g) was charged to a dry, nitrogen flushed reactor. Acetone (632.1 mL) was then charged to the reactor and the mixture was agitated for about 5 minutes at 20° C.-25° C. until a solution was obtained. Acetic acid (0.791 mL) was then charged to the reactor, followed by 1.215 mL of morpholine, and the solution was agitated at 20° C.-25° C. for about 48 hours. An aliquot (˜0.2 mL) was withdrawn for analysis of the conversion, which may be monitored by either GC or 1H-NMR. If the ratio of the area % of 2,2-dimethyl-5-(propan-2-ylidene)-1,3-dioxane-4,6-dione to Meldrum's acid is ≧80:20, proceed to the next step; if it is not, the batch should be aged for an additional 3 hours before repeating the check. The acetone was distilled at about 40° C. and 150-200 mmHg. After approximately two-thirds of the reaction volume was distilled out, 563 mL of methylcyclohexane was charged and the distillation continued until the acetone stopped distilling over. A total of 645 mL (508 g) of distillate was collected for this run. MTBE (500 mL) was charged to the batch at 40° C. and the batch was cooled to 20° C.-25° C. The solution was observed to make sure a cloudy solution was obtained (no solids). If there is solid present, additional MTBE may be charged to effect dissolution. The batch was quickly washed with two 50 g portions of 5 wt. % NaOH solution (prepared from 5 g of NaOH and 95 mL of water). The MTBE was distilled out at 40° C.-45° C. and 150-200 mmHg. A total of 400 mL (300 g) distillate was collected for this run. As distillation proceeds, a white slurry formed. The internal temperature was ramped to 0° C.-5° C. over 1 hour and then held at this temperature for at least 1 hour. The slurry was filtered, the cake was washed with two 100 mL portions of cold (˜0° C.-5° C.) methylcyclohexane, and the solid was dried at 20° C.-35° C. and 25-50 mmHg for no less than 4 hours. 2,2-Dimethyl-5-(propan-2-ylidene)-1,3-dioxane-4,6-dione was obtained as a white solid (93.7 g, 70.4% yield, 96.0 wt. % purity by assay).
Reaction SMILES: [N+:1]([C:4]12[CH2:13][N:8]3[CH2:9][N:10]([CH2:12][N:6]([CH2:7]3)[CH2:5]1)[CH2:11]2)([O-])=O.[H][H]>[Rh].C.C(O)C>[NH2:1][C:4]12[CH2:13][N:8]3[CH2:7][N:6]([CH2:12][N:10]([CH2:9]3)[CH2:11]1)[CH2:5]2
Reactant: [H][H]
Reactant: O=[N+]([O-])C12CN3CN(CN(C3)C1)C2
Agent: [Rh]
Solvent: CCO
Product: NC12CN3CN(CN(C3)C1)C2

Procedure:
7-Nitro-1,3,5-triazaadamantane (46.1 g., 0.25 mole), 175 ml. of 95% ethanol and 8.0 g. of 5% rhodium-charcoal catalyst were shaken with hydrogen in a Parr apparatus at 25° until hydrogen uptake ceased (13 hours). (The reaction bottle was refilled with hydrogen at intervals as required to keep the hydrogen pressure between 25-50 psi.) The reaction mixture was filtered with suction through Celite and the collected catalyst washed thoroughly with ethanol. The filtrate was concentrated to dryness under reduced pressure and the solid residue, after being ground to a powder, was pumped at 25° and 0.1 mm for 12 hours to remove traces of volatiles to yield 38.6 g. (99.5%) of high purity 2, m.p. 216°-219°. The product may be recrystallized from benzene (80% recovery) to yield long needles, m.p. 214°-217°; nmr (deuterium oxide): δ 4.70 (2, s, OH), 4.39, 3.97 (6, ABq, J = 12 Hz; 2,4,9 CH2), 3.17 (6, s, 6,8,10 CH2); TMS external standard.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:18])[C:15]([OH:17])=O)=[CH:4][CH:3]=1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([NH:26][C:15](=[O:17])[CH:14]([C:9]1[C:10]([CH3:13])=[N:11][O:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[OH:18])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)C(=O)O
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)C(=O)NCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-hydroxy-acetic acid and benzyl amine.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](C)=[CH:8][CH:7]=[CH:6]2.B(Br)(Br)Br.Cl[CH2:19]Cl>>[CH3:19][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH:4]=[C:3]([OH:2])[CH:12]=[CH:11]2
Reactant: COc1ccc2c(C)cccc2c1
Reactant: ClCCl
Agent: BrB(Br)Br
Product: Cc1ccc2cc(O)ccc2c1
Temperature: -60 °C
Reaction time: 3 h

Procedure:
To a solution of 6-methoxy-1-methylnaphthalene (6.4 g) in dichloromethane (500 ml), cooled to -60° C., was added boron tribromide (45 ml of a 1M solution in dichloromethane). The resulting mixture was stirred at -60° C. for 3 hours. The reaction was quenched with water (500 ml) and extracted with dichloromethane (2×500 ml). The organic extracts were combined, dried (MgSO4) and evaporated to give a solid. Purification by flash column chromatography on silica, eluting with ethyl acetate/hexane (5:95 v/v) gave 6-methyl-2-naphthol (3.76 g) as a white solid. This was used without further characterisation.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[N:5]=[CH:6][C:7]2[CH2:13][CH2:12][C:11](=[O:14])[NH:10][C:8]=2[N:9]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>O.CC(C)=O>[O:14]=[C:11]1[NH:10][C:8]2[N:9]=[C:4]([CH:3]=[O:2])[N:5]=[CH:6][C:7]=2[CH2:13][CH2:12]1
Reactant: COC(OC)c1ncc2c(n1)NC(=O)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: O=Cc1ncc2c(n1)NC(=O)CC2

Procedure:
To a solution of 2-[bis(methyloxy)methyl]-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (0.87 g, 3.91 mmol) in 1:1 H2O/acetone (10 mL) was added p-TsOH.H2O (0.074 g, 0.39 mmol) and the reaction was heated at reflux for 2 days. The reaction was not complete, so additional p-TsOH.H2O (0.20 g) was added and the solution was refluxed for an additional 1 day. After the disappearance of starting material, the solution was concentrated under vacuum to yield the desired product as a white solid and the crude material was used directly in the next step (1.023 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:33]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:20]([CH3:32])[N:21]=[CH:22][C:23]=4[C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:35][CH2:36][F:37].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:37][CH2:36][CH2:35][O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:33]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:20]([CH3:32])[N:21]=[CH:22][C:23]=4[C:24]([N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)=[O:25])=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: FCCBr
Reactant: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccn2nc(-c3cccc(O)c3)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccn2nc(-c3cccc(OCCF)c3)nc2c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 23.3 %

Procedure:
To a solution of 2-methyl-4-(morpholine-4-carbonyl)-2H-pyrazole-3-carboxylic acid [2-(3-hydroxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (Example 80) (350 mg, 0.782 mmol) in DMF (5 ml) was added 1-bromo-2-fluoroethane (250 mg, 1.96 mmol) and K2CO3 (108 mg, 0.782 mmol). The reaction mixture was stirred at 60° C. for 16 h. The reaction mixture was diluted with EtOAc (30 ml) and washed with water (2×10 ml) and brine (15 ml). The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated off in vacuum. The crude material thus obtained was purified by column chromatography over silica gel (5% MeOH/DCM) to afford 2-methyl-4-(morpholine-4-carbonyl)-2H-pyrazole-3-carboxylic acid {2-[3-(2-fluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-amide as off-white solid (90 mg, 23%). LC-MS: m/z=494.2 [M+H]+.
Reaction SMILES: [C:1]([Si:5]([CH3:37])([CH3:36])[O:6][CH:7]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:21]2[S:25][C:24]([S:26]([NH2:29])(=[O:28])=[O:27])=[C:23]([CH3:30])[CH:22]=2)([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:12][C:11]=1[CH3:31])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.[C:49](O)(=[O:51])[CH3:50]>CN(C1C=CN=CC=1)C.ClCCl>[C:49]([NH:29][S:26]([C:24]1[S:25][C:21]([C:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH:7]([O:6][Si:5]([C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:36])[CH3:37])[C:32]([CH3:35])([CH3:34])[CH3:33])=[C:11]([CH3:31])[CH:12]=2)([CH2:17][CH3:18])[CH2:19][CH3:20])=[CH:22][C:23]=1[CH3:30])(=[O:28])=[O:27])(=[O:51])[CH3:50]
Reactant: CCC(CC)(c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1cc(C)c(S(N)(=O)=O)s1
Reactant: CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(CC)(c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1cc(C)c(S(=O)(=O)NC(C)=O)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
A mixture of 5-(1-{4-[2-(tert-Butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-3-methyl-thiophene-2-sulfonic acid amide (227 mg, 0.4 mmol), EDCI (92 mg, 0.48 mmol), acetic acid (27 μL, 0.48 mmol) and DMAP (50 mg) in dichloromethane (10 ml) is stirred at RT overnight. The reaction is diluted with dichloromethane and washed with 1N HCl. The organic phase is concentrated and chromatographed (Hex to 20% EtOAc/Hex) to give the title compound (240 mg, 98%). 1H NMR (CDC3) δ 7.99 (s, 1H), 7.02 (d 1H, J=8.8 Hz), 6.96 (s, 1H), 6.69 (d, 1H, J=8.8 Hz), 6.59 (s, 1H), 3.98 (dd, 1H, J=3.4, 9.8 Hz), 3.85 (dd, 1H, J=5.8, 9.8 Hz), 3.67 (dd, 1H, J=3.4, 5.8 Hz), 2.43 (s, 3H), 2.20 (s, 3H), 2.13 9s, 3H), 2.06 (q, 4H), 0.96 (s, 9H), 0.89 (s, 9H), 0.70 (t, 6H), 0.11 (s, 3H), 0.05 (s, 3H);
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][S:8][CH3:9])[C:3]([O-:5])=[O:4].[Ca+2].[OH:11][CH:12](CCSC)[C:13]([O-])=O.C(Cl)(=O)C>>[C:12]([O:1][CH:2]([CH2:6][CH2:7][S:8][CH3:9])[C:3]([OH:5])=[O:4])(=[O:11])[CH3:13]
Reactant: CSCCC(O)C(=O)[O-]
Agent: [Ca+2]
Solvent: CC(=O)Cl
Product: CSCCC(OC(C)=O)C(=O)O
Reaction time: 0.5 h
Yield: 192.7 %

Procedure:
Calcium 2-hydroxy-4-(methylthio)butyrate (33.8 g, 0.1 g-mole) and acetyl chloride (110 g) are refluxed in a 250 ml round-bottom flask for 2.5 hours. The mixture is evaporated to a syrup and treated with 150 ml acetone. The brown mixture is stirred for 30 minutes, filtered, and the filtrate evaporated to dryness to give 37 g, 96.4% of brown viscous oil which is identified by TLC and nmr.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[C:5]3[CH:19]=[CH:18][CH:17]=[CH:16][C:6]3=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=2)[N:3]=1.[CH:20]1[C:28]2[C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[S:25][C:24]=2[C:23]([C:33]2[CH:34]=[C:35](B(O)O)[CH:36]=[C:37]([C:39]3[C:44]4[S:45][C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=5[C:43]=4[CH:42]=[CH:41][CH:40]=3)[CH:38]=2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C.O>[CH:20]1[C:28]2[C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[S:25][C:24]=2[C:23]([C:33]2[CH:34]=[C:35]([C:2]3[CH:11]=[N:10][C:9]4[C:4](=[C:5]5[CH:19]=[CH:18][CH:17]=[CH:16][C:6]5=[C:7]5[CH:15]=[CH:14][CH:13]=[CH:12][C:8]5=4)[N:3]=3)[CH:36]=[C:37]([C:39]3[C:44]4[S:45][C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=5[C:43]=4[CH:42]=[CH:41][CH:40]=3)[CH:38]=2)=[CH:22][CH:21]=1
Reactant: OB(O)c1cc(-c2cccc3c2sc2ccccc23)cc(-c2cccc3c2sc2ccccc23)c1
Reactant: Clc1cnc2c3ccccc3c3ccccc3c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: c1ccc2c(c1)sc1c(-c3cc(-c4cnc5c6ccccc6c6ccccc6c5n4)cc(-c4cccc5c4sc4ccccc45)c3)cccc12
Temperature: 320 °C
Yield: 31.1 %

Procedure:
Into a 200-mL three-neck flask were put 1.2 g (4.5 mmol) of 2-chlorodibenzo[f,h]quinoxaline, 2.2 g (4.5 mmol) of 3,5-bis(dibenzothiophen-4-yl)phenylboronic acid, and 1.2 g (9.0 mmol) of potassium carbonate. To this mixture were added 23 mL of toluene, 4.5 mL of water, and 5 mL of ethanol, and this mixture was degassed by being stirred under reduced pressure. To the mixture was added 104 mg (0.09 mmol) of tetrakis(triphenylphosphine)palladium(0), and this mixture was stirred under a nitrogen stream at 100° C. for 3.5 hours. After the stirring, the obtained mixture was filtrated, and the solid was washed with water and then with ethanol. To the obtained solid was added toluene, and the mixture was suction-filtered through Celite, alumina, and Florisil. The filtrate was concentrated to give a solid. This solid was recrystallized from toluene, so that 1.4 g of a white solid was obtained in a yield of 46%. By a train sublimation method, 1.3 g of the obtained solid was purified. In the purification by sublimation, 2DBT2PDBq-II was heated at 320° C. under a pressure of 2.8 Pa with a flow rate of argon gas of 5 mL/min. After the purification by sublimation, 0.94 g of a white solid was obtained at a collection rate of 72%. The synthesis scheme of Step 3 is shown in (b-3).
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:42])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH2:32][CH3:33])[N:23]=4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([CH:3]1[CH2:4][N:5]([C:7](=[O:42])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH2:32][CH3:33])[N:23]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:6]1)#[N:2]
Reactant: CCn1nc(-c2cnc3c(n2)c(C(=O)N[C@H](C)C(=O)N2CC(C#N)C2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1nc(-c2cnc3[nH]cc(C(=O)N[C@H](C)C(=O)N4CC(C#N)C4)c3n2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.8 %

Procedure:
To a solution of 2-(6-chloro-1-ethyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (150 mg, 0.25 mmol) in CH2Cl2 (2 mL) was added TFA (0.75 mL). The reaction mixture was stirred at room temperature for 5 h then concentrated. The residue was redissolved in 10:90:0.5 MeOH/CH2Cl2/NH4OH (3 mL) and stirred at room temperature for 3 h. The reaction mixture was concentrated and the residue was purified by silica gel chromatography with 0% to 5% MeOH/EtOAc followed by trituration with MeOH to afford 88 mg (75%) of 2-(6-chloro-1-ethyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a white powder. MS: (M+Na)+=499; mp=248-255° C.; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.92 (br. s., 1H), 9.14 (s, 1H), 8.71 (d, J=8.7 Hz, 1H), 8.47 (dd, J=7.6, 3.4 Hz, 2H), 8.02 (s, 1H), 7.25 (d, J=8.7 Hz, 1H), 4.48-4.79 (m, 5H), 4.04-4.28 (m, 2H), 3.77-3.92 (m, 1H), 1.47 (t, J=7.2 Hz, 3H), 1.39 (dd, J=6.8, 4.5 Hz, 3H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[O:11]1[CH2:32][CH:12]1[CH2:13][CH2:14][CH2:15][N:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[S:17]([CH3:20])(=[O:19])=[O:18].O>CN(C)C=O.C1C=CC=CC=1>[OH:11][CH:12]([CH2:32][O:10][C:7]1[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=1)[CH2:13][CH2:14][CH2:15][N:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[S:17]([CH3:20])(=[O:18])=[O:19]
Reactant: CCOC(=O)CCCCCCN(CCCC1CO1)S(C)(=O)=O
Reactant: Oc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCOC(=O)CCCCCCN(CCCC(O)COc1ccc(F)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of sodium hydride (57%) (278 mg., 0.0065 mole) in a solvent mixture of benzene (25 ml.) and dimethylformamide (25 ml.) is added, over 30 minutes, a solution of p-fluorophenol (730 mg., 0.065 mole) in dimethylformamide (10 ml.). This mixture is stirred 30 minutes at room temperature, then treated with a solution of ethyl 7-[N-(4,5-epoxypentyl)methanesulfonamido]heptanoate (2.2 g., 0.0065 mole) in benzene (10 ml.). The reaction is heated at 90° C. for eighteen hours, then cooled and poured into water (100 ml.). The organic phase is collected, washed with brine and dried over sodium sulfate. Evaporation in vacuo affords a heavy oil that is purified by chromatography over silica gel, using chloroform to elute. Evaporation of the appropriate fractions affords the subject compound. The yield is 1.4 g. (47%) of heavy oil.
Reaction SMILES: [NH2:1][NH2:2].[CH3:3][N:4]1[C:8](Cl)=[C:7]([N+:10]([O-:12])=[O:11])[C:6]([CH3:13])=[N:5]1>C(O)CC>[NH:1]([C:8]1[N:4]([CH3:3])[N:5]=[C:6]([CH3:13])[C:7]=1[N+:10]([O-:12])=[O:11])[NH2:2]
Reactant: Cc1nn(C)c(Cl)c1[N+](=O)[O-]
Reactant: NN
Solvent: CCCO
Product: Cc1nn(C)c(NN)c1[N+](=O)[O-]

Procedure:
39 gms. of hydrazine are dissolved in 500 ml. of n-propanol and 105 gms. of 1,3-dimethyl-4-nitro-5-chloro-1H-pyrazole dissolved in propanol are added dropwise at 100°. The reaction mixture is then refluxed for 4 hours. On cooling, 5-hydrazino-1,3-dimethyl-4-nitro-1H-pyrazole crystallizes in the form of yellow needles. By concentrating the mother liquor an additional quantity of product is obtained. The combined crude is recrystallized from propanol, yield 98 gms. of yellow needles, m.p. 177°-179°.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]2([OH:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:22][N:23](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:22]([C:2]1[N:7]=[CH:6][C:5]([C:8]2([OH:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)#[N:23]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Br)nc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(C#N)nc2)CC1
Temperature: 120 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a mixture of tert-butyl 4-(6-bromopyridin-3-yl)-4-hydroxypiperidine-1-carboxylate (compound 51.1, 1 g, 2.81 mmol, 1.00 equiv) in DMF (50 mL) under nitrogen at 50° C. was added Zn(CN)2 (400 mg, 3.42 mmol, 1.22 equiv) at 50° C. followed by Pd(PPh3)4 (200 mg, 0.17 mmol, 0.06 equiv) at 80° C. The resulting mixture was then stirred for 1 h at 120° C. After cooling to ambient temperature, the reaction was quenched by the addition of 200 mL of FeSO4 (aq., sat.) and diluted with ethyl acetate. The resulting mixture was stirred vigorously then filtered through celite and washed with 1 M FeSO4, water, and ethyl acetate. The layers were separated and the aqueous phase was extracted with 2×100 mL of ethyl acetate. The combined organic layers were washed with 1×200 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:5-1:3) as eluent to yield 0.6 g (70%) of the title compound as a light yellow oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][C:16]=1B1OC(C)(C)C(C)(C)O1)[C:9]([CH:11]1[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:32]([O:34][C:35](=[O:44])[CH2:36][C:37]1[CH:38]=[N:39][CH:40]=[C:41](Br)[CH:42]=1)[CH3:33].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:32]([O:34][C:35](=[O:44])[CH2:36][C:37]1[CH:38]=[N:39][CH:40]=[C:41]([C:16]2[CH:17]=[CH:18][C:19]([C:21]#[N:22])=[CH:20][C:15]=2[CH2:14][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]([CH:11]2[CH2:12][CH2:13]2)=[O:10])[CH:42]=1)[CH3:33]
Reactant: CC1(C)OB(c2ccc(C#N)cc2CN(Cc2ccccc2)C(=O)C2CC2)OC1(C)C
Reactant: CCOC(=O)Cc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)Cc1cncc(-c2ccc(C#N)cc2CN(Cc2ccccc2)C(=O)C2CC2)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Cyclopropanecarboxylic acid benzyl-[5-cyano-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-amide (1.33 g, 3.2 mmol), (5-bromo-pyridin-3-yl)-acetic acid ethyl ester (1.02 g, 4.2 mmol), and potassium carbonate (1.55 g, 11.2 mmol) were combined in DME (40 mL) and H2O (30 mL), and the solution was purged with N2 for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.370 g, 0.35 mmol) was added, and the reaction was stirred at 70° C. for 1 hour. The mixture was diluted with H2O and 1N aqueous HCl (15 mL), and extracted with EtOAc. The combined organic layers were concentrated and purified by preparative HPLC to give (5-{2-[(benzyl-cyclopropanecarbonyl-amino)-methyl]-4-cyano-phenyl}-pyridin-3-yl)-acetic acid ethyl ester, as well as the some of the hydrolyzed ester product.