Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][NH2:11].CC[O:14][C:15]([CH:17]1[C:22](=O)[CH2:21][CH2:20][CH2:19][CH2:18]1)=O.O>C1(C)C=CC=CC=1.C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]1[C:15](=[O:14])[C:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=2[NH:11]1
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: COc1ccc(NN)c(F)c1
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(-n2[nH]c3c(c2=O)CCCC3)c(F)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 6.28 g (0.040 mole) of 2-fluoro-4-methoxyphenylhydrazine in 200 mL of toluene was added with stirring 6.82 g (0.040 mole) of ethyl 2-cyclohexanonecarboxylate. This mixture was heated at reflux under a nitrogen atmosphere while water was removed with a Dean-Stark trap. When all water had been removed, the reaction mixture was cooled, and the solvent was evaporated under reduced pressure, leaving a residue which was then dissolved in acetic acid. This solution was heated at reflux for approximately sixteen hours, after which the solvent was evaporated under reduced pressure, leaving a residue. This residue was dissolved in toluene, which was also evaporated under reduced pressure. The residue was dissolved in ethyl acetate and placed on a silica gel column and eluted with ethyl acetate. An attempt to crystallize the product by dissolving it in diethyl ether after the ethyl acetate had been evaporated was unsuccessful. After the solvent had been evaporated from this product, it was again heated at reflux in acetic acid for 24 hours and allowed to cool to room temperature, where the solution stirred for an additional 48 hours. The solvent was evaporated under reduced pressure, leaving a residue weighing 4.32 g. Two additional fractions weighing 0.80 g and 2.75 g had been recovered by extracting the reaction mixture before the solvent was evaporated. The NMR spectrum of the residue showed it to be a mixture of 2-(2-fluoro-4-methoxyphenyl)-4,5,6,7-tetrahydro-1H-indazol-3-one and the 2-fluoro-4-methoxyphenylhydrazone of 2-cyclohexanonecarboxylic acid.
Reaction SMILES: [C:1]([O:7][C:8]([CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])([CH:10]=[CH2:11])[CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=C[CH:26]=2)[CH:21]=[CH:20][C:19]=1C(CC([O-])=O)=O>>[CH:26]1[C:27]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:5]=1[C:3](=[O:4])[CH2:2][C:1]([O:7][C:8]([CH3:9])([CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[CH:10]=[CH2:11])=[O:6]
Reactant: O=C([O-])CC(=O)c1ccc2ccccc2c1
Reactant: C=CC(C)(CCC=C(C)C)OC(=O)CC(C)=O
Product: C=CC(C)(CCC=C(C)C)OC(=O)CC(=O)c1ccc2ccccc2c1

Procedure:
Crude 3,7-dimethyl-1,6-octadien-3-yl 3-oxo-butyrate (154.51, 0.648 mol) from above is placed in a 3000 mL three-necked round-bottomed flask fitted with a condenser, argon inlet, addition funnel, magnetic stirrer and internal thermometer. The contents are dissolved in 350 mL of dichloromethane and treated with powdered calcium hydroxide (50.44 g, 0.681 mol). The mixture is stirred at 30° C. for 30 min and then heated to 40° C. 2-Naphthoyl chloride (142.12 g, 0.746 mol) dissolved in 20 mL of dichloromethane is added dropwise over 15 min. The mixture continues to be heated at this temperature for 1 h. Ammonium chloride (36.41 g, 0.681 mol) dissolved in 250 mL of water is added to the reaction mixture and the pH adjusted to ˜9 with 28% ammonium hydroxide. After stirring 30 min at 35° C. the pH is adjusted to ˜1 with 20% HCl. The mixture is transferred to a separatory fumnel containing diethyl ether (500 mL) and water (500 mL). The layers are separated and the organic phase is washed with saturated NaHCO3 solution (2×500 mL), dried over MgSO4, filtered and concentrated by rotary evaporation to give a yellow red oil. At this point a light yellow solid precipitates from the mixture. An equal volume of hexane is added and the solids is collected by filtration and dried. NMR analysis indicates the solid is 2-naphthoic acid. The eluent is concentrated again by rotary evaporation to give a red oil. The oil is taken up in an equal volume of dichloromethane, passed through a plug of silica gel (400 g) and eluted with dichloromethane. The mixture is concentrated by rotary evaporation and stripped by Kugelrohr distillation (40° C., 0.10 mm Hg, 30 min) to yield 173.26 g (76.3%) of the product as a red oil; this product is a mixture of a 1:10 molar ratio of linalyl acetoacetate to linalyl (2-naphthoylacetate. A portion of this material is purified by column chromatography (elution with 2.5% ethyl acetate in hexanes) to give the desired product as a light yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]2[C:20]([C:21]3[S:22][C:23]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:24]=4[N:25]=3)=[C:19]([O:31]C)[N:18]=[C:17]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[N:16]=2)[CH2:9]1)=O)(C)(C)C.[ClH:39]>>[ClH:39].[F:30][C:27]1[CH:28]=[CH:29][C:23]2[S:22][C:21]([C:20]3[C:19](=[O:31])[NH:18][C:17]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[N:16][C:15]=3[NH:14][C@@H:10]3[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)=[N:25][C:24]=2[CH:26]=1
Reactant: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1-c1nc2cc(F)ccc2s1
Agent: Cl
Product: O=c1[nH]c(N2CCOCC2)nc(N[C@@H]2CCCNC2)c1-c1nc2cc(F)ccc2s1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a 250 mL flask containing Compound 26 (255 mg, 0.469 mmol), hydrochloric acid, (37%, 7 ml) was added. This was then heated and stirred at 80° C. for approx 1 h. The reaction mixture was then concentrated to dryness to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=2)=[CH:4][CH:3]=1.[Mg].[CH2:17]([Si@H:22]1[CH2:27][CH2:26][C@H:25]([CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][CH:33](Br)[CH2:32][CH2:31]2)[CH2:24][CH2:23]1)[CH2:18][CH2:19][CH2:20][CH3:21]>[Cu]Cl.C1COCC1>[CH2:17]([Si@H:22]1[CH2:23][CH2:24][C@H:25]([CH2:28][CH2:29][C@H:30]2[CH2:35][CH2:34][C@H:33]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=4)=[CH:4][CH:3]=3)[CH2:32][CH2:31]2)[CH2:26][CH2:27]1)[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCC[Si@H]1CC[C@H](CCC2CCC(Br)CC2)CC1
Reactant: Fc1ccc(-c2ccc(Br)cc2)cc1F
Agent: Cl[Cu]
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(-c4ccc(F)c(F)c4)cc3)CC2)CC1

Procedure:
26.9 g (0.1 mol) of 4-bromo-3',4'-difluorobiphenyl was dripped into a mixture of 2.5 g (0.11 mol) of magnesium and 300 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 500 ml THF solution of 0.5 g of copper (I) chloride and 35.9 g (0.1 mol) of 4-(2-(trans-4-n-pentyl-4-silacyclohexyl)ethyl)cyclohexyl bromide. After a conventional after treatment, 4-(trans-4-(2-(trans-4-n-pentyl-4-silacyclohexyl)ethyl)cyclohexyl)-3',4'-difluorobiphenyl was obtained. The silacyclohexane rings of the product were a mixture of trans isomers and cis isomers. They were separated by means of chromatography to obtain 36.0 g (yield 76.9%) of the trans isomer.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]([OH:13])=[O:12])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14]CCCCCC=CCCC.CI>C1C=CC=CC=1>[CH3:14][O:12][C:11](=[O:13])[CH2:10][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH3:9]
Reactant: CCCC=CCCCCCC
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Solvent: CI
Solvent: c1ccccc1
Product: COC(=O)CN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 86.4 %

Procedure:
To a solution of N-t-butoxycarbonyl-sarcosine (50 g; 0.264 mol) in 700 ml of benzene was added 1,8-diazabicyclo 5.4.0!-undec-7-ene (DBU; 40.19 g, 0.264 mol) in one portion. To the above clear solution added 74.94 g (0.528 mol) of methyl iodide in one portion and the resulting clear solution was allowed to reflux for 7 hours. After adding additional methyl iodide (16 ml), the reaction mixture was refluxed with stirring and then cooled to room temperature, and stirred overnight. The reaction mixture was filtered, the residue washed with ether, and the combined filtrate was washed with water, a saturated sodium bicarbonate solution, and then brine. The resulting organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford 46.38 g (86.4%) of N-t-butoxycarbonyl-sarcosine methyl ester as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][CH:16]([C:19]2[CH:20]=[N:21][C:22]([CH3:25])=[N:23][CH:24]=2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:18][CH2:17][CH:16]([C:19]1[CH:24]=[N:23][C:22]([CH3:25])=[N:21][CH:20]=1)[CH2:15][CH:12]1[CH2:14][CH2:13]1)=[O:6]
Reactant: Cc1ncc(C(CN)CC2CC2)cn1
Reactant: O=C(O)c1c(Cl)cccc1Cl
Product: Cc1ncc(C(CNC(=O)c2c(Cl)cccc2Cl)CC2CC2)cn1

Procedure:
From 2,6-dichlorobenzoic acid and 3-cyclopropyl-2-(2-methylpyrimidin-5-yl)propan-1-amine. LCMS (MH+): m/z=364.1, tR (minutes, Method G)=2.43
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]([N+:16]([O-])=O)[C:13]2[C:12]3[C:7](=[CH:8][C:9]([Br:19])=[CH:10][CH:11]=3)[CH2:6][CH2:5][C:4]=2[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClC1C=CC=CC=1Cl>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:5][CH2:6][C:7]3=[CH:8][C:9]([Br:19])=[CH:10][C:11]4[NH:16][C:14]([CH:15]=1)=[C:13]2[C:12]=43
Reactant: O=[N+]([O-])c1cc(Br)cc2c1-c1ccc(Br)cc1CC2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Clc1ccccc1Cl
Product: Brc1cc2c3c(c1)[nH]c1cc(Br)cc(c13)CC2
Yield: 57.2 %

Procedure:
A dried flask fitted with a condenser was charged with 2,7-dibromo-4-nitro-9,10-dihydro-phenanthrene (1.1) (45.00 g, 383.0 mmol), triphenylphosphine (77.04 g, 262.3 mmol) and 1,2-dichlorobenzene (235 cm3). The resulting mixture was refluxed for 4 hours until completion of reaction, then was cooled down and the solvent wasremoved in vacuo. The crude product was purified by column chromatography (gradient, 90:10 to 70:30; petroleum ether:ethyl acetate as eluent) and then recrystallized in a mixture of petroleum ether (80-100° C.) and toluene (ca. 1:1). (24.03 g, yield 57.2%): NMR (1H, 300 MHz, DMSO): δ 11.09 (s, 1H), 7.46 (d, J=0.9 Hz, 2H), 7.12 (d, J=0.9 Hz, 2H), 3.25 (s, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].B.O1CCCC1>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:13])([F:14])[F:12])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1Br
Agent: B
Solvent: C1CCOC1
Product: OCc1cc(C(F)(F)F)ccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
To an ice-cooled solution of 2-bromo-5-(trifluoromethyl)benzoic acid (5.16 g, 19 mmol) in THF (50 mL) was added borane-tetrahydrofuran complex (70 mL of 1M solution in THF, 70 mmol). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with methanol. Solvent was removed. The residue was partitioned between ethyl acetate (3×40 mL) and 1M sodium bicarbonate (50 mL). The combined organic layers were washed with saturated NaCl (50 mL), dried (MgSO4) and concentrated to yield the title compound as an oil (4.85 g). 1H NMR (400 MHz, CDCl3) δ 4.8 (s, 2 H) 7.5 (m, 1 H) 7.7 (d, J=8.2 Hz, 1 H) 7.8 (d, J=1.6 Hz, 1 H).
Reaction SMILES: [I:1][C:2]1[NH:6][C:5]([CH3:7])=[N:4][CH:3]=1.Br[CH2:9][CH:10]([F:12])[F:11]>>[F:11][CH:10]([F:12])[CH2:9][N:4]1[CH:3]=[C:2]([I:1])[N:6]=[C:5]1[CH3:7]
Reactant: Cc1ncc(I)[nH]1
Reactant: FC(F)CBr
Product: Cc1nc(I)cn1CC(F)F

Procedure:
The title compound, MS: m/e=273.0 (M+H+), was prepared in accordance with the general method of example 1 from 5-iodo-2-methyl-1H-imidazole and 2-bromo-1,1-difluoroethane.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH:9]1([O:13][C:14]2[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=[C:20]([N+:28]([O-])=O)[C:15]=2[C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH2:11][CH2:10]1.[OH-].[Na+]>O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[NH2:28][C:20]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([O:13][CH:9]2[CH2:12][CH2:11][CH2:10]2)[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=1
Reactant: COC(=O)c1c([N+](=O)[O-])cc(OC)c(OC)c1OC1CCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])S(=O)[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1c(N)cc(OC)c(OC)c1OC1CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 108.4 %

Procedure:
A solution of sodium dithionite (3 g, 0.017 mol) in water (6 ml) was added to a solution of methyl 2-cyclobutyloxy-3,4-dimethoxy-6-nitrobenzoate (511 mg, 0.00164 mol) and tetra-n-butylammonium chloride (280 mg, 0.001 mol) in dichloromethane (15 ml) and the reaction stirred vigorously for 1 hour at room temperature. The mixture was basified with 2N aqueous sodium hydroxide solution (10 ml) and extracted with dichloromethane (3×20 ml). The combined organic extracts were washed with water (30 ml), dried (MgSO4), filtered and evaporated under reduced pressure. The residue was dissolved in a minimum volume of dichloromethane and an excess of ethereal hydrogen chloride added. The resulting precipitate was filtered and partitioned between saturated aqueous sodium bicarbonate solution and dichloromethane. The organic layer was evaporated under reduced pressure to give the subtitle compound (500 mg). Rf 0.70 (diethyl ether). 1H-NMR (CDCl3): δ=1.46 (1H, m), 1.70 (1H, m), 2.28 (4H, m), 3.72 (3H, s), 3.83 (3H, s), 3.90 (3H, s), 4.52 (1H, m), 5.20 (2H, bs), 5.82 (1H, s).
Reaction SMILES: [I:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[N:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.IC1N=CN(CCC2C=CC=CC=2)C=1C1C=CC=CC=1.[Li+].CC([N-]C(C)C)C.CN([CH:52]=[O:53])C>C1COCC1>[I:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([CH:52]=[O:53])=[N:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Ic1c(-c2ccccc2)ncn1CCc1ccccc1
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: Ic1ncn(CCc2ccccc2)c1-c1ccccc1
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1nc(-c2ccccc2)c(I)n1CCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of the mixture of 5-iodo-1-phenethyl-4-phenylimidazole and 4-iodo-1-phenethyl-5-phenylimidazole (example 247C) (0.7 g, 1.87 mmoles) in THF (9 mL) under argon is cooled to −78° C. A 2.0M LDA solution (1.9 mL, 3.8 mmoles) is added dropwise. After 30 minutes at −78° C., DMF (0.9 mL, 3.8 mmoles) is added dropwise. The reaction mixture is allowed to reach 0° C., then it is quenched by adding a half-saturated NaHCO3 solution. The aqueous phase is extracted three times with AcOEt. The organic phase is washed with water, brine, dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is re-crystallized from AcOEt to give 5-iodo-1-phenethyl-4-phenylimidazole-2-carbaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.CO[C:14](OC)([CH3:16])[CH3:15].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1.N1C=CC=CC=1.CCOC(C)=O.CCCCCC>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:14]([CH3:16])[CH3:15])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: COC(C)(C)OC
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Solvent: CCCCCC
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)Nc1ccc(Cl)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 78.3 %

Procedure:
4-chloro-2-nitroaniline (8.6 g; 0.05 mole), 2,2-dimethoxypropane (10.0 ml; 0.9 mole) and trifluoroacetic acid [TFA] (4.0 ml; 0.005 moles) were dissolved in toluene (100 ml) and stirred for 1 hr. BH3 pyridine (5.0 ml; 0.05 moles) was added in 1.0 ml increments. The reaction was exothermic, and the reaction progress was monitored by tlc 40%EtOAc/Hexane. Additional TFA, BH3 * pyridine and 2,2-dimethoxypropane were added until the tlc indicated that the 4-chloro-2-nitroaniline was consumed. The reaction mixture was placed on a bed of silica and eluted with toluene. The product was the first major component to elute, which produced 8.4 g (78%) of a yellow crystalline solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23])[C@H:12]([CH3:27])[N:11]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>[Pd].C(O)C>[Si:1]([O:8][CH2:9][C@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C@H:12]([CH3:27])[N:11]1[C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CCOC(=O)/C=C/c1cccc2c1C[C@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)[C@H]2C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1cccc2c1C[C@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)[C@H]2C
Reaction time: 1.5 h
Yield: 76.1 %

Procedure:
Add 10% palladium on carbon (0.09 g) to a 100 ml Parr bottle. Purge with nitrogen. Add ethanol (5 mL) to wet the catalyst. Add tert-butyl (1S,3R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-[(E)-3-ethoxy-3-oxo-prop-1-enyl]-1-methyl-3,4-dihydro-1H-isoquinoline-2-carboxylate (330 mg, 0.67 mmol) as a solution in ethanol (15 mL). Seal the bottle and purge with nitrogen. Purge the vessel with hydrogen and pressurize to 414 kPa of hydrogen. Shake at room temperature for 1.5 hours. Vent and open the vessel. Filter the reaction mixture. Concentrate the filtrate under reduced pressure. Purify the residue by silica gel chromatography, eluting with ethyl acetate:hexanes (0-10% gradient) to give the title compound as a clear colorless oil (252 mg, 0.51 mmol). MS (m/z): 392.2 (M-BOC+1).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1>O.C(O)C>[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[N:2][OH:3])=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=Cc1ccc(-c2ccccn2)cc1
Temperature: 80 °C
Yield: 57.5 %

Procedure:
Add hydroxylamine hydrochloride (0.379 g, 5.458 mmol) and a solution of NaOH (0.327 g, 8.187 mmol) in water (2 mL) to a solution of 4-(2-pyridyl)-benzaldehyde (0.5 g, 2.729 mmol) in ethanol (10 mL). Heat the mixture at 80° C. for 2 h. Cool to ambient temperature and remove the solvent in vacuo. Partition the residue between EtOAc and water. Separate and day the organic phase over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 4:1) to obtain the desired intermediate (311 mg, 58%). GC-MS m/z: 198 (M+).
Reaction SMILES: C([O:8][CH2:9][C:10]([N:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[N:22]=[C:23]([NH:30][CH:31]3[CH2:33][CH2:32]3)[C:24]3[CH:29]=[CH:28][NH:27][C:25]=3[N:26]=2)=[CH:16][CH:15]=1)[CH3:13])=[O:11])C1C=CC=CC=1>CCO.[Pd]>[CH:31]1([NH:30][C:23]2[C:24]3[CH:29]=[CH:28][NH:27][C:25]=3[N:26]=[C:21]([NH:20][C:17]3[CH:16]=[CH:15][C:14]([N:12]([CH3:13])[C:10](=[O:11])[CH2:9][OH:8])=[CH:19][CH:18]=3)[N:22]=2)[CH2:32][CH2:33]1
Reactant: CN(C(=O)COCc1ccccc1)c1ccc(Nc2nc(NC3CC3)c3cc[nH]c3n2)cc1
Agent: [Pd]
Solvent: CCO
Product: CN(C(=O)CO)c1ccc(Nc2nc(NC3CC3)c3cc[nH]c3n2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2-benzyloxy N-(4-(4-(cyclopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)-N-methylacetamide (0.015 g, 0.034 mmol) in EtOH (0.4 mL) was added Pd/C (10 mg), and was charged with H2 (1 atm). After stirring for 15 h at room temperature, it was purified by preparative HPLC to give N-(4-(4-(cyclopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)-2-hydroxy-N-methylacetamide (MS calcd for C18H20N6O2352.2. found [MH] 352.8; UV 206.3, 228.7, 297.3 nm).
Reaction SMILES: [N+:1]([O-:4])([O-:3])=[O:2].[CH3:5][NH+:6]1[CH2:10][CH2:9][N:8]([CH3:11])[CH:7]1Cl.[CH3:13][N-:14][CH3:15].[Li+]>C(#N)C>[N+:1]([O-:4])([O-:3])=[O:2].[CH3:5][NH+:6]1[CH2:10][CH2:9][N:8]([CH3:11])[CH:7]1[N:14]([CH3:15])[CH3:13]
Reactant: C[N-]C
Reactant: CN1CC[NH+](C)C1Cl
Agent: O=[N+]([O-])[O-]
Agent: [Li+]
Solvent: CC#N
Product: CN(C)C1N(C)CC[NH+]1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.3 %

Procedure:
3.00 g (15.34 mmol) of 1,3-dimethyl-2-chloroimidazolidinium nitrate and 0.78 g (15.29 mmol) of lithium dimethylamide are dissolved in 20 ml of acetonitrile under a protective-gas atmosphere (argon). The reaction mixture is stirred for 5 hours at room temperature, and LiCl is subsequently filtered off. The salt LiCl is washed with 5 ml of acetonitrile, and the organic phases are combined. The solvent is distilled off, and the residue is dried under reduced pressure at 7 Pa and 50° C., giving 2.91 g of 1,3-dimethyl-2-dimethylaminoimidazolidinium nitrate as a liquid, corresponding to a yield of 92.2%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:33]1[N:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][N:34]=1)[C:9]1[CH:10]=[C:11]([C:16]2[S:20][C:19]([C:21]3([OH:32])[CH2:26][CH2:25][CH:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][CH2:22]3)=[N:18][CH:17]=2)[CH:12]=[C:13]([CH3:15])[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH3:44].[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([C:33]1[N:38]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:36]=[CH:35][N:34]=1)[C:9]1[CH:10]=[C:11]([C:16]2[S:20][C:19]([C:21]3([O:32][CH3:44])[CH2:22][CH2:23][CH:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:25][CH2:26]3)=[N:18][CH:17]=2)[CH:12]=[C:13]([CH3:15])[CH:14]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CI
Reactant: CCOC(=O)C1CCC(O)(c2ncc(-c3cc(C)cc(N(C(=O)OC(C)(C)C)c4nccc(C(F)(F)F)n4)c3)s2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCC(OC)(c2ncc(-c3cc(C)cc(N(C(=O)OC(C)(C)C)c4nccc(C(F)(F)F)n4)c3)s2)CC1
Temperature: 0 °C

Procedure:
To a solution of ethyl 4-[5-(3-{(tert-butoxycarbonyl)[4-(trifluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)-1,3-thiazol-2-yl]-4-hydroxycyclohexanecarboxylate (0.148 g, 0.24 mmol) and DMF (1.2 mL) was added iodomethane (0.042 g, 0.29 mmol). The solution was cooled to 0° C. and then 60% sodium hydride in mineral oil (0.011 g, 0.27 mmol) was added and the reaction was allowed to warm up overnight. The next morning, iodomethane (1.14 g, 8.03 mmol) was added and the mixture was cooled to 0° C. Sodium hydride in mineral oil (60%, 0.011 g, 0.27 mmol) was added and the reaction was allowed to warm to room temperature. The reaction was complete after warming. The solution was cooled to 0° C. and carefully quenched with methanol and then water. The mixture was extracted with dichloromethane. The organic layer was washed three times with water, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography was used to yield ethyl 4-[5-(3-{(tert-butoxycarbonyl)[4-(trifluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)-1,3-thiazol-2-yl]-4-methoxycyclohexanecarboxylate. MS ESI: [M+H]+ m/z 621.2.
Reaction SMILES: Br[CH2:2][CH:3]1[O:15][C:14]2[C:5](=[C:6]3[C:11](=[C:12]([CH3:16])[CH:13]=2)[NH:10][C:9](=[O:17])[CH:8]=[CH:7]3)[CH2:4]1.[N-:18]=[N+:19]=[N-:20].[Na+].CN(C)C=O>C(Cl)(Cl)Cl>[N:18]([CH2:2][CH:3]1[O:15][C:14]2[C:5](=[C:6]3[C:11](=[C:12]([CH3:16])[CH:13]=2)[NH:10][C:9](=[O:17])[CH:8]=[CH:7]3)[CH2:4]1)=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)CC(CBr)O2
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc2c(c3ccc(=O)[nH]c13)CC(CN=[N+]=[N-])O2
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 96.3 %

Procedure:
2-Bromomethyl-5-methyl-1,2-dihydrofuro-[3,2-f]quinoline7-one (4.90 g, 16.7 mmol) and sodium azide (7.5 g, 115 mmol) were added to dimethylformamide (150 ml), and the mixture was stirred in a bath of 100° C. for 1.5 hours, followed by cooling and condensing. The residue was combined with chloroform, and washed with water. The washed material was dried and condensed. The resultant residue was recrystallized from chloroform--n-hexane. As a result, 4.12 g of 2-azidomethyl-5-methyl-1,2-dihydrofuro-[3,2-f]quinoline-7-one was obtained as brown prisms (96.6%).