Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[H-].[Na+].I[CH2:32][CH3:33].CO>CN(C=O)C.O>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][CH:19]([CH2:22][OH:23])[CH2:20][O:21][CH2:32][CH3:33])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCI
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(CO)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: CCOCC(CO)NC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
At 0° C., 750 mg (1.92 mmol) of 8-[(2,6-difluorobenzyl)oxy]-N-(1,3-dihydroxy-propan-2-yl)-2-methylimidazo[1,2-a]pyridine-3-carboxamide were initially charged in 19 ml of DMF, 52 mg (2.11 mmol) of sodium hydride (95%) were added and the mixture was stirred at 0° C. for 30 min. A solution of 239 mg (1.53 mmol) of iodoethane in 2 ml of DMF was then slowly added dropwise at 0° C., and the mixture was stirred at RT overnight. At room temperature, another 9.4 mg (0.38 mmol) of sodium hydride (95%) were added, the mixture was stirred for 30 min and another 59.8 mg (0.38 mmol) of iodoethane were then added dropwise, and the mixture was stirred at room temperature overnight. A little methanol was added and the reaction mixture was poured into 20 ml of water and extracted twice with ethyl acetate. The combined organic phases were washed with aqueous saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated. The residue was purified by silica gel chromatography (mobile phase dichloromethane:methanol=40:1, 20:1). This gave 280 mg of the target compound (33% of theory, purity 96%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:17][S:18][C:19]2[NH:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12].ClC1C=CC=C(C(OO)=[O:36])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:17][S:18]([C:19]2[NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[N:20]=2)=[O:36])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:16])([F:15])[C:11]([F:12])([F:14])[F:13]
Reactant: Cc1c(OCC(F)(F)C(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1c(OCC(F)(F)C(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 77.8 %

Procedure:
To a solution of 2-[[3-methyl-4-(2,2,3,3,3-pentafluoropropoxy)-2-pyridyl]methylthio]benzimidazole (2.2 g) in chloroform (20 ml), a solution of m-chloroperbenzoic acid (*1.3 g) in chloroform (15 ml) was added dropwise while ice-cooling over a period of 30 minutes and the resulting reaction mixture was washed with a saturated aqueous sodium hydrogen carbonate. After drying over magnesium sulfate, the solvent was concentrated. The residue was applied on a silica gel (50 g) column, eluted with ethyl acetate and then recrystallized from acetone-isopropyl ether to give 1.78 g of 2-[[3-methyl-4-(2,2,3,3,3-pentafluoropropoxy)-2-pyridyl]methylsulfinyl]benzimidazole as pale yellow prisms. Melting point: 161°~163° C. (decomposition).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C([N:11](CC)CC)C.[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19]>C(Cl)Cl>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:16][C:17]([CH3:22])([CH3:21])[C:18]([NH2:11])=[O:19])=[N:3][CH:4]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(Cl)cn1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(Cc1ccc(Cl)cn1)C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-amino-5-chloropyridine (10.0 g, 0.078 mol) (Aldrich) and triethylamine (12 mL, 0.086 mol) in methylene chloride (200 mL), at 0° C., was added dropwise trimethylacetyl chloride in methylene chloride (15 mL). The reaction was allowed to warm to room temperature while stirring overnight. The resulting mixture was washed with water, brine, and was dried over MgSO4 and filtered. Concentration of the filtrate in vacuo provided a colorless oil (19.2 g). The oil was dissolved in hexanes and cooled causing the precipitation of a solid. The solid was collected by filtration affording the amide as a white solid (14.96 g, 90%): mp 51.4–53.4° C. 1H NMR (CDCl3/300 MHz) 8.25–8.15 (m, 2H), 8.00 (br s, 1H), 7.68–7.60 (m, 1H), 1.28 (s, 9H). Anal. Calc'd for C10H13N2OCl: C, 56.47; H, 6.16; N, 13.17 Found: C, 56.72; H, 6.34; N, 12.88.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:16][C:17]1[N:18]=[C:19](/[CH:22]=[CH:23]/[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[F:31])[O:20][CH:21]=1.Cl>CN(C=O)C.O>[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1/[CH:23]=[CH:22]/[C:19]1[O:20][CH:21]=[C:17]([CH2:16][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:6][CH:7]=2)[N:18]=1
Reactant: Fc1ccc(/C=C/c2nc(CCl)co2)c(F)c1
Reactant: OCCCCc1ccc(O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCCCc1ccc(OCc2coc(/C=C/c3ccc(F)cc3F)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
To a solution of 4-(4-hydroxyphenyl)-1-butanol (1.99 g) in DMF (20 ml), 60% oily sodium hydride (528 mg) was added under ice cooling, followed by stirring at room temperature for 30 minutes. Under ice cooling, (E)-4-chloromethyl-2-[2-(2,4-difluorophenyl)ethenyl]oxazole (3.37 g) was added, followed by stirring overnight at room temperature. After water and 1 N hydrochloric acid was added, the reaction mixture was extracted with ethyl acetate. After the extract was dried over magnesium sulfate, it was concentrated under reduced pressure; the residue was recrystallized from ethyl acetate-diethyl ether-hexane to yield the titled compound (3.71 g) as colorless crystals.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([NH:7][CH2:8][CH2:9][CH3:10])=[CH2:6].Cl[C:13](=[CH2:16])[C:14]#N.C([N:19](CC)CC)C>C(#N)C>[CH2:10]([C:9]1[CH:3]=[CH:4][C:5]([C:6]#[N:19])=[N:7][CH:8]=1)[CH2:14][CH2:13][CH3:16]
Reactant: C=C(C=CN(C)C)NCCC
Reactant: C=C(Cl)C#N
Reactant: CCN(CC)CC
Solvent: CC#N
Product: CCCCc1ccc(C#N)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.4 %

Procedure:
0.1 mole of 1-dimethylamino-1-aza-3-n-butyl-1,3-butadiene, 0.1 mole of 2-chloroacrylonitrile and 0.2 mole of triethylamine are heated in 100 ml of acetonitrile for 20 hours to 60° C. The reaction mixture is concentrated by evaporation and the residue is dissolved in dioxane. The solution is filtered and gaseous HCl is introduced. The batch is stirred for 15 minutes at room temperature and then concentrated by evaporation. The residue is partitioned between CH2Cl2 and 1N NaHCO3. The organic phase is dried, concentrated by evaporation and distilled under a high vacuum, affording 10.0 g (63%) of a yellowish oil with a boiling point of 86°-87° C./3·10-1 mbar.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=[O:18])[CH:4]([CH3:17])[N:5]1[C:9](C)=C[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6]1.ClO[C:22](C)(C)C.BrBr.[C:28]([Cl:32])(Cl)(Cl)Cl>C(O)(=O)C>[Cl:32][C:28]1[C:7]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[N:6][N:5]([C:4]([CH3:17])([CH3:22])[C:3]([N:2]([CH3:1])[CH3:19])=[O:18])[CH:9]=1
Reactant: CC(C)(C)OCl
Reactant: ClC(Cl)(Cl)Cl
Reactant: Cc1cc(-c2ccccc2)nn1C(C)C(=O)N(C)C
Agent: BrBr
Solvent: CC(=O)O
Product: CN(C)C(=O)C(C)(C)n1cc(Cl)c(-c2ccccc2)n1

Procedure:
Following the procedure of Example 108, but substituting N,N,α,α-tetramethyl-3-phenylpyrazole-1-acetamide for N,N,α,5-tetramethyl-3-phenylpyrazole-1-acetamide, tert-butyl hypochlorite for bromine, and carbon tetrachloride for acetic acid as the reaction solvent, there was obtained 4-chloro-N,N,α,α-tetramethyl-3-phenylpyrazole-1-acetamide having a melting point of 117°-119° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:42]=[CH:41][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:31][CH:32]([CH2:36][CH2:37][C:38]([OH:40])=[O:39])[C:33]([OH:35])=[O:34])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].O[CH2:44][CH:45]([CH2:47][OH:48])[OH:46]>CN(C)C1C=CN=CC=1.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:31][CH:32]([CH2:36][CH2:37][C:38]([O:40][CH2:44][CH:45]([OH:46])[CH2:47][OH:48])=[O:39])[C:33]([O:35][CH2:44][CH:45]([OH:46])[CH2:47][OH:48])=[O:34])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:41][CH:42]=1)=[O:11]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NC(CCC(=O)O)C(=O)O)c[nH]4)c3)cc2)c1
Reactant: OCC(O)CO
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NC(CCC(=O)OCC(O)CO)C(=O)OCC(O)CO)c[nH]4)c3)cc2)c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 2-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanedioic acid (60 mg, 0.10 mmol), glycerol (0.5 ml), 1-Ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (EDC.HCl, 37 mg, 0.19 mmol) and 4-dimethylaminopyridine (DMAP, 5 mg, 0.04 mmol) in anhydrous THF (10 ml) was stirred at 60° C. for 3 hours. The mixture was cooled to room temperature, concentrated and purified by silica gel chromatography eluting with a gradient of 10˜15% MeOH/CHCl3 to give bis(2,3-dihydroxypropyl) 2-{[(5-{-4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanedioate as colorless oil. Yield: 40 mg, 53%.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[NH:8][CH:7]=1.BrCCSCC1C2C(=CC=C(C(OC)=[O:34])C=2)NC=1.SCCO>>[OH:34][CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[NH:8][CH:7]=1
Reactant: COC(=O)c1ccc2[nH]cc(CSCCCl)c2c1
Reactant: COC(=O)c1ccc2[nH]cc(CSCCBr)c2c1
Agent: OCCS
Product: COC(=O)c1ccc2[nH]cc(CSCCO)c2c1

Procedure:
A solution of 28.4 g of methyl 3-(4-chloro-2-thiabutyl)-indole-5-carboxylate [or 32.8 g of methyl 3-(4-bromo-2-thiabutyl)-indole-5-carboxylate; obtainable by reacting methyl gramine-5-carboxylate with 2-mercaptoethanol to give methyl 3-(4-hydroxy-2-thiabutyl)-indole-5-carboxylate and subsequently reacting the latter with SOCl2 or PBr3 ] and 16 g of 4-phenyl-1,2,3,6-tetrahydropyridine in 100 ml of acetonitrile is stirred for 12 hours at 20° and is worked up in the customary manner to give methyl 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-indole-5-carboxylate ("P"); hydrochloride, m.p. 202°-203°.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][C:8]([CH:11]=O)=[CH:9][N:10]=1.[NH2:13][C:14]1[C:19]([C:20]#[N:21])=[C:18]([O:22][CH2:23][CH3:24])[N:17]=[C:16]([C:25]([NH:27][CH2:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[O:26])[CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClC(Cl)C.C(O)(=O)C>[NH2:13][C:14]1[C:19]([C:20]#[N:21])=[C:18]([O:22][CH2:23][CH3:24])[N:17]=[C:16]([C:25]([NH:27][CH2:28][CH:29]2[CH2:34][CH2:33][N:32]([CH2:11][C:8]3[S:7][C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[N:10][CH:9]=3)[CH2:31][CH2:30]2)=[O:26])[CH:15]=1
Reactant: CCOc1nc(C(=O)NCC2CCNCC2)cc(N)c1C#N
Reactant: O=Cc1cnc(-c2cccs2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCOc1nc(C(=O)NCC2CCN(Cc3cnc(-c4cccs4)s3)CC2)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 17 h
Yield: 31.4 %

Procedure:
The compound prepared in Example 333 (31 mg) and the compound prepared in Example 334 (48 mg) were combined in dichloroethane (1.6 mL) and acetic acid (0.054 mL) was added. Sodium triacetoxyborohydride (0.101 g) was then added. The reaction mixture was stirred at ambient temperature for 17 hours. It was then treated with saturated sodium bicarbonate and extracted with dichloromethane. The combined organics were dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:methanol=98:2) to obtain the title compound (24 mg) having the following physical data.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[CH2:11][C:12](=[O:15])[CH2:13][CH3:14])=[CH:5][CH:4]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[H][H]>CO.O>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[CH2:11][C@@H:12]([OH:15])[CH2:13][CH3:14])=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: CCC(=O)CC(=O)Nc1ccc(C(F)(F)F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CO
Solvent: O
Product: CC[C@H](O)CC(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 60 °C
Yield: 95 %

Procedure:
N-[4-(trifluoromethyl)phenyl]-3-oxopentanoic acid amide 1.30 g (5.0 mmol) produced in Example 1 and ((S)-BINAP)RuBr2 50.0 mg (0.057 mmol) (BINAP denotes 2,2′-bisdiphenylphosphino-1,1′-binaphthyl. It was prepared according to the method described in Tetrahedron Asymmetry, 1994,5,675) were mixed with 20 mL of a methanol-water (10/1 in volume) solution. Hydrogen replacement was carried out three times and after the reaction solution was heated to 60° C., reaction was carried out under hydrogen pressure (3.0 kg/cm2) for 12 hours. After releasing hydrogen, the solution was concentrated under reduced pressure and purifying on silica gel chromatography was carried out to obtain (S)-N-[4-(trifluoromethyl)phenyl]-3-hydroxypentanoic acid amide as a white solid (1.23 g, isolated yield: 95%). The optical purity of the product was determined by HPLC analysis (column; Daicel Chiral Pack AD-H 4.6×250 mm: eluent; hexane/isopropanol=90/10: flow rate; 1.0 mL/min: column temperature; 30° C.: detector; UV 210 nm: retention time; (S) antipode=12.0 minutes, (R) antipode=9.3 minutes) to be 84.7% ee. 1H-NMR (CDCl3, 400 MHz/ppm): δ 1.00 (3H, t), 1.5-1.7 (2H, br), 2.50 (1H, dd), 2.59 (1H, dd), 2.75 (br, 1H), 4.06 (1H, m), 7.57 (2H, d), 7.64 (2H, d), 8.21 (1H, br)
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:15]=[CH:14][C:3]=1[C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][C:7]1=[O:13])=[O:5].[Br:22]Br>C(Cl)Cl>[Br:22][CH:8]1[CH2:9][CH2:10][C:11](=[O:12])[CH:6]([C:4](=[O:5])[C:3]2[CH:14]=[CH:15][C:16]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:17][C:2]=2[Cl:1])[C:7]1=[O:13]
Reactant: BrBr
Reactant: CS(=O)(=O)c1ccc(C(=O)C2C(=O)CCCC2=O)c(Cl)c1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(=O)C2C(=O)CCC(Br)C2=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 115.8 %

Procedure:
2-(2-Chloro-4-methanesulfonylbenzoyl)-cyclohexane-1,3-dione (6.6 g, 0.02 mole) was dissolved in 50 ml of methylene chloride. Bromine (2.9 g, 0.018 mole) dissolved in 50 ml of methylene chloride was added dropwise over a period of 75 minutes to the above solution which was cooled with a dry ice-isopropanol bath. Upon completion of the addition, the reaction mixture was stirred an additional 2 hours at room temperature. The reaction mixture was then concentrated under vacuum to afford 8.5 g of the desired product as a semi-solid. It was identified as such by nuclear magnetic resonance spectroscopy, infrared spectroscopy, and mass spectroscopy. The product can be further purified by column chromatography.
Reaction SMILES: [CH3:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Cl[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+]>>[CH:4]([C:3]1[C:2]([CH3:1])=[C:9]([CH:8]=[CH:7][CH:6]=1)[O:10][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=1)=[O:5]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: Cc1c(O)cccc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1c(C=O)cccc1Oc1ccc(C#N)cn1
Yield: 91.5 %

Procedure:
Using a method similar to Example 221, Step 1, using 2-methyl-3-hydroxy-benzaldehyde (see European Patent 0807621 A1) (965 mg, 6.42 mmol), 6-chloronicotinonitrile (890 mg, 6.42 mmol) and K2CO3 (1.33 g, 9.63 mmol) gives 6-(3-formyl-2-methyl-phenoxy)-nicotinonitrile (1.40 g) as a white solid. 1H NMR (CDCl3): 10.30 (s, 1H), 8.41 (s, 1H), 7.96 (d, 1H), 7.78 (d, 1H), 7.45 (t, 1H), 7.30 (d, 1H), 7.10 (d, 1H), 2.45 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[C:5]([O:11][CH3:12])=[C:6]([CH:8]([OH:10])[CH3:9])[CH:7]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl.CC(OC)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[C:5]([O:11][CH3:12])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: COc1cc(Cl)cc(C(C)O)c1OC
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: COc1cc(Cl)cc(C(C)=O)c1OC
Reaction time: 0.67 h
Yield: 72 %

Procedure:
1-(5-Chloro-2,3-dimethoxy-phenyl)-ethanol (204 g, 943 mmol) was dissolved in DCM (2.0 L) and PCC (was added to the reaction mixture in portions, over 2 hours. Over the first 1.5 hours the temperature increased from 17.2° C. to 30.7° C. while a total of 315 g PCC was added. Addition of the remaining PCC did not result in a temperature increase. The reaction mixture was tested by TLC 1 hour after the PCC addition was completed; full conversion was observed. After an additional 40 min, 2 L TBME was added and a 4° C. exotherm was observed. The dark slurry was poured into 0.2 kg celite, mixed, then filtered over an additional 0.2 kg celite. The tar-like material remained in the reaction flask. DCM/TBME solution was concentrated under reduced pressure. A coating of tar formed on the flask walls; a solid also formed. The solid was dissolved in 0.2 L DCM (the tar did not dissolve). The solution was mixed with 0.2 kg silica gel and the DCM was allowed to evaporate. The product pre-adsorbed on silica gel was placed on top of a silica gel plug (0.4 kg silica gel) and the organic material was eluted with TBME until no product was observed by TLC. The resulting yellow solution was concentrated to yield a yellow solid. This solid was re-dissolved in TBME and the solution was flushed through a 0.4 kg silica gel plug. The resulting solution was concentrated to yield 145.8 g dry solid (72% yield, 95% pure by HPLC).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[N+]([C:14]1[CH:19]=CC(O)=C[CH:15]=1)([O-])=O.S(=O)(=O)(O)O.OCC(CO)O.[OH-].[Na+]>>[N:1]1[C:2]2[C:10](=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH:19]=[CH:14][CH:15]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: OCC(O)CO
Product: O=C(O)c1ccc2ncccc2c1
Temperature: 0 °C
Reaction time: 48 h
Yield: 112.8 %

Procedure:
To a mixture of 4-aminobenzoic acid (1.75 g, 1.28 mol), 4-nitrophenol (88.75 g, 0.64 mol) and sulphuric acid (1.2 lit.), glycerol (234.8 g, 2.55 mol) was added dropwise at 135° C. After 48 h, the reaction mixture was cooled to 0° C. and the pH adjusted to 3-5 with 10% sodium hydroxide solution. The resulting precipitate was collected by filtration and washed with water and dried under vacuum to afford the title compound as a black solid (125 g. 56%).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([O-:4])=[O:3].Cl[C:14](=[O:22])[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:14](=[O:22])[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:12]=1)([O-:4])=[O:3]
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)CCC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCC(=O)NCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
A mixture of 4-nitrobenzylamine hydrochloride (8.0 g), ethyl 4-chloro-4-oxobutanoate (10.47 g), saturated aqueous sodium hydrogen carbonate (100 ml) and ethyl acetate (100 ml) was stirred at room temperature for 2 hrs. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. Recrystallization of the residue from ethyl acetate-hexane gave ethyl 4-[(4-nitrobenzyl)amino]-4-oxobutanoate (10.3 g, 87%) as colorless prism crystals. melting point: 104-106° C.
Reaction SMILES: [CH3:1][N:2]([CH3:30])[C:3](=[O:29])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([CH2:20][O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:13])[CH:6]=1.C(N(CC)C(C)C)(C)C.Cl[C:41]1[C:42]2[C:49]([CH3:50])=[CH:48][NH:47][C:43]=2[N:44]=[CH:45][N:46]=1>C(O)(C)C.CCOC(C)=O>[CH3:1][N:2]([CH3:30])[C:3](=[O:29])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([CH2:20][O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:15][CH2:16][N:17]([C:41]3[C:42]4[C:49]([CH3:50])=[CH:48][NH:47][C:43]=4[N:44]=[CH:45][N:46]=3)[CH2:18][CH2:19]2)=[O:13])[CH:6]=1
Reactant: CN(C)C(=O)Oc1cccc(NC(=O)C2(COCc3ccccc3)CCNCC2)c1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: Cc1c[nH]c2ncnc(N3CCC(COCc4ccccc4)(C(=O)Nc4cccc(OC(=O)N(C)C)c4)CC3)c12
Temperature: 85 °C
Yield: 37.6 %

Procedure:
To a solution of 3-(4-(benzyloxymethyl)piperidine-4-carboxamido)phenyl dimethylcarbamate from step D (0.2 g, 0.49 mmol) in isopropanol (5 mL) was added N,N-diisopropylethylamine (0.167 mL, 0.98 mmol) and 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (0.08 g, 0.49 mmol). The reaction was heated at 85° C. overnight, diluted with EtOAc, washed with brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by flash chromatography (40 g SiO2, 0-80% ethylacetate:hexanes) to give the title compound (0.1 g, 38%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]#[N:10])[CH:4]=1)#[N:2].[Li+].CC([N-]C(C)C)C.[B:19](OC)([O:22]C)[O:20]C.O>C1COCC1.CC(O)=O>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]#[N:10])[C:4]=1[B:19]([OH:22])[OH:20])#[N:2]
Reactant: COB(OC)OC
Reactant: N#Cc1cccc(C#N)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1cccc(C#N)c1B(O)O
Temperature: -96 °C
Reaction time: 0.5 h

Procedure:
1,3-Dicyanobenzene (1.00 g) was dissolved in freshly distilled THF (70 mL). This solution was cooled to −96° C. and LDA (4.2 mL of a 2M solution) was added dropwise to the cold solution under N2. The mixture was stirred for 30 min at −96° C. and (MeO)3B (1.3 mL) was added. The resulting mixture was allowed to warm to room temperature and stirred overnight. Water was added and the resulting mixture was stirred for 0.5 h, then acidified with HOAc and extracted with EtOAc. The organic layer was further washed with water and brine, dried (MgSO4), filtered and evaporated. The residue was taken up in CH2Cl2, filtered and evaporated to yield 2,6-dicyanobenzeneboronic acid (0.56 g).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1.O[CH2:12][C@@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:18]([O:17][C:16]([NH:15][C@@H:13]([CH3:14])[CH2:12][O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1)=[O:22])([CH3:21])([CH3:20])[CH3:19]
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: COC(=O)c1cc(O)no1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OC[C@H](C)NC(=O)OC(C)(C)C)no1
Temperature: 25 °C
Yield: 59.6 %

Procedure:
To a solution of methyl 3-hydroxyisoxazole-5-carboxylate (20 g), tert-butyl [(1S)-2-hydroxy-1-methylethyl]carbamate (25 g) and triphenylphosphine (55.1 g) in THF (800 mL) was added dropwise a toluene solution (1.9 M, 110 mL) of diisopropyl azodicarboxylate, and the mixture was refluxed for 5 hr. The reaction mixture was allowed to cool to room temperature, and ethyl acetate was added thereto. The mixture was washed with water and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (25 g).