Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=1F)[NH2:7])([O-:3])=[O:2].[CH3:12][O-:13].[Na+].Cl.O>CO>[CH3:12][O:13][C:10]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: C[O-]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(N)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 21 h
Yield: 97.3 %

Procedure:
To a 1M solution of 3-nitro-4-fluoroaniline (16.7 g, 107 mmol, from Aldrich Chemical Co., Milwaukee, Wis. USA) in anhydrous methanol at ambient temperature was added sodium methoxide (23.1 g, 428 mmol) and the resulting solution was refluxed with stirring for 21 hours. The reaction mixture was then cooled to 0° C. and a 12M solution of HCl (13.4 mL) was added dropwise followed by water (250 mL). The crude mixture was extracted three times with Et2O (200 mL). The organic layers were combined, washed with brine (300 mL), dried over Na2SO4, and concentrated under vacuum to yield 17.5 g (97%) of product as a dark brown solid, which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.09 (d, J=9 Hz, 1H), 7.01 (dd, J=2.8, 1.3 Hz, 1H), 6.85 (ddd, J=9, 2.8, 1.4 Hz, 1H), 5.2 (s, 2H), 3.75 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[OH:19][C@H:20]([CH3:23])[CH2:21][NH2:22]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:22][CH2:21][C@H:20]([OH:19])[CH3:23])=[O:14]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: C[C@@H](O)CN
Product: C[C@@H](O)CNC(=O)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N-[(2R)-2-hydroxypropyl]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 2 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 3 mmol of 2-(R)-hydroxypropylamine LC/MS [8.33 min; 416 (M+1)]
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[C:13]([C:14]([OH:16])=[O:15])[C:12]([OH:18])=[C:11]([I:19])[CH:10]=1.[CH2:20](O)[CH3:21]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[C:13]([C:14]([O:16][CH2:20][CH3:21])=[O:15])[C:12]([OH:18])=[C:11]([I:19])[CH:10]=1
Reactant: CCO
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)cc(I)c1O
Product: CCOC(=O)c1cc(-c2ccc(F)cc2F)cc(I)c1O
Temperature: 25 °C

Procedure:
A solution of 5-(2,4-difluorophenyl)-3-iodo-salicylic acid (1.69 g, 4.61 mmol) in ethanol (20 ml) was cooled to 0° C. and a flow of anhydrous hydrochloride gas was bubbled through for 5 min. The solution was heated under reflux for 4 hr and cooled to room temperature, the solvents were evaporated at low pressure. The residue was dissolved in dichloromethane and the product was worked up. The reaction crude was purified by chromatography on silica gel using hexane/ethyl acetate (7:3) as the eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](=[O:19])[NH:13][C:14](C(OC)=O)=[C:10]3[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:6]=2[CH:27]=1.CO.[OH-].[K+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](=[O:19])[NH:13][CH:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:6]=2[CH:27]=1
Reactant: COC(=O)c1[nH]c(=O)n2c1CN=C(c1ccccc1F)c1cc(Cl)ccc1-2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=c1[nH]cc2n1-c1ccc(Cl)cc1C(c1ccccc1F)=NC2

Procedure:
A mixture of 0.386 g (1 mmole) of 8-chloro-1,2-dihydro-6-(2-fluorophenyl)-1-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid, methyl ester, 10 ml of methanol, 1 ml of water and 0.225 g (4 mmole) of potassium hydroxide was heated to reflux for 31/2 hours under an atmosphere of nitrogen. The solvent was evaporated and the residue was acidified with acetic acid and extracted with methylene chloride. The extracts were dried and evaporated and the residue was heated in mineral oil up to 230° for 5 min. The reaction mixture was partitioned between 1 N hydrochloric acid and methylene chloride/hexane. The acid extract was made alkaline with sodium carbonate solution and extracted with methylene chloride. The residue obtained after evaporation of the dried extracts was chromatographed over 10 g of silica gel using methylene chloride/ethyl acetate 1:2. Crystallization of the combined clean fractions from ethyl acetate/hexane yielded colorless crystals with mp 247°-250°. Uv λ max 212 mμ (ε=42250) sh 262 (10000) ir (KBr) 1695 cm-1 (CO) 3150 (NH). Nmr (CDCl3) 4.18 ppm (d, 1) and 4.88 (d, 1) (AB-system, J=12.5 Hz, C4 --H) 6.28 (d, 1, J=2 Hz, C3 --H) 6.9-7.7 (m, 5, aromatic H) 8.13 (d, 1, J=8.5 Hz, C10 --H) 10.46 (broad s, 1, NH).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@@H:7]([NH2:10])[CH2:8][OH:9])=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:17][C:18]1([C:21](Cl)=[O:22])[CH2:20][CH2:19]1.[OH-].[Na+]>C(Cl)Cl.O>[OH:9][CH2:8][C@H:7]([NH:10][C:21]([C:18]1([Br:17])[CH2:20][CH2:19]1)=[O:22])[C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: O=C(Cl)C1(Br)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=C(N[C@@H](CO)c1ccccc1)C1(Br)CC1
Reaction time: 8 h
Yield: 71.2 %

Procedure:
739 mg of D-(−)-α-phenylglycinol is dissolved in 27 ml of methylene chloride, and 678 mg of sodium carbonate is added to 11 ml of water and 1.09 g of acid chloride 107 at room temperature. It is stirred overnight and then mixed with methanolic sodium hydroxide solution, the organic phase is separated, dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate/hexane, whereby 1.09 g of (1R)-1-bromocyclopropanecarboxylic acid-2-hydroxy-1-phenylethylamide 110 is isolated as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[CH3:18][C:19]1[NH:20][C:21]2[CH:27]=[C:26]([NH2:28])[CH:25]=[CH:24][C:22]=2[N:23]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:28][C:26]1[CH:25]=[CH:24][C:22]2[NH:23][C:19]([CH3:18])=[N:20][C:21]=2[CH:27]=1
Reactant: Cc1nc2ccc(N)cc2[nH]1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3ccc4[nH]c(C)nc4c3)c2cc1OC

Procedure:
Using an analogous procedure to that described in Example 150, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 294.4 mg (2.0 mmol) of 2-methyl-5-aminobenzimidazol and 115.6 mg (1 mmol) of pyridine hydrochloride in 10 mL of 2-ethoxyethanol was refluxed for 4 hr. The work up gave 220.2 mg (61.3%) of the product as a sand color solid, m.p. 207° C. (dce.), mass (electrospray, m/e): M+H 359.9. HRCIMS: calcd 359.138 for C20H17N5O2 (M+), obsd 359.1403.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2.[CH3:15][S:16]([C:19]1[CH:20]=[C:21]([C:31](O)=[O:32])[C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)(=[O:18])=[O:17]>>[CH3:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:21]([C:31]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=3)[CH2:9]2)=[O:32])[CH:20]=1)(=[O:17])=[O:18]
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)O)c1
Reactant: FC(F)(F)c1ccc2c(c1)CCNC2
Product: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)N2CCc3cc(C(F)(F)F)ccc3C2)c1

Procedure:
Prepared in analogy to example 1.1 from 6-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline and 4-methanesulfonyl-biphenyl-2-carboxylic acid (example 2.5).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:9]=[C:10]([CH2:16][CH3:17])[C:11](=[O:15])[NH:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[CH3:18][N:19]([CH3:29])[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>>[CH3:18][N:19]([CH3:29])[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH:1][CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:9]=[C:10]([CH2:16][CH3:17])[C:11](=[O:15])[NH:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1)=[O:24]
Reactant: CCc1cc(-c2ccc(CN)o2)c(C)[nH]c1=O
Reactant: CN(C)c1cccc(C(=O)Cl)c1
Product: CCc1cc(-c2ccc(CNC(=O)c3cccc(N(C)C)c3)o2)c(C)[nH]c1=O

Procedure:
Example 269 is substantially repeated except for utilizing 5-(5-aminomethylfuran-2-yl)-3-ethyl-6-methyl-1H-pyridin-2-one and 3-dimethylamino-benzoyl chloride to afford the title compound. MS: m/e=380 (M+H).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH3:15])[C:10](O)=[O:11])[N:8]=1)=[O:2].S(Cl)([Cl:18])=O>CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH3:15])[C:10]([Cl:18])=[O:11])[N:8]=1)=[O:2]
Reactant: CON=C(C(=O)O)c1csc(NC=O)n1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CON=C(C(=O)Cl)c1csc(NC=O)n1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
N,N-Dimethylformamide (3 drops) was added to a suspension of 2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer, 23 g.) in thionyl chloride (230 ml.), and stirred, at 60° C. for 5 minutes. After concentrating the solution in vaco, benzene was added to the residue. The presipitates were collected by filtration, washed with benzene (30 ml.) three times and diethyl ether in turn to give 2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetyl chloride (anti isomer, 18 g.). On the other hand, trimethylsilylacetamide (46 g.) was added to a suspension of 4-nitrobenzyl 7-amino-3-cephem-4-carboxylate (16.8 g.) in methylene chloride (168 ml.), and stirred at 40° C. for an hour. To the suspension was gradually added 2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetyl chloride (anti isomer, 13.6 g.) at -5° to 0° C., and stirred at the same temperature for an hour. Water (150 ml.) was added to the resultant solution and stirred for 15 minutes. The recipitates were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (anti isomer, 25.7 g.).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][NH:5][CH2:4][C@H:3]1[NH:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH2:17]([N:5]1[CH2:6][CH2:7][C@@H:2]([CH3:1])[C@H:3]([NH:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])[CH2:4]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: CCOP(=O)(N[C@@H]1CNCC[C@H]1C)OCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOP(=O)(N[C@@H]1CN(Cc2ccccc2)CC[C@H]1C)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
A mixture of diethyl trans-4-methylpiperidin-3-ylphosphoramidate (0.63 g, 2.52 mmol), benzaldehyde (0.38 mL, 3.78 mmol) and acetic acid (0.29 mL, 5.03 mmol) in methanol (20 mL) was stirred at 0° C. for 30 minutes. NaCNBH3 (0.24 g, 3.78 mmol) was added at 0° C. The resulting solution was warmed to room temperature and stirred at room temperature for 1 hour. The solvent was removed in vacuo, and saturated sodium bicarbonate (20 mL) and ethyl acetate (30 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate) and concentrated in vacuo to give diethyl trans-1-benzyl-4-methylpiperidin-3-ylphosphoramidate (0.85 g, 99%), which was used directly in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[C:8]([Br:11])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH3:15][C:16]1[O:20][N:19]=[CH:18][C:17]=1[C:21](Cl)=[O:22]>O>[C:12]([C:3]1[O:4][C:5]2[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=2[C:2]=1[NH:1][C:21]([C:17]1[CH:18]=[N:19][O:20][C:16]=1[CH3:15])=[O:22])(=[O:14])[CH3:13]
Reactant: CC(=O)c1oc2ccc(Br)cc2c1N
Reactant: Cc1oncc1C(=O)Cl
Solvent: O
Product: CC(=O)c1oc2ccc(Br)cc2c1NC(=O)c1cnoc1C
Temperature: 27 °C
Reaction time: 0.08 h

Procedure:
To a solution (10 ml) of 1-(3-amino-5-bromobenzofuran-2-yl)ethanone (0.2 g, 0.79 mmol) in water-free THF was added dropwise a solution (5 ml) of 5-methylisoxazole-4-carbonyl chloride (0.10 g, 0.79 mmol) in water-free THF under a nitrogen gas with vigorous stirring at 26-28° C. over 5 min. The reaction solution was heated at 65° C. for 2 hr. The reaction mixture was cooled to room temperature and the precipitate was collected by filtration. The precipitate was recrystallized from ethyl acetate to give N-(2-acetyl-5-bromobenzofuran-3-yl)-5-methylisoxazole-4-carboxamide as pale-yellow needle crystals (0.19 g, yield 68.0%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][N:23]2[C:27](=[O:28])[C:26]3=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]3[C:24]2=[O:33])[CH:18]=[CH:19][CH:20]=1.[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[OH:28][C:27]1([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[C:26]2[C:25](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:24](=[O:33])[N:23]1[CH2:22][CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH3:13])[CH:16]=1
Reactant: Brc1cccnc1
Reactant: COc1cccc(CCN2C(=O)c3ccccc3C2=O)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cccc(CCN2C(=O)c3ccccc3C2(O)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At −70° C., a 1.6 M butyllithium solution (3.99 mmol) in absolute diethyl ether was admixed dropwise with a solution of 0.56 g (3.56 mmol) of 3-bromopyridine in absolute diethyl ether. The color of the mixture changed to yellow, and a precipitate was formed. After 1 h at −70° C., a solution of 0.5 g (1.78 mmol) of N-(2-(3-methoxyphenyl)ethyl)phthalimide in 10 ml of absolute tetrahydrofuran was added dropwise. The reaction mixture was warmed to room temperature, stirred for another 1 h and then admixed with 10 ml of saturated ammonium chloride solution. The mixture was extracted three times with diethyl ether. The combined organic phases were washed once with saturated sodium chloride solution, dried and evaporated to dryness using a rotary evaporator. The colorless oily crude product was purified by chromatography. Elution was carried out using a dichloromethane/methanol gradient (0 to 3% methanol). The resulting colorless oil solidified on standing at room temperature. Yield: 0.34 g. M.p.: 97° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[C@H:10]([C:23]([OH:25])=[O:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si](C=[N+]=[N-])(C)(C)[CH3:27]>C(Cl)Cl.CO>[C:17]1([C@H:15]([NH:14][C@@H:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][C@H:10]2[C:23]([O:25][CH3:27])=[O:24])[CH3:16])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C[C@@H](N[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C(=O)O)c1ccccc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 261A (280 mg, 0.80 mmol) in 6 mL of 1:1 CH2Cl2/MeOH was added a solution of TMSCHN2 (0.82 ml, 1.64 mmol, 2N in hexane). The mixture was stirred at room temperature for 30 min, then concentrated in vacuo and purified by flash chromatography (hexane/EtOAc: 80:20) on silica gel to give Compound 261B as an oil. It had an analytical HPLC retention time=2.187 min. (Chromolith SpeedROD column 4.5×50 mm, 10-90% aqueous methanol containing 0.1% TFA over 4 min, 4 mL/min, monitoring at 220 nm). Mass (M+1)+=363.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[C:22](Cl)(=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1.C(N(CC)CC)C>C1COCC1>[O:21]=[C:15]1[CH:14]([N:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: COc1cccc(C(=O)Cl)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)NCc2cccc3c2CN(C2CCC(=O)NC2=O)C3=O)c1
Temperature: 5 °C
Reaction time: 5 h
Yield: 93.5 %

Procedure:
A suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and m-anisoyl chloride (0.4 g, 2.5 mmol) in THF 30 mL) was cooled to 5° C. Triethylamine (0.5 g, 4.8 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The mixture was concentrated, and the residue was stirred with 1N HCl (40 mL). The mixture was filtered, and the solid was slurried with hot ethanol (20 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-methoxy-benzamide (0.8 g, 93%) as a white solid: mp 244-246° C.; 1H NMR (DMSO-d6) δ 2.01-2.07 (m, 1H), 2.36-2.65 (m, 2H), 2.86-3.00 (m, 1H), 3.80 (s, 3H, CH3), 4.41-4.61 (m, 4H, 2CH2), 5.12-5.19 (dd, J=5.1 and 13.2 Hz, 1H, CH), 7.08-7.12 (m, 1H, Ar), 7.35-7.65 (m, 6H, Ar), 9.09 (t, J=5.6 Hz, 1H, NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.59, 31.17, 46.29, 51.59, 55.24, 112.41, 117.19, 119.44, 121.65, 128.31, 129.46, 130.67, 131.61, 134.68, 135.46, 140.12, 159.18, 166.08, 168.06, 171.00, 172.82; Anal. calcd. for C22H21N3O5: C, 64.86; H, 5.20; N, 10.31. Found: C, 64.62; H, 5.06; N, 10.23.
Reaction SMILES: [CH3:1]/[C:2](=[CH:6]\[CH2:7][CH3:8])/[C:3](O)=[O:4].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[Cl-].[Li+].[C:25]1([C@H:31]2[C@@H:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:34][C:33](=[O:42])[NH:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[CH3:1]/[C:2](=[CH:6]\[CH2:7][CH3:8])/[C:3]([N:32]1[C@@H:31]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@H:35]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[O:34][C:33]1=[O:42])=[O:4]
Reactant: CC/C=C(\C)C(=O)O
Reactant: O=C1N[C@@H](c2ccccc2)[C@@H](c2ccccc2)O1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC/C=C(\C)C(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To a solution of (E)-2-methyl-2-pentenoic acid (5.3 g, 47 mmol) in 250 mL of THF at 0° C. was added 16.3 mL (117 mmol) of triethylamine, then 5.8 mL (47 mmol) of pivaloyl chloride resulting in a thick suspension. The mixture was stirred for 1 hour at 0° C. at which time 2.0 g (47 mmol) of lithium chloride was added in one portion, followed by 10 g (42 mmol) of (4S,5R)-4,5-diphenyl-2-oxazolidinone in four batches. Stirring was maintained throughout the solid additions. The reaction mixture was stirred for 1 hour at 0° C., and for 1 hour at ambient temperature, and was vacuum filtered through a coarse frit and concentrated. The residue was partitioned between EtOAc/water, and the organics were dried over MgSO4 and concentrated. To the residue was added 200 mL of MTBE and the mixture was warmed cautiously with swirling. The warm slurry was filtered to provide 13.0 g (83% yield) of the titled compound as a colorless solid: 1H NMR (CDCl3) δ 7.12 (m, 3H), 7.08 (m, 3H), 6.93 (m, 2H), 6.86 (m, 2H), 6.14 (m, 1H), 5.90 (d, J=7.8 Hz, 1H), 5.69 (d, J=7.8 Hz, 1H), 2.23 (pent, J=7.6 Hz, 2H), 1.92 (s, 3H), 1.07 (t, J=7.6 Hz, 3H). The titled acylated oxazolidinone may be used in the next step instead of (S)-3-((E)-2-Methyl-pent-2-enoyl)-4-phenyl-oxazolidin-2-one.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[C:7]=1[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:5])[CH3:2].[Cl:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:31])[CH:37]=3)[CH:13]=2)[N:8]([C:16]2[CH:17]=[CH:18][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=2)[C:7]=1[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(C(C)C)cc1
Reactant: OB(O)c1cccc(Cl)c1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3cccc(Cl)c3)ccc2n1-c1ccc(C(C)C)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-(4-isopropylphenyl)indole-3-carboxylic acid ethyl ester (150 mg, 0.37 mmol, see step (b) Example 10) and 3-chlorophenylboronic acid (116 mg, 0.74 mmol). Yield 130 mg (68%).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[N:18]=[CH:19][N:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=34)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[N:18]=[CH:19][N:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=34)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3ncn4cc(F)ccc34)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3ncn4cc(F)ccc34)nc12
Yield: 92.4 %

Procedure:
To a stirred solution of N-tert-butyl-2-(6-fluoroimidazo[1,5-a]pyridin-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (95 mg, 197 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (449 mg, 303 μL, 3.94 mmol) at room temperature. After 16 h the reaction was concentrated. The residue was dissolved in dichloromethane (3 mL), methanol (1.5 mL) and ammonium hydroxide (0.45 mL). After 1 h the reaction was concentrated. The residue was triturated with water and filtered. The solid was washed water and ether then dried under vacuum to give N-tert-butyl-2-(6-fluoroimidazo[1,5-a]pyridin-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (64 mg, 182 μmol, 92%) as a yellow solid. MS: (M+H)+=353; 1H NMR (CD3OD) δ: 9.10 (s, 1H), 8.48 (d, J=5.1 Hz, 1H), 8.45 (s, 1H), 8.42 (m, 1H), 8.25 (s, 1H), 7.03 (m, 1H), 1.62 (s, 9H).
Reaction SMILES: N1C=CN=C1.[I:6]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:27][C@H:28]([CH2:38]O)[CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34]>C(Cl)Cl>[F:27][C@H:28]([CH2:38][I:6])[CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34]
Reactant: II
Reactant: CC(C)(C)OC(=O)NC[C@H](F)CO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC[C@H](F)CI
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61 %

Procedure:
Imidazole (19.8 g, 0.29 mol) was dissolved in methylene chloride (900 mL) at room temperature. Iodine (73.9 g, 0.29 mol) was added and the reaction mixture was stirred for 10 min at room temperature and then cooled to 0° C. Triphenylphosphine (76.3 g, 0.29 mol) was added portionwise over 10 min such that the internal temperature remained below 10° C. A solution of tert-butyl (2S)-2-fluoro-3-hydroxypropylcarbamate (45.0 g, 0.23 mol) in methylene chloride (300 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirring was continued for 12 h. The reaction mixture was filtered through a pad of Celite® and washed with additional methylene chloride. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluting with methylene chloride. This procedure afforded tert-butyl (2S)-2-fluoro-3-iodopropylcarbamate as a colorless oil (42.5 g, 62%). 1H NMR (300 MHz, CDCl3) δ 4.80-5.10 (br s, 1H), 4.58-4.72 (m, 0.5H), 4.42-4.56 (m, 0.5H), 3.48-3.70 (m, 1H), 3.20-3.46 (m, 3H), 1.48 (s, 9H).