Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].FC(F)(F)S(O[C:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH:18]=1)(=O)=O.[C:28]([NH:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)(=[O:30])[CH3:29]>C(COC)OC.[Pd].P>[C:28]([NH:31][C:32]1[CH:37]=[C:36]([C:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH:18]=2)[CH:35]=[CH:34][CH:33]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: P
Solvent: COCCOC
Product: CC(=O)Nc1cccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c1

Procedure:
_The reaction of saturated of aqueous Na2CO3 solution (25 mL), tert-butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-1,2,3,6-tetrahydro-1-pyridine-carboxylate (20 mmol), 3-acetamidophenylboronic acid (30 mmol) and tetrakis-triphenyl)phosphine palladium (0) (1.15 g) in dimethoxyethane (40 mL) at reflux temperature overnight gave tert-butyl 4-[3-(acetylamino)phenyl]-3,6-dihydro-1(2H)-pyridinecarboxylate. Deprotection of the BOC group using HCl in dioxane followed by basification (pH 11-12) gave the desired product.
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]1[CH2:24][O:23][CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:21][CH2:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Br:31]N1C(=O)CCC1=O.C(=O)([O-])[O-].[Ba+2]>ClCCl>[C:22]([O:21][CH2:20][CH:19]([CH2:24][Br:31])[CH2:18][O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:23])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCCCCCCCCCCCCCCCOCC1COC(c2ccccc2)OC1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [Ba+2]
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCOCC(CBr)COC(=O)c1ccccc1
Temperature: 0 °C
Yield: 79.2 %

Procedure:
A mixture of 14.703 g (35.2 mM) of 5-n-hexadecyloxymethyl-2-phenyl-1,3-dioxane n2, 6.90 g (38.4 mM) of N-bromosuccinimide and 700 mg of barium carbonate in 200 ml of dichloromethane is heated under refluxing for 1 hour. After cooling, the mixture is poured into an ice cooled saturated aqueous sodium bicarbonate and the product is isolated by dichloromethane extraction. The dichloromethane layer is washed with 10% aqueous sodium thiosulfate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated. Purification of the residue by column silica gel chromatography using n-hexane-ethyl acetate (9:1) mixture as an eluent affords 13.843 g (79.3% yield) of the titled compound n3.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[N:3]=1.[Cl:19][C:20]1[C:21](B(O)O)=[CH:22][C:23]([F:26])=[N:24][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:19][C:20]1[C:21]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[N:3]=2)=[CH:22][C:23]([F:26])=[N:24][CH:25]=1
Reactant: OB(O)c1cc(F)ncc1Cl
Reactant: N#Cc1ccc(Cl)nc1NCc1cccc(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: N#Cc1ccc(-c2cc(F)ncc2Cl)nc1NCc1cccc(F)c1
Temperature: 120 °C
Yield: 32.8 %

Procedure:
6-chloro-2-(3-fluorobenzylamino)nicotinonitrile (0.602 g, 2.30 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (1.21 g, 6.91 mmol), and sodium carbonate (2.99 mL, 5.99 mmol, 2M in H2O) were dissolved in DME (10.5 mL). The resulting solution was then degassed by sparging with argon for 5 min. It was then treated with PdCl2(dppf) CH2Cl2 adduct (0.376 g, 0.460 mmol). The resulting reaction mixture was heated in the microwave at 120° C. for 10 min. It was then filtered through a pad of Celite. The filtrate was concentrated in vacuo. The resulting residue was subjected to silica gel column chromatography. Elution using 5 EtOAc/95 hexanes to 50 EtOAc/50 hexanes yielded 0.2689 g (33%) of 5′-chloro-2′-fluoro-6-(3-fluorobenzylamino)-2,4′-bipyridine-5-carbonitrile. LCMS (m/z): 357.2 (MH+), retention time=1.02 min.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:11].[S:12]([Cl:16])(=O)(=[O:14])[OH:13]>>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([S:12]([Cl:16])(=[O:14])=[O:13])=[CH:10][C:5]=2[O:4][C:3]1=[O:11]
Reactant: O=S(=O)(O)Cl
Reactant: Cn1c(=O)oc2ccccc21
Product: Cn1c(=O)oc2cc(S(=O)(=O)Cl)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.5 %

Procedure:
3-methylbenzo[d]oxazol-2(3H)-one (620 mg, 4.16 mmol) was added, in several batches, to chilled sulfurochloridic acid (17.5 g, 150.86 mmol) at 0° C. The resulting solution was stirred at room temperature for 3 hours, then quenched by adding it slowly to 200 mL of ice/salt. The resulting solution was extracted with ethyl acetate (3×40 mL). The organic layers were combined, dried (Na2SO4), filtered and concentrated to afford 0.5 g (46%) of 3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-6-sulfonyl chloride as a light brown solid. 1H NMR (CDCl3) δ 8.00 (d, 1H), 7.97 (s, 1H), 7.16 (d, 1H), 3.52 (s, 3H).
Reaction SMILES: Cl.[CH2:2]([O:4][C@H:5]1[CH2:9][NH:8][C@H:7]([C:10]([OH:12])=[O:11])[CH2:6]1)[CH3:3].C(=O)([O-])[O-].[K+].[K+].[C:19](=O)([O:35]N1C(=O)CCC1=O)[O:20][CH2:21][CH:22]1[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2>O1CCOCC1.O>[CH:33]1[C:34]2[CH:22]([CH2:21][O:20][C:19]([N:8]3[CH2:9][C@H:5]([O:4][CH2:2][CH3:3])[CH2:6][C@H:7]3[C:10]([OH:12])=[O:11])=[O:35])[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]=2[CH:30]=[CH:31][CH:32]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: CCO[C@H]1CN[C@H](C(=O)O)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCO[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 114.9 %

Procedure:
(2S,4R)-4-Ethoxypyrrolidine-2-carboxylic acid hydrochloride (Compound SP820) (45 g, 230 mmol) was dissolved in a mixture of 1,4-dioxane (500 ml) and water (500 ml), potassium carbonate (79.4 g, 574 mmol) and (9H-fluoren-9-yl)methyl (2,5-dioxopyrrolidin-1-yl) carbonate (Fmoc-OSu, 69.8 g, 207 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was washed with diethyl ether, and the aqueous layer was adjusted to pH 3 with an aqueous potassium bisulfate solution and extracted with ethyl acetate. The resulting organic extract was washed with brine, dried over sodium sulfate and then concentrated under reduced pressure to afford (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-ethoxypyrrolidine-2-carboxylic acid (Compound SP813, Fmoc-Hyp(Et)-OH) (90.7 g, 103%).
Reaction SMILES: Cl.[NH2:2][OH:3].C(N(CC)CC)C.[Cl:11][C:12]1[CH:13]=[C:14]([C@@H:18]2[C@@H:23]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[N:22]([CH:31]([CH2:34][CH3:35])[CH2:32][CH3:33])[C:21](=[O:36])[C@:20]([CH2:38][C:39]#[N:40])([CH3:37])[CH2:19]2)[CH:15]=[CH:16][CH:17]=1>CS(C)=O>[Cl:11][C:12]1[CH:13]=[C:14]([C@@H:18]2[C@@H:23]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[N:22]([CH:31]([CH2:34][CH3:35])[CH2:32][CH3:33])[C:21](=[O:36])[C@:20]([CH2:38][C:39](=[N:2][OH:3])[NH2:40])([CH3:37])[CH2:19]2)[CH:15]=[CH:16][CH:17]=1
Reactant: CCC(CC)N1C(=O)[C@@](C)(CC#N)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: NO
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCC(CC)N1C(=O)[C@@](C)(CC(N)=NO)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 75 °C
Reaction time: 0.08 h

Procedure:
To a suspension of 1.49 g (20.6 mmol) of hydroxylamine hydrochloride in DMSO (10 mL) was added 2.88 mL (20.6 mmol) of triethylamine. The slurry was stirred for 5 min and then filtered twice through cotton, rinsing with THF, to remove the solids. The filtrate was partially concentrated under reduced pressure to remove THF, and then was added to a flask containing 915 mg (2.06 mmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)acetonitrile (Example 82, Step B). The resulting yellow solution was heated at 75° C. for 22 h, and then was partitioned between water and EtOAc. The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by flash chromatography on silica gel (1 to 7% MeOH/DCM, gradient elution) provided the title compound as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.CC(C)([O-])C.[K+].I[CH2:21][CH2:22][CH2:23][CH3:24]>CS(C)=O>[CH2:21]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCI
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCn1ccc2ccc(C(=O)OC)cc21
Temperature: 25 °C

Procedure:
Methyl 1H-indole-6-carboxylate (4.17 g) was dissolved in DMSO (30 mL), and potassium tert-butoxide (2.93 g) was added. The mixture was stirred for ten min at room temperature. Iodobutane (3.0 mL) was added. The mixture was allowed to stir for three additional hours. The mixture was partitioned between ethyl acetate and water and brine, dried over sodium sulfate, filtered, and concentrated to give methyl 1-butyl-1H-indole-6-carboxylate (4.53 g). MS (ESI+) for C14H17NO2+H1 m/z 232.12 (M+H)+.
Reaction SMILES: [Cl:1][CH:2]([CH2:11][CH3:12])[CH2:3][CH:4]1[O:8][C:7](=[O:9])[N:6]([CH3:10])[CH2:5]1.[ClH:13].[CH2:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH3:15].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC>[ClH:1].[ClH:13].[CH2:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:24][CH2:25][N:26]([CH2:12][CH2:11][CH2:2][CH2:3][CH:4]2[O:8][C:7](=[O:9])[N:6]([CH3:10])[CH2:5]2)[CH2:27][CH2:28]1)[CH3:15]
Reactant: CCOc1ccccc1N1CCNCC1
Reactant: CCC(Cl)CC1CN(C)C(=O)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCCCO
Product: CCOc1ccccc1N1CCN(CCCCC2CN(C)C(=O)O2)CC1
Yield: 10 %

Procedure:
Following the procedure of Example 5, a mixture of 5-(2-chlorobutyl)-3-methyl-2-oxazolidinone (5.2 g, 0.0272 mol), 1-(2-ethoxyphenyl)piperazine monohydrochloride (6.61 g, 0.0272 mol), potassium carbonate (15.05 g, 0.109 mol), and potassium iodide (1.0 g) in n-butanol (100 mL) gave an oil which was dissolved in a mixture of ethyl acetate/isopropyl ether/light pet ether (removing the impurities by filtration) and acidified with ethereal hydrogen chloride. The mixture was evaporated under reduced pressure and recrystallized once from isopropanol/methanol/isopropyl ether and then from isopropanol/isopropyl ether and dried under high vacuum at 60° C. to give 1.18 g (10% yield), mp 207°-212° C.
Reaction SMILES: [Cl:1][C:2]1[C:33]([C:34]2([C:37]#[N:38])[CH2:36][CH2:35]2)=[CH:32][CH:31]=[CH:30][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[N:19]=[C:18]3[S:20][C:21]([NH:23][C:24]([CH:26]4[CH2:28][CH2:27]4)=[O:25])=[N:22][C:17]3=[CH:16][CH:15]=2)[CH:10]=[CH:9][C:8]=1[F:29])=[O:5].[CH:39]1([C:42](Cl)=[O:43])[CH2:41][CH2:40]1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[C:33]([C:34]2([C:37]#[N:38])[CH2:36][CH2:35]2)=[CH:32][CH:31]=[CH:30][C:3]=1[C:4]([N:6]([C:42]([CH:39]1[CH2:41][CH2:40]1)=[O:43])[C:7]1[CH:12]=[C:11]([O:13][C:14]2[N:19]=[C:18]3[S:20][C:21]([NH:23][C:24]([CH:26]4[CH2:28][CH2:27]4)=[O:25])=[N:22][C:17]3=[CH:16][CH:15]=2)[CH:10]=[CH:9][C:8]=1[F:29])=[O:5]
Reactant: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc5nc(NC(=O)C6CC6)sc5n4)ccc3F)c2Cl)CC1
Reactant: O=C(Cl)C1CC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: N#CC1(c2cccc(C(=O)N(C(=O)C3CC3)c3cc(Oc4ccc5nc(NC(=O)C6CC6)sc5n4)ccc3F)c2Cl)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62.7 %

Procedure:
To a solution of 2-chloro-3-(1-cyanocyclopropyl)-N-[5-({2-[(cyclopropylcarbonyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-2-fluorophenyl]benzamide (3.5 g, 6.39 mmol) produced in Example C127(x) in pyridine (35 mL) were added N,N-dimethylpyridine-4-amine (3.87 g, 31.7 mmol) and cyclopropanecarbonyl chloride (3.0 mL, 33.1 mmol) at 10° C., and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was poured into ice water (70 mL), and the mixture was extracted with ethyl acetate (80 mL×3). The organic layers were combined, washed successively with water (50 mL) and saturated brine (30 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5→20/80). The obtained residue was recrystallized from ethyl acetate to give the title compound (2.47 g, 63%) as white crystals.
Reaction SMILES: C([N:4]1[CH:10]([CH3:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[NH:7][C:6](=[O:16])[CH:5]1[CH:17]=[CH:18][C:19]1C=CC=CC=1)C=C.Cl>CCOCC.C=CC1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ru]Cl>[CH3:11][CH:10]1[N:4]2[CH2:19][CH:18]=[CH:17][CH:5]2[C:6](=[O:16])[NH:7][C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]1=2
Reactant: C=CCN1C(C=Cc2ccccc2)C(=O)Nc2ccccc2C1C
Agent: Cl[Ru]Cl
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C=Cc1ccccc1
Solvent: CCOCC
Product: CC1c2ccccc2NC(=O)C2C=CCN21
Reaction time: 72 h
Yield: 46.7 %

Procedure:
The product of Example 15 (103 mg, 0.32 mmol) was first converted to the HCl salt with excess 1M HCl in ether, and all of the volatiles were removed. The resulting solid was then dissolved in dry dichloromethane (15 mL) and bis(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride (132 mg, 0.16 mmol) was added, and the flask was flushed with Ar(g). The reaction was allowed to proceed at room temperature for three days, after which time, the reaction was diluted with an additional 10 mL of dichloromethane, and transferred to a separatory funnel. The organic layer was washed with a saturated solution of sodium bicarbonate (3×15 mL), the aqueous layers were then combined and extracted with dichloromethane (2×10 mL). The organic layers were then combined, washed once with brine (15 mL), dried over magnesium sulfate, filtered and evaporated to yield a crude residue which was purified by flash column chromatography using ethyl acetate-hexane (3:1) to yield 32 mg (61% yield) of a dark oil. 1H NMR (360 MHz, CDCl3) δ 7.60 (bs, 1H), 7.42 (d, J=7.6 Hz, 1H), 7.32-7.19 (m, 2H), 7.00-6.95 (m, 1H), 6.16-6.10 (m, 1H), 5.88-5.82 (m, 1H), 4.34 (bs, 1H), 3.96-3.81 (m, 2H), 3.55-3.46 (m, 1H), 1.58 (d, J=6.5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:21])=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][C:6]1[C:7]([O:16][CH3:17])=[CH:8][C:9]([F:15])=[C:10]([CH:14]=1)[C:11](O)=[O:12].S(Cl)([Cl:24])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([F:21])=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][C:6]1[C:7]([O:16][CH3:17])=[CH:8][C:9]([F:15])=[C:10]([CH:14]=1)[C:11]([Cl:24])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(F)c(C(=O)O)cc1Cc1cccc(Cl)c1F
Solvent: Cc1ccccc1
Product: COc1cc(F)c(C(=O)Cl)cc1Cc1cccc(Cl)c1F
Reaction time: 1 h

Procedure:
5-(3-Chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoic acid (10 g) obtained in Step IV was suspended in toluene (50 ml), and thionyl chloride (4.56 g) was added dropwise at 65-75° C. After the dropwise addition, the mixture was stirred for 1 hr and concentrated under reduced pressure. Toluene (30 ml) was added to the residue, and the mixture was concentrated again under reduced pressure. The residue was dissolved in toluene (30 ml) to give a solution of 5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl chloride in toluene. This was identified as the title compound by HPLC.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][CH2:11][CH2:10][C:9]=2[CH:13]=1)=[O:4].[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([CH2:36][C:37]([O:39][CH3:40])=[O:38])=C(C(C3N=CC4CCCCC=4C=3)=O)[NH:21]2)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([CH2:36][C:37]([O:39][CH3:40])=[O:38])=[C:2]([C:3]([C:5]3[CH:6]=[CH:7][C:8]4[O:12][CH2:11][CH2:10][C:9]=4[CH:13]=3)=[O:4])[NH:21]2)=[CH:17][CH:16]=1
Reactant: COC(=O)Cc1c(C(=O)c2cc3c(cn2)CCCC3)[nH]c2cc(Cl)ccc12
Reactant: O=C(CBr)c1ccc2c(c1)CCO2
Product: COC(=O)Cc1c(C(=O)c2ccc3c(c2)CCO3)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 5-bromoacetyl-2,3-dihydro-1-benzofuran* and methyl trans-4-chloro-2-[(Phenylsulfonyl)amino]cinnamate (Example 1, step 1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][C:9](=[NH:12])OC)=[CH:5][CH:4]=1.[NH3:15]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][C:9]([NH2:12])=[NH:15])=[CH:13][CH:14]=1
Reactant: COC(=N)COc1ccc(OC)cc1
Reactant: N
Solvent: CCO
Product: COc1ccc(OCC(=N)N)cc1
Reaction time: 48 h

Procedure:
23.9 g (0.122 mole) of methyl 2-(4-methoxyphenoxy)acetimidate are added to a solution, maintained at 10° C., of 10.4 g (0.61 mole) of ammonia in 480 ml of absolute ethanol. The reaction mixture is left for 2 days at room temperature and the excess ammonia is then driven off with a stream of nitrogen. The solution obtained is used in the next step without further purification.
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl:4][C:5]1[C:12]([O:13][CH:14]([CH3:16])[CH3:15])=[CH:11][C:8]([CH2:9]Br)=[C:7]([F:17])[CH:6]=1.O>CN(C=O)C>[Cl:4][C:5]1[C:12]([O:13][CH:14]([CH3:16])[CH3:15])=[CH:11][C:8]([CH2:9][C:1]#[N:2])=[C:7]([F:17])[CH:6]=1
Reactant: CC(C)Oc1cc(CBr)c(F)cc1Cl
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(CC#N)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
26 g (0.53 mol) of sodium cyanide was dissolved in 700 ml of DMF, and 143 g (0.50 mol) of 4-chloro-2-fluoro-5-isopropoxybenzyl bromide was dropwise added thereto at room temperature. After stirring at room temperature for 8 hours, the reaction solution was poured into water and extracted with ethyl acetate. After washing with water, the organic layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure to obtain 107 g (yield: 92%) of the desired product.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]1.C([N-]C(C)C)(C)C.[Li+].[CH:24](OCC)=[O:25]>O1CCCC1>[CH:24]([CH:8]1[C:2](=[O:1])[CH2:3][CH2:4][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH2:7]1)=[O:25]
Reactant: CCOC=O
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=O)C(C=O)CC1
Temperature: 25 °C

Procedure:
1,1-Dimethylethyl 4-oxohexahydro-1H-azepine-1-carboxylate (commercially available from e.g. Magic Chemicals) (2.0 g, 9.4 mmol) in tetrahydrofuran at −78° C. was treated with a 2M solution of lithium diisopropylamide (4.7 ml, 9.4 mmol) in tetrahydrofuran. After 20 minutes neat ethyl formate (0.7 g, 9.4 mmol) was added and the reaction mixture was allowed to warm to room temperature. After 2 hours the reaction was quenched, poured into water and extracted several times with ethyl acetate. The combined organic layers were then dried and reduced in vacuo to furnish the title compound which may be used without further purification (D8).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12](Cl)([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:12](=[O:13])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Cl)c([N+](=O)[O-])c1)OCc1ccccc1

Procedure:
In one example, 4-chloro-3-nitroaniline reacted with CbzCl in dichloromethane in the presence of diisopropylethylamine. The product benzyl 4-chloro-3-nitrophenylcarbamate was isolated following flash chromatography. Following procedures in Examples 12, 13, and 15, final product benzyl 1-(2-acetamidoethyl)-3-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxalin-6-ylcarbamate was isolated following reverse-phase HPLC with C(18) column eluting with water and acetonitrile. The product of the reaction, benzyl 1-(2-acetamidoethyl)-3-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxalin-6-ylcarbamate, is a compound of formula I in which R1 is —CH2CH2NHAc, R2 is benzyloxycarbonyl, R3 is 4-methoxyphenyl.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[NH:4][C:3]1=[O:14].[CH2:15]1[C@H:24]2[C@H:19]([CH2:20][CH2:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=32)[NH:18][CH2:17][CH2:16]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:15]1[C@H:24]2[C@H:19]([CH2:20][CH2:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=32)[N:18]([C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3](=[O:14])[NH:4][C:5]=3[CH:10]=2)=[O:13])[CH2:17][CH2:16]1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Reactant: Cn1c(=O)[nH]c2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1c(=O)[nH]c2cc(C(=O)N3CCC[C@@H]4c5ccccc5CC[C@@H]43)ccc21
Yield: 15 %

Procedure:
The title compound is prepared from 1-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 15% of theory; LC (method 4): tR=1.92 min; Mass spectrum (ESI+): m/z=362 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:30])=[C:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29])[C:10]([O:17][CH:18]([F:20])[F:19])=[N:11]2.CO.O.[OH-].[Na+]>C(O)(=O)C>[F:29][C:23]1[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:22]=1[CH2:21][C:9]1[C:10]([O:17][CH:18]([F:19])[F:20])=[N:11][C:12]2[C:7]([C:8]=1[CH3:30])=[C:6]([O:5][CH2:4][C:3]([OH:31])=[O:2])[CH:15]=[CH:14][C:13]=2[F:16]
Reactant: COC(=O)COc1ccc(F)c2nc(OC(F)F)c(Cc3ccc(F)cc3F)c(C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: Cc1c(Cc2ccc(F)cc2F)c(OC(F)F)nc2c(F)ccc(OCC(=O)O)c12

Procedure:
A solution of [3-(2,4-difluorobenzyl)-2-difluoromethoxy-8-fluoro-4-methylquinolin-5-yloxy]acetic acid methyl ester (0.20 g), methanol (10 mL), water (0.8 mL) and 5.0 M aqueous sodium hydroxide solution (0.4 mL) was stirred at room temperature for 2 hour. The pH of the mixture was adjusted to 5 by the addition of glacial acetic acid and the solvent removed under reduced pressure. The residue was diluted with water and the solid collected by filtration, washed with water and dried to afford title compound as a white solid, 0.030 g.
Reaction SMILES: C([Li])CCC.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([CH:19]=[C:20](Br)Br)[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[C:23](Cl)(=[O:26])[O:24][CH3:25].[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]#[C:20][C:23]([O:24][CH3:25])=[O:26])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(C=C(Br)Br)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)C#CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (1.57N hexane solution, 3.11 ml) was added dropwise to a solution with 1-(tert-butoxycarbonyl)-4-(2,2-dibromovinyl)piperidine (WO9806720) (900 mg) dissolved in tetrahydrofuran (16 ml) at −78° C., and the mixture was stirred for 1 hour. Methyl chlorocarbonate (377 μl) was added to the reaction mixture to heat the mixture to room temperature in 1 hour. Diethyl ether (30 ml) and a saturated aqueous solution (50 ml) of ammonium chloride were added to the reaction mixture to separate an organic layer. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1) to obtain the title compound (634 mg) as a colorless transparent oil.