Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[NH:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14].C(=O)([O-])[O-].[K+].[K+].[C@@H]1(N)CCCC[C@H]1N>O1CCOCC1.[Cu].CO.C(OCC)(=O)C>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])=[N:3][CH:4]=1
Reactant: Nc1cnc(Br)cn1
Reactant: O=C1CCCN1
Agent: [Cu]
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Nc1cnc(N2CCCC2=O)cn1
Yield: 30.4 %

Procedure:
A mixture of 5-bromopyrazin-2-amine (5 g, 29 mmol), pyrrolidin-2-one (11 mL, 144 mmol), copper (T) iodide (1.1 g, 5.75 mmol), potassium carbonate (7.94 g, 57.5 mmol), and (1R,2R)-cyclohexane-1,2-diamine (1.38 mL, 11.49 mmol) was refluxed under nitrogen in dioxane (100 mL) for 18 h. After cooling, 200 mL ethyl acetate and 20 mL methanol were added to the reaction. This was filtered through celite, concentrated, and absorbed onto sodium sulfate for purification by column chromatography (0-5% methanol/methylene chloride). The purified product was recrystallized from ether/ethyl acetate to afford 1-(5-aminopyrazin-2-yl)pyrrolidin-2-one (1.57 g, 8.81 mmol, 30.7% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.74 (1 H, d, J=1.51 Hz), 7.69 (1 H, d, J=1.51 Hz), 6.20 (2 H, s), 3.84 (2 H, t, J=7.05 Hz), 2.49 (2 H, t, J=7.93 Hz), 2.04 (2 H, dq, J=7.68, 7.51 Hz). MS (LC/MS) R.T.=0.48; [M+H]+=179.27.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:7]=1[N+:21]([O-:23])=[O:22])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[N:30]=[C:29]([O:31][CH3:32])[C:28](Br)=[CH:27][N:26]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:28]2[C:29]([O:31][CH3:32])=[N:30][C:25]([NH2:24])=[N:26][CH:27]=2)=[CH:8][C:7]=1[N+:21]([O-:23])=[O:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1[N+](=O)[O-]
Reactant: COc1nc(N)ncc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1nc(N)ncc1-c1ccc(NC(C)(C)C)c([N+](=O)[O-])c1
Temperature: 110 °C
Reaction time: 18 h
Yield: 86.1 %

Procedure:
To a vial is added tert-butyl-[2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-amine (300 mg, 0.937 mmol), 2-amino-5-bromo-4-methoxypyrimidine (215 mg, 1.054 mmol) and 2M Na2CO3 (2 mL, 4 mmol) in DMF (10 mL), followed by the addition of tetrakis(triphenylphosphine)palladium(0) (108 mg, 0.093 mmol). The vial is sealed under Argon gas. The reaction mixture is stirred at 110° C. for 18 hours. The reaction mixture is diluted with EtOAc and washed with water. The organic layer is separated, washed with brine, dried under Na2SO4, filtered and concentrated. The residue is loaded onto a silica gel column. The column is eluted with 0-5% MeOH/CH2Cl2. The product fractions are collected and concentrated to afford 5-(4-tert-butylamino-3-nitro-phenyl)-4-methoxy-pyrimidin-2-ylamine (256 mg, 86%) as a red solid. LCMS (ESMS): m/z 318.72 (M++1)
Reaction SMILES: [C:1]1(=[O:10])[C@H:9]2[C@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][O:2]1.C[O-].[Na+].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>CO>[OH:2][CH2:3][C@H:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C@@H:9]1[C:1]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:10]
Reactant: C1CCNC1
Reactant: O=C1OC[C@H]2CCCC[C@@H]12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C([C@H]1CCCC[C@@H]1CO)N1CCCC1

Procedure:
4 g of (3aS,cis) hexahydro-1-(3H)-isobenzofuranone in 20 ml of methanol and 4.76 ml of pyrrolidine with 0.386 g of sodium methylate were refluxed for 20 hours and one half of the methanol was distilled off at 50° C. under reduced pressure. Water and ice were added and the pH was adjusted to 1 by adding 2N hydrochloric acid. Extraction was done with methylene chloride and the extracts were washed with water, dried, filtered, evaporated to dryness under reduced pressure and crystallized from isopropyl ether to obtain 3.89 g of (1S,trans) 1-[(2hydroxymethyl-1-cyclohexyl)-carbonyl]-pyrrolidine melting at 115° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([NH:14][CH3:15])[C:4]=1[C:5]([NH2:7])=[O:6].Cl[C:17]([C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([O:26][C:27](=[O:29])[CH3:28])=[C:21]([CH3:30])[CH:20]=1)=O>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:4]=1[C:5](=[O:6])[N:7]=[C:17]([C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([O:26][C:27](=[O:29])[CH3:28])=[C:21]([CH3:30])[CH:20]=1)[N:14]2[CH3:15]
Reactant: CNc1cc(OC)cc(OC)c1C(N)=O
Reactant: CC(=O)Oc1c(C)cc(C(=O)Cl)cc1C
Solvent: c1ccncc1
Product: COc1cc(OC)c2c(=O)nc(-c3cc(C)c(OC(C)=O)c(C)c3)n(C)c2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 67 %

Procedure:
A solution of 2,4-dimethoxy-6-methylamino-benzamide (0.28 g, 1.33 mmol) in pyridine (10 mL) was added to acetic acid 4-chlorocarbonyl-2,6-dimethyl-phenyl ester (1.1 eq.) and stirred at room temperature for 14 h. The solvent was removed and the reaction mixture was acidified with 1 N HCl and extracted with ethyl acetate. The solvent was removed and the crude was purified by silica gel column chromatography (40 g) employing 1% methanol in dichloromethane to give acetic acid 4-(5,7-dimethoxy-1-methyl-4-oxo-1,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenyl ester (0.34 g, 67%). Acetic acid 4-(5,7-dimethoxy-1-methyl-4-oxo-1,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenyl ester (0.34 g, 0.89 mmol) was dissolved in ethanol (5 mL), 5% aqueous NaOH solution (10 mL) was added dropwise and the mixture was stirred at room temperature for 1.5 h. The compound was extracted with ethyl acetate and washed with ether to give 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-1-methylquinazolin-4(1H)-one (0.13 g, 43%). Selected data: MS (ES) m/z: 340.17; MP 188.5-189.1° C.
Reaction SMILES: C([Si](C)(C)[O:6][C@H:7]1[C@H:11]2[O:12][CH2:13][C@@H:14]([O:15][C:16]3[N:17](COCC[Si](C)(C)C)[C:18]4[C:19]([N:39]=3)=[N:20][C:21]([C:25]3[CH:30]=[CH:29][C:28]([C:31]#[C:32][CH:33]5[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]5)=[CH:27][CH:26]=3)=[C:22]([Cl:24])[CH:23]=4)[C@H:10]2[O:9][CH2:8]1)(C)(C)C.CCN(C(C)C)C(C)C.[CH:59]1([S:62](Cl)(=[O:64])=[O:63])[CH2:61][CH2:60]1.CCOC(C)=O>ClCCl>[Cl:24][C:22]1[CH:23]=[C:18]2[NH:17][C:16]([O:15][C@H:14]3[C@H:10]4[O:9][CH2:8][C@@H:7]([OH:6])[C@H:11]4[O:12][CH2:13]3)=[N:39][C:19]2=[N:20][C:21]=1[C:25]1[CH:26]=[CH:27][C:28]([C:31]#[C:32][CH:33]2[CH2:34][CH2:35][N:36]([S:62]([CH:59]3[CH2:61][CH2:60]3)(=[O:64])=[O:63])[CH2:37][CH2:38]2)=[CH:29][CH:30]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(C#CC4CCNCC4)cc3)c(Cl)cc2n1COCC[Si](C)(C)C
Reactant: O=S(=O)(Cl)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=S(=O)(C1CC1)N1CCC(C#Cc2ccc(-c3nc4nc(O[C@@H]5CO[C@H]6[C@@H]5OC[C@H]6O)[nH]c4cc3Cl)cc2)CC1
Reaction time: 2 h

Procedure:
To a stirred solution of 2-(((3R,3aR,6R,6aS)-6-((tertbutyldimethylsilyl)oxy)hexa-hydrofuro[3,2-b]furan-3-yl)oxy)-6-chloro-5-(4-(piperidin-4-ylethynyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-imidazo[4,5-b]pyridine (33 mg, 0.045 mmol) in anhydrous dichloromethane (1.00 mL) was added DIEA (0.016 mL, 0.091 mmol) and cyclopropylsulfonyl chloride (14.6 mg, 0.113 mmol). After 2 hours, the mixture was directly loaded onto a Biotage™ 10 G silica gel SNAP cartridge and employing a linear gradient: 0-50% EtOAc in 1:1 Hex/DCM over 25 column volumes. The desired product fractions were combined and concentrated under reduced pressure to afford a colorless oil. The resultant colorless oil was dissolved in formic acid (1.0 mL), then saturated aqueous KHSO4 (0.25 mL) was added and the mixture was stirred at 50° C. After 2 hours, the reaction mixture was poured into saturated aqueous sodium bicarbonate (120 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were concentrated under reduced pressure to afford a white solid which was dissolved in methanol (5 mL) and then treated with aqueous sodium hydroxide (3N, 1.0 mL). After stirring for 10 minutes, the mixture was neutralized with 1N aqueous HCl (3.0 mL), and poured into saturated aqueous sodium bicarbonate (40 mL). The aqueous mixture was extracted with ethyl acetate (2×60 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The resultant white solid was dissolved in acetonitrile/water mixture, cooled to −78° C., and then lyophilized to dryness to afford the title compound as a white solid. LC-MS: calculated for C28H29ClN4O6S 584.15, observed m/e: 585.14 (M+H)+ (Rt 1.95/4 min); 1H NMR δ (ppm) (CD3OD): 7.78 (s, 1H), 7.60 (d, J=4.3 Hz, 2H), 7.45 (d, J=4.3 Hz, 2H), 5.52 (q, J=5.5 Hz, 1H), 4.95 (t, J=5.5 Hz, 1H), 4.45 (t, J=5.0 Hz), 4.27 (m, 1H), 4.15 (dd, J=10.0, 6.0 Hz, 1H), 4.09 (dd, J=10.0, 6.0 Hz, 1H), 3.88 (dd, J=8.0, 7.0 Hz, 1H), 3.59 (m, 4H), 3.21 (m, 2H), 2.88 (m, 1H), 2.49 (m, 1H), 2.03 (m, 2H), 1.80 (m, 2H), 1.03 (m, 4H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[NH2:9][CH2:10][C:11]1[N:15]=[C:14]([C:16]2[CH:21]=[N:20][C:19]3[N:22]([CH2:25][CH3:26])[N:23]=[CH:24][C:18]=3[C:17]=2[NH:27][CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[O:13][N:12]=1.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:9][CH2:10][C:11]1[N:15]=[C:14]([C:16]2[C:17]([NH:27][CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[C:18]3[CH:24]=[N:23][N:22]([CH2:25][CH3:26])[C:19]3=[N:20][CH:21]=2)[O:13][N:12]=1)=[O:7]
Reactant: O=C(Cl)CCCCCl
Reactant: CCn1ncc2c(NC3CCOCC3)c(-c3nc(CN)no3)cnc21
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCn1ncc2c(NC3CCOCC3)c(-c3nc(CNC(=O)CCCCCl)no3)cnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
5-chloropentanoyl chloride (0.12 mmol) was added to a stirred solution of Intermediate 118 (0.1 mmol) and diisopropylethylamine (0.3 mmol) in chloroform (1 ml) at room temperature. After stirring at room temperature for 16 h, the reaction mixture was applied to a SPE cartridge (aminopropyl, 2 g) and the cartridge was eluted sequentially with chlororm, ethyl acetate and methanol. Fractions containing the desired product were combined and blown down under nitrogen. The resulting residue was further purified on a SPE cartidge (silica, 1 g) eluting with a gradient of 30-100% ethyl acetate in petroleum ether to afford Intermediate 120 as a white solid (46 mg). LCMS showed MH+=462, TRET=2.86 min.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:10]=[CH:9][C:8]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][C:19]=3[Cl:20])[NH:16][CH:15]=[C:14]4[CH:21]=[O:22])=[CH:7][CH:6]=2)[CH2:2]1.P([O-])(O)(O)=[O:24].[Na+].Cl([O-])=O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>CC(=CC)C.CC(O)(C)C.O>[NH:1]1[CH2:4][CH:3]([C:5]2[CH:10]=[CH:9][C:8]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][C:19]=3[Cl:20])[NH:16][CH:15]=[C:14]4[C:21]([OH:24])=[O:22])=[CH:7][CH:6]=2)[CH2:2]1
Reactant: O=P([O-])(O)O
Reactant: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(C4CNC4)cc3)cc12
Agent: CC=C(C)C
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(C4CNC4)cc3)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 10.2 %

Procedure:
To 5-[4-(azetidin-3-yl)phenyl]-6-chloro-1H-indole-3-carbaldehyde (94 mg, 0.30 mmol) in 2-methyl-2-butene/t-BuOH/H2O (v/v/v=1/1/1, 4 mL) was added sodium dihydrogen phosphate (364 mg, 3.04 mmol) and sodium chlorite (274 mg, 3.04 mmol) at room temperature. The resulting mixture was stirred at room temperature for 24 hours. To the reaction mixture was added sodium sulfite (383 mg, 3.04 mmol), then concentrated in vacuo and purified via reverse phase HPLC to give the title compound (10 mg, 10% yield). 1H NMR (400 MHz, CD3OD) δ 8.03-80.4 (d, 2H), 7.62 (s, 1H), 7.48-7.52 (m, 4H), 4.44-4.48 (m, 2H), 4.32-4.34 (m, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH:21]3[CH2:24][CH2:23][CH2:22]3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)(=O)C.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH:21]1([C:17]2[CH:18]=[C:19]([CH3:20])[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:15][CH:16]=2)[CH2:22][CH2:23][CH2:24]1
Reactant: Cc1cc(C2CCC2)cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1cc(C2CCC2)cnc1N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
To a mixture of 4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (4.8 g), bis(tricyclohexylphosphine)palladium (II) dichloride (515 mg), tripotassium phosphate (16 g) and cyclobutylboronic acid (2.6 g) were added toluene (39 mL) and water (2 mL), and the mixture was refluxed for 8 hr. After cooling, the mixture was extracted with ethyl acetate, washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(5-cyclobutyl-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (560 mg). 4-(5-cyclobutyl-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (560 mg) was dissolved in chloroform (1.5 mL), 4N hydrogen chloride/ethyl acetate (1.5 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1N aqueous sodium hydroxide solution (8 mL), and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated to give the title compound (350 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14](NC(=O)C)=[CH:13][CH:12]=2)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[OH-].[NH4+:22]>B(F)(F)F.CO>[Cl:1][C:2]1[C:3]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH2:22])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: CC(=O)Nc1ccc(OCc2nc(Cl)ccc2Cl)cc1
Agent: FB(F)F
Agent: [OH-]
Solvent: CO
Product: Nc1ccccc1OCc1nc(Cl)ccc1Cl
Temperature: 0 °C

Procedure:
N-(4-((3,6-Dichloro-2-pyridinyl)methoxy)phenyl)-acetamide (30.27 grams; 0.097 mole) was mixed with a 270 ml. solution of boron trifluoride-methanol (1 gram per 10 ml.) and the resulting reaction mixture refluxed for a period of 4 1/2 hours. The reaction mixture was then diluted and cooled with ice water to a temperature of between about 0° to about 10°C. Concentrated ammonium hydroxide was added until the reaction mixture was basic. The reaction mixture was then extracted with portions of methylene chloride, the extracts combined and the solvent removed by evaporation. The residue thus obtained was extracted with five 500 ml. portions of hexane. The crystalline material which precipitated from the hexane mixture upon cooling was recovered by filtration. As a result of these operations, the desired 4-((3,6-dichloro-2-pyridinyl)-methoxy)benzenamine compound was recovered as a light yellow crystalline solid having a melting point of 74°-75°C.
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([CH3:30])=[O:29])[CH2:18][C:19]([OH:21])=[O:20])=[O:15])=[CH:6][CH:5]=1.[OH2:31].OO>C(O)(=O)C>[NH2:1][N:2]=[CH:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([CH3:30])(=[O:31])=[O:29])[CH2:18][C:19]([OH:21])=[O:20])=[O:15])=[CH:8][CH:9]=1
Reactant: O
Reactant: CS(=O)c1ccccc1C(CC(=O)O)NC(=O)CCCCc1ccc(C=NN)cc1
Agent: OO
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccccc1C(CC(=O)O)NC(=O)CCCCc1ccc(C=NN)cc1
Reaction time: 48 h

Procedure:
(±)-β-[[5-[4-(Aminoiminomethyl)phenyl]-1-oxopentyl]amino]-2-(methylsulfinyl)benzenepropanoic acid (2.5 g) was added to water (15 ml), acetic acid (5 ml) and followed by the addition of 30% H2O2 (10 mL). The oxidation was allowed to proceed for 48 hours after which the reaction mixture was purified by reverse phase chromatography (water/acetonitrile) and lyophilized to give 1.6 g of the title compound as a white solid: 1H NMR (d6 -DMSO) δ1.52 (m, 4H), 2.01 (m, 2H), 2.63 (m, 4H), 3.50 (s, 3H), 5.82 (m, 1H), 7.35 (m, 9H), 7.7 (m, 1H), 9.10 (bs, 2H), 9.20 (bs, 2H); MS (FAB) m/e 446.2 (M+H+).
Reaction SMILES: [C:1]([CH:4]([C:12](=O)[CH3:13])[CH:5]([C:9](=[O:11])[CH3:10])[C:6](=O)[CH3:7])(=[O:3])[CH3:2].[CH3:15][O:16][C:17]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:18]=1[NH2:19]>>[C:9]([C:5]1[C:4]([C:1](=[O:3])[CH3:2])=[C:12]([CH3:13])[N:19]([C:18]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:17]=2[O:16][CH3:15])[C:6]=1[CH3:7])(=[O:11])[CH3:10]
Reactant: COc1ccc(N)c(OC)c1
Reactant: CC(=O)C(C(C)=O)C(C(C)=O)C(C)=O
Product: COc1ccc(-n2c(C)c(C(C)=O)c(C(C)=O)c2C)c(OC)c1

Procedure:
Utilizing the general procedure outlined in Example 48, 1,1,2,2-tetraacetylethane (400 mg, 2.0 mol), 2,4-dimethoxyaniline (305 mg, 2.0 mmol) reacted to give 1-[4-acetyl-1-(2,4-dimethoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone as yellow solid: MS (ESI) 316 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:36]([O:38]CC)=[O:37])[O:10][C:9]2[CH:11]=[CH:12][C:13]([CH2:15][CH:16]([N:18]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:19][CH:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[OH:21])[CH3:17])=[CH:14][C:8]=2[O:7]1)=[O:5])C.CO.[OH-].[Na+]>O>[C:32]([O:31][C:29]([N:18]([CH2:19][CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)[OH:21])[CH:16]([CH3:17])[CH2:15][C:13]1[CH:12]=[CH:11][C:9]2[O:10][C:6]([C:36]([OH:38])=[O:37])([C:4]([OH:5])=[O:3])[O:7][C:8]=2[CH:14]=1)=[O:30])([CH3:33])([CH3:34])[CH3:35]
Reactant: CCOC(=O)C1(C(=O)OCC)Oc2ccc(CC(C)N(CC(O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2O1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)N(CC(O)c1cccc(Cl)c1)C(=O)OC(C)(C)C
Reaction time: 19 h
Yield: 99.2 %

Procedure:
To a stirred solution of 5-(2-{tert-butoxycarbonyl-[2-(3-chloro-phenyl)-2-hydroxy-ethyl]-amino}-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-ethyl ester (4.42 g, 7.65 mmol), MeOH (100 mL) and H2O (25 mL) was added 5 N NaOH (7.64 mL, 38.2 mmol). After 19 h, the solution was concentrated to an aqueous mixture and acidified to pH=1 with 1 N aq. HCl which turns the solution milky-white. Extraction with 3×100 mL EtOAc, washing the combined organics with 1×200 mL brine, drying over Na2SO4, filtration and concentration gave 3.96 g (99%) of product as a white solid; 1H NMR (300 MHz, DMSO-d6): δ 1.16 (d, J=6.7 Hz, 3H), 1.31 (s, 9H), 2.55-2.70 (m, 1H), 2.80-2.92 (m, 1H), 3.05-3.23 (m, 2H), 3.71-3.93 (m, 2H), 4.62-4.87 (m, 2H), 5.30-5.90 (brs, 1H), 6.59-6.99 (complexm, 4H), 7.14-7.47 (complexm, 3H), 8.60-8.80 (brs, 1H); MS (ES) m/z (relative intensity): 522. (M+ +H, 50).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:23])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:19](=[CH:20][CH:21]=1)[O:18][C:12]1([CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1)[CH2:11][C:10]2=[O:22].CC(O)=O.[CH:28](=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:23])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:19](=[CH:20][CH:21]=1)[O:18][C:12]1([CH2:17][CH2:16][CH2:15][N:14]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:13]1)[CH2:11][C:10]2=[O:22]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCNC1)O2
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(Cc3ccccc3)C1)O2
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
(−)-(E)-3-[4-Oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid methyl ester hydrochloride (505 mg, 1.49 mmol) was suspended in DCM (50 ml). TEA (0.208 ml, 1.49 mmol) was added and the pH was adjusted to 5 with AcOH. Benzaldehyde (190 mg, 1.794 mmol) and NaBH(OAc)3 (475 mg, 2.24 mmol) were added and the mixture was stirred at RT for 3 h. The resulting solution was washed with 5% NaHCO3 and brine, then dried over Na2SO4 and evaporated to dryness. The crude product was purified by column chromatography (eluent:petroleum ether:EtOAc 9:1 to 7:3) to give (−)-(E)-3-[1′-benzyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid methyl ester (547 mg).
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)[O:12][C@H:13]([C:15](=[O:33])[NH:16][C@@H:17]2[C:23](=[O:24])[N:22]([CH3:25])[C:21]3[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=3[N:19]([C:30](=[O:32])[CH3:31])[CH2:18]2)[CH3:14])=CC=1)([O-])=O.[F:35][C:36]1[C:43]([F:44])=[CH:42][C:41]([F:45])=[CH:40][C:37]=1[CH2:38][NH2:39]>O1CCOCC1>[C:30]([N:19]1[CH2:18][C@H:17]([NH:16][C:15]([C@@H:13]([O:12][C:11](=[O:10])[NH:39][CH2:38][C:37]2[CH:40]=[C:41]([F:45])[CH:42]=[C:43]([F:44])[C:36]=2[F:35])[CH3:14])=[O:33])[C:23](=[O:24])[N:22]([CH3:25])[C:21]2[CH:26]=[CH:27][CH:28]=[CH:29][C:20]1=2)(=[O:32])[CH3:31]
Reactant: CC(=O)N1C[C@H](NC(=O)[C@H](C)OC(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N(C)c2ccccc21
Reactant: NCc1cc(F)cc(F)c1F
Solvent: C1COCCO1
Product: CC(=O)N1C[C@H](NC(=O)[C@H](C)OC(=O)NCc2cc(F)cc(F)c2F)C(=O)N(C)c2ccccc21

Procedure:
In an analogous manner to that described in Example 57 d), the aminolysis of the carbonic acid (S)-1-((S)-5-acetyl-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamoyl)-ethyl ester 4-nitro-phenyl ester by 2,3,5-trifluoro-benzylamine in dioxane yielded the title compound as a light yellow solid; MS: m/e=510 (M+NH4)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH2:9].N1C=CC=CC=1.Cl[C:17]([O:19][CH3:20])=[O:18]>ClCCl>[CH3:20][O:19][C:17](=[O:18])[NH:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: COC(=O)Cl
Reactant: Nc1ccc(F)cc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
Into a reaction flask under nitrogen, 2,4-difluoro-phenylamine (1, 50.00 g, 390 mmol) is combined with 550 mL of anhydrous dichloromethane and anhydrous pyridine (61.27 g, 770 mmol). Methyl chloroformate (43.92 g, 460 mmol) is added dropwise while cooling to maintain the temperature in the range of 20-30° C. The reaction is stirred overnight, then concentrated under vacuum. The resulting material is diluted with 250 mL of water, adjusted to pH 2 with 2M hydrochloric acid, and extracted with 3×250 mL of ethyl acetate. The organic layers are combined, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is slurried from hexane and the resulting solid is collected by filtration and dried to provide the desired compound (2, 71.06 g, 98%).
Reaction SMILES: Cl.[NH2:2][OH:3].C[O-].[Na+].[Na].[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[S:18]([CH2:21][C:22]#[N:23])(=[O:20])=[O:19]>CO>[OH:3][N:2]=[C:22]([NH2:23])[CH2:21][S:18]([C:9]1[CH:10]=[CH:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=1)(=[O:20])=[O:19]
Reactant: N#CCS(=O)(=O)c1ccc2ccccc2c1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: NC(CS(=O)(=O)c1ccc2ccccc2c1)=NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
According to General Procedure A, hydroxylamine hydrochloride (2.26 g, 32.5 mmol), was added in one portion to a solution of NaOMe, freshly prepared from sodium (0.75 g, 32.5 mmol) in methanol. The resulting mixture was stirred 1 hour at room temperature, during which time a precipitate was formed. (2-Naphthalenylsulfonyl)acetonitrile (3.0 g, 13.0 mmol), was added in one portion and the resulting mixture heated to reflux a total of 24 hours. The mixture was cooled to room temperature and then to 0° C. to give a precipitate. The precipitate was collected by filtration, washed with water, and dried in vacuo to give a white crystalline solid (2.75 g, 80%) which was of sufficient purity for use in the subsequent reaction.