Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].Cl>C(Cl)Cl.CO.O>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([C:5](=[O:7])[CH3:6])=[CH:15][C:14]=1[OH:19])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)c1ccccc1O
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Al+3]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1ccc(C(C)(C)C)c(O)c1
Temperature: 0 °C

Procedure:
To a solution of aluminum chloride (162.3 g, 1.22 mol) in methylene chloride (600 mL) at −75° C. was added acetyl chloride (95.7 g, 1.22 mol) while stirring under an atmosphere of argon. 2-tert-Butyl-phenol (167 g, 1.11 mol) was added dropwise over 1 hr. The resulting mixture was allowed to warm to 0° C. for 10 min. The resulting mixture was then quenched with ice and extracted with EtOAc (1.5 L). The organic layer was separated and dried with brine. The organic layer was evaporated in vacuo to yield a white solid. The white solid was dissolved in methanol (300 mL) and treated with potassium carbonate (100 g) and the resulting mixture allowed to stir 18 h at room temperature. Water (300 mL) was added and pH adjusted to 5 to 6 using concentrated hydrochloric acid. The resulting mixture was extracted with EtOAc. The organic layer was rinsed with brine and dried over sodium sulfate, then evaporated in vacuo to yield 1-(4-tert-butyl-3-hydroxy-phenyl)-ethanone as a tan solid. C12H16O2; MS (ESI) m/z 193.2 (MH)+.
Reaction SMILES: [CH2:1]([N:8]([CH3:30])[C:9](=[O:29])[C@@H:10]([N:18]([CH2:26][CH:27]=C)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[O:37]=O.CSC>ClCCl.CO.C(OCC)(=O)C>[CH2:1]([N:8]([CH3:30])[C:9](=[O:29])[C@@H:10]([N:18]([CH2:26][CH:27]=[O:37])[C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)N(C)Cc1ccccc1
Reactant: O=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CSC
Product: CN(Cc1ccccc1)C(=O)[C@H](Cc1ccccc1)N(CC=O)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 16 h

Procedure:
Combine (S)-N-benzyl-N-methyl-2-[N'-(t-butoxycarbonyl)-allylamino]-3-phenyl-propionamide (10.04 g, 24.5 mmol), and pyridine (0.13 ml) in dichloromethane/methanol (300 mL/30 mL). Cool to -78° C. Pass ozonized oxygen through the solution until a persistent light blue color is obtained. Pass nitrogen through the solution until the blue color dissipates. Add dimethyl sulfide (55 mL). Allow the reaction mixture to warm to ambient temperature and stir for 16 hours. Concentrate in vacuo to obtain a residue. Dilute the residue with ethyl acetate and extract with water. Separate the layers, dry the organic layer over MgSO4, filter, and evaporate in vacuo. Chromatograph on silica gel eluting with 10% ethyl acetate/hexane to give the title compound: TLC Rf =0.53 (silica gel, 10% ethyl acetate/hexane).
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:16]([CH2:18][OH:19])[CH:17]=1>CN(C)C=O>[CH2:21]([O:20][C:15]1[CH:14]=[CH:13][C:12]([NH:11][C:2]2[C:3]3[NH:10][CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:17][C:16]=1[CH2:18][OH:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Nc1ccc(OCc2ccccc2)c(CO)c1
Reactant: Clc1ncnc2cc[nH]c12
Solvent: CN(C)C=O
Product: OCc1cc(Nc2ncnc3cc[nH]c23)ccc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 40.3 %

Procedure:
A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (307 mg), [5-amino-2-(benzyloxy)phenyl]methanol (459 mg) and N,N-dimethylformamide (10 mL) was stirred at 80° C. for 4 hrs. The reaction mixture was concentrated under reduced pressure, aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate containing tetrahydrofuran. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, methanol:ethyl acetate=0:100→30:70). Ethanol and ethyl acetate were added and the precipitate was collected by filtration to give the title compound (279 mg) as a brown powder.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:22][C:23]1[C:24]([C:28]#[N:29])=[CH:25][S:26][CH:27]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:22][C:23]2[C:24]([C:28]#[N:29])=[CH:25][S:26][CH:27]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cscc1CBr
Reactant: Cc1cccnc1[C@@H]1CCC[C@H](c2ncccc2C)N1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1Cc1cscc1C#N
Yield: 82.1 %

Procedure:
Using General Procedure A: A solution of 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-cis-[2,2′;6′,2″]terpyridine (0.097 g, 0.37 mmol), 4-bromomethyl-thiophene-3-carbonitrile (0.168 g, 0.83 mmol) (Terpstra, J. W., et al., J. Org. Chem. (1986) 51:230-238), KI (21 mg, 0.13 mmol), and DIPEA (0.15 mL, 0.86 mmol) in DMF (3 mL) was heated at 60° C. for 21 hours. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2—CH3OH—NH4OH) provided 118 mg (84%) of 4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-thiophene-3-carbonitrile as a tan solid.
Reaction SMILES: C(OC([NH:8][C@@H:9]([C@H:25]([O:27][CH3:28])[CH3:26])[CH2:10][S:11]([CH2:14][C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:13])=[O:12])=O)(C)(C)C.[ClH:29]>O1CCOCC1>[ClH:29].[ClH:29].[NH2:8][C@@H:9]([C@H:25]([O:27][CH3:28])[CH3:26])[CH2:10][S:11]([CH2:14][C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:12])=[O:13]
Reactant: CO[C@H](C)[C@@H](CS(=O)(=O)Cc1cnc2ccccc2c1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CO[C@H](C)[C@H](N)CS(=O)(=O)Cc1cnc2ccccc2c1

Procedure:
A stirred solution of (2S,3R)-2-(N-t-butoxycarbonylamino)-3-methoxy-1-(3-quinolylmethanesulfonyl)butane (1 g) in MDC (10 ml) at rt was treated with 4M hydrogen chloride in dioxan (10 ml). After 1 h the mixture was evaporated to give the subtitle compound (0.93 g). MS (APCI+ve ion) 309 (MH+), 1H NMR δ(DMSO-d6) 9.04 (1H, m), 8.71 (1H, s), 8.3 (3H, broad s), 8.2 (2H, m), 7.91 (1H, t, J=8 Hz), 7.78 (1H, t, J=8 Hz), 5.08 (2H, m), 3.3–3.88 (4H, m), 3.31 (3H,s), 1.7 (2H, m), 1.19 (3H, d,J=6.3 Hz),
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([C@@H:21]4[CH2:26][CH2:25][C@H:24]([CH2:27][S:28][C:29]5[NH:30][C:31]([NH2:34])=[N:32][N:33]=5)[CH2:23][CH2:22]4)[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.CC#N.O>C(O)(C(F)(F)F)=O>[N:12]1[C:11]2[NH:7][CH:8]=[CH:9][C:10]=2[C:15]([C:16]2[CH:17]=[N:18][N:19]([C@@H:21]3[CH2:26][CH2:25][C@H:24]([CH2:27][S:28][C:29]4[NH:30][C:31]([NH2:34])=[N:32][N:33]=4)[CH2:23][CH2:22]3)[CH:20]=2)=[N:14][CH:13]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H]4CC[C@@H](CSc5nnc(N)[nH]5)CC4)c3)ncnc21
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc(SC[C@H]2CC[C@@H](n3cc(-c4ncnc5[nH]ccc45)cn3)CC2)[nH]1
Reaction time: 2 h

Procedure:
5-[(cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethyl)thio]-4H-1,2,4-triazol-3-amine (9a) was dissolved in TFA (1 mL) and was stirred for 2 h. The solution was concentrated using a rotary evaporator to remove TFA. The residue was dissolved in methanol (1 mL) and ammonium hydroxide (1 mL) added. The solution was stirred overnight. LCMS showed complete de-protection. The solution was concentrated using a rotary evaporator. The product was isolated by prep LCMS using a 30 mm×100 mm C18 column; 11% CH3CN—H2O (0.1% TFA), 1.5 min, to 33% at 6 min; 60 mL/min; detector set at m/z 396; retention time, 5.5 min (2 runs). The eluate was freeze dried. Yield 21 mg (di-TFA salt). LC/MS (M+H)+: 396, 1H NMR (d6-DMSO) δ 12.9 (br s, 1H, NH); 8.9 (2 singlets, 2H); 8.5 (s, 1H); 7.9 (m, 1H); 7.3 (m, 1H); 4.4 (m, 1H, NCH); 3.1 (d, 2H); 2.2 (m, 2H); 1.9 (m, 3H); 1.7 (m, 2H); 1.6 (m, 2H). MS(ES) 396 (M+1).
Reaction SMILES: Br[C:2]1[C:3]([N:12]2[CH2:16][CH2:15][C@@H:14]([OH:17])[CH2:13]2)=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[N:24]1[C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][CH:26]=[N:25]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:17][C@@H:14]1[CH2:15][CH2:16][N:12]([C:3]2[C:2]([C:28]3[N:24]([CH:19]4[CH2:20][CH2:21][CH2:22][CH2:23][O:18]4)[N:25]=[CH:26][CH:27]=3)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=2)[CH2:13]1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: COC(=O)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)c1cnc(N2CC[C@@H](O)C2)c(-c2ccnn2C2CCCCO2)c1
Temperature: 92 °C
Reaction time: 16 h

Procedure:
A mixture of (R)-methyl 5-bromo-6-(3-hydroxypyrrolidin-1-yl)nicotinate (Stage 9.6, 90 g, 299 mmol), 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (103.9 g, 373.6 mmol), K3PO4 (126.9 g, 597.7 mmol), Pd(PPh3)2Cl2 (6.29 g, 8.97 mmol) in toluene (900 mL) was stirred at 92° C. and for 16 h. After cooling the mixture to RT, the solution was washed with water (450 mL), 5% NaHCO3 solution (430 mL) and the solvent was evaporated off under reduced pressure to give a residue which was used without further purifications in the next step. HPLC (Condition 7) tR=6.929 min, LC-MS (Condition 8) tR=4.30 min, m/z=373.0 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.19-1.28 (m, 1H), 1.35-1.63 (m, 4H), 1.63-1.86 (m, 3H), 1.89 (br. s, 1H), 2.12-2.39 (m, 1H), 3.11 (br. s, 1H), 3.18-3.48 (m, 4H), 3.78 (s, 4H), 3.88 (d, J=11.54 Hz, 1H), 4.08-4.24 (m, 1H), 4.86 (dd, J=18.20, 2.89 Hz, 1H), 5.02 (d, J=8.28 Hz, 1H), 6.39 (br. s, 1H), 7.58 (d, J=1.25 Hz, 1H), 7.78 (br. s, 1H), 8.69 (t, J=2.01 Hz, 1H).
Reaction SMILES: CC1(C)C[O:5][C:4]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=N1.Cl.[OH-:32].[Na+]>C(O)C>[C:24]1([C:21]2[CH:20]=[CH:19][C:18]([CH2:17][C:10]3[C:9]4[C:14](=[CH:15][CH:16]=[C:7]([C:4]([OH:5])=[O:32])[CH:8]=4)[N:13]=[CH:12][CH:11]=3)=[CH:23][CH:22]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: [OH-]
Reactant: CC1(C)COC(c2ccc3nccc(Cc4ccc(-c5ccccc5)cc4)c3c2)=N1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1ccc2nccc(Cc3ccc(-c4ccccc4)cc3)c2c1

Procedure:
A mixture of 6-(4,5-dihydro-4,4-dimethyloxazol-2-yl)-4-(4-phenylbenzyl)-quinoline (132 mg), ethanol (1 ml) and 3N hydrochloric acid (3 ml) was refluxed under heating for 2 hr. Then 6N hydrochloric acid (3 ml) was added and the mixture was refluxed for 4 hr. The mixture was basified with aqueous sodium hydroxide solution, and washed once with chloroform. The aqueous layer was adjusted to pH 4 with 1N hydrochloric acid. The resulting precipitate was collected by filtration and washed with water to give the objective compound (87 mg) as a white powder.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]([CH3:10])([CH2:7][O:8][CH3:9])[CH2:5][OH:6].IC.[CH3:13]CO>CCOCC>[CH3:9][O:8][CH2:7][C:4]([NH2:3])([CH2:5][O:6][CH3:13])[CH3:10]
Reactant: COCC(C)(N)CO
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOCC
Product: COCC(C)(N)COC
Reaction time: 1 h
Yield: 68.3 %

Procedure:
To a 3-necked 3 L RB flask equipped with overhead stirrer, condenser and N2 inlet line was added NaH (Morton Thiokol, Inc. - Alfa Products, 60% in mineral oil, 44 g, 1.1 mol). After washing with hexane (3×200 mL), dry THF (1.1 L) was added to the flask. After cooling to 0°, 2-amino-3-methoxy-2-methyl-1-propanol (61C, 119.16 g, 1.0 mol) was added dropwise to the flask at such a rate that the reaction temperature remained below 30°. The resulting slurry was cooled to 0°. Iodomethane (Aldrich, 141.94 g, 1.0 mol, 62.25 mL) was added dropwise to the mixture at such a rate that the reaction temperature remained below 30°. After the mixture was stirred for 1 h, EtOH (25 mL) was added to quench the reaction. The volume of the reaction was reduced to 200 mL. This material was diluted to 2 L with Et2O, filtered and the solvent removed. Fractional distillation of this material gave 91.02 g (68.3% yield of 1,1-bis-(methoxymethyl)ethylamine, bp 146°-149°, (C,H,N).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.F[C:22]1[CH:27]=[C:26]([C:28]([OH:30])=[O:29])[CH:25]=[CH:24][N:23]=1>CN1C(=O)CCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:27]=[C:26]([C:28]([OH:30])=[O:29])[CH:25]=[CH:24][N:23]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: O=C(O)c1ccnc(F)c1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CN1CCCC1=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ccn3)CC1)C(=O)N2

Procedure:
6.0 g (22 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 1.5 g (11 mmol) 2-fluoropyridine-4-carboxylic acid in 20 mL NMP were stirred overnight at 110° C. The reaction mixture was cooled and the precipitate formed was suction filtered. This was stirred with water, additionally combined with 15% potassium carbonate solution and extracted several times with DCM. The aqueous phase was acidified, the precipitate formed was suction filtered and dried.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[Br:13][CH2:14][CH2:15]O.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>O1CCCC1.O>[Br:13][CH2:14][CH2:15][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:9]([F:10])([F:11])[F:12]
Reactant: OCCBr
Reactant: Oc1ccc(F)cc1C(F)(F)F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc(OCCBr)c(C(F)(F)F)c1
Reaction time: 0.08 h

Procedure:
A mixture of 4-fluoro-2-(trifluoromethyl)phenol (1.05 g, 5.83 mmol), 2-bromoethanol (0.62 mL, 8.7 mmol) and triphenylphosphine (2.29 g, 8.73 mmol) in tetrahydrofuran (20 mL) was stirred for 5 minutes. Diisopropyl azodicarboxylate (94%, 1.84 mL, 8.71 mmol) was then added drop-wise over 20 minutes, and the reaction was stirred at room temperature for 16 hours. Water (50 mL) was added, and the mixture was extracted with dichloromethane (2×75 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over magnesium sulfate, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 10% ethyl acetate in heptane) afforded the title compound as a white solid. Yield: 600 mg, 2.09 mmol, 36%. GCMS m/z 286. 1H NMR (400 MHz, CDCl3) δ 3.66 (dd, J=6.6, 6.4 Hz, 2H), 4.35 (dd, J=6.5, 6.4 Hz, 2H), 6.97 (br dd, J=9.0, 4.1 Hz, 1H), 7.18-7.24 (m, 1H), 7.32 (br dd, J=8.3, 3.2 Hz, 1H).
Reaction SMILES: [NH2:1][N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=[NH2+:8].CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[OH-].[Na+].[Cl:24][CH2:25][C:26](OC)=O>CCO>[Cl:24][CH2:25][C:26]1[N:8]=[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]2[N:1]=1
Reactant: Nn1ccccc1=[NH2+]
Reactant: COC(=O)CCl
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: ClCc1nc2ccccn2n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
A mixture of 1-aminopyridin-2(1H)-iminium-2,4,6-trimethylbenzenesulfonate (crude product from the previous step) and sodium hydroxide (NaOH) (0.55 g, 13.8 mmol) in EtOH (30 mL) was stirred at 60° C. for 1 h, then methyl 2-chloroacetate (1.12 g, 10.4 mmol) was added. The reaction mixture was refluxed for 4 h, then the solvent was removed. The product was purified by silica gel column chromatography (eluting with 20% v/v EtOAc in PE) to give the title compound (512 mg, yield: 29%, 2 steps). ESI MS: m/z 168 [M+H]+.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:28])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C:10](=[O:21])[C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:8]2)=[O:4].[NH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH:16]1([CH2:15][N:11]2[C:12]3[C:7](=[C:6]([OH:28])[C:5]([C:3]([NH:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:4])=[N:14][CH:13]=3)[CH:8]=[C:9]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:10]2=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2CC2CCCC2)c1O
Reactant: NCCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2CC2CCCC2)c1O
Temperature: 25 °C
Yield: 40.8 %

Procedure:
A mixture of 1-cyclopentylmethyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (45 mg, 0.12 mmol), 4-aminobutyric acid (736 mg, 7.1 mmol) and NaOMe solution (10.7 mL, 5.4 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added until pH was about 2-3. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (5-40% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 22 mg of the title compound as a yellow solid. MS: (+) m/z 450.36 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([CH2:11]O)[CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6](=[O:7])[NH:8][CH2:11]2
Reactant: NC(=O)c1ccc(Br)cc1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1NCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 24 %

Procedure:
To a solution of 4-bromo-2-(hydroxymethyl)benzamide III-2 (3.50 g, 15.2 mmol) in THF (100 mL) was added Ph3P (4.78 g, 18.3 mmol) and DIAD (3.38 g, 16.7 mmol). The reaction was stirred at room temperature 20 h. The reaction mixture was concentrated under vacuum and purified by column chromatography (silica gel) using 0 to 25% EtOAc in hexanes to afford 5-bromoisoindolin-1-one III-3 as a white solid (786 mg, 24%) as a white solid; 1H-nmr (400 MHz, CDCl3) δ 7.80 (d, J=8.0 Hz, 1H), 7.70 (s, 1H), 7.67 (s, 2H), 5.31 (s, 2H); LC (254 nM) 4.88 min (>98%); MS (ESI) m/z=212.8, 214.8.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.CON(C)[C:16]([CH:18]([NH:27][C:28]([CH:30]([NH:35][C:36](=[O:45])[O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:31][CH:32]([CH3:34])[CH3:33])=[O:29])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17].C(O)(=O)C>C1COCC1.CCCCC.C(OCC)C>[CH3:33][CH:32]([CH3:34])[CH2:31][CH:30]([NH:35][C:36](=[O:45])[O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:28](=[O:29])[NH:27][CH:18]([C:16]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:17])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CON(C)C(=O)C(CCc1ccccc1)NC(=O)C(CC(C)C)NC(=O)OCc1ccccc1
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)CC(NC(=O)OCc1ccccc1)C(=O)NC(CCc1ccccc1)C(=O)c1ccccn1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 26.6 %

Procedure:
A solution comprised of 2-bromopyridine (0.291 mL, 3.06 mmol) in dry THF (2 mL) was cooled to −78° C. and then a solution of n-butyllithium (1.6 mL, 2.72 mmol) in pentane was added dropwise over 2 minutes. The mixture was stirred at −78° C. for 10 minutes and then a solution of benzyl 1-[1-(N-methoxy-N-methylcarbamoyl)-3-phenylpropylcarbamoyl]-3-methylbutylcarbamate (0.3 g, 0.64 mmol) in THF (2 mL) was added slowly. The mixture was stirred, while allowing to slowly warm to room temperature, and then poured into a solution comprising acetic acid (0.163 mL) in diethyl ether (50 mL). The organic phase was washed with brine (40 mL), dried (MgSO4) and concentrated in vacuo. Product was purified from the residue by flash chromatography on silica gel eluting with 1:2 ethyl acetate/hexanes to provide benzyl 3-methyl-1-(1-pyrid-2-ylcarbonyl-3-phenylpropylcarbamoyl)butylcarbamate (82 mg, 0.17 mmol) as a white solid. MS (ESI) m/z=488 (M+1); 1H NMR (CDCl3): δ 0.8-1.05 (d, J=4 Hz, 6H), 1.5 (m, 1H), δ 1.6-1.78 (t, 2H), δ 1.99-2.20 (m, 1H), δ 2.6-2.9 (m, 1H), δ 2.55-2.85 (m, 2H), δ 4.25 (m, 1H), δ 5.17 (s, 2H), δ 5.25 (m, 1H), δ 6.00 (m, 1H), δ 6.85-6.95 (d, J=10 Hz, 1H), δ 7.1-7.4 (m, 10H) 7.50(t, J=4 Hz, 1H), δ 7.85 (t, J=6 Hz, 1H) 8.01 (d, J=8 hz, 1H), δ 8.69 (m, 1H). Anal (C29H33N3O4).
Reaction SMILES: C1C=CC=CC=1.[C:7]1([CH3:35])[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([CH3:14])[C:8]=1[NH:15][CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]=1[C:27]1[N:32]=[C:31]([CH:33]=O)[CH:30]=[CH:29][CH:28]=1.[CH:36]([C:39]1[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]([CH3:48])[CH3:47])[C:40]=1[NH2:41])([CH3:38])[CH3:37].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[CH:46]([C:42]1[CH:43]=[CH:44][CH:45]=[C:39]([CH:36]([CH3:38])[CH3:37])[C:40]=1[N:41]=[CH:33][C:31]1[N:32]=[C:27]([C:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:25]=[CH:26][C:17]=2[CH2:16][NH:15][C:8]2[C:7]([CH3:35])=[CH:12][C:11]([CH3:13])=[CH:10][C:9]=2[CH3:14])[CH:28]=[CH:29][CH:30]=1)([CH3:48])[CH3:47]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: Cc1cc(C)c(NCc2ccc3ccccc3c2-c2cccc(C=O)n2)c(C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: O
Solvent: c1ccccc1
Product: Cc1cc(C)c(NCc2ccc3ccccc3c2-c2cccc(C=Nc3c(C(C)C)cccc3C(C)C)n2)c(C)c1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
Benzene (200 mL) was added to compound 5b (6.69 g, 17.6 mmol), and 2,6-diisopropylaniline (3.12 g, 17.6 mmol), and p-toluenesulfonic acid monohydrate (5 mg) in a 500 mL round-bottomed flask fitted with a Dean-Stark trap. The mixture was heated to reflux under nitrogen. After 2 hours, 1H NMR spectroscopy of an aliquot indicated that the reaction had proceeded to around 90% completion. All but about 50 mL of the benzene was removed by distillation and toluene (200 mL) was added. The mixture was heated to reflux and most of the toluene was removed by distillation. Drying of the residue under reduced pressure afforded a dirty yellow solid. Dissolution of the solid in warm Et2O, followed by filtration and cooling to −20° C. afforded 6b as nice yellow crystals. Yield from two crops: 6.5 g, 69%. 1H NMR (500 MHz, CD2Cl2): 8.36 (d, 1H), 8.33 (s, 1H), 7.97 (t, 1H), 7.93 (d, 2H), 7.59 (d, 1H), 7.39-7.51 (m, 4H), 7.17 (d, 2H), 7.10 (m, 1H), 6.72 (s, 2H), 4.01 (br d, 1H), 3.92 (d, 1H), 3.39 (br, 1H), 3.03 (sept, 2H), 2.18 (s, 3H), 2.03 (s, 6H), 1.18 (d, 12H).