Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:23][C:24]([CH3:29])([CH3:28])[C:25](Cl)=[O:26]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C@@H:11]([O:14][C:25](=[O:26])[C:24]([CH3:29])([CH3:28])[CH3:23])[C@H:10]([CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CN(Cc2ccccc2)CCC1O
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(Cc2ccccc2)CC[C@H]1OC(=O)C(C)(C)C

Procedure:
To a cis/trans mixture of 1-benzyl-3-methyl-piperidin-4-ol (50 g, 243 mmol, prepared as described in Can. J. Chem. (1972) 50, 803) in THF is added triethylamine (51 ml, 365 mmol) followed by 2,2-dimethyl-propionyl chloride (45 ml, 365 mmol). The reaction is exothermic and a precipitate is formed. The mixture is heated under reflux for 18 hours, cooled, filtered and washed with ether. The organic layers are washed with 1N—NaOH and brine, dried and evaporated. The crude is purified by chromatography on silicagel using hexane and EtOAc (5%) to give pure trans-isomer as a colourless oil.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:15][CH:14]([OH:16])[CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1.[NH3:17]>C(O)(C)C>[NH2:17][C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:15][CH:14]([OH:16])[CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1
Reactant: N
Reactant: OC1CC(c2nc(I)c3c(Cl)nccn23)C1
Solvent: CC(C)O
Product: Nc1nccn2c(C3CC(O)C3)nc(I)c12
Temperature: 110 °C

Procedure:
In a Parr pressure reactor 3-(8-chloro-1-iodo-imidazo[1,5-a]pyrazin-3-yl)-cyclobutanol (4.159 g, 0.0119 mol) was dissolved with 2.0M ammonia in isopropyl alcohol (40 mL). The mixture was cooled to −20° C. and saturated with ammonia. The reaction was heated at 110° C. for 63 h at which point it was cooled and concentrated in vacuo. The crude product was purified using HPFC Jones 25 g silica gel column eluting with 5-8% MeOH: CH2Cl2 to yield the title compounds; MS (ES+): m/z 330.88 (100) [MH+], 331.89 (10) [MH++]; HPLC: tR=0.48 min (OpenLynx, polar—5 min); 1H NMR (CDCl3, 400 MHz) δ 2.55-2.76 (m, 2H) 3.06-3.22 (m, 2H) 3.32-3.50 (m, 1H) 4.51-4.69 (m, 1H) 6.15 (br. s., 2H) 7.24 (d, J=5.05 Hz, 1H) 7.39 (d, J=5.05 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12][CH3:13])[C:6](O)=[O:7].S(Cl)([Cl:19])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12][CH3:13])[C:6]([Cl:19])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(C(=O)O)cc([N+](=O)[O-])c1OC
Product: COc1cc(C(=O)Cl)cc([N+](=O)[O-])c1OC
Reaction time: 1 h

Procedure:
9.5 g of 3,4-dimethoxy-5-nitrobenzoic acid are suspended in 95 ml of thionyl chloride. The suspension is stirred at 80° for 1 hour. By two-fold evaporation with the addition of absolute toluene there are obtained 10 g of 3,4-dimethoxy-5-nitrobenzoyl chloride which is dissolved in 100 ml of tetrahydrofuran. This solution is added dropwise to 300 ml of 28 percent aqueous ammonia. The mixture is subsequently stirred at 40° for 2 hours and cooled to 5°. The crystalline precipitate is filtered off. There is obtained 3,4-dimethoxy-5-nitrobenzamide of m.p. 182°-185°.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH:13]1[C:18]([OH:19])=[CH:17][CH:16]=[C:15]([CH3:20])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:10]([C:7]1[CH:8]=[CH:9][C:2]([O:19][C:18]2[CH:13]=[CH:14][C:15]([CH3:20])=[CH:16][CH:17]=2)=[C:3]([CH:6]=1)[CH:4]=[O:5])([O-:12])=[O:11]
Reactant: Cc1ccc(O)cc1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc([N+](=O)[O-])cc2C=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.4 %

Procedure:
2-Fluoro-5-nitrobenzaldehyde (0.13 g, 0.79 mmol) was dissolved in N,N-dimethylformamide (6.7 mL), and p-cresol (0.22 g, 2.0 mmol) and potassium carbonate (0.27 g, 2.0 mmol) were added thereto, followed by stirring at 25° C. for 1.5 hours. After a conventional treatment, the residue was purified by silica gel chromatography (eluted with chloroform), to obtain 5-nitro-2-(4methylphenoxy)benzaldehyde (0.20 g, 98%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:7][C:8]([Cl:12])=[N:9]2)=[CH:4][CH:3]=1.[N:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[N:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>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.O>[Cl:12][C:8]1[N:7]=[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[C:10](=[CH:11][C:2]([C:23]3[CH:24]=[N:19][CH:20]=[N:21][CH:22]=3)=[CH:3][CH:4]=2)[N:9]=1
Reactant: Clc1nc(N2CCOCC2)c2ccc(Br)cc2n1
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1nc(N2CCOCC2)c2ccc(-c3cncnc3)cc2n1
Temperature: 95 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
To a 50 mL round bottom flask, 7-bromo-2-chloro-4-morpholin-4-yl-quinazoline (0.2 g, 0.0006 mol), pyrimidine-5-boronic acid (0.068 g, 0.0005 mol), sodium carbonate (0.129 g, 0.0012 mol), DMF (10 mL) and water (3 mL) were added and degassed the reaction vessel with N2 for 5-10 min. To the same reaction mixture, Pd(PPh3)2Cl2 (0.029 g, 0.00004 mol) was added and again degassed with N2 for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude product. The crude product was purified; using column chromatography (60-120 silica gel, 60% ethyl acetate in hexane) to yield the desired product [150 mg, 75%]. 1H NMR (300 MHz, CDCl3): δ 9.27 (s, 1H), 9.04 (s, 2H), 7.85-8.45 (m, 2H), 7.60-7.64 (m, 1H), 3.82-3.91 (m, 8H); LC-MS (ESI): Calculated mass: 327.09; Observed mass: 328.0 [M+H]+ (RT: 0.98 min).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7]([CH2:10][C:11](O)=O)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[F:16][C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:18]=1C=O>>[F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7](/[CH:10]=[CH:11]/[C:22]2[CH:21]=[CH:18][C:17]([F:16])=[CH:24][C:23]=2[F:25])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(O)CS(=O)(=O)Cc1ccc(F)cc1
Reactant: O=Cc1ccc(F)cc1F
Product: O=S(=O)(/C=C/c1ccc(F)cc1F)Cc1ccc(F)cc1
Yield: 68 %

Procedure:
A solution of 4-fluorobenzyl sulfonylacetic acid (0.01 mol) and 2,4-difluorobenzaldehyde (0.01 mol) was subjected to Procedure 1, Part B. The title compound was obtained in 68% yield.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][C@H:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH2:27][CH2:26]2)[C:21]([Cl:36])=[CH:20][N:19]=1>>[Cl:36][C:21]1[C:22]([NH:24][C@@H:25]2[CH2:26][CH2:27][C@H:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH2:29][CH2:30]2)=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: CS(=O)(=O)N[C@H]1CC[C@@H](Nc2nc(Cl)ncc2Cl)CC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@H]4CC[C@@H](NS(C)(=O)=O)CC4)n3)cc2CC1

Procedure:
cis-N-(4-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-methanesulfonamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and cis-N-[4-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner to Example 308c. Product isolated as a white foam (99 mg, 55%). LCMS (m/e) 523 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 7.91 (s, 1H), 7.36-7.23 (m, 2H), 7.02 (d, 1H, J=8.1 Hz), 6.78 (s, 1H), 5.18 (d, 1H, J=7.0 Hz), 4.36-4.30 (m, 1H), 4.18-4.08 (m, 1H), 3.70-3.61 (m, 1H), 3.56 (t, 2H, J=5.6 Hz), 3.39 (s, 3H), 3.03 (s, 3H), 2.96-2.88 (m, 4H), 2.80-2.69 (m, 6H), 2.01-1.84 (m, 4H), 1.84-1.70 (m, 4H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)C2(COC3C=[C:37]4[C:41](=[CH:42][C:32]2=3)[CH2:40][CH2:39][O:38]4)C1=O>>[O:38]1[CH2:37][CH2:41][CH2:42][CH2:32][CH:39]1[CH2:40][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Product: O=C1N(CC2CCCCO2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, 1′-(tetrahydro-2H-pyran-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (45%) as a colorless solid: mp 158-166° C. (hexanes); 1H NMR (300 MHz, CDCl3) (diastereomers) δ7.31-7.25 (m, 1H), 7.13 (d, J=7.5 Hz, 1H), 7.08-7.00 (m, 2H), 6.48 (s, 1H), 6.24 (s, 0.5H), 6.22 (s, 0.5H), 4.89 (d, J=9.0 Hz, 0.5H), 4.88 (d, J=9.0 Hz, 0.5H), 4.64 (d, J=9.0 Hz, 0.5H), 4.63 (d, J=9.0 Hz, 0.5H), 4.21-4.16 (m, 2H), 4.14-4.09 (m, 2H), 4.01-3.93 (m, 1H), 3.91-3.82 (m, 1H), 3.74-3.63 (m, 2H), 3.44-3.33 (m, 1H), 1.91-1.81 (m, 1H), 1.68-1.31 (m, 5H); 13C NMR (75 MHz, CDCl3) (diastereomers) δ177.89, 177.80, 155.30, 155.27, 144.61, 143.25, 143.11, 138.34, 132.46, 132.35, 128.78, 128.73, 123.66, 123.64, 123.19, 123.17, 121.51, 121.45, 111.76, 111.62, 109.90, 109.77, 99.41, 99.36, 80.14, 75.75, 75.58, 68.57, 68.53, 64.63, 64.02, 58.08, 58.04, 45.83, 45.77, 29.70, 29.57, 25.88, 23.13; MS (ES+) m/z 394.2 (M+1); Anal. Calcd for C23H23NO5: C, 70.21; H, 5.89; N, 3.56. Found: C, 70.03; H, 5.97; N, 3.17.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][S:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=O)=[CH:16][CH:15]=1.[OH-].[Na+]>O>[CH3:12][S:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]2[NH:1][C:2]3=[N:3][CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=[C:7]3[N:8]=2)=[CH:16][CH:15]=1
Reactant: Nc1cc([N+](=O)[O-])cnc1N
Reactant: CSc1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1ccc(-c2nc3cc([N+](=O)[O-])cnc3[nH]2)cc1
Reaction time: 15 h

Procedure:
1.0 g 2,3-diamino-5-nitropyridine and 1.125 g 4-methylsulfanylbenzoic acid in 20 ml polyphosphoric acid were heated to 160° C. with stirring for 15 hrs. The mixture was cooled and poured into water. The pH was adjusted to 4-5 by addition of sodium hydroxide and the precipitate collected by filtration. The filtration residue was stirred in 50 ml pyridine at 60° C., cooled and insoluble components removed by filtration. The filtrate was evaporated and the residue used without further purification in the next steps.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:22][CH2:21][CH2:20]3)[CH2:15][CH2:14]2)=[CH:8][CH:7]=1)=[O:4].[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:19]1([N:16]2[CH2:17][CH2:18][CH:13]([O:12][C:9]3[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:7][CH:8]=3)[CH2:14][CH2:15]2)[CH2:22][CH2:21][CH2:20]1
Reactant: O=C(CCl)Nc1ccc(OC2CCN(C3CCC3)CC2)cc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(CN1CCOCC1)Nc1ccc(OC2CCN(C3CCC3)CC2)cc1
Reaction time: 5 h
Yield: 80.7 %

Procedure:
A mixture of 2-Chloro-N-[4-(1-cyclobutyl piperidin-4-yloxy)phenyl]acetamide (76.0 g, 0.236, obtained in above step), morpholine (30.8 g, 0.353 moles) and potassium carbonate (98 g, 0.71 moles) in acetonitrile (1.5 L) was stirred for 5 hours at reflux temperature. The mixture was partitioned between ethyl acetate (1 L) and water (1 L). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2×500 mL). The combined organic layers were washed with water twice, dried over sodium sulfate and concentrated under vacuum. The crude compound was purified by flash chromatography using (methanol:chloroform, 2:8) to afford the title compound 71 g (Yield: 80%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:21]=[C:22]1[S:26][C:25](=[O:27])[NH:24][C:23]1=[O:28].O>CN(C)C=O>[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:21]=[C:22]1[S:26][C:25](=[O:27])[N:24]([CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]2[N:12]3[CH:13]=[CH:14][N:15]=[C:11]3[CH:10]=[CH:9][CH:8]=2)[C:23]1=[O:28]
Reactant: O=C1NC(=O)C(=Cc2cccs2)S1
Reactant: ClCCCCSc1cccc2nccn12
Solvent: CN(C)C=O
Solvent: O
Product: O=C1SC(=Cc2cccs2)C(=O)N1CCCCSc1cccc2nccn12
Temperature: 80 °C

Procedure:
To a solution of 1.81 g (7.5 mmol) of 5-(4-chlorobutylthio)imidazo[1,2-a]pyridine and 1.59 g (7.5 mmol) of 5-(2-thienylmethylene)thiazolidine-2,4-dione in 70 ml of N,N-dimethylformamide, 1.12 ml (7.5 mmol) of 1,8-diazabicyclo[5.4.0-7-undecene was added, followed by heating at 80° C. for 16 hours. After cooling, the reaction mixture was poured into water, extracted with ethyl acetate, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, hexane/ethyl acetate=2/1→1/1→ethyl acetate). The resulting crude crystal was purified by recrystallization (solvent, chloroform/diethyl ether) to yield 1.54 g (49.5%, light yellow crystal) of the desired product.m.p. 116.0°-117.0° C.; 1H-NMR (CDCl3, 200 MHz) δ 1.64-1.92 (4H, m), 3.03 (2H, t, J=7.0 Hz), 3.76 (2H, t, J=7.0 Hz), 6.92 (1H, dd, J=1.0, 7.0 Hz), 7.15 (1H, dd, J=7.2, 9.2 Hz), 7.21 (1H, dd, J=3.8, 5.2 Hz), 7.42 (1H, d, J=3.6 Hz), 7.58 (1H, d, J=9.0 Hz), 7.68 (1H, d, J=5.0 Hz), 7.70 (1H, d, J=1.4 Hz), 7.85 (1H, s), 8.05 (1H, s); IR (KBr) 1728, 1678, 1599, 1369, 1128, 773, 727 cm-1 ; Anal. Calcd for C19H17N3O2S3 : C, 54.92; H, 4.12; N, 10.11. Found: C, 54.67, H, 4.18; N, 10.03
Reaction SMILES: [CH2:1]([CH:4]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:5][C@@H:6]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[NH:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:2]=[CH2:3].[OH-:41].[Na+].OO.O>C1COCC1>[OH:41][CH2:3][CH2:2][CH2:1][CH:4]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:5][C@@H:6]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[NH:7][C:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C=CCC(C[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)C(CCCO)C[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 44 %

Procedure:
Borane tetrahydrofuran complex (1M, 2.8 mL, 2.8 mmol) was added drop wise to a solution of di-tert-butyl 4-allyl-N-trityl-L-glutamate (1.00 g, 1.85 mmol) in THF (10 mL) at 0° C. The resulting mixture was stirred for 2 h at 0° C. and for 16 h at room temperature. The solution was cooled to 0° C. NaOH (1M, 3 mL) and H2O2 (30% in water, 3 mL) were added drop wise. The mixture was stirred at 0° C. for 1 h. Water (5 mL) was added and the mixture was concentrated under reduced pressure. The aqueous residue was extracted with ethyl acetate. The combined organic fraction was washed with brine, dried over sodium sulfate, filtrated and concentrated. The crude product was purified by flash chromatography (silica, ethyl acetate/hexane) to afford di-tert-butyl 4-(3-hydroxypropyl)-N-trityl-L-glutamate (0.46 g, 44%) as a mixture of (4S,4S)/(2S,4R) diastereoisomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][CH:16]([CH2:19][O:20][CH3:21])[CH2:17][CH3:18])[C:10]=1[N+:22]([O-])=O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][CH:16]([CH2:19][O:20][CH3:21])[CH2:17][CH3:18])[C:10]=1[NH2:22]
Reactant: CCC(COC)Nc1nccc(-c2ccc(Cl)cc2Cl)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: CCC(COC)Nc1nccc(-c2ccc(Cl)cc2Cl)c1N
Yield: 58.6 %

Procedure:
[4-(2,4-Dichloro-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine (2.11 g, 5.72 mmol) and Na2S2O4 (8.03 g, 46.1 mmol) were treated substantially as described in Part E of Example 9 to yield 1.14 g (59%) of 4-(2,4-dichloro-phenyl)-N2-(1-methoxymethyl-propyl)-pyridine-2,3-diamine: MS (AP) m/z 340.2 [(M+H)+, 100].
Reaction SMILES: Br[CH2:2][C:3]([NH2:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].[C:12]1([S:18]([CH2:21][C:22]2[C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[C:26]([OH:35])[C:25]([Br:36])=[CH:24][CH:23]=2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CC(C)=O>[C:12]1([S:18]([CH2:21][C:22]2[C:27]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])=[C:26]([O:35][CH2:2][C:3](=[O:4])[NH2:5])[C:25]([Br:36])=[CH:24][CH:23]=2)(=[O:19])=[O:20])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: NC(=O)CBr
Reactant: CC(C)(C)OC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OCC(N)=O
Reaction time: 18 h
Yield: 77.8 %

Procedure:
2-Bromoacetamide (0.12 g) and potassium carbonate (0.28 g) were added to solution of tert-butyl 6-(benzenesulfonylmethyl)-3-bromo-2-hydroxybenzoate (Intermediate 38, 0.34 g) in acetone (10 mL) and the mixture was stirred for 18 hours. The mixture was evaporated to dryness and the residue was suspended in DCM and the insoluble material was removed by filtration. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and pentane with a gradient of 50-60% to give tert-butyl 6-(benzenesulfonylmethyl)-3-bromo-2-carbamoylmethoxybenzoate (0.30 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][CH2:11][CH:12]([C:16]([F:19])([F:18])[F:17])[C:13](Cl)=[O:14])=[CH:5][CH:4]=1.[O:20]=[C:21]1[CH2:25][NH:24][C@H:23]([C:26]([OH:28])=[O:27])[CH2:22]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][CH2:11][CH:12]([C:16]([F:19])([F:18])[F:17])[C:13]([N:24]2[CH2:25][C:21](=[O:20])[CH2:22][C@H:23]2[C:26]([OH:28])=[O:27])=[O:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(CSCC(C(=O)Cl)C(F)(F)F)cc1
Reactant: O=C1CN[C@H](C(=O)O)C1
Product: COc1ccc(CSCC(C(=O)N2CC(=O)C[C@H]2C(=O)O)C(F)(F)F)cc1

Procedure:
The 3-[[(4-methoxy)phenylmethyl]thio]-2-trifluoromethylpropionyl chloride from part (a) is reacted with 4-keto-L-proline to yield 1-[3-[[(4-methoxy)phenylmethyl]thio]-2-trifluoromethyl-1-oxopropyl]-4-oxo-L-proline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[N:9])[C:3]=1[CH2:10][C:11]([OH:13])=O.O=S(Cl)[Cl:16]>ClCCl>[Cl:16][C:8]1[C:4]2[C:3](=[C:2]([Cl:1])[CH:7]=[CH:6][CH:5]=2)[CH:10]=[C:11]([OH:13])[N:9]=1
Reactant: N#Cc1cccc(Cl)c1CC(=O)O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Oc1cc2c(Cl)cccc2c(Cl)n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
2-(2-chloro-6-cyanophenyl)acetic acid (10.5 g, 53.7 mmol) and SOCl2 (20 mL, 274 mmol) were stirred in dichloromethane (25 mL) at RT. The suspension became a solution over 4 h. The reaction was stirred overnight. The volitile organics were removed under vacuum and the residue was taken up in DCM and filtered. The filtrate was concentrated and then dissolved in 4 N HCl dioxane (30 mL) and transfered to a sealed vessel and heated to 60° C. for 3 h. The reaction was cooled and the solid was collected, washed with dioxane, and dried under vacuum to give the product 1,5-dichloroisoquinolin-3-ol (8 g, 69.6% yield) as a solid 1H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 8.11 (dt, J=8.6, 1.0 Hz, 1H), 7.90 (dd, J=7.6, 1.0 Hz, 1H), 7.46 (dd, J=8.6, 7.6 Hz, 1H), 7.11 (d, J=1.0 Hz, 1H). MS: MS m/z 214.08(M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-:17])=[O:10])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].C(OO)(=[O:23])C.S(=O)(=O)(O)[O-].[Na+].O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-:17])(=[O:23])=[O:10])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19]
Reactant: CC(=O)OO
Reactant: O=[N+]([O-])c1cc(CS(=O)c2cccc[n+]2[O-])ccc1Cl
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(CS(=O)(=O)c2cccc[n+]2[O-])ccc1Cl
Temperature: 70 °C

Procedure:
To a mixture of 14.0 g (0.0426 mole) of 2-[[(4-chloro-3-nitrophenyl)methyl]sulfinyl]-pyridine-N-oxide in 35 ml of acetic acid was added 10.1 g of peracetic acid (40% in acetic acid) dropwise over one hour. The temperature of the reaction mixture rose to 27° C. before a water bath was placed on the flask to hold the temperature at 25° C. After addition, the mixture was heated to 70° C. for five hours. The mixture was cooled, and 20 ml additional acetic acid and solid sodium bisulfate and water were added to destroy the excess peracetic acid. The aqueous mixture was neutralized with potassium carbonate and chilled in an ice bath to precipitate an almost white solid. The precipitate was filtered off, washed with water, dried under vacuum overnight, and found to have a melting point of 162–164° C. Infrared and NMR spectra were both consistent with the proposed structure. The product was recrystallized from ethanol to give needle-like white crystals, melting point 168–170° C. C,H,N calculated for C12H9ClN2O5S: C=43.85%; H=2.76%; N=8.52%. Found: C=43.27%; H=2.65%; N=8.21%
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.F[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:16]=1[C:17]([OH:19])=[O:18].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:15]2[CH:14]=[N:13][CH:12]=[CH:11][C:16]=2[C:17]([OH:19])=[O:18])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(I)ccc1N
Reactant: O=C(O)c1ccncc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(I)ccc1Nc1cnccc1C(=O)O
Temperature: -78 °C
Yield: 59 %

Procedure:
4-Iodo-2-methylaniline (233 mg, 1.00 mmol) and 3-fluoropyridine-4-carboxylic acid (141 mg, 1.00 mmol) were dissolved in dry THF (6.0 ml) under argon and the mixture was cooled to −78° C. A solution of LiHMDS (1.0M in THF, 3.5 ml) was added and the reaction mixture was allowed to warm to ambient temperature. After 36 h the reaction was quenched by adding solid NH4Cl. After filtration the volatiles were removed in vacuo and the crude material was purified by flash chromatography using silica gel and a gradient of 0-10% methanol in DCM as eluent to give 208 mg (588 μmol; 59% yield) of pure desired product.