Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:7]([CH:8]([OH:13])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:14])[N:5]=[C:4]2[S:15][C:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[C:3]=12.C(O[C:26]([CH3:29])([CH3:28])[CH3:27])(=O)C.Cl(O)(=O)(=O)=O>>[I:1][C:2]1[C:7]([CH:8]([O:13][C:26]([CH3:29])([CH3:28])[CH3:27])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:14])[N:5]=[C:4]2[S:15][C:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[C:3]=12
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)C(O)c1c(C)nc2sc3c(c2c1I)CCCC3
Agent: [O-][Cl+3]([O-])([O-])O
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1I)CCCC3
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.6 %

Procedure:
To a solution of methyl 2-[4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-hydroxyacetate (2.1 g; 5.03 mmol) in tert-butyl acetate (15 mL; 112 mmol) under a nitrogen atmosphere was added perchloric acid 70% (0.342 mL; 5.52 mmol). The reaction was stirred at room temperature for 3 days and quenched by adding a saturated solution of sodium bicarbonate. The mixture was diluted with dichloromethane and the phases were separated. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethylacetate (1-40%) in heptane furnished 0.776 g (32%) of the title compound as a solid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[CH:6]=[C:5]1[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:23][O:22][C:20]([CH2:19][CH2:18][CH2:17][C:5]1[NH:4][C:12]2[C:7]([CH:6]=1)=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)=[O:21]
Reactant: COC(=O)CCCc1cc2ccc(C(=O)OC)cc2n1C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)CCCc1cc2ccc(C(=O)OC)cc2[nH]1
Yield: 60.6 %

Procedure:
To a solution of methyl 1-acetyl-2-(3-methoxycarbonylpropyl)indole-6-carboxylate (2.34 g) in methanol (20 ml) was added powdered potassium carbonate (1.04 g), and the mixture was stirred under reflux for 10 minutes. The resulting mixture was evaporated in vacuo and the residue was acidified with 1N hydrochloric acid and extracted with chloroform. The organic phase was washed with aqueous sodium bicarbonate and brine, dried over sodium sulfate and then evaporated in vacuo. The residue was triturated with ether to give methyl 2-(3-methoxycarbonylpropyl)indole-6-carboxylate (1.23 g) as solid.
Reaction SMILES: C(OC(C)C)(C)C.P(OP(O)(O)=O)(O)(O)=O.[CH:17]1([C:20](=O)[CH2:21][C:22]#[N:23])[CH2:19][CH2:18]1.[NH2:25][C:26]1[CH:40]=[CH:39][CH:38]=[CH:37][C:27]=1[C:28]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)=O>>[CH:17]1([C:20]2[C:21]([C:22]#[N:23])=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C:27]3[C:26](=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:25]=2)[CH2:19][CH2:18]1
Reactant: Nc1ccccc1C(=O)c1ccc(F)cc1
Reactant: N#CCC(=O)C1CC1
Agent: O=P(O)(O)OP(=O)(O)O
Solvent: CC(C)OC(C)C
Product: N#Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.5 %

Procedure:
Into a glass flask having an internal volume of 10 mL, equipped with a stirring apparatus, a thermometer, a reflux condenser and a Dean-Stark apparatus, 5 mL of diisopropyl ether was put in an atmosphere of nitrogen, and 0.82 g (4.6 mmol) of pyrophosphoric acid, 0.29 g (2.5 mmol) of 3-cyclopropyl-3-oxopropanenitrile and 0.50 g (2.3 mmol) of 2-amino-4′-fluorobenzophenone were added thereto with stirring at room temperature. Then, the temperature was raised to 70° C., and reaction was carried out for 3 hours. After completion of the reaction, the reaction liquid was cooled to room temperature, and analyzed by high performance liquid chromatography (absolute quantitative analysis), whereupon 0.60 g (yield: 91%) of 2-cyclopropyl-4-(4′-fluorophenyl)quinoline-3-carbonitrile was formed.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[C:11]([Cu])#[N:12].CN1C(=O)CCC1>O>[NH2:6][C:5]1[C:7]([F:9])=[CH:8][C:2]([C:11]#[N:12])=[CH:3][C:4]=1[F:10]
Reactant: N#C[Cu]
Reactant: Nc1c(F)cc(Br)cc1F
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1cc(F)c(N)c(F)c1
Temperature: 25 °C
Yield: 42.9 %

Procedure:
340 g (1.63 mol) of 4-bromo-2,6-difluoroaniline, 223 g (2.5 mol) of CuCN and 800 cm3 of NMP were refluxed for 1.5 hours on a mantle heater. The reaction solution was cooled to room temperature, and after adding 300 cm3 of EDA, it was poured into 2,000 cm3 of water, extracted with hexane, and washed with an aqueous EDA solution and ice. The hexane was removed, and the residue was distilled under reduced pressure (b. p. 143° C./6mmHg) to obtain 108 g (0.7 mol) of 4-amino-3,5-difluorobenzonitrile.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]([NH2:11])=O)=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CN(C)C=O.N>O>[CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]#[N:11])=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1
Reactant: Cc1[nH]c(=O)c(C(N)=O)cc1-c1ccc(N2CCC(c3ccccc3)CC2)cc1
Agent: N
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: CN(C)C=O
Product: Cc1[nH]c(=O)c(C#N)cc1-c1ccc(N2CCC(c3ccccc3)CC2)cc1
Temperature: 25 °C
Yield: 12.2 %

Procedure:
A mixture of 0.9 g (0.00232 mole) of 1,2-dihydro-6-methyl-2-oxo-5-[4-(4-phenyl-1-piperidinyl)phenyl]-3-pyridinecarboxamide, 1.8 g of P2O5, and 10 ml of dimethylformamide was refluxed for one hour, cooled to room temperature, and poured into 100 ml of water. The solution was adjusted to pH 6.7 with NH3 and the solid collected. After recrystallizing twice from MeOH (using charcoal treatment), 105 mg of a light brown solid was obtained. Approximately 80 mg of this solid was stirred overnight in 5 ml of saturated NaHCO3 (to which two drops of MeOH were added), then it was collected, washed, and dried. Sixty one mg of light brown solid was obtained.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.O[CH2:28][CH2:29][N:30]1[CH:34]=[CH:33][N:32]=[CH:31]1>>[N:30]1([CH2:29][CH2:28][O:24][C:21]2[CH:22]=[CH:23][C:18]([N:15]3[CH2:14][CH2:13][N:12]([C:9]4[CH:10]=[CH:11][C:6]5[N:7]([C:3]([C:2]([F:1])([F:25])[F:26])=[N:4][N:5]=5)[N:8]=4)[CH2:17][CH2:16]3)=[CH:19][CH:20]=2)[CH:34]=[CH:33][N:32]=[CH:31]1
Reactant: OCCn1ccnc1
Reactant: Oc1ccc(N2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Product: FC(F)(F)c1nnc2ccc(N3CCN(c4ccc(OCCn5ccnc5)cc4)CC3)nn12
Yield: 6 %

Procedure:
Obtained in 6% yield by an analogous method to Example 514, starting from 4-[4-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]phenol and 1-(2-hydroxyethyl)imidazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:5]([CH3:17])[CH:4]=1.C([Li])(CC)C.[CH3:23][C:24]([CH3:28])([CH3:27])[CH:25]=[O:26].Cl>O1CCCC1.O>[C:12]([O:11][C:10](=[O:16])[NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:17][CH:25]([OH:26])[C:24]([CH3:28])([CH3:27])[CH3:23])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)C=O
Reactant: COc1ccc(NC(=O)OC(C)(C)C)c(C)c1
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(NC(=O)OC(C)(C)C)c(CC(O)C(C)(C)C)c1
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl (4-methoxy-2-methylphenyl)carbamate (475 mg) in tetrahydrofuran (7 mL) was added dropwise sec-butyllithium (1.04 mol/L hexane-cyclohexane solution, 4.3 mL) at −40° C. under an argon atmosphere, and the mixture was stirred for 15 minutes. Then a solution of trimethylacetaldehyde (0.287 mL) in tetrahydrofuran (1 mL) was added dropwise, and the mixture was stirred at −40° C. for 15 minutes and at room temperature for additional one hour. Water and μmol/L hydrochloric acid were added to the reaction mixture and this resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (234 mg).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15].CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:23])([F:24])[C:3]1[CH:4]=[C:5]([CH:16]=[C:17]([C:19]([F:20])([F:22])[F:21])[CH:18]=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[O:15]
Reactant: OCCCCCCCOCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=CCCCCCCOCc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The above alcohol (1 g) was oxidised under Swern conditions (dimethyl sulphoxide (450 mg), oxalyl chloride (248 μl), triethylamine (1.58 ml)) in dichloromethane (25 ml) to give 7-(3,5-bistrifluoromethylbenzyloxy)heptan-1al. This was used directly in the next stage.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[Br:9][CH2:10][C:11](=O)[C:12](=O)[CH2:13][Br:14]>C1C=CC=CC=1>[Br:9][CH2:10][C:11]1[C:12]([CH2:13][Br:14])=[N:8][C:1]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:7]=1
Reactant: O=C(CBr)C(=O)CBr
Reactant: Nc1ccccc1N
Solvent: c1ccccc1
Product: BrCc1nc2ccccc2nc1CBr
Yield: 93 %

Procedure:
A mixture of 1,2-phenylenediamine (0.1 mole, 10.8 g) and 1,4-dibromo-2,3-butanedione (0.1 mole, 24.4 g) was refluxed in benzene (200 mL) using a Dean-Stark trap for one hour. The reaction mixture was then evaporated to dryness in vacuo and the residue flash chromatographed on silica gel (15:1). Elution with 15% hexane/chloroform afforded 29.38 g of 2,3-bis(bromomethyl)quinoxaline, m.p. 150°-151° C.; 1H NMR (CDCl3, 200 MHz): δ4.92 (s, 4H, CH2), 7.8 (m, 2H, ArH), 8.05 (m, 2H, ArH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[H-].[Na+].[Br:12][C:13]1[C:14]([CH3:24])=[N:15][C:16]2[N:17]([N:20]=[C:21]([CH3:23])[CH:22]=2)[C:18]=1Cl>O1CCCC1>[Br:12][C:13]1[C:14]([CH3:24])=[N:15][C:16]2[N:17]([N:20]=[C:21]([CH3:23])[CH:22]=2)[C:18]=1[O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: Cc1cc2nc(C)c(Br)c(Cl)n2n1
Reactant: Oc1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc2nc(C)c(Br)c(Oc3ccc(F)cc3F)n2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
A solution of 2,4-difluorophenol (0.156 mL, 0.960 mmol) in tetrahydrofuran (3.0 mL) was treated with sodium hydride (0.0242 g, 0.960 mmol) at 0° C. The resultant reaction mixture was warmed to RT and stirred at that temperature for 30 min. The reaction mixture was then cooled to 0° C., treated with 6-bromo-7-chloro-2,5-dimethylpyrazolo[1,5-a]pyrimidine (0.125 g, 0.480 mmol), warmed to RT and stirred at RT for 14 h. The reaction mixture was cooled to 0° C., quenched with saturated ammonium chloride solution, and diluted with ethyl acetate. Layers were separated and the organic layer was washed with water and brine, dried with sodium sulfate, filtered, and concentrated to give a crude residue. Purification by flash column chromatography (100% hexanes to 30% Et2O/hexanes) gave the desired product (162 mg, 95%) as a white solid. LCMS calculated for C14H11BrF2N3O (M+H)+: m/z=354.0, 356.0. found: 353.9, 356.0.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:40])[C@:7]1([O:35][C:36](=[O:39])[CH2:37][CH3:38])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C@@H:22]([O:26]C(=O)C(F)(F)F)[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:33])[CH2:17][CH2:18]2)[C@@H:13]([CH3:34])[CH2:12]3)[CH2:9][CH2:8]1)(=[O:3])[CH3:2].C(N(CC)CC)C>CO>[C:1]([O:4][CH2:5][C:6](=[O:40])[C@:7]1([O:35][C:36](=[O:39])[CH2:37][CH3:38])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C@@H:22]([OH:26])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:33])[CH2:17][CH2:18]2)[C@@H:13]([CH3:34])[CH2:12]3)[CH2:9][CH2:8]1)(=[O:3])[CH3:2]
Reactant: CCC(=O)O[C@]1(C(=O)COC(C)=O)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](OC(=O)C(F)(F)F)C[C@@]21C
Solvent: CCN(CC)CC
Solvent: CO
Product: CCC(=O)O[C@]1(C(=O)COC(C)=O)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Yield: 72.1 %

Procedure:
2.0 g of 21-acetoxy-6α-methyl-17-propionyloxy-11β-trifluoroacetoxy-4-pregnene-3,20-dione is agitated in 50 ml of methanol and 2.5 ml of triethylamine for 4 hours at room temperature. The crude product is purified on 300 g of silica gel with a methylene chloride-acetone gradient (0-15% acetone), thus isolating 1.2 g of 21-acetoxy-11β-hydroxy-6α-methyl-17-propionyloxy-4-pregnene-3,20-dione.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13]([O:15]CC)=[O:14].[OH-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)c1nc(-c2ccccc2)sc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1sc(-c2ccccc2)nc1C(=O)O
Yield: 112.8 %

Procedure:
0.8 g of ethyl 5-methyl-2-phenyl-1,3-thiazole-4-carboxylate was dissolved in 10 ml ethanol. 2 ml of 5N sodium hydroxide was added thereto, followed by heating under reflux for 1 hour. The reaction solution was ice-cooled and neutralized with 2N hydrochloric acid, followed by extracting with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated, to give 0.8 g of 5-methyl-2-phenyl-1,3-thiazole-4-carboxylic-acid.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:11]3[C:12](=[O:26])[N:13]([CH3:25])[C:14]([CH2:23][OH:24])=[C:15]([C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=4)[C:10]=3[C:9]3[CH2:27][O:28][CH2:29][CH2:30][C:8]2=3)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3[C:12](=[O:26])[N:13]([CH3:25])[C:14]([CH:23]=[O:24])=[C:15]([C:16]4[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=4)[C:10]=3[C:9]3[CH2:27][O:28][CH2:29][CH2:30][C:8]2=3)=[CH:31][CH:32]=1
Reactant: Cc1ccc(-c2c(CO)n(C)c(=O)c3c2c2c(n3Cc3ccc(F)cc3)CCOC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(-c2c(C=O)n(C)c(=O)c3c2c2c(n3Cc3ccc(F)cc3)CCOC2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 45.2 %

Procedure:
An ice cold suspension of 5-(4-fluorobenzyl)-8-(hydroxymethyl)-7-methyl-9-(p-tolyl)-3,4,5,7-tetrahydropyrano[3′,4′:4,5]pyrrolo[2,3-c]pyridin-6(1H)-one (333 mg, 0.770 mmol) and NaHCO3 (323 mg, 3.85 mmol) in Dichloromethane (DCM) (7700 μl) was treated with DMP (653 mg, 1.540 mmol). Upon complete addition of the DMP the cooling bath was removed. After 2 h, the reaction mixture was quenched by the addition of sat. aq. Na2S2O3 and the mixture was stirred for 10 min. EtOAc was added and the layers partitioned. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by ISCO (0-50% EtOAc-hexanes) to afford 5-(4-fluorobenzyl)-7-methyl-6-oxo-9-(p-tolyl)-1,3,4,5,6,7-hexahydropyrano[3′,4′:4,5]pyrrolo[2,3-c]pyridine-8-carbaldehyde (150 mg, 0.348 mmol, 45.3% yield). LCMS (m/z) ES+=431 (M+1).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.CN(C1C=CC=CN=1)C.[NH2:50][CH:51]([CH:60]([OH:63])[CH2:61][F:62])[CH2:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54]>C1COCC1>[C:1]([NH:11][C@H:12]([C:16]([NH:50][CH:51]([CH:60]([OH:63])[CH2:61][F:62])[CH2:52][C:53]([O:55][C:56]([CH3:57])([CH3:58])[CH3:59])=[O:54])=[O:18])[CH:13]([CH3:14])[CH3:15])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)CC(N)C(O)CF
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Reaction time: 0.08 h
Yield: 63.3 %

Procedure:
To a solution of Cbz-Valine (396 mg, 1.58 mmol) in THF (20 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (300 mg, 1.57 mmol), 1-hydroxybenzotriazole hydrate (HOBT) (240 mg, 1.57 mmol) and dimethylaminopyridine (DMAP) 129 mg 1.06 mmol). The resulting mixture was stirred for 5 min, then was added a solution of t-butyl 3-amino-5-fluoro-4-hydroxy-pentanoate (215 mg, 1.04 mmol) in THF (10 mL) and it was stirred at rt for 18 h. The mixture was filtered and the THF solution was evaporated, and the residue was purified by chromatography over silica gel (hexane-EtOAc, 3:2) to give 290 mg (68%) of the titled compound as a white solid. 1HNMR (CDCl3), 0.905 (d, 3H, J=7), 0.965 (d, 3H, J=7), 1.428 (s, 9H), 2.07-2.16 (m, 1H), 2.50-2.57 (m, 1H), 2.64-2.70 (m, 1H), 3.52 (bs, 1H, OH), 3.92-3.96 (m, 2H), 4.20-4.27 (m, 1H), 4.40 (bs, 1H), 4.49 (bs, 1H), 5.10 (s, 2H), 5.31-5.4 (m, 1H, NH), 6.86-6.93 (m, 1H, NH), 7.350(s, 5H).
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH2:14]Br)=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9]C)=O)([O-:3])=[O:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:27]([O:34][C:35](=[O:50])[C@H:36]([CH2:38][CH2:39][C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41])[NH2:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[CH2:27]([O:34][C:35]([CH:36]([N:37]1[CH2:14][C:5]2[C:6](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[C:7]1=[O:9])[CH2:38][CH2:39][C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41])=[O:50])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1CBr
Reactant: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCC(C(=O)OCc1ccccc1)N1Cc2c(cccc2[N+](=O)[O-])C1=O)OCc1ccccc1
Yield: 59.5 %

Procedure:
A mixture of methyl 3-nitro-2-(bromomethyl)benzoate (2.5 g, 9.12 mmol), L-glutamic acid dibenzyl ester p-toluenesulfonate salt (3.0 g, 9.12 mmol) and triethylamine (2.0 g, 20.0 mmol) in THF (50 mL) is heated at reflux for 16 hours. The mixture is diluted with methylene chloride (150 mL) and washed with water (2×40 mL), brine (40 mL), dried and concentrated to an oil. The oil is purified by chromatography (silica gel, Hexane:ethoxyacetic acid 7:3) to give 1-(4-nitro-1-oxoisoindolin-2-yl)propane-1,3-dicarboxylic acid dibenzyl ester (2.65 g, 59%); 1H NMR (CDCl3) δ8.39 (d, J=7.8 Hz, 1H), 8.16 (d, J=7.3 Hz, 1H), 7.69 (t, J=7.9 Hz, 1H), 7.30 (m, 10H), 5.29 (s, 2H), 5.29-5.13 (m, 1H), 5.03 (s, 2H), 4.98 (d, J=19.1 Hz, 1H), 4.85 (d, J=19.2 Hz, 1H), 2.54-2.39 (m, 4H); 13C NMR (CDCl3) δ171.79, 169.92, 166.72, 143.47, 137.25, 135.49, 135.04, 134.99, 130.17, 129.67, 128.62, 128.52, 128.29, 128.25, 128.23, 127.04, 67.49, 66.58, 53.70, 48.35, 30.87, 24.79.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][OH:10])[CH:3]=1.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](Br)([F:20])[F:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CC(O)C>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[CH2:9][OH:10])=[CH:14][CH:13]=1
Reactant: FC(F)(Br)c1ccc(Br)cc1
Reactant: OCc1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: OCc1cc(F)ccc1OC(F)(F)c1ccc(Br)cc1
Yield: 35.8 %

Procedure:
A suspension of 1.17 g (8.23 mmol) of 4-fluoro-2-(hydroxymethyl)phenol from Example 34A, 2.59 g (12.63 mmol) of 1-bromo-4-[bromo(difluoro)methyl]benzene from Example 33A and 1.25 g (9.06 mmol) of potassium carbonate in 10 ml of 2-propanol is heated to reflux for 12 hours. The mixture is then concentrated to dryness. The residue is suspended in methylene chloride, absorbed on silica gel, dried in vacuo and purified by chromatography (mobile phase: cyclohexane/ethyl acetate 10:1, then 100% ethyl acetate). 1.02 g (2.95 mmol, 35% yield) of the title compound are obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:31]([Cl:34])=[CH:32][N:33]=1)[C:5]([NH:7][C:8]1[CH:30]=[CH:29][C:11]2[CH2:12][CH2:13][C:14]3[C:15]([C:26]([NH2:28])=[O:27])=[N:16][N:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[C:18]=3[C:10]=2[CH:9]=1)=[O:6].[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][NH:39][CH3:40]>>[Cl:34][C:31]1[C:4]([C:5]([NH:7][C:8]2[CH:30]=[CH:29][C:11]3[CH2:12][CH2:13][C:14]4[C:15]([C:26]([NH2:28])=[O:27])=[N:16][N:17]([C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=5)[C:18]=4[C:10]=3[CH:9]=2)=[O:6])=[CH:3][C:2]([N:39]([CH2:38][CH2:37][N:36]([CH3:41])[CH3:35])[CH3:40])=[N:33][CH:32]=1
Reactant: CNCCN(C)C
Reactant: NC(=O)c1nn(-c2ccc(F)cc2)c2c1CCc1ccc(NC(=O)c3cc(Cl)ncc3Cl)cc1-2
Product: CN(C)CCN(C)c1cc(C(=O)Nc2ccc3c(c2)-c2c(c(C(N)=O)nn2-c2ccc(F)cc2)CC3)c(Cl)cn1
Reaction time: 24 h
Yield: 47.1 %

Procedure:
The title compound was synthesized by the same procedure as in Example 214 starting with the title compound of Example 248 (0.8 g, 0.0016 mol) and N,N,N′-trimethylethylene diamine (3.3 g, 0.032 mol). The reaction was run at 100° C. for 24 h. After removal of the volatiles under vacuum, the residue was partitioned between water and CH2Cl2. The organic layer was washed an additional time with water and dried over MgSO4. The crude product mixture was purified by preparative HPLC to give 0.424 g of the title product, yield: 47%. 1H NMR (400 MHz, d6-DMSO): 2.13 (s, 6H), 2.34 (t, 2H, J=6.7 Hz), 2.87-2.95 (m, 4H), 2.96 (s, 3H), 3.59 (t, 2H, J=6.7 Hz), 6.58 (s, 1H), 7.2 (d, 1H, J=2 Hz), 7.27 (s, 1H), 7.29-7.37 (m, 3H), 7.41-7.44 (dd, 1H, J=8 Hz, 2 Hz), 7.53-7.58 (m, 3H), 8.13 (s, 1H), 10.36 (s, 1H). M+1=563.
Reaction SMILES: [CH:1]1([N:4]2[CH2:13][C:12]([CH3:15])([CH3:14])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH2:16][OH:17])[CH:10]=3)[CH2:5]2)[CH2:3][CH2:2]1.C[N+]1([O-])CCOCC1.C(OCC)(=O)C>ClCCl.C(#N)C.CCCCCC.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH:1]1([N:4]2[CH2:13][C:12]([CH3:14])([CH3:15])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH:16]=[O:17])[CH:10]=3)[CH2:5]2)[CH2:3][CH2:2]1
Reactant: CC1(C)CN(C2CC2)Cc2ccc(CO)cc21
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: CCCCCC
Solvent: ClCCl
Product: CC1(C)CN(C2CC2)Cc2ccc(C=O)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
A solution of 2-cyclopropyl-6-hydroxymethyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline (Intermediate 24, 0.74 g, 3.2 mmol) in dichloromethane (10 mL) and acetonitrile (2.5 mL) was treated sequentially with 4 A0 molecular sieves powder (1.06 g), tetra-n-propyl ammonium perruthenate (0.050 g, 0.14 mmol) and N-methyl morpholine N-oxide (1.1 g, 9.8 mmol). After stirring at ambient temperature for 0.5 h, it was diluted with 5 mL of hexane and subjected to flash column chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent to afford the title compound as an oil (0.27 g, 37%).