Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][S:7][C:8]1[N:13]=[C:12]([NH2:14])[C:11]([NH2:15])=[C:10]([NH2:16])[N:9]=1.O.O.[Cl-:19].[Ba+2].[Cl-].C1(C)C=CC=CC=1>O>[ClH:19].[ClH:19].[NH2:16][C:10]1[C:11]([NH2:15])=[C:12]([NH2:14])[N:13]=[C:8]([S:7][CH3:6])[N:9]=1
Reactant: [Cl-]
Agent: CSc1nc(N)c(N)c(N)n1
Agent: O=S(=O)(O)O
Agent: [Ba+2]
Solvent: Cc1ccccc1
Solvent: O
Product: Cl
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a suspension of a 2-methylmercapto-4,5,6-triamino-pyrimidine sulfate (44.3 mmole), which may be prepared and characterised for instance as disclosed by Taylor et al. in J. Am. Chem. Soc. (1952) 74:1644-1647, in water (135 ml) at 80° C. was added dropwise a solution of barium chloride dihydrate (39.8 mmole) in water (25 ml). The suspension was stirred for 30 minutes at 80° C. The reaction mixture was cooled down and barium sulfate was filtered off over Celite. The filtrate was evaporated in vacuo and co-evaporated with toluene yielding the title compound as a yellow powder (10.2 g, 94% yield).
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[CH:7]([CH2:10][CH3:11])[C:6](=O)[NH:5][C:4]1=[S:13])[CH3:2].P(Cl)(Cl)([Cl:16])=O>O>[CH2:1]([N:3]1[C:8](=[O:9])[C:7]([CH2:10][CH3:11])=[C:6]([Cl:16])[NH:5][C:4]1=[S:13])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCC1C(=O)NC(=S)N(CC)C1=O
Solvent: O
Product: CCc1c(Cl)[nH]c(=S)n(CC)c1=O
Yield: 70 %

Procedure:
10 G. OF 3,5-DIETHYL-2-THIOBARBITURIC ACID IS CHLORINATED, AFTER THE ADDITION OF A FEW DROPS OF WATER, WITH EXCESS PHOSPHORUS OXYCHLORIDE (APPROXIMATELY 100 ML.) UNDER HEATING FOR 3/4 HOUR. The excess phosphorus oxychloride is distilled off, and the residue is poured on ice. The desired reaction product is crystallized during this step and melts, after recrystallization from aqueous ethanol, completely at 228° C. Yield: 70%
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=2)[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([NH:23]C(=O)C)=[CH:19][CH:18]=2)[C:3]=1[C:27]#[N:28].Cl>C(O)C.O>[NH2:1][C:2]1[C:3]([C:27]#[N:28])=[C:4]([C:17]2[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=2)[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=2)[N:7]=1
Reactant: CC(=O)Nc1ccc(-c2nc(SCc3cccc(C)n3)nc(N)c2C#N)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cccc(CSc2nc(N)c(C#N)c(-c3ccc(N)cc3)n2)n1
Temperature: 80 °C
Yield: 46.9 %

Procedure:
The compound (5.5 g) of Example 2 was suspended in a mixture of 50 mL of ethanol and 50 mL of water, and to the suspension was added 50 mL of 5N hydrochloric acid, and the resulting mixture was heated at 80° C. for 5 hours under stirring. After cooling the reaction mixture, the ethanol was removed under reduced pressure, and the residue was neutralized with 5N aqueous sodium hydroxide at ice temperature. The resulting crystal was filtrated, and recrystallized with ethanol to give 2.3 g of 4-amino-6-(4-aminophenyl)-2-(6-methylpyridin-2-ylmethylsulfanyl)-pyrimidine-5-carbonitrile as a light yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9][CH:10]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:11][NH:12]C(=O)OC(C)(C)C>Cl.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9][CH:10]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:11][NH2:12]
Reactant: CC(C)(C)OC(=O)NCC(Sc1cc(Cl)ccc1Cl)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: NCC(Sc1cc(Cl)ccc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 142.8 %

Procedure:
The product from step (b) (0.4 g) was dissolved in 4M HCl in dioxane (5 ml). The resulting solution was stirred at room temperature for 6 h, the solvent was evaporated and the residue triturated with ethyl acetate to give of the title compound (0.24 g) as, a white solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:10]=2)O1.Br[CH2:26][C:27]1[CH:28]=[N:29][C:30]([S:33][CH3:34])=[N:31][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1COCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[CH3:34][S:33][C:30]1[N:31]=[CH:32][C:27]([CH2:26][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:10]=2)=[CH:28][N:29]=1
Reactant: CSc1ncc(CBr)cn1
Reactant: CCOC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c2ccccc2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(Cc2cnc(SC)nc2)c2ccccc2n1
Temperature: 77 °C

Procedure:
In a microwave vial containing ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-2-carboxylate (K4) (0.15 g, 0.46 mmol), 5-(bromomethyl)-2-(methylsulfanyl)pyrimidine (N3) (0.12 g, 0.55 mmol), cesium carbonate (0.45 g, 1.4 mmol), and PdCl2(dppf)-CH2Cl2 adduct (0.037 g, 0.05 mmol) was added 4.1 mL THF and 0.41 mL water. The reaction mixture was heated to 77° C. for 1 h. The reaction mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered, and concentrated. The resultant residue was subjected to silica gel chromatography eluting with 0-70% ethyl acetate in hexanes to afford ethyl 4-{[2-(methylsulfanyl)pyrimidin-5-yl]methyl}quinoline-2-carboxylate (N4) that gave a mass ion (ES+) of 340.3 for M+H+. The above compound was converted to the titled compound by the procedure described in Example 11 that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 411.1481 for M+H30 . 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 2H), 8.37 (d, J=6.4 Hz, 1H), 8.19 (d, J=8.2 Hz, 1H), 8.14 (s, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.84-7.80 (m, 1H), 7.70-7.66 (m, 1H), 4.44 (s, 2H), 4.13 (dd, J=4.9, 11.2 Hz, 1H), 4.08-4.00 (m, 2H), 3.77-3.71 (m, 1H), 3.55-3.49 (m, 1H), 3.30-3.25 (m, 1H), 2.54 (s, 3H), 2.15-2.11 (m, 1H) 1.95-1.85 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:16])[CH2:11][CH2:10]2)[CH:4]=1)#[N:2].C[Si]([N:27]=[N+:28]=[N-:29])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[NH:27]1[C:1]([C:3]2[CH:8]=[CH:7][N:6]=[C:5]([N:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:16])[CH2:13][CH2:14]3)[CH:4]=2)=[N:2][N:29]=[N:28]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)(C)COC(=O)N1CCN(c2cc(C#N)ccn2)CC1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)COC(=O)N1CCN(c2cc(-c3nnn[nH]3)ccn2)CC1

Procedure:
2,2-Dimethylpropyl 4-(4-cyanopyridin-2-yl)piperazine-1-carboxylate (120 mg) obtained in Example 2 was dissolved in toluene (5 mL), and trimethylsilylazide (0.105 mL) and a catalytic amount of dibutyltin (IV) oxide were added thereto and heated under reflux for 8 hours. The solvent was evaporated away, and the resulting residue was isolated and purified through thin-layer silica gel chromatography (chloroform/methanol=9/1) to obtain 16.5 mg of the entitled compound as a colorless solid.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[S:21][C:20]3[CH:22]=[C:23]([C:26](O)=[O:27])[CH:24]=[CH:25][C:19]=3[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29].C(Cl)CCl.Cl.C[O:39][C:40](=[O:43])[CH2:41][NH2:42]>CN(C1C=CN=CC=1)C>[CH3:32][C:2]([CH3:1])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[S:21][C:20]3[CH:22]=[C:23]([C:26]([NH:42][CH2:41][C:40]([OH:39])=[O:43])=[O:27])[CH:24]=[CH:25][C:19]=3[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29]
Reactant: COC(=O)CN
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2ccc(C(=O)O)cc2s1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2ccc(C(=O)NCC(=O)O)cc2s1
Yield: 91.3 %

Procedure:
2-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzo[b]thiophene-6-carboxylic acid (175 mg, 0.387 mmol), DMAP (142 mg, 1.16 mmol), EDC (111 mg, 0.580 mmol), and glycine methyl ester hydrochloride (73 mg, 0.580 mmol) are reacted and hydrolyzed in a sequence analogous to Example 5 to afford the title compound (180 mg, 91%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([CH2:12][N+:13]([O-:15])=[O:14])=O.C([O-])(=O)C.[NH4+:20]>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9]/[C:10](/[NH2:20])=[CH:12]/[N+:13]([O-:15])=[O:14]
Reactant: [NH4+]
Reactant: O=C(Cc1ccc(F)cc1F)C[N+](=O)[O-]
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Product: N/C(=C\[N+](=O)[O-])Cc1ccc(F)cc1F

Procedure:
The mixture of 1-(2,4-difluorophenyl)-3-nitroacetone (9.4 g, 43.7 mmol) and ammonium acetate (16.8 g, 219 mmol) in 250 ml benzene was refluxed with Dean-Stark setup for 5 hours. The reaction mixture was then partitioned between ether and water. The organic portion was washed with brine and dried over sodium sulfate. Removing the solvent afforded 8.5 g light brown solid. 1H-NMR (400 MHz, CD3OD) δ 7.20 (m, 1H), 6.84 (m, 3H), 3.65 (s, 2H) ppm. ESI-MS m/z 215 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>CN(C=O)C.O>[CH2:1]([O:8][CH2:9][C:10](=[O:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)COCc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)COCc1ccccc1
Temperature: 65 °C
Reaction time: 3 h
Yield: 78.7 %

Procedure:
3-Benzyoxypropan-2-ol 16 (40 g, 0.24 mol) was added to a suspension of pyridinium chlorochromate (155.2 g, 0.72 mol) in DMF (150 ml) at 25° C., stirred at 65° C. for 3 h, and then diluted with water (75 mL) (Step 14). The mixture was extracted with ether (2×50 mL) and the combined ether layers were washed with water (3×50 mL) dried (MgSO4) and the solvent removed by roto-evaporation. Distillation gave 31 g (77%) of 3-benzyloxypropan-2-one; 17 bp 104-106 (10 mm). 1H NMR (CDCl3) δ 2.16 (s, 3H, CH3), 4.05 (s, 1H, OH), 4.59 (s, 2H, OCH2), 7.5 (s, 5H, phenyl).
Reaction SMILES: [CH2:1]([Si:3]([CH2:7][CH3:8])([CH2:5][CH3:6])Cl)[CH3:2].[O:9]1[CH2:13][CH2:12][NH:11][C:10]1=[O:14]>>[CH2:1]([Si:3]([CH2:7][CH3:8])([CH2:5][CH3:6])[N:11]1[CH2:12][CH2:13][O:9][C:10]1=[O:14])[CH3:2]
Reactant: CC[Si](Cl)(CC)CC
Reactant: O=C1NCCO1
Product: CC[Si](CC)(CC)N1CCOC1=O

Procedure:
Following the previous example, but replacing the trimethylchlorosilane with triethylchlorosilane (63.3 g; 0.42 mol) and operating under similar conditions, the result is the compound of the above heading; a colourless fluid liquid, obtained with a similar yield. 2-oxazolidinone, calculated: 42.82%; found: 42.70%. Distils at 100° C between 2 and 4 mm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[Br:13]N1C(=O)CCC1=O>ClCCl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:12][Br:13])[C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ncc(Br)cc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Product: COC(=O)c1ncc(Br)cc1CBr
Yield: 96.4 %

Procedure:
Methyl 5-bromo-3-methylpicolinate (800 mg) in dichloromethane (5 mL) was treated with N-bromosuccinimide (619 mg) and AIBN (14.28 mg). The mixture was stirred and irradiated with a 500 W halogen lamp for 3.5 h. The reaction mixture was cooled and diluted with dichloromethane, and washed with water. The organic layer was dried over magnesium sulfate, filtered and evaporated to afford the sub-titled compound (1036 mg).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:47])[CH2:25][C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:37]=[C:36]([CH2:38][O:39]C3CCCCO3)[O:35][N:34]=2)[CH:28]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:39][CH2:38][C:36]1[O:35][N:34]=[C:33]([C:29]2[CH:28]=[C:27]([C:26]3[CH2:25][C:24](=[O:47])[NH:23][C:9]4[CH:10]=[C:11]([C:19]([F:21])([F:22])[F:20])[C:12]([N:14]5[CH2:15][CH2:16][CH2:17][CH2:18]5)=[CH:13][C:8]=4[N:7]=3)[CH:32]=[CH:31][CH:30]=2)[CH:37]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cc(COC3CCCCO3)on2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3cc(CO)on3)c2)=Nc2cc(N3CCCC3)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from (RS)-[2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-3-yl]-phenyl}-propionylamino)-5-pyrrolidin-1-yl-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example M51) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (224 mg).
Reaction SMILES: C(OC([C:6]1[N:7]=C[O:9][C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([F:19])[CH:13]=1)=O)C.Cl>>[ClH:18].[NH2:7][CH2:6][C:10](=[O:9])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([F:19])[CH:13]=1
Reactant: CCOC(=O)c1ncoc1Cc1ccc(Cl)c(F)c1
Agent: Cl
Product: NCC(=O)Cc1ccc(Cl)c(F)c1
Temperature: 25 °C
Yield: 135.6 %

Procedure:
A mixture of the product of example 25 (2.5 g, 10.53 mmol) with hydrochloride acid (6 mol/1, 30 ml) was refluxed for about 3 hours and then cooled to room temperature. The solids were collected by filtration, washed with EA and dried to give the titled product (1.7 g, 81%)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8]/[C:9](=[CH:14]\[C:15]([CH3:18])([CH3:17])[CH3:16])/[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCOCC1.[H][H]>C(O)C>[CH3:13][O:12][C:10](=[O:11])[C@@H:9]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: [H][H]
Reactant: COC(=O)/C(=C/C(C)(C)C)NC(=O)OC(C)(C)C
Solvent: C1COCCO1
Solvent: CCO
Product: COC(=O)[C@@H](CC(C)(C)C)NC(=O)OC(C)(C)C

Procedure:
Methyl (2Z)-2-[(tert-butoxycarbonyl)amino]-4,4-dimethylpent-2-enoate (example 4A, 60 g, 233.2 mmol) is dissolved in ethanol p.a./dioxane 3:1 (1000 ml). An argon protective gas atmosphere is passed through with a needle (˜10 min). The solution is placed in an ultrasonic bath (about 5 min) and (+)-1,2-bis[(2R,5R)-diethylphospholano]benzene(cyclooctadiene)rhodium(I) triflate (600 mg, 1% by weight) is added. The mixture is hydrogenated under a pressure of 3.5 bar of hydrogen and at RT for 3 days. The reaction mixture is filtered through kieselguhr, and the eluate is concentrated. The crude product is chromatographed (silica gel, eluent: cyclohexane/ethyl acetate 4:1). 60 g (99% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[C:25]=3[CH3:33])=[CH:18][CH:17]=2)=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].CCN(C(C)C)C(C)C.Br[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[F:51]>CN(C)C=O.CCOCC>[Cl:1][C:2]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][N:23]([CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[F:51])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[C:25]=3[CH3:33])=[CH:20][CH:21]=2)=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: Fc1ccccc1CBr
Reactant: CCOC(=O)COc1cc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)ccc1Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)COc1cc(Oc2ccc(CN(Cc3ccccc3F)c3cccc([N+](=O)[O-])c3C)cc2)ccc1Cl
Temperature: 90 °C

Procedure:
The product from Example 306A (86 mg, 0.18 mmoles) in anhydrous dimethylformamide (1 mL) was treated with Hunig's base (0.107 mL, 0.5 mmoles) and 1-(bromomethyl)-2-fluorobenzene (0.198 mL, 0.9 mmoles) in anhydrous dimethylformamide (1 mL) and heated at 90° C. for 72 hours. The reaction was diluted with ether, washed with saturated NH4Cl, water, brine, dried (Na2SO4), filtered, and filtrate concentrated under reduced pressure. The residue purified by using ethyl acetate and hexane gradient on 10 g silica column to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:22])[C:3]=1C(OC)=O.C(C1(CCCC)C2C(=CC=CC=2)C(O)=C(C(OCC)=O)C1=O)CCC>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])([CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])[C:4](=[O:22])[CH:3]=1
Reactant: COC(=O)C1=C(O)c2ccccc2C(CCC(C)C)(CCC(C)C)C1=O
Agent: CCCCC1(CCCC)C(=O)C(C(=O)OCC)=C(O)c2ccccc21
Product: CC(C)CCC1(CCC(C)C)C(=O)C=C(O)c2ccccc21

Procedure:
The title compound was prepared according the procedure of Example 5B, substituting the product of Example 6F for the product of Example 4F. 1H NMR (300 MHz, CDCl3): δ 0.44 (m, 2 H) 0.73 (m, 14 H) 1.32 (m, 2 H) 1.94 (m, 2 H) 2.30 (m, 2 H) 7.49 (t, J=7.54 Hz, 2 H) 7.72 (m, 1 H) 8.26 (m, 1 H) 15.77, 15.72 (two s, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][C:24]2[CH:29]=[C:28]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[CH:27]=[CH:26][C:25]=2[NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:22])=[CH:17][CH:16]=1)[C:10]([O:12]CC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.O.Cl>[C:1]([O:5][C:6]([NH:8][CH:9]([C:15]1[CH:16]=[CH:17][C:18]([C:21]([NH:23][C:24]2[CH:29]=[C:28]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[CH:27]=[CH:26][C:25]=2[NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:22])=[CH:19][CH:20]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)c1ccc(C(=O)Nc2cc(-c3cccs3)ccc2NC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(C(NC(=O)OC(C)(C)C)C(=O)O)cc1

Procedure:
Ethyl [(tert-butoxycarbonyl)amino][4-({[2-[(tert-butoxycarbonyl)amino]-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]acetate (1.08 g, 1.813 mmol) and 1N lithium hydroxide (3.99 mL, 3.99 mmol) were stirred in THF (16 mL) at room temperature for 2 days. The reaction was diluted with water, 2 mL of 2N HCl was added and the products extracted into EtOAc. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo to give the desired product as a pale yellow powder. 1H NMR (DMSO-d6, 600 MHz) δ 12.90 (br s, 1H), 9.90 (s, 1H), 8.72 (s, 1H), 7.94 (d, J=8.4 Hz, 2H), 7.81 (d, J=1.2 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.51 (m, 2H), 7.44 (d, J=3.6 Hz, 1H), 7.12 (dd, J=5.1 and 3.6 Hz, 1H), 5.23 (d, J=8.4 Hz, 1H), 1.45 (s, 9H), 1.39 (s, 9H). MS: cal'd 568 (MH+), exp 412, 456, 468 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:32])[C@@H:4]([OH:31])[CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)=[CH:11][CH:10]=1)=[O:8].[OH-].[Na+].OS([O-])(=O)=O.[K+]>C(O)C>[C:24]([N:21]1[CH2:22][CH2:23][CH:18]([CH2:17][CH2:16][O:15][C:12]2[CH:11]=[CH:10][C:9]([C:7]([NH:6][CH2:5][C@H:4]([OH:31])[C:3]([OH:32])=[O:2])=[O:8])=[CH:14][CH:13]=2)[CH2:19][CH2:20]1)([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25]
Reactant: COC(=O)[C@@H](O)CNC(=O)c1ccc(OCCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(C(=O)NC[C@H](O)C(=O)O)cc2)CC1
Yield: 103.1 %

Procedure:
A solution of 17-2 (45 mg, 0.10 mmol), 1N NaOH (400 L), and ethanol (500 μl) was stirred at ambient temperature for 1.0 h. The reaction was acidified with 10% KHSO4 and then extracted with EtOAc. The EtOAc portion was washed with brine, dried (MGSO4), and concentrated to give 17-3 (45 mg) as a white solid. Rf 0.26 (silica, 10:1:1 CH2Cl2 /CH3OH/AcOH).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[C:30](Cl)(=[O:33])[O:31][CH3:32]>C(Cl)Cl>[F:20][C:2]([F:19])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][N:10]2[C:30]([O:31][CH3:32])=[O:33])=[CH:7][CH:8]=1
Reactant: COC(=O)C1CCNC(c2ccc(C(F)(F)F)cc2)C1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 101.2 %

Procedure:
Methyl 2-(4-(trifluoromethyl)phenyl)piperidine-4-carboxylate (4.973 g, 17.31 mmol) was dissolved in DCM (100 mL) and DIPEA (3.62 mL, 20.77 mmol) added followed by methyl carbonochloridate (1.636 mL, 20.77 mmol). The solution was stirred at room temperature for 1 h 45 min. The reaction mixture was washed with 0.1 M HCl and satd NaHCO3. The organic phase was passed through a phase separator and evaporated to yield crude dimethyl 2-(4-(trifluoromethyl)phenyl)piperidine-1,4-dicarboxylate (6.05 g, 101%) as a brown oil. MS m/z 346 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17]C[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:18][C:19]3[C:24](=[O:25])[N:23]([CH3:26])[CH:22]=[C:21](C4C=C(F)C=C(N5CCN6C7CCCCC=7C=C6C5=O)C=4COC(=O)C)[N:20]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].NC1C=C2C(=CC=1)CN(C(OC(C)(C)C)=O)C2.[Br:70]C1C(=O)N(C)C=C(Br)N=1>>[Br:70][C:21]1[N:20]=[C:19]([NH:18][C:13]2[CH:12]=[C:11]3[C:10](=[CH:15][CH:14]=2)[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:17]3)[C:24](=[O:25])[N:23]([CH3:26])[CH:22]=1
Reactant: Cn1cc(Br)nc(Br)c1=O
Reactant: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3ccc4c(c3)CCN(C(=O)OC(C)(C)C)C4)n2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: CC(C)(C)OC(=O)N1Cc2ccc(N)cc2C1
Product: Cn1cc(Br)nc(Nc2ccc3c(c2)CN(C(=O)OC(C)(C)C)C3)c1=O

Procedure:
Following the procedures as described for 129a and starting with 600 mg of tert-butyl 5-aminoisoindoline-2-carboxylate (231c) and 685 mg of 3,5-dibromo-1-methylpyrazin-2(1H)-one, 231d was obtained as a yellow solid (732 mg, 68%). MS: [M+H]+ 421.
Reaction SMILES: [H-].[Na+:2].[P:3]([O-:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[C:11]1([CH2:17][O:18][CH2:19][C@:20]2([O:42][C@H:41]([CH2:43][O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C@@H:32]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@@H:23]2[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:21]O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCCCCC>O1CCCC1.O.CCOCC>[P:3]([O-:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[Na+:2].[CH2:5]([O:4][P:3]([O:7][CH2:8][CH3:9])([CH2:21][C@:20]1([CH2:19][O:18][CH2:17][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[O:42][C@H:41]([CH2:43][O:44][CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C@@H:32]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@@H:23]1[O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:10])[CH3:6]
Reactant: OC[C@]1(COCc2ccccc2)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: CCOP([O-])OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOP(=O)(C[C@]1(COCc2ccccc2)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1)OCC
Temperature: 45 °C
Reaction time: 1.5 h

Procedure:
A fresh solution of sodium diethyl phosphite was prepared from sodium hydride and diethyl phosphite in tetrahydrofuran at a concentration of 2 milliequivalents/ml and added, as described below, to a solution of 260 mg of 2,5-anhydro-2-C-[(phenylmethoxy)methyl]-3,4,6-tris-O-(phenylmethyl)-D-glucitol, 1-(trifluoromethanesulfonate) in 1 ml of tetrahydrofuran. A 0.5 ml portion of the stock solution was added and the mixture stirred 1.5 hours; 0.25 ml was added and stirring continued for 2.5 hours; 0.22 ml was added, the mixture warmed to 45° C. for 20 minutes then cooled to room temperature. The mixture was worked up with hexane, ether and water, giving an oil. This oil was purified by flash chromatography, eluting with 1% methanol in dichloromethane, giving 203 mg of the desired compound.