Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([C:19]([NH:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[O:20])[C:10]1=[O:30]>>[CH3:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])[C:10]1=[O:30]
Reactant: Cn1c(=O)c(C(=O)NCC(=O)OC(C)(C)C)cc2ccccc21
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)c(C(=O)NCC(=O)O)cc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 29 %

Procedure:
Trifluoroacetic acid (1.00 ml, 13 mmol) was added to tert-butyl 2-(1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetate (0.021 g, 0.07 mmol) and stirred at room temperature for 15 minutes. Trifluoroacetic acid was removed under vacuum and the resulting solids were washed with water (3×), ether (3×) and dried in a vacuum oven at 50° C. to afford 2-(1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetic acid in 29% yield.
Reaction SMILES: [CH:1]1[N:5]([CH2:6][O:7][CH2:8][CH2:9][OH:10])[C:4]2[N:11]=[C:12]([NH2:16])[N:13]=[C:14]([OH:15])[C:3]=2[N:2]=1.CN(C)C=O.[C:22](Cl)(=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26]>CN(C)C1C=CN=CC=1.CO.O>[C:22]([O:10][CH2:9][CH2:8][O:7][CH2:6][N:5]1[CH:1]=[N:2][C:3]2[C:14](=[O:15])[NH:13][C:12]([NH2:16])=[N:11][C:4]1=2)(=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCC(=O)Cl
Reactant: Nc1nc(O)c2ncn(COCCO)c2n1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(=O)OCCOCn1cnc2c(=O)[nH]c(N)nc21
Temperature: 5 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
A mixture of acyclovir prepared according to UK Patent No. 1523865 (3.11 moles), 4-dimethylaminopyridine (4.91 moles) and dimethylformamide (5.6 L) was stirred under nitrogen with heating on steam bath to give a homogeneous solution. On cooling to room temperature valeryl chloride (4.91 moles) was added dropwise while the temperature was maintained at 20°-25° C. Progress of the reaction was monitored by HPLC (Partisil ODS-3, methanol:water 50:50) and the reaction was terminated when the level of residual acyclovir was less than 0.5% (AUC). The mixture was cooled to 5° C., filtered and the cake was washed with dimethylformamide (200 ml). The combined filtrates were diluted with absolute ethanol (1 L), stirred for two hours at ambient temperature and concentrated to a thick oil. Methanol (16 L) was added and the resulting suspension was refluxed for 1.5 hours, cooled to 5° C. and filtered. The crude product was washed with methanol (200 mL) and dried under vacuum to constant weight to give 819 g (85.1% yield) of 9-(2-valeryloxyethoxymethyl) guanine, M.p. 215°-217° C.
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][C:5]=2[S:4][CH:3]=1.CCOCC.C([Li])CCC.[C:29]1(=[O:33])[CH2:32][CH2:31][CH2:30]1>O.CCCCCC>[O:10]1[C:11]2[C:2]([C:29]3([OH:33])[CH2:32][CH2:31][CH2:30]3)=[CH:3][S:4][C:5]=2[CH2:6][NH:7][CH2:8][CH2:9]1
Reactant: O=C1CCC1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)csc2C1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: OC1(c2csc3c2OCCNC3)CCC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 58.5 %

Procedure:
To a solution of tert-butyl 8-bromo-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (334 mg) obtained in Example 1, steps 1-3, and Et2O (10 mL) was added dropwise 1.6 N hexane solution of n-butyllithium (72.4 ml) at −78° C., and the mixture was stirred at −78° C. for 15 min. Cyclobutanone (0.0747 ml) was added, and the mixture was stirred at −78° C. for 1 hr. To the reaction mixture was added water (10 mL), and the organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent gradient; 0→50% ethyl acetate/hexane) to give the title compound (190 mg, 58.5%) as an oil.
Reaction SMILES: [CH:1]1([NH:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([OH:17])=[C:9]([C:18]3[NH:23][C:22]4[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:21]=4[S:20](=[O:30])(=[O:29])[N:19]=3)[C:8]2=[O:31])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:39][C:40]([NH2:42])=[O:41]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH:1]1([NH:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([OH:17])=[C:9]([C:18]3[NH:23][C:22]4[CH:24]=[CH:25][C:26]([O:28][CH2:39][C:40]([NH2:42])=[O:41])=[CH:27][C:21]=4[S:20](=[O:29])(=[O:30])[N:19]=3)[C:8]2=[O:31])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NC(=O)CBr
Reactant: O=c1c(C2=NS(=O)(=O)c3cc(O)ccc3N2)c(O)c2ccccc2n1NC1CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC(=O)COc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NC3CCCC3)c1=O)N2
Temperature: 165 °C
Yield: 83 %

Procedure:
The product of Example 305C (0.10 g, 0.23 mmol) was reacted with cesium carbonate (0.30 g, 0.92 mmol), 2-bromoacetamide (0.050 g, 0.37 mmol) and a catalytic amount of tetrabuylammonium iodide in N,N-dimethylformamide (5 mL) at 25° C. for 2 hours. The reaction was concentrated to half the volume under a stream of nitrogen warmed through a manifold heated to 165° C. The resulting solution was diluted with water and the precipitate was collected by filtration and dried to give the title compound (0.095 g, 85%). MS (ESI−) m/z 496 (M−H)−. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.52 (m, 6 H) 1.76 (m, 2 H) 3.70 (m, 1 H) 4.47 (s, 2 H) 5.68 (d, J=4.88 Hz, 1 H) 7.03 (t, J=7.63 Hz, 1 H) 7.20 (m, 5 H) 7.46 (t, J=7.32 Hz, 1 H) 7.70 (d, J=8.54 Hz, 1 H) 8.06 (d, J=7.32 Hz, 1 H) 16.15 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([NH:11][CH2:12][CH2:13][OH:14])=[O:10])[CH:5]=[CH:4][C:3]=1[C:15]1[N:16]=[C:17]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]2C)[C:18]2[CH2:23][N:22]([C:24]([O:26][CH2:27]C)=[O:25])[CH2:21][C:19]=2[N:20]=1.ClC1N=C(N2CCOCC2)C2CN(C(OC)=O)CC=2N=1>>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([NH:11][CH2:12][CH2:13][OH:14])=[O:10])[CH:5]=[CH:4][C:3]=1[C:15]1[N:16]=[C:17]([N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)[C:18]2[CH2:23][N:22]([C:24]([O:26][CH3:27])=[O:25])[CH2:21][C:19]=2[N:20]=1
Reactant: CCOC(=O)N1Cc2nc(-c3ccc(NC(=O)NCCO)cc3F)nc(N3CCOC[C@@H]3C)c2C1
Agent: COC(=O)N1Cc2nc(Cl)nc(N3CCOCC3)c2C1
Product: COC(=O)N1Cc2nc(-c3ccc(NC(=O)NCCO)cc3F)nc(N3CCOCC3)c2C1
Yield: 16 %

Procedure:
Method as (S)-Ethyl 2-(2-fluoro-4-(3-(2-hydroxyethyl)ureido)phenyl)-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (Example 167) using methyl 2-chloro-4-morpholino-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 25). Residue was then purified by prep. HPLC at low pH then high pH to afford a colourless solid (16% yield).
Reaction SMILES: Br.[CH2:2]([N:4]([CH2:29][CH3:30])[CH2:5][CH2:6][N:7]1[C:23](=[O:24])[C:22]2[C:21]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([O:25]C)[CH:19]=4)[NH:14][C:13]=3[C:12]([CH2:27][CH3:28])=[CH:11][C:10]=2[C:8]1=[O:9])[CH3:3].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:29]([N:4]([CH2:2][CH3:3])[CH2:5][CH2:6][N:7]1[C:23](=[O:24])[C:22]2[C:21]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([OH:25])[CH:19]=4)[NH:14][C:13]=3[C:12]([CH2:27][CH3:28])=[CH:11][C:10]=2[C:8]1=[O:9])[CH3:30]
Reactant: CCc1cc2c(c3c1[nH]c1ccc(OC)cc13)C(=O)N(CCN(CC)CC)C2=O
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCc1cc2c(c3c1[nH]c1ccc(O)cc13)C(=O)N(CCN(CC)CC)C2=O
Yield: 45.4 %

Procedure:
4.0 ml of an aqueous 47% hydrobromide solution was added to 80 mg of N-(2-diethylaminoethyl)-1-ethyl-6-methoxycarbazole-3,4-dicarboximide. The mixture was refluxed for 40 minutes. Thereto was added 30 ml of water. The resulting mixture was adjusted to pH 9 with potassium carbonate, and extracted with 50 ml of ethyl acetate. The extract was washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from isopropyl alcohol to obtain 35 mg (yield: 45%) of N-(2-diethylaminoethyl)-1-ethyl-6-hydroxycarbazole-3,4-dicarboximide as yellow crystals.
Reaction SMILES: [CH2:1]([C:8]1[C:13]([Br:14])=[CH:12][CH:11]=[C:10]([O:15][CH2:16][CH2:17][CH2:18][OH:19])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:27][O:28][C:29]([CH2:31][CH2:32][C:33](Cl)=[O:34])=[O:30].O>ClCCl>[CH2:1]([C:8]1[C:13]([Br:14])=[CH:12][CH:11]=[C:10]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:33](=[O:34])[CH2:32][CH2:31][C:29]([O:28][CH3:27])=[O:30])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCOc1ccc(Br)c(Cc2ccccc2)n1
Reactant: COC(=O)CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)CCC(=O)OCCCOc1ccc(Br)c(Cc2ccccc2)n1

Procedure:
509 mg of 2-benzyl-3-bromo-6-(3-hydroxypropyl)oxypyridine (Example 165a) was dissolved in 5 ml of dichloromethane. While stirring under ice-cooling, 0.33 ml of triethylamine and 0.29 ml of 3-methoxycarbonylpropionyl chloride were added thereto. After the temperature of the reaction solution was returned to room temperature and the reaction solution was stirred for 30 minutes, water was added to the reaction solution. The mixture was extracted with ethyl acetate, and the organic phase was further washed with brine, dried over anhydrous sodium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography using 20% ethyl acetate/hexane as an eluent for separation and purification, to give 643 mg of the target compound.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[O-:13][C:14]#[N:15].[K+]>N1C=CC=CC=1.[Cu]Br>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:2]2[NH:15][C:14](=[O:13])[O:6][C:4](=[O:5])[C:3]=2[CH:7]=1
Reactant: N#C[O-]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: [Cu]Br
Agent: [K+]
Solvent: c1ccncc1
Product: COc1ccc2[nH]c(=O)oc(=O)c2c1
Reaction time: 0.5 h

Procedure:
5.00 g (21.6 mmol) 2-Bromo-5-methoxy-benzoic acid, 620 mg (4.32 mmol) copper (I) bromide and 2.63 g (32.4 mmol) potassium cyanate were dissolved in pyridine and boiled for 30 min. The solvent was removed and the residue was dissolved in 150 ml 2N hydrogen chloride acid and 150 ml ethyl acetate. The organic solvent was treated with water and brine, dried over magnesium sulfate and removed. The residue was digested with methanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:26][CH3:27])=[C:17]([C:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=3)[CH:18]=2)[N:13]=[N:12][C:11]=1[C:28]#[N:29].[CH3:30][C:31]([CH3:33])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:26][CH3:27])=[C:17]([C:20]3[CH2:21][CH2:22][N:23]([CH:31]([CH3:33])[CH3:30])[CH2:24][CH:25]=3)[CH:18]=2)[N:13]=[N:12][C:11]=1[C:28]#[N:29]
Reactant: CC(C)=O
Reactant: COc1cc2nnc(C#N)c(Nc3ccc(C)cc3F)c2cc1C1=CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1cc2nnc(C#N)c(Nc3ccc(C)cc3F)c2cc1C1=CCN(C(C)C)CC1
Temperature: 55 °C
Reaction time: 6 h
Yield: 54.5 %

Procedure:
To a solution of 4-(2-fluoro-4-methylphenylamino)-7-methoxy-6-(1,2,3,6-tetrahydropyridin-4-yl)cinnoline-3-carbonitrile (Method 88, 200 mg, 0.51 mmol) in dichloroethane (5 mL), acetone (0.566 mL, 7.70 mmol), and acetic acid (0.147 mL, 2.57 mmol) was added sodium triacetoxyborohydride (544 mg, 2.57 mmol) and the reaction stirred at 55° C. for 6 hours. The reaction mixture was concentrated under reduced pressure and the residue purified with silica chromatography (MeOH/EtOAc (1:1)) to give 120 mg (50%) product. m/z 432.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:13]=[C:12]([C:14](=[O:20])[N:15]([CH3:19])[CH2:16][CH2:17][CH3:18])[CH:11]=[C:7]([C:8](O)=[O:9])[CH:6]=1)[CH3:2].ClCCl.Cl.[F:26][C:27]1([F:32])[CH2:31][CH2:30][NH:29][CH2:28]1.C(N(CC)CC)C>ON1C2C=CC=CC=2N=N1.C(O)(C)(C)C.C(OCC)(=O)C.C(#N)C>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:6]=[C:7]([C:8]([N:29]2[CH2:30][CH2:31][C:27]([F:32])([F:26])[CH2:28]2)=[O:9])[CH:11]=[C:12]([C:14]([N:15]([CH3:19])[CH2:16][CH2:17][CH3:18])=[O:20])[CH:13]=1)[CH3:2]
Reactant: CCCN(C)C(=O)c1cc(C(=O)O)cc(C(=O)OCC)c1
Reactant: FC1(F)CCNC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(C)(C)O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCN(C)C(=O)c1cc(C(=O)OCC)cc(C(=O)N2CCC(F)(F)C2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30.7 %

Procedure:
Dissolve 5-(methyl-propylcarbamoyl)-isophthalic acid monoethyl ester (667 mg, 2.3 mmol) in a 0.1 N 1-hydroxybenzotriazole solution of 1:1:5 tert-butanol:acetonitrile:dichloromethane (23 mL, 2.3 mmol). Stir the solution at room temperature for 5 min, add 3,3-difluoropyrrolidine hydrochloride (331 mg, 2.3 mmol) and triethylamine (640 μL, 4.6 mmol). Stir the reaction at room temperature for 2 h, add ethyl acetate (100 mL) and wash with saturated aqueous ammonium chloride (2×30 mL), saturated aqueous sodium chloride (30 mL), dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with 50:50 ethyl acetate:hexanes) to give the title compound (270 mg, 31%).
Reaction SMILES: [C:1]([NH:10][NH2:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C(O)(=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1.S(Cl)(Cl)=O>ClC1C=CC=CC=1>[C:1]([NH:10][NH:11][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: NNC(=O)c1ccccc1O
Reactant: O=C(O)c1ccccc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: Clc1ccccc1
Product: O=C(NNc1ccccc1)c1ccccc1O
Temperature: 130 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
15.2 g (0.1 mol) of salicylic acid hydrazide and 12.2 g (0.1 mol) of benzoic acid are suspended in 200 ml of chlorobenzene, 3.0 g (0.038 mol) of pyridine are added and the mixture is heated to 130° C. 13.1 g (0.11 mol) of thionyl chloride are added dropwise at this temperature. The product immediately separates as a white precipitate. After stirring for 1 hour at 130° C, the mixture is cooled and filtered and the product is washed with petroleum ether. N-Salicyloyl-N'-phenyl-hydrazine of melting point 260° C is thus obtained in 62% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1([CH3:29])[CH2:16][S:15](=[O:18])(=[O:17])[C:14]([CH3:20])([CH3:19])[C:13]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[N:12]1.[CH:30]([N-]C(C)C)([CH3:32])[CH3:31].[Li+].C(Br)C=C>C1COCC1.O1CCCC1.CCCCCCC.C(C1C=CC=CC=1)C>[CH2:32]([CH:16]1[S:15](=[O:18])(=[O:17])[C:14]([CH3:20])([CH3:19])[C:13]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[N:12][C:11]1([C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[F:1])[CH3:29])[CH:30]=[CH2:31]
Reactant: CC(C)(C)OC(=O)NC1=NC(C)(c2cc([N+](=O)[O-])ccc2F)CS(=O)(=O)C1(C)C
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCC1C(C)(c2cc([N+](=O)[O-])ccc2F)N=C(NC(=O)OC(C)(C)C)C(C)(C)S1(=O)=O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 7.9 %

Procedure:
To a solution of tert-butyl (5-(2-fluoro-5-nitrophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (230 mg, 0.536 mmol) in THF (5 ml) was added lithium diisopropylamide, (2.0 M solution in tetrahydrofuran/heptane/ethylbenzene) (0.803 ml, 1.607 mmol) dropwise at −78° C. and the mixture was stirred for 20 min at the −78° C. To a resulting dark solution, allyl bromide (0.139 ml, 1.607 mmol) was added dropwise and the mixture was stirred for another 20 min. The reaction was quenched with NH4Cl solution at −78° C., the flask was removed from the bath and allowed to reach RT. The mixture was extracted with ethyl acetate, organic layer was washed with brine, concentrated and the concentrated crude residue was separated on 12 g RediSep Gold column using 5-50% EtOAc in heptane solvent gradient to afford tert-butyl ((5RS,6RS)-6-allyl-5-(2-fluoro-5-nitrophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (120 mg, 0.256 mmol, 47.7% yield) as major diastereomer and tert-butyl ((5RS,6SR)-6-allyl-5-(2-fluoro-5-nitrophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (20 mg, 0.043 mmol, 7.9% yield) as minor diastereomer.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[C:4]([C:22](=[O:26])[N:23]([CH3:25])[CH3:24])[CH:3]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:24][N:23]([CH3:25])[C:22]([C:4]1[CH:3]=[C:2]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)=[O:26]
Reactant: CN(C)C(=O)c1cc(Br)ccc1CN1CCN(C(=O)OC(C)(C)C)CC1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CN(C)C(=O)c1cc(-c2ccccc2)ccc1CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
A 100 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was charged with tert-butyl 4-[[4-bromo-2-(dimethylcarbamoyl)phenyl]methyl]piperazine-1-carboxylate (130 mg, 0.300 mmol, 1.00 equiv), phenylboronic acid (113 mg, 0.930 mmol, 3.00 equiv), potassium carbonate (128 mg, 0.930 mmol, 3.00 equiv), tetrakis(triphenylphosphine)palladium (36.0 mg, 0.030 mmol, 0.10 equiv), dioxane (4 mL), H2O (0.4 mL). The resulting solution was stirred overnight at 80° C. and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (25/75) to provide 100 mg (79% yield) of tert-butyl 4-[[2-(dimethylcarbamoyl)-4-phenylphenyl]methyl]piperazine-1-carboxylate as light yellow oil. LCMS (ESI, m/z): 424 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C@:4]1([CH3:18])[C@H:9]2[O:10][C@H:8]2[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][CH2:30][C:31]1[NH:32][CH:33]=[CH:34][N:35]=1>>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C@:4]1([CH3:18])[C@@H:9]([OH:10])[C@H:8]([N:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[O:22][CH3:21])[CH2:30][C:31]2[NH:35][CH:34]=[CH:33][N:32]=2)[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H]2O[C@@H]21
Reactant: COc1ccccc1NCc1ncc[nH]1
Product: COc1ccccc1N(Cc1ncc[nH]1)[C@@H]1c2cc([N+](=O)[O-])ccc2O[C@](C)(C(OC)OC)[C@H]1O
Yield: 82.6 %

Procedure:
The title compound (500 mg, 58%) was prepared using (2S,3S,4S)-3,4-dihydro-2-dimethoxymethyl-3,4-epoxy-2-methyl-6-nitro-2H-1-benzopyran (500 mg, 1.78 mmol) and 2-methoxyphenyl-1H-imidazol-2-ylmethylamine (253 mg, 1.25 mmol), according to the same procedure used for the preparation of example 1 above.
Reaction SMILES: [CH3:1][O:2]CCO.[H-].[Na+].[C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[C:25]3[C:24](=[O:26])[CH2:23][CH2:22][CH2:21][C:20]=3[N:19]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=3)[C:18](=[O:37])[N:17]2[C:38]([O:40][C:41]2[CH:46]=CC([N+]([O-])=O)=CC=2)=[O:39])=[CH:12][CH:11]=1)#[N:9].O>O1CCCC1>[C:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[C:25]3[C:24](=[O:26])[CH2:23][CH2:22][CH2:21][C:20]=3[N:19]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=3)[C:18](=[O:37])[N:17]2[C:38]([O:40][CH2:41][CH2:46][O:2][CH3:1])=[O:39])=[CH:14][CH:15]=1)#[N:9]
Reactant: COCCO
Reactant: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCCOC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-methoxyethanol (7 μL, 89 μmol) in dry tetrahydrofuran (500 μL) is cooled at 78° C. and treated with sodium hydride (60% in mineral oil, 9 mg, 0.14 mmol). After 30 min, 4-nitrophenyl 4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,5,6,7,8-hexahydroquinazoline-3(4H)-carboxylate (intermediate 37, 50 mg, 87 μmol) is added and the mixture is stirred at room temperature for 2 h. Water is added and the mixture is purified by preparative HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3). Yield: 8 mg; ESI mass spectrum [M+H]+=514; Retention time HPLC: 0.64 min (X012_S01).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.[C:12]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]=[CH:16][C:15]([C:18](O)=[O:19])=[CH:14][CH:13]=1>>[CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][C:18]([C:15]2[CH:16]=[CH:17][C:12]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:13][CH:14]=2)=[O:19])[CH:7]=[CH:8][N:9]=1
Reactant: Nc1cccc2ccncc12
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Product: O=C(Nc1cccc2ccncc12)c1ccc(-c2ccccc2)cc1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 8-aminoisoquinoline (D95) (85 mg, 0.59 mmol) and 4-biphenylcarboxylic acid (177 mg, 0.89 mmol) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.48 (s, 1H), 8.61 (d, 1H), 8.42 (br.s, 1H), 8.22 (d, 1H), 8.10 (d, 2H), 7.79 (d, 2H), 7.68-7.76 (m, 5H), 7.51 (t, 2H), 7.43 (t, 1H).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:7](=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11]Cl)=[CH:5][CH:6]=1.[I-].[Na+].[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:24][CH2:25][CH2:26][N:27]=2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[S:3][C:4]([C:7](=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[O:24][CH2:25][CH2:26][N:27]=3)=[CH:21][CH:22]=2)=[CH:5][CH:6]=1
Reactant: O=C(CCCCCl)c1ccc(Cl)s1
Reactant: Oc1ccc(C2=NCCO2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=C(CCCCOc1ccc(C2=NCCO2)cc1)c1ccc(Cl)s1
Yield: 96.8 %

Procedure:
A mixture consisting of 2-chloro-5-(5-chloropentanoyl)thiophene (3c) (2.13 g, 0.009 mol), sodium iodide (1.1 g, 0.0073 mol), 2-(4-hydroxyphenyl)-4,5-dihydro-oxazole (1.99 g, 0.010 mol), and anhydrous potassium carbonate (5.2 g, 0.045 mol) in acetonitrile (50 ml) was refluxed for 48 hrs., cooled and filtered. The resulting solution was deprived of the solvent and the residue was taken up with ethyl acetate (100 ml). After washing with water and subsequent drying on anydrous sodium sulfate the solution was evaporated to dryness. The resulting solid was crystallized via benzene:cyclohexane (1:1) to give pure 4c (3.17 g; 97%). M.p. 143°-144° C. Anal. (C18H18ClNO3S).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH:11]1([CH2:17][OH:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[H-].[Na+]>>[CH:11]1([CH2:17][O:18][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: OCC1CCCCC1
Agent: [H-]
Agent: [Na+]
Product: O=C(O)c1ccc(OCC2CCCCC2)nc1

Procedure:
6-(Cyclohexylmethoxy)nicotinic acid was prepared from 6-chloronicotinic acid (0.50 g), cyclohexylmethanol (0.41 ml) and sodium hydride (60%, 0.32 g) according to the method described in Example 54 to give the product as a white solid (0.42 g, 56%): δH (400 MHz, DMSO-d6) 12.97 (1H, br), 8.70 (1H, d, J 2.5 Hz), 8.12 (1H, dd, J 8.5, 2.5 Hz), 6.88 (1H, d, J 8.5 Hz), 4.14 (2H, d, J 6 Hz), 1.81–1.60 (6H, m), 1.20 (3H, sept of triplets, J 12, 2.5 Hz) and 1.03 (2H, dq, J 11, 2.5 Hz); HPLC (XTERRA, 50/80,220 nm) 100% (1.47 min).