Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[S:20][C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][CH:28]=3)=[C:22]([CH3:25])[C:23]=2Br)[O:7][C@@H:6]1[CH2:35][O:36]C(=O)C)(=O)C.[CH3:40][O-:41].[Na+]>>[CH2:33]([C:30]1[CH:29]=[CH:28][C:27]([CH2:26][C:21]2[S:20][C:19]([C@H:8]3[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:35][OH:36])[O:7]3)=[C:23]([O:41][CH3:40])[C:22]=2[CH3:25])=[CH:32][CH:31]=1)[CH3:34]
Reactant: C[O-]
Reactant: CCc1ccc(Cc2sc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c(Br)c2C)cc1
Agent: [Na+]
Product: CCc1ccc(Cc2sc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c(OC)c2C)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 18.6 %

Procedure:
To a solution of (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(3-bromo-5-(4-ethylbenzyl)-4-methylthiophen-2-yl)-tetrahydro-2H-pyran-3,4,5-triyl triacetate (56) (200 mg, 0.320 mmole) in NaOMe (25 wt % in MeOH, 10 mL, 43.2 mmole) were added cupric oxide (25.5 mg, 0.320 mmole) and KI (53.1 mg, 0.320 mmole). The resulting solution was stirred at 120° C. overnight. The reaction mixture was filtered through Celite® bed and concentrated in vacuo. The crude residue was purified on reverse phase preparative HPLC to yield the title compound 59 (24.3 mg, 0.0595 mmole, 19%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4](Cl)[N:3]=1.[C:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][C:28]=1[F:36])#[N:26].C([O-])(O)=O.[Na+]>O1CCOCC1.O.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>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:30]2[CH:31]=[CH:32][C:27]([C:25]#[N:26])=[C:28]([F:36])[CH:29]=2)[N:3]=1
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: C[C@@H]1CC[C@H](C(=O)Nc2ccccc2)CN1c1cc(Cl)nc(N)n1
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1CC[C@H](C(=O)Nc2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Yield: 100.6 %

Procedure:
To a solution of (3S,6R)-1-(2-amino-6-chloro-4-pyrimidinyl)-6-methyl-N-phenyl-3-piperidinecarboxamide (8 g, 23.1 mmol) in 1,4-dioxane (250 mL) was added (4-cyano-3-fluorophenyl)boronic acid (5.72 g, 34.7 mmol), Pd(PPh3)4 (2.67 g, 2.3 mmol), and sat. aqueous NaHCO3 (125 mL). The resulting mixture was refluxed overnight, cooled, and diluted with H2O (˜400 mL) to form precipitate. The mixture was filtered, and the gummy solid was dissolved in EtOAc (˜800 mL) and concentrated in vacuo to about 50 mL solvent left. The crude solution was purified by silica gel chromatography (400 g column) eluting with 20% EtOAc/hexanes to 70% EtOAc/hexanes. The fractions that contained the desired product were combined and concentrated in vacuo to afford the title compound (10 g). LC-MS (ES) m/z=431 [M+H]+.
Reaction SMILES: [N:1]1([C:7]([NH:9][CH:10]([CH2:14][S:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:17])=[O:16])[C:11](O)=[O:12])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:25][CH:26]1[CH2:30][O:29][CH2:28][CH:27]1[OH:31].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>CN(C=O)C>[O:31]=[C:27]1[CH2:28][O:29][CH2:30][CH:26]1[NH:25][C:11]([CH:10]([NH:9][C:7]([N:1]1[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1)=[O:8])[CH2:14][S:15]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)(=[O:17])=[O:16])=[O:12]
Reactant: O=C(O)C(CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1
Reactant: NC1COCC1O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C1COCC1NC(=O)C(CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.1 %

Procedure:
2-[(Morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionic acid (100 mg, 0.28 mmol), 4-aminotetrahydrofuran-3-ol (100 mg, 0.96 mmol), EDC (200 mg, 1.04 mmol), and HOBt (200 mg, 1.28 mmol) were combined. DMF (2 mL) was added and then 4-methylmorpholine (0.2 mL). The mixture was stirred at ambient temperature for 2 h. After dilution with ethyl acetate (100 mL) the solution was washed with 1N aqu. HCl (30 mL), sat. aqu. NaHCO3 (30 mL) and brine (30 mL), dried with MgSO4 and evaporated under vacuum. The crude product was dissolved in dichloromethane (10 mL). Dess-Martin periodinane (300 mg, 0.71 mmol) was added, and the reaction mixture was stirred at ambient temperature for 1 h. After dilution with ethyl acetate (100 mL), the solution was washed with 0.26M Na2S2O3 in sat. aqu. NaHCO3 (30 mL), sat. aqu. NaHCO3 and brine, dried with MgSO4, and evaporated under vacuum. Purification by flash-chromatography on silica gel (ethyl acetate) gave morpholine-4-carboxylic acid [1-(4-oxo-tetrahydro-furan-3-ylcarbamoyl)-2-phenylmethanesulfonyl-ethyl]-amide (8.6 mg, 0.020 mmol) as a colorless glass. Mixture of diastereomers: 1H NMR: (DMSO) [8.42 (d, J=6.8 Hz), 7.15 (d, J=7.2 Hz), 1H], 7.40–7.32 (m, 5H), [7.06 (d, J=8 Hz), 7.05 (d, J=8 Hz), 1H], 4.78–4.68 (m, 1H), 4.49 (s), 4.48 (s), 2H], 4.32–3.75 (m, 5H), 3.60–3.23 (m, 10H). MS: (M+H)+ 440.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:5]=[C:4]([O:19][C@@H:20]([CH3:24])[CH2:21][O:22][CH3:23])[CH:3]=1.[C:25]([O:29][C:30]([N:32]1[CH:36]=[CH:35][CH:34]=[C:33]1B(O)O)=[O:31])([CH3:28])([CH3:27])[CH3:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[CH3:23][O:22][CH2:21][C@H:20]([CH3:24])[O:19][C:4]1[CH:3]=[C:2]([C:33]2[N:32]([C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH:36]=[CH:35][CH:34]=2)[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:5]=1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: COC[C@H](C)Oc1cc(Br)cc(Oc2ccc(S(C)(=O)=O)cc2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2cccn2C(=O)OC(C)(C)C)c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 94.3 %

Procedure:
1-Bromo-3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]benzene (2.38 g, 5.73 mmol) synthesized in Example (13a) and 1-(t-butoxycarbonyl)pyrrole-2-boronic acid (1.45 g, 6.87 mmol) were dissolved in a mixed solvent of 1,2-dimethoxyethane (50 mL) and water (6 mL), and palladium (II) acetate (40 mg, 0.178 mmol), triphenylphosphine (180 mg, 0.686 mmol) and potassium carbonate (2.38 g, 17.2 mmol) was added, followed by stirring at 90° C. for 18 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (30 mL) and ethyl acetate (50 mL) were added, and the solution was separated. The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=20%-40%) to afford the desired compound (2.71 g, yield 94%) as a brown oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH3:13])[N:6]([CH3:14])[C:5]2=[O:15].[CH3:16][S:17]([O-:19])=[O:18].[Na+]>[Cu]I>[CH2:12]([C:7]1[N:6]([CH3:14])[C:5](=[O:15])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([S:17]([CH3:16])(=[O:19])=[O:18])[CH:3]=2)[N:8]=1)[CH3:13]
Reactant: CS(=O)[O-]
Reactant: CCc1nc2ccc(Br)cc2c(=O)n1C
Agent: [Cu]I
Agent: [Na+]
Product: CCc1nc2ccc(S(C)(=O)=O)cc2c(=O)n1C
Temperature: 25 °C
Yield: 24.8 %

Procedure:
The substrate of 6-bromo-2-ethyl-3-methyl-3H-quinazolin-4-one (50.0 mg, 0.189 mmol), sodium methanesulfinate (28.8 mg, 0.29 mmol) and copper (I) iodide (53.7 mg, 0.29 mmol) was placed in a flask, which was flushed with N2. DMF (2 ml) was added via syringe. The resulting mixture was irradiated at 180° C. for 30 minutes in the SmithSynthesizer Microwave reactor (Personal Chemistry) with vigorous agitation by a magnetic stirrer. The mixture was cooled to room temperature, diluted with ethyl acetate (5 ml), and then filtered. The filtrate was washed with water and brine, dried over anhydrous MgSO4, and concentrated by rotary evaporation. Purification was accomplished by HPLC (Gilson-215, 0.035% TFA in acetonitrile and 0.05% water as mobile phase). The product was collected and dried under reduced pressure to give 2-Ethyl-6-methanesulfonyl-3-methyl-3H-quinazolin-4-one (Yield 12.5 mg, 25.1%). 1H NMR (400 MHz, CDCl3): δ 1.35 (t, 3H, J=7.58 Hz), 2.83 (dd, 2H, J=14.65, 7.58 Hz), 3.02 (s, 3H), 3.58 (s, 3H), 7.73 (d, 1H, J=8.84 Hz), 8.12 (dd, 1H, J=8.84 Hz), 8.77 (d, 1H, J=2.02 Hz). MS m/z calc. 265.1, found (ESI); 266.0 (M+1)+. Retention time 2.41 minutes.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:13][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][NH2:12])[CH:10]=[C:5]2[CH:4]=1.Cl[C:17]1[C:22]([CH3:23])=[C:21]([CH2:24][CH3:25])[N:20]=[CH:19][N:18]=1.CCN(C(C)C)C(C)C.CN1CCCC1=O>C(OCC)(=O)C>[CH2:24]([C:21]1[N:20]=[CH:19][N:18]=[C:17]([NH:12][CH2:11][C:9]2[CH:10]=[C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:14])[F:15])[NH:13][C:6]3=[N:7][CH:8]=2)[C:22]=1[CH3:23])[CH3:25]
Reactant: NCc1cnc2[nH]c(C(F)(F)F)cc2c1
Reactant: CCc1ncnc(Cl)c1C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ncnc(NCc2cnc3[nH]c(C(F)(F)F)cc3c2)c1C
Temperature: 120 °C
Yield: 29.8 %

Procedure:
1-[2-(Trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methanamine (Intermediate 5, 129 mg, 0.6 mmol), 4-chloro-6-ethyl-5-methylpyrimidine (Intermediate 41, 141 mg, 0.900 mmol) and DIPEA (0.210 mL, 1.200 mmol) were added together with N-methyl-2-pyrrolidone (1 mL) and the resulting mixture was stirred and heated to 120° C. for 6 hours. The reaction mixture was diluted with ethyl acetate and washed with sodium hydrogen carbonate solution, water and brine. The organic layer was separated, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by MDAP. Product containing fractions were combined and evaporated under reduced pressure. The resulting solid was triturated with ether/isohexane (1:1) and the resulting solid was collected and dried affording the title compound (60 mg);
Reaction SMILES: C([C:3]1([C:9]2[N:10]=[CH:11][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]=2[CH3:14])[CH2:7][C:6](=[O:8])[CH2:5][S:4]1)C.O>>[CH2:15]([N:12]1[C:13]([CH3:14])=[C:9]([CH:3]2[CH2:7][C:6](=[O:8])[CH2:5][S:4]2)[N:10]=[CH:11]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCC1(c2ncn(Cc3ccccc3)c2C)CC(=O)CS1
Solvent: O
Product: Cc1c(C2CC(=O)CS2)ncn1Cc1ccccc1

Procedure:
Ethyl 2-(1-benzyl-5-methyl-4-imidazolyl)-4-oxotetrahydrothiophene-5(and/or 3)-carboxylate (12.6 g., 0.037 mole) is dissolved in 20 ml. of water containing concentrated sulfuric acid (1.11 ml., 0.02 mole) and the solution is refluxed for 31/4 hours. The reaction mixture is diluted with 50 ml. of water and is washed with ether. The aqueous layer is made basic with sodium carbonate and the oil which separates is extracted into chloroform. The extract is washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product 2-(1-benzyl-5-methyl-4-imidazolyl)-4-oxotetrahydrothiophene is isolated a brown gum (7.8 g.).
Reaction SMILES: Cl[C:2]1C=CC(OC)=C([CH:42]=1)C[C@H]1CN2C(O)=NN=C2CN(C(N[C@@H](C2C=CC(C(OC(C)(C)C)=O)=C([N+]([O-])=O)C=2)CC)=O)C1=O.[Cl:45][C:46]1[CH:47]=[CH:48][C:49]([O:84][CH3:85])=[C:50]([CH:83]=1)[CH2:51][C@H:52]1[CH2:58][N:57]2[C:59]([OH:62])=[N:60][N:61]=[C:56]2[CH2:55][N:54]([C:63]([NH:65][C@@H:66]([C:69]2[CH:70]=[C:71]([CH:79]=[CH:80][CH:81]=2)[C:72]([O:74]C(C)(C)C)=[O:73])[CH2:67][CH3:68])=[O:64])[C:53]1=[O:82]>>[Cl:45][C:46]1[CH:47]=[CH:48][C:49]([O:84][CH3:85])=[C:50]([CH:83]=1)[CH2:51][C@H:52]1[CH2:58][N:57]2[C:59](=[O:62])[N:60]([CH2:2][CH3:42])[N:61]=[C:56]2[CH2:55][N:54]([C:63]([NH:65][C@@H:66]([C:69]2[CH:70]=[C:71]([CH:79]=[CH:80][CH:81]=2)[C:72]([OH:74])=[O:73])[CH2:67][CH3:68])=[O:64])[C:53]1=[O:82]
Reactant: CC[C@@H](NC(=O)N1Cc2nnc(O)n2C[C@H](Cc2cc(Cl)ccc2OC)C1=O)c1cccc(C(=O)OC(C)(C)C)c1
Reactant: CC[C@@H](NC(=O)N1Cc2nnc(O)n2C[C@H](Cc2cc(Cl)ccc2OC)C1=O)c1ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Product: CC[C@@H](NC(=O)N1Cc2nn(CC)c(=O)n2C[C@H](Cc2cc(Cl)ccc2OC)C1=O)c1cccc(C(=O)O)c1

Procedure:
Instead of the starting material, that is, the compound 91a, of Example 91, Step (2), the compound 92a was used for a similar procedure as in Example 91, Step (2) and Example 87, Step (3) to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[C:25]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].COCCOC>CCOC(C)=O.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.C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([C:36]3[CH:35]=[C:34]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:39]=[CH:38][CH:37]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: CCO
Product: CC(NC(=O)c1coc(-c2cccc(-c3ccccc3)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 54.1 %

Procedure:
In a 5 ml glass tube were placed 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (100 mg, 0.26 mmol), 3-biphenyl boronic acid (104 mg, 0.53 mmol), Cs2CO3 (257 mg, 0.79 mmol), Pd(PPh3)2Cl2 (15 mg, 0.021 mmol), DME (0.8 mL), ethanol (0.2 mL), and a magnetic stir bar. The vial was sealed with septum and placed into the Microwave cavity. The vial was irradiated in a Microwave synthesizer at 140° C. for 20 min. The mixture was diluted with EtOAc and washed with 1N HCl and water. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude residue was purified by column chromatography (gradient 12% to 100% EtOAc in n-hexane) to give title compound (70 mg, 54%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[C:6]([C:14]([O:16]CCC)=[O:15])[C:5]=1[C:20]1[C:25]([C:26]([O:28]C)=[O:27])=[CH:24][C:23]([O:30][CH3:31])=[C:22]2[O:32][CH2:33][O:34][C:21]=12)[CH3:2].[OH-].[K+].Cl>O1CCOCC1>[CH2:1]([O:3][C:4]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[C:6]([C:14]([OH:16])=[O:15])[C:5]=1[C:20]1[C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]([O:30][CH3:31])=[C:22]2[O:32][CH2:33][O:34][C:21]=12)[CH3:2]
Reactant: CCCOC(=O)c1cc(OC)c(OC)c(OCC)c1-c1c(C(=O)OC)cc(OC)c2c1OCO2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCOc1c(OC)c(OC)cc(C(=O)O)c1-c1c(C(=O)O)cc(OC)c2c1OCO2
Temperature: 70 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
In 4 ml of dioxane was dissolved 48 mg of methyl 2-ethoxy-2',3'-methylenedioxy-6-propoxycarbonyl-3,4,4'-trimethoxy-1,1'-biphenyl-6'-carboxyla te obtained in Example 9, and 1 ml of a 5% aqueous solution of potassium hydroxide was added to the solution. The mixture was heated at 70° C. and stirred overnight, the pH value was adjusted to 1 by 3N hydrochloric acid, and the mixture was extracted with chloroform. The solvent was removed from the extract to obtain 36 mg of 2-ethoxy-2',3'-methylenedioxy-3,4,4'-trimethoxy-1,1'-biphenyl-6,6'-dicarboxylic acid having the following physical properties (the yield was 86%).
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[F:8][C:9]([F:38])([F:37])[O:10][C:11]1[CH:36]=[CH:35][C:14]([CH2:15][C@:16]23[CH2:23][C@H:22]([NH2:24])[CH2:21][N:20]2[C:19](=[O:25])[N:18]([C:26]2[CH:31]=[C:30]([Cl:32])[N:29]=[C:28]([Cl:33])[CH:27]=2)[C:17]3=[O:34])=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C>C1COCC1>[F:38][C:9]([F:37])([F:8])[O:10][C:11]1[CH:36]=[CH:35][C:14]([CH2:15][C@:16]23[CH2:23][C@H:22]([NH:24][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5])[CH2:21][N:20]2[C:19](=[O:25])[N:18]([C:26]2[CH:31]=[C:30]([Cl:32])[N:29]=[C:28]([Cl:33])[CH:27]=2)[C:17]3=[O:34])=[CH:13][CH:12]=1
Reactant: CCCCC(=O)Cl
Reactant: N[C@@H]1CN2C(=O)N(c3cc(Cl)nc(Cl)c3)C(=O)[C@@]2(Cc2ccc(OC(F)(F)F)cc2)C1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC(=O)N[C@@H]1CN2C(=O)N(c3cc(Cl)nc(Cl)c3)C(=O)[C@@]2(Cc2ccc(OC(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.7 %

Procedure:
Valeryl chloride (0.031g) was added to a solution of the compound from Example 63 (0.1 g) and DIEA (0.84 g) in THF (5 mL) and the reaction mixture was stirred at room temperature for 24 hours. The mixture was concentrated and the residue was purified via HPLC (CH3CN/0.1 M AcOH) to yield 0.075 g of the titled compound. MS (m/z) 559 (MH+) and 581 (MNa+). mp 66.8° C.
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7](Cl)=[N:6][C:5]=2[CH:4]=1.[NH:19]1[CH:23]=[CH:22][CH:21]=[N:20]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:19]1([CH2:2][C:3]2[S:11][C:10]3[C:9]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)=[N:8][C:7]([C:5]4[CH:4]=[CH:3][CH:2]=[C:21]5[C:22]=4[CH:23]=[N:19][NH:20]5)=[N:6][C:5]=3[CH:4]=2)[CH:23]=[CH:22][CH:21]=[N:20]1
Reactant: c1cn[nH]c1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cc(-c2nc(N3CCOCC3)c3sc(Cn4cccn4)cc3n2)c2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-(bromomethyl)-2-chloro-4-morpholinothieno[3,2-d]pyrimidine 30 from Example 9 (90 mg, 0.3 mmol) in DMF (3 mL) was added pyrazole (18 mg, 0.3 mmol) and K2CO3 (50 mg, 0.4 mmol). The resulting solution stirred at room temperature overnight then was concentrated in vacuo. The residue was diluted with water and filtered. The crude product was utilized in a Suzuki coupling using General Procedure A with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to provide 325 after reverse phase HPLC purification (13 mg). MS (Q1) 418 (M)+
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](Cl)=[O:13])([CH3:4])([CH3:3])[CH3:2].C([NH:26][NH:27][CH:28]([CH3:30])[CH3:29])(OCC1C=CC=CC=1)=O.C(N(CC)CC)C>C1COCC1>[C:1]([O:5][C:6](=[O:15])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:13])[N:27]([CH:28]([CH3:30])[CH3:29])[NH2:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)NNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)N(N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Yield: 65.7 %

Procedure:
Carbamoyl chloride 1 (4 mmol, crude), prepared as described above, was combined with carbazide 4 (3.50 mmol; 0.728 g) and triethylamine (0.557 ml; 4.00 mmol) in dry THF (2 ml). The mixture was heated at reflux for 7 hours, then filtered and evaporated to a thick oil. This was dissolved in benzene (10 ml) and hydrogenated with 10% Pd(C) (0.35 g) at 1 atm. for 6 hours. Filtration of the catalyst and evaporation gave a light yellow oil which was purified by flash chromatography on silica gel (CH2Cl2 --CH3OH, 50:1). There was obtained pure carbazide 5 (0.622 g; 2.30 mmol; 66%) as a light yellow solid. Recrystallization from hexanes gave a sample, mp 87°-91° C. TLC (silica gel; CH2Cl2 --CH3OH; 20:1) Rf=0.4. MS m/e 271 (M+). Analysis: Calculated for C13H25N 3 O3 : C, 57.54; H, 9.29; N, 15.48. Found: C, 57.67; H, 9.46; N, 15.44. NMR (CDCl3): δ1.08 (3H,d, J=6); 1.13 (3H, d, J=6); 1.43 (9H,s); 1.7-2.2 (4H,m); 2.4-2.7 (2H,m); 3.3 (2H,bs); 4.07 (1H, septet, J=6); 4.3-4.5 (1H,m). lR(CHCl3): 3600-3300, 1730, 1630 cm-1. [α]D =15.9°±b 0.5°. [α]d =15.9°±0.5°.
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CCOCC.[O:12]=[C:13]1[NH:17][C:16](=O)[CH2:15][N:14]1[CH2:19][C@@H:20]1[CH2:24][C@@H:23]([OH:25])[CH2:22][N:21]1[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=1)=[O:27].CO>O1CCCC1>[OH:25][C@H:23]1[CH2:22][N:21]([C:26]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=2)=[O:27])[C@H:20]([CH2:19][N:14]2[CH2:15][CH2:16][NH:17][C:13]2=[O:12])[CH2:24]1
Reactant: O=C1CN(C[C@@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: O=C1NCCN1C[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.17 h
Yield: 68.7 %

Procedure:
To a suspension of sodium borohydride (0.42 g) in tetrahydrofuran (20 ml) was dropwise added boron trifluoride etherate (5.25 ml) under ice-cooling and the mixture was stirred at the same temperature for 10 minutes. To this solution was added a solution of (2S,4R)-2-(2,4-dioxoimidazolidin-1-yl)methyl-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.1 g) in tetrahydrofuran (10 ml) under ice-cooling and the mixture was stirred at ambient temperature for 3 hours. To the reaction mixture was dropwise added methanol (5 ml) and the mixture was filtered off. The filtrate was evaporated in vacuo. The resulting residue was dissolved in methanol (30 ml) and 1.7M hydrogen chloride-methanol solution (6 ml) and the solution was allowed to stand overnight at ambient temperature. The reaction mixture was evaporated in vacuo and dissolved in ethyl acetate (60 ml). The solution was washed successively with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over magnesium sulfate, and evaporated in vacuo to give precipitates. The precipitates were washed with ethyl acetate (20 ml) and air-dried to give (2S,4R)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)-2-(2-oxoimidazolidin-1-yl)methyl pyrrolidine (1.39 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[O:9][CH2:8][CH2:7][O:6]1.[C-:10]#[N:11].[Na+].[I-].[Na+].O>CN(C=O)C>[O:6]1[CH2:7][CH2:8][O:9][CH:5]1[CH2:4][CH2:3][CH2:2][C:10]#[N:11]
Reactant: [C-]#N
Reactant: ClCCCC1OCCO1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCCCC1OCCO1
Temperature: 80 °C
Yield: 75.8 %

Procedure:
A mixture of 2-(3-chloropropyl)-1,3-dioxolane (15.88 g; 0.1054 moles), sodium cyanide (6.46 g; 0.132 moles) and sodium iodide (1.57 g; 0.0105 moles) in DMF (100 mL) was heated at 80° C., with magnetic stirring, under a nitrogen atmosphere for 15 hours. The mixture was allowed to cool, added to water (300 mL) and extracted with ethyl acetate (3×200 mL). The combined extracts were washed with water (200 mL) and saturated aqueous sodium chloride solution (100 mL) and then dried over sodium sulfate. Filtration and evaporation of solvent gave a crude yellow oil which was purified by chromatography on silica gel, eluting with hexane/ethyl acetate (5:2). Removal of solvent under vacuum gave the product 4-(1,3-dioxolan-2-yl)-butanenitrile (11.28 g; 76%) as a colorless oil. 1H NMR (CDCl3) δ 4.89–4.91 (1H, m), 3.92–4.01 (2H, m), 3.82–3.90 (2H, m), 2.40–2.46 (2H, m), 1.77–1.85 (4H, m).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]([C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH2:21][OH:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[CH2:12]([C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH:21]=[O:22])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: OCc1ccc(Cl)cc1Cc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1ccc(Cl)cc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 238 g (1.1 mole) of pyridinium chlorochromate and 800 ml of methylene chloride was added 79.3 g (0.34-mole) of 2-benzyl-4-chlorobenzyl alcohol. The mixture was stirred at room temperature for 2 hr. The chromium salts were precipitated by the addition of 2.4 liters of 1:1 ether:petroleum ether, and the precipitate was removed by filtration through Celite. The solvent was removed at reduced pressure to give a yellow oil, which was used without further purification.