Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[N:8]=[CH:9][S:10][CH:11]=1.[C:12]1(=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[O:13]1>CC(C)=O.C1COCC1>[CH3:6][C:7]1[N:8]=[C:9]([C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=2[C:12]([OH:22])=[O:13])=[O:21])[S:10][CH:11]=1
Reactant: Cc1cscn1
Reactant: O=C1OC(=O)c2ccccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: Cc1csc(C(=O)c2ccccc2C(=O)O)n1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A dry 250 mL RBF under nitrogen was charged with THF (35.3 mL, 0.4 M), and cooled to −78° C., via dry ice bath in acetone. n-Butyllithium (6.3 mL, 15.8 mmol) was added via syringe. While keeping reaction mixture at −78° C., 4-methylthiazole (1.4 g, 15.1 mmol) in 40 mL of THF was added via addition funnel over 15 minutes. The reaction mixture was stirred at −78° C. for 2 hrs, allowed to warm up to 0° C. over half an hour, then cooled back to −78° C. and isobenzofuran-1,3-dione (3.4 g, 22.7 mmol) in 25 ml of THF rapidly added. The reaction was allowed to warm up to RT and stirred overnight. Reaction mixture was concentrated down to 30 mL, diluted with 60 mL of water, cooled to 0° C. and acidified with 6N HCl to pH4, and extracted with DCM (3×100 mL). The organic layers were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The resulting residue was triturated with DCM to afford 2-(4-methylthiazole-2-carbonyl)benzoic acid. MS m/z=248 [M+H]+. Calc'd for C12H9NO3S: 247.3.
Reaction SMILES: [OH:1][C:2]([C:5]1[O:6][CH:7]=[C:8]([C:10]([OH:12])=O)[N:9]=1)([CH3:4])[CH3:3].[NH2:13][C@@H:14]([CH3:30])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[CH:22]=2)=[N:17]1>>[Cl:29][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:10]([C:8]3[N:9]=[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])[O:6][CH:7]=3)=[O:12])[CH3:30])[N:17]=2)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]
Reactant: CC(C)(O)c1nc(C(=O)O)co1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1coc(C(C)(C)O)n1
Yield: 57.7 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 2-(2-hydroxypropan-2-yl)oxazole-4-carboxylic acid (197 mg, 1.151 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (250 mg, 0.959 mmol). The product was purified by flash chromatography. Yield 57.7%. 1H-NMR (400 MHz; DMSO-d6): δ 1.12 (d, 3H), 1.53 (s, 6H), 4.31 (dd, 1H), 4.40 (dd, 1H), 4.43-4.52 (m, 1H), 5.66 (s, 1H), 6.97 (d, 1H), 7.84 (d, 1H), 7.94-8.00 (m, 2H), 8.08-8.10 (m, 1H), 8.17 (d, 1H), 8.48 (s, 1H).
Reaction SMILES: [CH:1]([C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=O.[CH3:19][C:20]([S@@:23]([NH2:25])=[O:24])([CH3:22])[CH3:21]>C1COCC1.CCO.CCO.CCO.CCO.[Ti]>[C:20]([S@@:23](/[N:25]=[CH:1]/[C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:24])([CH3:22])([CH3:21])[CH3:19]
Reactant: Cc1cccc(CCC(=O)OC(C)(C)C)c1C=O
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Ti]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cccc(CCC(=O)OC(C)(C)C)c1/C=N/[S@@](=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.8 %

Procedure:
To a solution of 305 mg of tert-butyl 3-(2-formyl-3-methylphenyl)propanoate in 3 ml of THF 3 ml were added 298 mg of (S)-2-methyl-2-propanesulfinamide and 0.62 ml of tetraethyl orthotitanate, followed by stirring at room temperature for 16 hours. The reaction mixture was poured into ice water and the insoluble material was filtered through Celite. To the filtrate was added chloroform to carry out a layer separation operation. The organic layer was washed with water and subsequentially with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 336 mg of tert-butyl 3-{2-[(E)-{[(S)-tert-butylsulfinyl]imino}methyl]-3-methylphenyl}propanoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[C:13]([O:22][CH3:23])=[C:14]3[C:19](=[O:20])[N:18]([CH3:21])[CH2:17][CH2:16][N:15]3[C:9]=2[C:8]([CH2:24][C:25]#[N:26])=[N:7]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:42][C:43]([O:45][CH3:46])=[O:44]>CN(C=O)C.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[C:13]([O:22][CH3:23])=[C:14]3[C:19](=[O:20])[N:18]([CH3:21])[CH2:17][CH2:16][N:15]3[C:9]=2[C:8]([CH:24]([C:25]#[N:26])[CH2:42][C:43]([O:45][CH3:46])=[O:44])=[N:7]1
Reactant: COC(=O)CBr
Reactant: COc1c2n(c3c(CC#N)nn(Cc4ccc(F)c(Cl)c4)c(=O)c13)CCN(C)C2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)CC(C#N)c1nn(Cc2ccc(F)c(Cl)c2)c(=O)c2c(OC)c3n(c12)CCN(C)C3=O
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of 2-(3-chloro-4-fluorobenzyl)-4-(cyanomethyl)-10-methoxy-8-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (0.11 g, 0.25 mmol; Example 118, step 1) in anhydrous DMF (1 mL), a solution of lithium bis(trimethylsilyl)amide (0.28 mL, 0.28 mmol; 1M) in THF was added over a period of 5 minutes. The reaction solution was stirred at the same temperature for 30 minutes and treated with methyl bromoacetate (43 mg, 0.28 mmol). After stirring at room temperature for two hours, the product mixture was concentrated under vacuum. The residue was partitioned between dichloromethane and aqueous ammonium chloride. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 0 to 10% methanol in chloroform gradient. Collection and concentration of appropriate fractions afforded the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11](O)=[O:12])=[C:8]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]=2[CH:22]=1.C(N1C=CN=C1)([N:25]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH2:25])=[O:12])=[C:8]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]=2[CH:22]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc2oc(C(=O)O)c(OCc3ccccc3)c2c1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2oc(C(N)=O)c(OCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
A suspension of 5-methoxy-3-(phenylmethoxy)-2-benzofurancarboxylic acid (157 mg, 0.50 mmol) and 1,1'-carbonyldiimidazole (96 mg, 0.59 mmol) in 15 mL of tetrahydrofuran is heated at reflux for 1.5 hours. The reaction solution is cooled to room temperature, aqueous ammonium hydroxide (1 mL) is added and the reaction mixture is stirred at room temperature for 1 hour. The reaction is diluted with ethyl acetate and washed with brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography eluting with ethyl acetate:hexane (1:1) provides 5-methoxy-3-(phenylmethoxy)-2-benzofurancarboxamide in 47% yield; mp=70°-72° C.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](\[C:10]([NH:12][C@@H:13]1[C:16](=[O:17])[N:15]2[C:18]([C:27]([OH:29])=[O:28])=[C:19]([CH2:22][O:23][C:24]([NH2:26])=[O:25])[CH2:20][S:21][C@H:14]12)=[O:11])/[C:5]1[O:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:37][O:38][C:39](=[O:45])[C:40]([O:43][CH3:44])([CH3:42])[CH3:41].O>CN(C)C=O>[C:24]([O:23][CH2:22][C:19]1[CH2:20][S:21][C@@H:14]2[C@H:13]([NH:12][C:10](=[O:11])/[C:4](/[C:5]3[O:9][CH:8]=[CH:7][CH:6]=3)=[N:3]\[O:2][CH3:1])[C:16](=[O:17])[N:15]2[C:18]=1[C:27]([O:29][CH2:37][O:38][C:39](=[O:45])[C:40]([O:43][CH3:44])([CH3:42])[CH3:41])=[O:28])(=[O:25])[NH2:26]
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Reactant: COC(C)(C)C(=O)OCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)OC)=C(COC(N)=O)CS[C@H]12)c1ccco1
Reaction time: 0.58 h
Yield: 69.1 %

Procedure:
Cefuroxime (1.697 g) and powdered potassium carbonate (276 mg) were stirred in anhydrous N,N-dimethylformamide (20 ml) at 22° for 1 hour and the resulting solution was cooled in an ice/salt bath to -8°. A solution of crude 2-methoxy-2-methylpropanoic acid iodomethyl ester (1.52 g) in anhydrous N,N-dimethylformamide (6 ml) was added and the solution was stirred for 35 mins. Water (75 ml) was added and the mixture was extracted with ethyl acetate (2×100 ml). The combined organic layers were washed successively with 50 ml each of 2N hydrochloric acid (3×), water, saturated aqueous sodium bicarbonate, water, 10% aqueous sodium metabisulphite, water (2×) and saturated brine, dried over magnesium sulphate and concentrated under vacuum to ca 10 ml. The solution was added dropwise to stirred petroleum ether (100 ml) to give a precipitate which was filtered off, washed with petroleum ether and dried under reduced pressure to give the title ester (1.532 g); λmax (ethanol 277) nm E11 323; νmax (CHBr3) 3520 and 3400 (NH and NH2), 1788 (β-lactam C=O); 1735 (ester and carbamate C=O) and 1685 and 1510 cm-1 (amide C=O).
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[N:7]([CH2:9][CH:10]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[N:24]=[C:23](Cl)[CH:22]=[C:21]([N:26]([CH3:33])[CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:20]=2)[CH:14]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[N:49]1[CH:54]=[CH:53][C:52](B(O)O)=[CH:51][CH:50]=1>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>[C:1]([O:5][C:6](=[O:42])[N:7]([CH2:9][CH:10]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[N:20]=[C:21]([N:26]([CH3:33])[CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:22]=[C:23]([C:52]3[CH:53]=[CH:54][N:49]=[CH:50][CH:51]=3)[N:24]=2)[CH:14]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccncc1
Reactant: CN(CC(COc1cccc(-c2nc(Cl)cc(N(C)C3CCOCC3)n2)c1)O[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C
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: C1COCCO1
Solvent: O
Product: CN(CC(COc1cccc(-c2nc(-c3ccncc3)cc(N(C)C3CCOCC3)n2)c1)O[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
To a solution of [2-(tert-Butyl-dimethyl-silanyloxy)-3-(3-{4-chloro-6-[methyl-(tetrahydro-pyran-4-yl)-amino]-pyrimidin-2-yl}-phenoxy)-propyl]-methyl-carbamic acid tert-butyl ester (160 mg, 0.26 mmol) in degassed dioxane and H2O (4/1, 25 mL) was added Na2CO3 (83 mg, 0.78 mmol); Pd(PPh3)4 (30 mg, 0.026 mmol) and pyridin-4-ylboronic acid (64 mg, 0.52 mmol). The system was purged with N2 stream and the mixture was stirred 100° C. for 2 h., cooled down to room temperature, diluted with water (25 mL) and extracted with EtOAc (25 mL×2). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatographic column on silica gel (petroleum ether/EtOAc=10/1 to 1/1) to give [2-(tert-Butyl-dimethyl-silanyloxy)-3-(3-{4-[methyl-(tetrahydro-pyran-4-yl)-amino]-6-pyridin-4-yl-pyrimidin-2-yl}-phenoxy)-propyl]-methyl-carbamic acid tert-butyl ester (128 mg, 75% yield). ESI-LCMS (m/z): 664.4 [M+1]+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([O:9][CH2:10][O:11][CH3:12])[CH:3]=1.[CH2:13](N(CC)CC)[CH3:14].C(#N)C.C([Si](C)(C)C)#C>C(OCC)C.[Cu]I.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:13]([C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([O:9][CH2:10][O:11][CH3:12])[CH:3]=1)#[CH:14]
Reactant: CCN(CC)CC
Reactant: COCOc1cc(I)ccc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#C[Si](C)(C)C
Solvent: CC#N
Solvent: CCOCC
Product: C#Cc1ccc(C)c(OCOC)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Argon was bubbled into a mixture of the 4-iodo-2-methoxymethoxy-1-methyl-benzene (7.63 g, 27.5 mmol) (from example 18 supra), triethylamine (55 mL) (Aldrich) and acetonitrile (100 mL) in a pressure reactor for 20 minutes at room temperature. Ethynyltrimethylsilane (9.2 mL, 64.5 mmol) (Aldrich), copper(I) iodide (245 mg, 1.28 mmol) (Aldrich) and dichlorobis(triphenylphosphine)palladium(II) (911 mg, 1.29 mmol) (Aldrich) were added. Reactor was capped and mixture heated at 100° C. for 5 hours with magnetic stirring. After cooling to room temperature, mixture was suspended in diethyl ether (250 mL) and water (250 mL) and filtered through Celite®. Layers were separated. Organic layer washed with water (250 mL) and brine (250 mL). Aqueous layers were back washed with ether (250 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was dissolved in methanol (50 mL) and potassium carbonate (500 mg) was added. Mixture was stirred at room temperature overnight. After concentrating, residue was partitioned between diethyl ether (2×250 mL) and water (2×250 mL). Organic layers were washed with brine (200 mL), combined, dried (MgSO4), filtered and concentrated. Residue was purified by flash chromatography (Biotage 40 L, hexanes, then hexanes-dichloromethane 9:1 and 3:1 as solvent) to give 4-ethynyl-2-methoxymethoxy-1-methyl-benzene as a brown oil. (Yield 4.65 g, 96.2%).
Reaction SMILES: C(N(CC)CC)C.F[C:9]([N:11]([CH3:40])[S:12][N:13]([C:15]([O:17][N:18]=[C:19]([CH3:39])[C:20](=[N:22][O:23][C:24]([N:26]([CH3:38])[S:27][N:28]([C:30]([O:32][N:33]=[C:34]([S:36][CH3:37])[CH3:35])=[O:31])[CH3:29])=[O:25])[CH3:21])=[O:16])[CH3:14])=[O:10].[CH3:41][N:42]([CH3:50])[C:43](=[O:49])[C:44]([S:47][CH3:48])=[N:45][OH:46]>C(Cl)Cl>[CH3:39][C:19](=[N:18][O:17][C:15]([N:13]([CH3:14])[S:12][N:11]([C:9]([O:46][N:45]=[C:44]([S:47][CH3:48])[C:43]([N:42]([CH3:50])[CH3:41])=[O:49])=[O:10])[CH3:40])=[O:16])[C:20]([CH3:21])=[N:22][O:23][C:24]([N:26]([CH3:38])[S:27][N:28]([CH3:29])[C:30]([O:32][N:33]=[C:34]([S:36][CH3:37])[CH3:35])=[O:31])=[O:25]
Reactant: CSC(=NO)C(=O)N(C)C
Reactant: CSC(C)=NOC(=O)N(C)SN(C)C(=O)ON=C(C)C(C)=NOC(=O)N(C)SN(C)C(=O)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSC(C)=NOC(=O)N(C)SN(C)C(=O)ON=C(C)C(C)=NOC(=O)N(C)SN(C)C(=O)ON=C(SC)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 13.1 %

Procedure:
A solution of 1 g of triethylamine in 10 ml of methylene chloride was added dropwise to a solution of 3 g of the crude carbamic fluoride and 1.1 g of methyl 2-(dimethylamino)-N-hydroxy-2-oxoethanimidothioate in 50 ml of methylene chloride at 10° to 20° C. and stirred at room temperature for 2.5 hours. The solution was washed with three 50 ml portions of water, and the organic layer was dried over anhydrous magnesium sulfate. The mixture was filtered, and the filtrate was evaporated. Ether was added to the crude product followed by dilution with methylene chloride until the mass could flow freely. The solid was separated by filtration to give a mixture. The mother liquor was concentrated and diluted with ethers to give 0.5 g of the title compound, m.p. 87°-110° C. (glass).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]#[C:7][CH2:8][S:9][CH2:10][CH2:11][OH:12].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(OCC)C>[CH3:20][S:21]([O:12][CH2:11][CH2:10][S:9][CH2:8][C:7]#[C:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:23])=[O:22]
Reactant: OCCSCC#Cc1cccs1
Reactant: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCSCC#Cc1cccs1
Reaction time: 0.5 h

Procedure:
A solution of 1.28 g of 9c and 1.5 ml of triethyl amine in 10 ml of diethyl ether was treated at 0° C. with 0.78 g of methanesulphonyl chloride in 5 ml of diethyl ether. The reaction mixture was stirred for ½ h and then quenched by addition of 20 ml of water. The product was extracted into ethyl acetate and the combined extracts were washed once with 1M K2CO3 and once with water, dried and concentrated, to provide 1.7 g as essentially pure 9d and was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH3:13][S:14]([NH2:17])(=[O:16])=[O:15].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:17][S:14]([CH3:13])(=[O:16])=[O:15])=[O:8]
Reactant: CS(N)(=O)=O
Reactant: Cc1cc(F)c(C(=O)O)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(F)c(C(=O)NS(C)(=O)=O)cc1Cl
Yield: 115.8 %

Procedure:
A solution of 5-chloro-2-fluoro-4-methylbenzoic acid (1 g, 5.2 mmol), methanesulfonamide (760 mg, 8.0 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.5 g, 8.0 mmol) and 4-dimethylaminopyridine (1.5 g, 8.0 mmol) in DCM (20 mL) was stirred at room temperature for 16 hrs. The reaction was quenched by water (5 mL), adjusted pH to 1 with HCl (1 M) and the resulting mixture was extracted with DCM (100 mL×3). The combined organic layers were concentrated in vacuo and the residue was recrystallized with petroleum ether and ethyl acetate to give desired product (1.6 g crude). LCMS (ESI) m/z: 263.9 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:6][C:7]2[C:8](=[CH:12][CH:13]=1)[N:9]=[N:10][N:11]=2)=[O:4].[H-].[Na+].[CH3:16]I>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]2[N:9]([CH3:16])[N:10]=[N:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)C1=CC=C2N=NN=C2C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)nnn2C
Reaction time: 0.33 h

Procedure:
To a stirred, cold (0° C.) solution of 1,2,3-benzotriazole-5-carboxylic acid methyl ester (2.51 g) in dimethylformamide was added 60% sodium hydride (370 mg) portion wise. After 20 minutes, methyl iodide (0.87 mL) was added. The reaction was quenched by the addition of water after 30 minutes. The mixture was extracted with ethyl acetate; the extracts were washed with water, and brine, and dried (sodium sulfate). Filtration and concentration of the filtrate gave a residue from which 716 mg of 1-methyl-1H-benzotriazole-5-carboxylic acid methyl ester crystallized (hot ethyl acetate). The mother liquor was purified by flash chromatography (eluting with 3:2 hexanes/ethyl acetate) to give 890 mg of 2-methyl-2H-benzotriazole-5-carboxylic acid methyl ester and 490 mg of 3-methyl-3H-benzotriazole-5-carboxylic acid methyl ester. Structural assignments were made on the basis of proton NMR and nOe experiments.
Reaction SMILES: O.C(=O)([O-])[O-].[K+].[K+].[C:8]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.[CH2:23]([O:25][C:26]([C:28]1[N:29]([CH3:38])[C:30]([CH2:36][CH3:37])=[C:31]([C:34]#[N:35])[C:32]=1I)=[O:27])[CH3:24]>[Pd].C(O)C>[CH2:23]([O:25][C:26]([C:28]1[N:29]([CH3:38])[C:30]([CH2:36][CH3:37])=[C:31]([C:34]#[N:35])[C:32]=1[C:11]1[CH:12]=[CH:13][C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:9][CH:10]=1)=[O:27])[CH3:24]
Reactant: CCOC(=O)c1c(I)c(C#N)c(CC)n1C
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(-c3ccccc3)cc2)c(C#N)c(CC)n1C
Temperature: 80 °C
Yield: 88.7 %

Procedure:
Charge deionized water (0.50 L), potassium carbonate (66.3 grams, 0.48 mol), and 4-biphenyl boronic acid (62.4 grams, 0.315 mol) and ethanol (1.4 L) to a 3 L 3-neck reaction flask equipped with a mechanical stirrer, condenser, heating mantle, thermocouple, and nitrogen inlet. Stir the mixture to dissolve the solids. Add 4-cyano-5-ethyl-3-iodo-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (Preparation 38), additional ethanol (0.90 L) and stir the mixture while the flask is inerted with nitrogen. Add palladium black to the reaction mixture and heat the mixture to reflux at 80° C. Stir the reaction mixture at reflux for 70 minutes. Add ethyl acetate (0.50 L) and filter the mixture through Whatman® GF/F to remove palladium black. Concentrate the filtrate to about 0.6 L by distillation and filter the resulting suspension to collect the precipitate. Rinse the filter cake with ethanol (0.441 L) and vacuum-dry to afford 95.6 grams of the title compound in 88.7% yield.
Reaction SMILES: [OH:1][C@@H:2]([CH2:24][OH:25])[CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:23])[C:8](=[O:22])[N:9]([CH3:21])[C:10]2=[O:20])=[CH:5]1.[O-]S(C(F)(F)F)(=O)=O.[Bi+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[Cl:51][C:52]1[O:56][C:55]([CH:57]=O)=[CH:54][CH:53]=1>C(O)C>[Cl:51][C:52]1[O:56][C:55]([CH:57]2[C:5]3=[C:6]4[N:7]([CH3:23])[C:8](=[O:22])[N:9]([CH3:21])[C:10](=[O:20])[C:11]4=[C:12]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=4)[N:4]3[CH2:3][C@H:2]([CH2:24][OH:25])[O:1]2)=[CH:54][CH:53]=1
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)n(C[C@@H](O)CO)cc2n(C)c1=O
Reactant: O=Cc1ccc(Cl)o1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Bi+3]
Solvent: CCO
Product: Cn1c(=O)c2c(-c3cccc(F)c3)n3c(c2n(C)c1=O)C(c1ccc(Cl)o1)O[C@@H](CO)C3
Temperature: 100 °C

Procedure:
A mixture of (R)-6-(2,3-dihydroxypropyl)-5-(3-fluorophenyl)-1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (step 2) (806 mg, 2.320 mmol), bismuth triflate (305 mg, 0.464 mmol) and 5-chlorofuran-2-carbaldehyde (commercial) (333 mg, 2.55 mmol) in ethanol (13.6 mL) was heated under microwave irradiation at 100° C. for 25 mins. The mixture was evaporated under vacuum. The residue was partitioned between 0.1 M HCl (50 mL) and DCM (100 mL) and extracted with DCM (3×100 mL). The combined organic extracts were dried over magnesium sulfate and evaporated under vacuum. Purification by chromatography on silica, eluting with 0-60% EtOAc/hexane afforded the title compound as a mixture of diastereomers.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]2=[N:6][C:7]=1[Cl:8].Cl.[F:14][C:15]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:16]=1[O:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:8][C:7]1[N:6]=[C:5]2[CH:9]=[N:10][CH:11]=[CH:12][C:4]2=[N:3][C:2]=1[N:21]1[CH2:20][CH2:19][CH:18]([O:17][C:16]2[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:15]=2[F:14])[CH2:23][CH2:22]1
Reactant: Clc1nc2ccncc2nc1Cl
Reactant: Fc1ccc(OC2CCNCC2)c(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(OC2CCN(c3nc4ccncc4nc3Cl)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
A solution of 2,3-dichloropyrido[3,4-b]pyrazine (492 mg, 2.460 mmol) in DCM (5 mL) at 0° C. was treated with 4-(2,4-difluorophenoxyl)piperidine hydrochloride (676 mg, 2.71 mmol) and DIPEA (1.29 mL, 7.38 mmol). The reaction mixture was allowed to stir overnight, gradually warming to room temperature. The reaction mixture was quenched with the addition of saturated aqueous NH4Cl and was extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography using a gradient of 20% to 60% EtOAc in heptanes to give the title compound as a pale yellow solid (736.2 mg, 79%). ESI-MS m/z [M+H]+ 377.4.