Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:13]([F:16])([F:15])[F:14].[O:17]=[CH:18][C:19]1[CH:27]=[CH:26][C:24]([OH:25])=[C:21]([O:22][CH3:23])[CH:20]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[F:14][C:13]([F:16])([F:15])[C:4]1[CH:5]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:8][C:3]=1[CH2:2][O:25][C:24]1[CH:26]=[CH:27][C:19]([CH:18]=[O:17])=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Temperature: 70 °C
Reaction time: 15 h
Yield: 100.2 %

Procedure:
To a flask was added 1-bromomethyl-2,4-bis-trifluoromethyl-benzene (2.27 g, 7.39 mmol), vanillin (1.12 g, 1 equiv), DMF (23 mL) and fine mesh K2CO3 (5.11 g, 37 mmol). The reaction slurry was stirred at 70° C. for 15 h. The reaction solution was diluted with EtOAc (120 mL), filtered through a Buchner funnel, washed with sat NH4Cl (50 mL×2), dried over Na2SO4, filtered, and concentrated. The crude material was chromatographed (SiO2, Hex/EtOAc: 100:0 to 70:30) to yield intermediate product (2.79 g, 86%). 1H NMR (400 MHz, CDCl3) δ 9.88 (s, 1H), 7.97 (d, J=8 Hz, 1H), 7.96 (s, 1H), 7.85 (d, J=8 Hz, 1H), 7.48 (s, 1H), 7.42 (d, J=8 Hz, 1H), 6.93 (d, J=8 Hz, 1H), 5.48 (s, 2H), 3.99 (s, 3H); MS (ESI) 379 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:14][CH:13]=1>C1(C)C=CC=CC=1.C1COCC1>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:17]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)CCC(=O)c1ccc(NC(=O)c2ccc(C)cc2)cc1
Yield: 40.4 %

Procedure:
A mixture of 4-methyl-benzoyl chloride (0.74 mL, 0.0056 mol) and 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.93 g, 0.0045 mol) in toluene (22 mL) was refluxed under nitrogen for 17 hours and allowed to cool. The mixture was diluted with THF (20 mL), and washed with 0.1 M aqueous sodium hydroxide. The solids that remained undisolved were filtered, washed with water, and dried in house vacuum (40° C., air bleed) to give 0.592 g of 4-[4-(4-methyl-benzoylamino)-phenyl]-4-oxo-butyric acid, methyl ester as an off-white solid; mp 192-195° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:9][CH2:10][Cl:11]>>[ClH:11].[Cl:11][CH2:10][CH2:9][N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: ClCCBr
Reactant: CN1CCNCC1
Product: CN1CCN(CCCl)CC1
Product: Cl

Procedure:
N-methyl piperazine and 1-bromo-2-chloroethane are reacted using the procedure for Example OO to afford 1-(2-chloroethyl)-4-methylpiperazine hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:51]([O:54][C@@H:55]1[C@@H:61]([O:62][C:63](=[O:65])[CH3:64])[C@H:60]([O:66][C:67](=[O:69])[CH3:68])[CH2:59][S:58][CH:56]1O)(=[O:53])[CH3:52]>C1COCC1>[CH3:3][C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH:56]3[S:58][CH2:59][C@@H:60]([O:66][C:67](=[O:69])[CH3:68])[C@H:61]([O:62][C:63](=[O:65])[CH3:64])[C@H:55]3[O:54][C:51](=[O:53])[CH3:52])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])[CH3:2]
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)CSC(O)[C@@H]1OC(C)=O
Reactant: CC(C)(C)OC(=O)n1ccc2cc(O)ccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)CSC(Oc2ccc3c(ccn3C(=O)OC(C)(C)C)c2)[C@@H]1OC(C)=O
Temperature: 45 °C
Reaction time: 3 h
Yield: 11 %

Procedure:
A solution of 1.75 g (7.51 mM) of 5-hydroxy-1H-indole-1-carboxylic acid tert-butyl ester in 25 ml of THF, 2.73 g (13.5 mM) of diisopropylazodicarboxylate and 3.54 g (13.5 mM) of triphenylphosphine are added to a solution of 2.85 g (9.75 mM) of 2,3,4-tri-O-acetyl-5-thio-D-xylopyranose in 50 ml of THF. The reaction mixture is stirred at 45° C. for 3 hours and then concentrated under reduced pressure. The evaporation residue is dissolved in ethyl acetate and the organic phase is washed with a 1N solution of sodium hydroxide, and then with a concentrated aqueous solution of ammonium chloride. The organic phase is subsequently dried over magnesium sulfate and concentrated under reduced pressure. The evaporation residue is purified by C18-grafted silica chromatography, elution being carried out with an acetonitrile/water mixture (7/3; v/v). The desired product is obtained in the form of a pale yellow solid with a yield of 11%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[F:8].Br[C:13]1[CH:14]=[CH:15][C:16]([OH:22])=[C:17]([CH:21]=1)[C:18]([OH:20])=[O:19].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[CH:15][C:16]([OH:22])=[C:17]([C:18]([OH:20])=[O:19])[CH:21]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: O=C(O)c1cc(Br)ccc1O
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: COCCOC
Product: O=C(O)c1cc(-c2ccc(F)c(Cl)c2)ccc1O
Temperature: 80 °C
Yield: 43.8 %

Procedure:
3-Chloro-4-fluoro-phenylboronic acid (3.2 g, 18.4 mmol), 5-bromo-2-hydroxy-benzoic acid (4.0 g, 18.4 mmol), and Pd (PPh3)4 (1.67 g, 1.84 mmol) were dissolved in 250 mL of DME, a 1 M Na2CO3 solution (46 mL, 46.0 mmol) added and the mixture heated to 80° C. for 20 h. The reaction mixture was filtered, partially evaporated and EtOAc (200 mL) and 1 N HCl (100 mL) added. The organic layer washed with 1N HCl and saturated sodium bicarbonate, dried over sodium sulfate, and evaporated. The crude material was filtered through a silica plug (THF) to give 3′-chloro-4′-fluoro-4-hydroxy-biphenyl-3-carboxylic acid (2.15 g).
Reaction SMILES: C(Cl)Cl.C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:18]=[C:19]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)[C:20]([Cl:23])=[CH:21][CH:22]=1)=[O:16])(C)(C)C.FC(F)(F)C(O)=O>O>[NH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:18]=[C:19]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)[C:20]([Cl:23])=[CH:21][CH:22]=1)=[O:16]
Reactant: CC(C)(C)OC(=O)NCCCNC(=O)c1ccc(Cl)c(-c2ccc(-c3ccccc3)cc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: NCCCNC(=O)c1ccc(Cl)c(-c2ccc(-c3ccccc3)cc2)c1
Reaction time: 1 h
Yield: 73.5 %

Procedure:
To an oven dried 10 mL round bottom flask was added 5 mL of DCM, 10 mg (0.022 mmol) of 328, 1.5 mL trifluoroacetic acid (TFA), and 50 μL H2O. The solution was stirred for 1 hour and quenched with 1 mL of saturated NaHCO3. The product was taken up in 10 mL of DCM and washed with (3×5 mL) H2O and dried over Na2SO4. The organic solution was rotary evaporated to leave 5.9 mg of a pale yellow oil (73.6% yield). MS (ES+) m/z 365 (M+H); HPLC (214 nm), rt 7.06 min, 99.8%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH2:19]([O:26][C:27](=[O:37])[C@H:28]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH2:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO.C(Cl)Cl>[CH2:19]([O:26][C:27](=[O:37])[C@H:28]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH:29][C:15](=[O:17])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1

Procedure:
Following General Procedure B and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-phenylalanine benzyl ester hydrochloride (Bachem), the title compound was prepared as a solid (mp=170-171° C.). The reaction was monitored by tlc (Rf=0.7 in 5% MeOH/methylene chloride) and the product was purified by recrystallization from MeOH.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][CH2:7][O:8][C:9]1[CH:35]=[CH:34][C:12]2[C@:13]3([OH:33])[C@@H:18]([OH:19])[CH2:17][C@@H:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C@:14]3([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[O:15][C:11]=2[CH:10]=1>CN(C=O)C>[N:1]([CH2:6][CH2:7][O:8][C:9]1[CH:35]=[CH:34][C:12]2[C@:13]3([OH:33])[C@@H:18]([OH:19])[CH2:17][C@@H:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C@:14]3([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)[O:15][C:11]=2[CH:10]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O[C@H]1C[C@@H](c2ccccc2)[C@]2(c3ccc(Cl)cc3)Oc3cc(OCCCl)ccc3[C@]12O
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCOc1ccc2c(c1)O[C@@]1(c3ccc(Cl)cc3)[C@H](c3ccccc3)C[C@H](O)[C@@]21O
Temperature: 100 °C

Procedure:
56.9 mg (0.87 mmol) of sodium azide are added to 200 mg (0.44 mmol) of (1S*,3S*,3aR*,8bS*)-6-(2-chloroethoxy)-3a-(4-chlorophenyl)-3-phenyl-2,3,3a,8b-tetrahydrocyclopenta[b]benzofuran-1,8b-(1H)-diol (Example 48A) in 4 ml of DMF under argon, and the mixture is heated at 100° C. overnight. After cooling and concentration, the residue is taken up in water and dichloromethane, the phases are separated, the aqueous phase is extracted twice with dichloromethane, and the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. Gradient chromatography on silica gel 60 (mobile phase: toluene/ethyl acetate) results in 190 mg (94% of theory) of the product.
Reaction SMILES: [C:1]([OH:12])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([N:15]([CH2:23][CH3:24])[CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21]O)[CH3:14]>>[C:1]([O:12][CH2:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][N:15]([CH2:23][CH3:24])[CH2:13][CH3:14])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CCN(CC)CCOCCCO
Product: CCCCCCC/C=C/C(=O)OCCCOCCN(CC)CC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and 3-(2-(diethylamino)ethoxy)propan-1-ol as starting materials to give the aimed compound. Compound 14 was obtained by the purification using silica gel column chromatography.
Reaction SMILES: [C:1]([CH2:3][C:4]([N:6]([CH2:8][CH3:9])[CH3:7])=[O:5])#[N:2].C(N(CC)CC)C.[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[C:20]([N+:27]([O-:29])=[O:28])[CH:19]=1.[OH-].[Na+]>C1COCC1.CCOCC>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([CH:3]([C:1]#[N:2])[C:4]([N:6]([CH2:8][CH3:9])[CH3:7])=[O:5])=[O:23])=[C:20]([N+:27]([O-:29])=[O:28])[CH:19]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CCN(C)C(=O)CC#N
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCN(C)C(=O)C(C#N)C(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.8 %

Procedure:
2-cyano-N-ethyl-N-methylacetamide (5.56 g; 0.044 mol) and triethylamine (13.36 g; 0.132 mol) were dissolved in dry THF (100 ml) under dry nitrogen, and 4-chloro-2-nitrobenzoyl chloride (9.68 g; 0.044 mol) in dry THF (100 ml) added dropwise over 45 min. The mixture was stirred at room temperature under dry nitrogen for 18 hours, during which time a precipitate was formed. The solution was filtered, washing the solid with THF and adding the washings to the solution, and evaporated, giving a residue which was treated with 2M sodium hydroxide solution (200 ml), and this then washed with CH2Cl2 (2×100 ml). The aqueous solution was acidified to pH 1 with concentrated hydrochloric acid, and extracted into CH2Cl2 (3×200 m). The extracts were combined, dried (Na2SO4), filtered and evaporated, giving a very viscous oil which solidified. Trituration with ether (20 ml) gave 2-(4-chloro-2-nitrobenzoyl)-2-cyano-N-ethyl-N-methylacetamide (6.10 g; 45%) as a solid, m.p. 95°-98° C., (Found, C: 49.60; H: 3.87; N: 13.25; Cl: 12.28. C13H12ClN3O4 requires C: 50.40; H: 3.88; N: 13.57; Cl: 11.47%, d (CDCl3); 60 MHz) 1.3 (3H, t, J=7, Hz), 3.2 (3H, s), 3.7 (2H, q, J=7 Hz), 7.4-7.55 (1H, d, J=8 Hz), 7.6-7.8 (1H, dd, J=8, 2 Hz), 8.1 (1H, d, J=2 Hz) and 16.4 (1H, br, s), vmax (nujol) 2200, 1590 (shoulder) and 1500.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:15])[C:5]([C:12]([OH:14])=O)=[CH:6][NH:7]2.[NH2:16][C:17]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]3[CH2:30][CH2:31][CH:26]2[CH2:27][CH2:28]3)=[CH:21][C:18]=1[C:19]#[N:20].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.N1C=CC=CC=1>CC1CCCO1.C(OCC)(=O)C>[CH:29]12[N:25]([C:22]3[CH:23]=[CH:24][C:17]([NH:16][C:12]([C:5]4[C:4](=[O:15])[C:3]5[C:8](=[CH:9][CH:10]=[CH:11][C:2]=5[CH3:1])[NH:7][CH:6]=4)=[O:14])=[C:18]([C:19]#[N:20])[CH:21]=3)[CH:26]([CH2:31][CH2:30]1)[CH2:27][CH2:28]2
Reactant: N#Cc1cc(N2C3CCC2CC3)ccc1N
Reactant: Cc1cccc2[nH]cc(C(=O)O)c(=O)c12
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CC1CCCO1
Solvent: c1ccncc1
Product: Cc1cccc2[nH]cc(C(=O)Nc3ccc(N4C5CCC4CC5)cc3C#N)c(=O)c12
Temperature: 100 °C
Yield: 49.3 %

Procedure:
To a solution of 5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 35 (162 mg, 0.80 mmol) and 2-amino-5-(7-azabicyclo[2.2.1]heptan-7-yl)benzonitrile 23 (170 mg, 0.80 mmol) in 2-methyltetrahydrofuran (1.5 mL) was added propyl phosphonic acid cyclic anhydride (50% solution in ethyl acetate, 949.5 μL, 1.605 mmol) and pyridine (126 mg, 129 μL, 1.60 mmol). The reaction was capped and heated at 100° C. for 65 min with microwave irradiation. The reaction was cooled to room temperature, diluted with ethyl acetate (10 mL), and quenched with saturated Na2CO3 solution (6 mL). The organic layer was dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (0-35% ethyl acetate in dichloromethane) provided N-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-cyanophenyl)-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxamide (157 mg, 49% yield). LC/MS m/z 399.3 [M+H]+, retention time 1.47 min (RP—C18, 10-99% CH3CN/0.05% TFA over 3 min). 1H NMR (400.0 MHz, DMSO-d6) δ 12.77 (s, 1H), 12.75 (s, 1H), 8.77 (s, 1H), 8.11 (d, J=9.1 Hz, 1H), 7.64-7.60 (m, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.34 (d, J=2.8 Hz, 1H), 7.27 (dd, J=2.8, 9.1 Hz, 1H), 7.23 (d, J=7.2 Hz, 1H), 4.32 (s, 2H), 2.91 (s, 3H), 1.65 (d, J=7.2 Hz, 4H), 1.42 (d, J=6.8 Hz, 4H).
Reaction SMILES: CN(OC)[C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]#[C:11][CH2:12][O:13][CH3:14].[CH2:18]([Mg]Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH3:14][O:13][CH2:12][C:11]#[C:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3](=[O:15])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COCC#Cc1ccccc1C(=O)N(C)OC
Reactant: Cl[Mg]Cc1ccccc1
Solvent: C1CCOC1
Product: COCC#Cc1ccccc1C(=O)Cc1ccccc1
Yield: 53 %

Procedure:
N-Methyl-N-(methyloxy)-2-[3-(methyloxy)-1-propyn-1-yl]benzamide (143) (0.35 g, 1.50 mmol) was treated with benzylmagnesium chloride in THF to give 0.21 g (53%) of the title compound (144) as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 3.44 (s, 3H), 4.34 (s, 2H), 4.38 (s, 2H), 7.20-7.26 (m, 3H), 7.27-7.38 (m, 3H), 7.38-7.44 (m, 1H), 7.54 (d, J=7.7 Hz, 1H), 7.57 (d, J=7.7 Hz, 1H). LCMS (ESI): m/z 265 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:26][C:25]=3[O:27][CH3:28])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: COc1ccc(B(O)O)c(OC)c1
Product: CCCNC(=O)c1nnc2c(-c3ccc(OC)cc3OC)cccc2c1N
Yield: 72.8 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (100 mg, 0.33 mmol) and 2,4-dimethoxyphenyl boronic acid (148 mg, 0.97 mmol) were reacted to afford the title compound (88 mg, 75.1% yield) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.57 (br, 1H), 7.84 (dd, J=8.2 Hz, J′=1.4 Hz, 1H), 7.75 (dd, J=7.1 Hz, J′=1.4 Hz, 1H), 7.68 (t, J=7.6 Hz, 1H), 7.29 (m, overlapped with CHCl3), 6.58-6.60 (m, 2H), 3.87 (s, 3H), 3.69 (s, 3H), 3.45 (q, 6.7 Hz, 2H), 1.65 (m, J=7.3 Hz, 2H), 0.99 (t, J=7.4 Hz, 3H) MS APCI, m/z=367 (M+H) HPLC 1.94 min.
Reaction SMILES: [C:1](OC)(=O)[CH:2]([CH3:4])C.[O-:8][CH2:9][CH3:10].[Na+].[C:12](#[N:14])[CH3:13]>CO>[CH3:1][CH:2]([CH3:4])[C:10](=[C:9]=[O:8])[CH2:13][C:12]#[N:14]
Reactant: CC#N
Reactant: CC[O-]
Reactant: COC(=O)C(C)C
Agent: [Na+]
Solvent: CO
Product: CC(C)C(=C=O)CC#N
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a 1 L of round bottom flask were added methyl isobutyrate (100 g, 0.98 mol), sodium ethoxide (66.63 g, 0.98 mol), acetonitrile (53.9 g, 0.98 mol) and 300 ml of methanol at room temperature. The resultant mixture was slowly warmed and refluxed. The reaction was kept for 6 hr. The reaction was stopped and cooled to room temperature. The solvent was rotary-evaporated. The product was distilled under reduced pressure (12 mmHg) to collect at 102-104° C. 56.2 g of the pure title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:3][C@H:4]([OH:23])[C@@H:5]([NH:13][C:14]([O:16][CH2:17][C:18]1[S:22][CH:21]=[N:20][CH:19]=1)=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1C=CC2N(O)N=NC=2C=1.[CH3:41][N:42]([C:52]([NH:54][C@H:55]([C:59](O)=[O:60])[CH:56]([CH3:58])[CH3:57])=[O:53])[CH2:43][C:44]1[N:45]=[C:46]([CH:49]([CH3:51])[CH3:50])[S:47][CH:48]=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[CH3:41][N:42]([C:52]([NH:54][C@H:55]([C:59]([NH:1][C@@H:2]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:3][C@H:4]([OH:23])[C@@H:5]([NH:13][C:14]([O:16][CH2:17][C:18]1[S:22][CH:21]=[N:20][CH:19]=1)=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:60])[CH:56]([CH3:58])[CH3:57])=[O:53])[CH2:43][C:44]1[N:45]=[C:46]([CH:49]([CH3:51])[CH3:50])[S:47][CH:48]=1
Reactant: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the product of Example 70 (9.1 g, 21.4 mmol), HOBT (3.6 g, 23.5 mmol) and N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)-carbonyl)-L-valine (7.37 g, 23.5 mmol) in THF (170 mL) was added DCC (4.85 g, 23.5 mmol). The solution was stirred at ambient temperature for 16 hours (DCU precipitates). THF was removed under vacuum and the resulting paste was stirred with cold 1N HCl (106 mL at 5° C.) for 3 hours to dissolve the the crude product. The DCU was removed by filtration and the filter cake was washed with 1N HCl (30 mL). KH2PO4 (3.2 g) was dissolved in the combined HCl filtrates. The solution was mixed with ethyl acetate (80 mL) and neutralized to pH 7 with aqueous NaOH (60.3 g of 10% w/w NaOH). The aqueous layer was extracted with another 25 mL ethyl acetate and the combined ethyl acetate extracts were washed with aqueous NaHCO3 (2×37 mL of 5% w/w NaHCO3). The organic layer was dried with Na2SO4 (13 g), filtered, and concentrated under vacuum at ≤45° C. The residue was dissolved in a 1:1 ethyl acetate/heptane mixture (200 mL) at 70° C. The solution was allowed to cool slowly and stirred overnight at room temperature to provide a thick slurry. The product was collected by filtration and washed with 1:1 ethyl acetate/heptane (20 mL). The product was dried briefly at 55° C. in a vacuum oven to obtain an approximate weight prior to the second crystallization (12.85 g, 83%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[N:14]([CH3:15])[CH:13]=[CH:12][C:7]=2[C:8](Cl)=[N:9][CH:10]=1)=[O:4].[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].CS(O)(=O)=O>O1CCOCC1.CO>[CH3:1][O:2][C:3]([C:5]1[C:6]2[N:14]([CH3:15])[CH:13]=[CH:12][C:7]=2[C:8]([NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:17]([Cl:16])[CH:18]=2)=[N:9][CH:10]=1)=[O:4]
Reactant: Nc1cccc(Cl)c1
Reactant: COC(=O)c1cnc(Cl)c2ccn(C)c12
Agent: CS(=O)(=O)O
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1cnc(Nc2cccc(Cl)c2)c2ccn(C)c12

Procedure:
4-Chloro-1-methyl-1H-pyrrolo[3,2-c]pyridine-7-carboxylic acid methyl ester (1.04 g), 3-chloroaniline (0.97 ml) and methanesulfonic acid (0.60 ml) in 1,4-dioxan (10 ml) were irradiated at 180° C. for 30 minutes with microwaves. The solid mass obtained was dissolved in methanol and the solvent evaporated. The residue was dissolved in ethyl acetate and washed with water followed by saturated brine solution then dried (MgSO4)), filtered and evaporated to yield a brown oil (1.6 g). The brown oil was purified by column chromatography on a Biotage® 40M column eluting in 20% ethyl acetate/iso-hexane, to give the title compound as an off-white solid (0.62 g).
Reaction SMILES: CN(C)C1C=CC=CC=1.[CH2:10]([S:17][C:18]1[N:28]=[C:21]2[CH:22]=[C:23]([CH3:27])[CH:24]=[C:25](O)[N:20]2[N:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCCCCC.P(Cl)(Cl)([Cl:37])=O>C(OCC)(=O)C>[CH2:10]([S:17][C:18]1[N:28]=[C:21]2[CH:22]=[C:23]([CH3:27])[CH:24]=[C:25]([Cl:37])[N:20]2[N:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)n2nc(SCc3ccccc3)nc2c1
Solvent: CCOC(C)=O
Solvent: CN(C)c1ccccc1
Solvent: CCCCCC
Product: Cc1cc(Cl)n2nc(SCc3ccccc3)nc2c1

Procedure:
N,N-Dimethylaniline (21,9 g, 0.18 mol) was added slowly to a mixture of 2-benzylthio-5-hydroxyl7-methyl[1,2,4]triazolo[1,5-a]pyridine (44.5 g, 0.164 mol) in 150 mL of phosphorus oxychloride with stirring. The mixture was heated at reflux with stirring for 20 hours. The excess phosphorus oxychloride was then removed by evaporation under reduced pressure. The residue obtained was dissolved in ethyl acetate, washed well with water and quickly concentrated by evaporation under reduced pressure to drive off the excess water. The residue was again dissolved in ethyl acetate and the resulting mixture was filtered with suction through a bed of silica gel. The filtrate was concentrated by evaporation under reduced pressure and the residue obtained was mixed with hexane. The resulting mixture was filtered to recover the solids and dried to obtain the 37.5 g. (79 percent of theory) of the title compound as a tan powder melting at 108°-110° C.