Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10].[CH3:12][C:13]1([CH3:27])[C:17]([CH3:19])([CH3:18])[O:16][B:15]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[O:14]1>>[CH3:18][C:17]1([CH3:19])[C:13]([CH3:12])([CH3:27])[O:14][B:15]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N+:9]([O-:11])=[O:10])=[CH:22][CH:21]=2)[O:16]1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: O=[N+]([O-])c1ccccc1CBr
Product: CC1(C)OB(c2ccc(OCc3ccccc3[N+](=O)[O-])cc2)OC1(C)C
Yield: 62 %

Procedure:
Alkylation of 1-Bromomethyl-2-nitro-benzene with 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol was carried out according to procedures in Step 5A for Example 2A to give 4,4,5,5-Tetramethyl-2-[4-(2-nitro-benzyloxy)-phenyl]-[1,3,2]dioxaborolane in 62% yield. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.3 (s, 12 H) 5.5 (s, 2 H) 7.0 (d, J=8.6 Hz, 2 H) 7.5 (m, 1 H) 7.7 (m, 1 H) 7.8 (d, J=8.6 Hz, 2 H) 7.9 (dd, J=7.8, 1.0 Hz, 1 H) 8.2 (dd, J=8.1, 1.3 Hz, 1 H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@H:6]2[C@H:5]([N:13]2[C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=4[O:32][CH3:33])[C:16]=3[CH:15]=[CH:14]2)[O:4]1.O=[C:35]1[CH2:38][CH:37]([CH2:39][CH2:40][C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:42])[CH2:36]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.CO.C(Cl)Cl>[CH3:33][O:32][C:25]1[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:24]=1[CH2:23][NH:22][C:21]1[C:16]2[CH:15]=[CH:14][N:13]([C@H:5]3[C@@H:6]4[O:10][C:9]([CH3:12])([CH3:11])[O:8][C@@H:7]4[C@@H:3]([CH2:2][NH:1][CH:35]4[CH2:38][CH:37]([CH2:39][CH2:40][C:41]([O:43][CH2:44][C:45]5[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=5)=[O:42])[CH2:36]4)[O:4]3)[C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: O=C1CC(CCC(=O)OCc2ccccc2)C1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CNC3CC(CCC(=O)OCc4ccccc4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 30 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
A solution of 7-((3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (20 g, 43.91 mmol), benzyl 3-(3-oxocyclobutyl)propanoate (12.2 g, 52.69 mmol) and HOAc (15 mL) in DCE (200 mL) was stirred at 30° C. for 3 h. NaBH(OAc)3 (18.6 g, 87.81 mmol) was added and the reaction mixture was stirred at 30° C. for another 1 h. The mixture was washed with water (100 mL×2) and brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography using EA:DCM:MeOH=10:10:1 as eluent to afford the desired compound (21 g, yield: 65%, cis/trans=52/47) as a yellow solid. 1H NMR (500 MHz, MeOD): δH 8.16 (brs, 1H), 7.36-7.29 (m, 5H), 7.22 (d, J=3.5 Hz, 1H), 7.15 (d, J=8.5 Hz, 1H), 6.66 (brs, 1H), 6.54 (d, J=2.0 Hz, 1H), 6.43 (dd, J=8.5 and 2.0 Hz, 1H), 6.20 (brs, 1H), 5.41-5.39 (m, 1H), 5.08 (d, J=3.0 Hz, 1H), 4.99-4.95 (m, 1H), 4.66 (s, 2H), 4.30-4.25 (m, 1H), 3.83 (s, 3H), 3.76 (s, 3H), 3.38-3.35 (m, 0.5H), 3.11-3.06 (m, 0.5H), 2.92-2.82 (m, 2H), 2.29-2.18 (m, 3H), 2.12-2.05 (m, 0.5H), 1.90-1.68 (m, 4H), 1.63-1.61 (m, 1H), 1.60 (s, 3H), 1.38 (s, 3H), 1.35-1.28 (m, 0.5H), 1.25 (t, J=6.5 Hz, 2H), 1.15-1.12 (m, 0.5H) ppm; ESI-MS (negative mode, m/z): 670.3 [M−1]+.
Reaction SMILES: [ClH:1].[C:2]1([CH:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[NH2:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14](O)[CH3:15]>>[ClH:1].[CH3:8][CH:9]1[NH:13][C:15](=[N:13][CH:9]2[CH2:10][CH2:11][CH2:12][CH:8]2[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:14][CH2:10]1
Reactant: CCO
Reactant: NC1CCCC1c1ccccc1
Agent: Cl
Product: CC1CCC(=NC2CCCC2c2ccccc2)N1
Temperature: -20 °C
Reaction time: 144 h

Procedure:
A slurry of 3.0 g (0.0152 mole) of powdered 2-phenylcyclopentylamine hydrochloride and 3 ml of 5,O-dimethylbutyrolactim is allowed to stand at room temperature for 6 days with occasional stirring during which time sufficient ethanol is added to maintain the slurry. The slurry is then cooled to -20° C., and after about four hours a precipitate forms. The precipitate is collected and recrystallized several times from acetone-methanol to give 5-methyl-2-[(2-phenylcyclopentyl)imino]pyrrolidine hydrochloride, M.P. 175°-178° C.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:19]2=[O:51])=[N:9]1)=O)(C)(C)C.Cl.C(OCC)C>O1CCOCC1>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:19]2=[O:51])=[N:9]1
Reactant: COc1ccccc1N(C(=O)CN1C(=O)C(Cc2nn(C(=O)OC(C)(C)C)c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21)C(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COc1ccccc1N(C(=O)CN1C(=O)C(Cc2n[nH]c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-[3-(1-tert-butoxycarbonyl-1H-indazol-3-ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(2-methoxy-phenyl) acetamide, prepared as in Intermediate 73, (260 mg, 0.377 mmol) and 4N HCl in dioxane (2 mL) is stirred at RT for 2 h. Diethyl ether (40 mL) is added and the resultant mixture stirred vigorously for 20 min. The solids were allowed to settle and the solvent is decanted. This procedure is repeated three times and the final gum dried by concentration in vacuo. Recrystallisation from 5% methanol in ethyl acetate afforded the title compound (126 mg) as a white powdery solid, which exists as 3:2 mixture of rotamers (major rotamer recorded): 1H NMR (300 MHz, CDCl3) δ7.98 (t, 1H, J=8.0), 7.70 (m, 1H), 7.61 (s, 1H), 7.40-6.90 (m, 15H), 5.05 (m, 1H, J=6.9), 4.45 (d, 2H, J=16.4), 4.25 (d, 1H, J=17.5), 4.07 (d, 1H, J=16.4), 3.74 (m, 5H), 1.16 (m, 6H); Low resolution MS (FAB) m/e 588 (M+); Tr =27.29 min (RP-HPLC, 100% A to 100% C, 30 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:18])[C:7]=1[CH2:8][S:9][C:10]1[N:15]=[C:14]([NH2:16])[CH:13]=[C:12]([CH3:17])[N:11]=1.C([O-])(O)=O.[Na+].[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[Cl:18][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][S:9][C:10]1[N:15]=[C:14]([NH:16][C:24](=[O:26])[CH3:25])[CH:13]=[C:12]([CH3:17])[N:11]=1
Reactant: Cc1cc(N)nc(SCc2c(Cl)cncc2Cl)n1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)Nc1cc(C)nc(SCc2c(Cl)cncc2Cl)n1
Temperature: 25 °C
Yield: 23 %

Procedure:
A mixture of 2-{[(3,5-dichloropyridin-4-yl)methyl]sulfanyl}-6-methylpyrimidin-4-amine (500 mg, 1.7 mmol) in acetic anhydride (10 mL) was stirred at reflux overnight. After cooling to room temperature, the mixture was neutralized slowly with a saturated solution of NaHCO3 (aq.) until pH 7-8 was reached. The mixture was extracted with ethyl acetate (2×25 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude product was purified by flash chromatography (0-3% MeOH/CH2Cl2), affording the title compound (136 mg, 23% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.11 (s, 3H), 2.51 (s, 3H), 4.70 (s, 2H), 7.70 (s, 1H), 8.67 (s, 2H), 10.87 (s (br), 1H); M+ 287.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:9]=[CH:10]/[C:11]2[N:16]=[C:15](O)[CH:14]=[C:13]([CH3:18])[N:12]=2)[CH:6]=[CH:7][CH:8]=1.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:15]1[CH:14]=[C:13]([CH3:18])[N:12]=[C:11](/[CH:10]=[CH:9]/[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:16]=1
Reactant: COc1cccc(/C=C/c2nc(C)cc(O)n2)c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cccc(/C=C/c2nc(C)cc(Cl)n2)c1
Yield: 82 %

Procedure:
In analogy to example 12c),by heating (E)-2-[2-(3-methoxy-phenyl)-vinyl]-6-methyl-pyrimidin-4-ol (0.6 g, 2.48 mmol) in POCl3 (4.6 ml, 29.5 mmol) at 130° C. for 4.5 h there was obtained (E)-4-chloro-2-[2-(3-methoxy-phenyl)-vinyl]-6-methyl-pyrimidine (0.53 g, 82%) as an orange solid. ISP mass spectrum, m/e: 261.2 (M+1 calculated for C14H13ClN2O: 261).
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([CH3:15])([CH3:14])[C:7](=[O:13])[N:8]2[CH3:12])=[CH:4][CH:3]=1.[C:16](O)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1>>[F:11][C:10]1[C:2]([NH:1][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=2)=[CH:3][CH:4]=[C:5]2[C:9]=1[N:8]([CH3:12])[C:7](=[O:13])[C:6]2([CH3:15])[CH3:14]
Reactant: O=C(O)c1cccnc1
Reactant: CN1C(=O)C(C)(C)c2ccc(N)c(F)c21
Product: CN1C(=O)C(C)(C)c2ccc(NC(=O)c3cccnc3)c(F)c21

Procedure:
Prepared in analogy to example 26 from 6-amino-7-fluoro-1,3,3-trimethylindolin-2-one (example 13d) and nicotinic acid. The title compound was obtained as off-white crystals.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][N:13]1[CH:21]([CH2:22][CH2:23]O)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:25]>C(Cl)Cl>[CH3:12][N:13]1[CH:21]([CH2:22][CH2:23][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:25]
Reactant: CN1C(=O)c2ccccc2C1CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)CCC2c3ccccc3C(=O)N2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
p-Toluene sulfonyl chloride (2.3 g, 12.1 mmol) is added to a solution of TEA (3.5 g, 34.5 mmol) and 1,3-dihydro-2-methyl-3-(2-hydroxyethyl)-2H-isoindol-1-one (2.2 g, 11.5 mmol) in 50 mL of CH2Cl2 at room temperature under argon. The mixture is stirred at room temperature overnight and washed with water (3×50 mL). The organic layer is dried over Na2SO4 and evaporated to give an oil which is chromatographed in ethyl acetate over silica gel to give 1.5 g (38% yield) of 1,3-dihydro-2-methyl-3-(2-tosylethyl)-2H-isoindol-1-one.
Reaction SMILES: Cl/[C:2](=[N:8]\[NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])/[C:3]([O:5][CH2:6][CH3:7])=[O:4].CS[C:20]1[NH:24][N:23]=[CH:22][N:21]=1.C(N(CC)CC)C>O1CCOCC1>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:9]1[C:22]2=[N:23][N:24]=[CH:20][N:21]2[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:8]1
Reactant: CCOC(=O)/C(Cl)=N/NCc1ccccc1F
Reactant: CSc1ncn[nH]1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nn(Cc2ccccc2F)c2nncn12

Procedure:
Ethyl(2Z)-chloro[(2-fluorobenzyl)hydrazono]acetate (807 mg, 3.12 mmol) from example 2A, 5-(methylthio)-1H-1,2,4-triazole (359 mg, 3.12 mmol) and triethylamine (316 mg, 3.12 mmol) are dissolved in dioxane (5 ml) and heated under reflux for 6 h. This is followed by dilution with water and extraction with ethyl acetate. The organic phase is dried over sodium sulfate, and the crude product is purified by chromatography on silica gel (eluent: dichloromethane/methanol 50:1). 124 mg (9.5% of theory) of the desired product are obtained with 69% purity.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[S:30][C:11]3=[N:12][C:13]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:14][C:15](=[O:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C(O)C.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>[O:16]=[C:15]1[N:10]2[N:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:34]4[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=4)[CH:3]=3)[S:30][C:11]2=[N:12][C:13]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[CH:14]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(=O)n3nc(-c4cccc(Br)c4)sc3n2)CC1
Reactant: OB(O)c1ccncc1
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: CCO
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(=O)n3nc(-c4cccc(-c5ccncc5)c4)sc3n2)CC1
Temperature: 120 °C

Procedure:
To a solution of tert-butyl 4-(2-(3-bromophenyl)-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-1-carboxylate (40 mg, 0.081 mmol, 1.0 equiv) in 1 mL DMF, 0.5 mL ethanol and 0.25 mL water in a microwave vial is added 4-pyridineboronic acid (19.97 mg, 0.162 mmol, 2.0 equiv), sodium carbonate (25.8 mg, 0.244 mmol, 3.0 equiv), and tetrakis(triphenylphosphine)palladium(0) (4.69 mg, 4.06 μmol, 0.05 equiv). The mixture is heated in a microwave reactor for 30 min at 120° C. Upon completion the mixture is filtered through a thiol-SPE column (Stratospheres) and the resulting solution is concentrated in vacuo to give crude tert-butyl 4-(5-oxo-2-(3-(pyridin-4-yl)phenyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-1-carboxylate as a yellow oil. The residue is then taken on crude to the next reaction, which follows the same deprotection procedure as described in Step 3 of Example 1 to give 7-(piperazin-1-yl)-2-(3-(pyridin-4-yl)phenyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (12 mg, 38%) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.67 (dd, J=4.30, 1.57 Hz, 2H), 8.18 (s, 1H), 8.02 (dd, J=16.43, 8.22 Hz, 2H), 7.70-7.82 (m, 3H), 5.40 (s, 1H), 3.42-3.51 (m, 4H), 2.68-2.75 (m, 4H); LCMS: (electrospray+ve), m/z 391.1 (MH)+; HPLC: tR=2.82 min, UV254=100%. HRMS (ESI): m/z calcd for C20H19N6OS [M+H]+391.1321. found 391.1322.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][OH:10].[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]=[CH2:19])=[CH:14][CH:13]=1.CCN(CC)CC>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.CN(C=O)C>[F:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:9][OH:10])=[C:2](/[CH:19]=[CH:18]/[C:15]2[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: C=Cc1ccc(F)cc1
Reactant: OCc1ccc(F)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OCc1ccc(F)cc1/C=C/c1ccc(F)cc1
Temperature: 150 °C
Yield: 49.7 %

Procedure:
Charged (2-bromo-4-fluorophenyl)methanol (954 mg, 4.65 mmol), 4-fluoro-1-vinylbenzene (1.14 g, 9.31 mmol), Pd(PPh3)2Cl2 (49 mg, 0.07 mmol), Et3N (942 mg, 9.31 mmol) and DMF (5 mL) to a sealed tube, the mixture was then purged with nitrogen, heated to 150° C. for 3 h in microwave oven. The reaction mixture was filtered, the filtrate was then extracted with ethyl acetate, concentrated and purified by flash column chromatograph to give 569 mg of the title compound (50%). 1H NMR (400 MHz, CDCl3): δ 1.60 (1H, t, J=6.4 Hz), 4.78 (2H, d, J=6.4 Hz), 6.93-7.08 (4H, m), 7.31-7.35 (3H, m), 7.48-7.52 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:41])[C:5]([CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1)=[CH:6][N:7]2[CH:32]1CC1.CN>>[Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[C:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:41])[C:5]([CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1)=[CH:6][N:7]2[CH3:32]
Reactant: COc1ccc(COc2cc3c(c(Cl)c2OCc2ccc(OC)cc2)c(=O)c(CN2CCCC2)cn3C2CC2)cc1
Agent: CN
Product: COc1ccc(COc2cc3c(c(Cl)c2OCc2ccc(OC)cc2)c(=O)c(CN2CCCC2)cn3C)cc1

Procedure:
This compound was prepared according to the procedures for the preparation of 5-chloro-1-cyclopropyl-6,7-bis((4-methoxybenzyl)oxy)-3-(pyrrolidin-1-ylmethyl)quinolin-4(1H)-one as described in Examples 50a-50b and 54a-54g, utilizing methanamine in place of cyclopropanamine in Example 50a. LCMS: (M+H)+: 549.3.
Reaction SMILES: [O:1]([CH2:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:12][NH:13][CH2:14][CH2:15][CH2:16][P:17](=[O:20])([OH:19])[OH:18].[OH-].[Na+]>CC(C)=O>[OH:12][N:13]([CH2:14][CH2:15][CH2:16][P:17](=[O:18])([OH:20])[OH:19])[C:9](=[O:10])[CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(O)(O)CCCNO
Reactant: O=C(Cl)COc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(COc1ccccc1)N(O)CCCP(=O)(O)O
Yield: 3.6 %

Procedure:
A solution of phenoxyacetyl chloride (3.4 g.) in dried acetone (10 ml.) was added dropwise to a solution of 3-(N-hydroxyamino)propylphosphonic acid (1.51 g.) in mixture of 1 N aqueous sodium hydroxide solution (30 ml.) and acetone (20 ml.) under ice-cooling in the course of 10 minutes, and the mixture was stirred for an hour at the same temperature, and then adjusted to pH 10 with 1 N aqueous sodium hydroxide solution. The acetone was distilled off from the reaction mixture, and the remaining aqueous solution was adjusted to pH 2.0 with 10% hydrochloric acid, washed with ethyl ether, and then adjusted to pH 1.0 with 10% hydrochloric acid and saturated with sodium chloride. This solution was extracted twice with ethyl acetate (each 100 ml. portion) (insoluble materials (0.2 g.) produced at this stage were collected by filtration) and the combined extracts were dried over magnesium sulfate and evaporated to dryness under reduced pressure to give 3-(N-hydroxy-N-phenoxyacetylamino)propylphosphonic acid (0.1 g.). Insoluble materials produced above were identified with the same object compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][CH:7]=1.Cl[CH:16]([C:21](=O)[CH3:22])[C:17]([O:19][CH3:20])=[O:18]>C(O)C>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]2[O:11][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:21]([CH3:22])[N:12]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)C(Cl)C(C)=O
Reactant: NC(=O)c1ccc(OCCCCl)cc1
Solvent: CCO
Product: COC(=O)c1oc(-c2ccc(OCCCCl)cc2)nc1C
Yield: 96.6 %

Procedure:
A solution of 4-(3-chloro-propoxy)-benzamide (0.5 g, 2.34 mmol, 1 eq) and methyl 2-chloro-3-oxobutanoate (0.7 ml, 5.62 mmol, 2.4 eq) in ethanol (5 ml) is heated at 110° C. in a sealed tube for 24 h. The mixture is concentrated, taken up in dichloromethane and washed with water. The organic phase is dried over magnesium sulfate and concentrated. The residue is purified by chromatography over silicagel (eluent: dichloromethane) to afford 0.7 g of methyl 2-[4-(3-chloropropoxy)phenyl]-4-methyl-1,3-oxazole-5-carboxylate ax60 as a pale yellow solid.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[O:7][CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1.[C:24]([O:28][C:29]([N-:31][S:32](N1C=CC(=[N+](C)C)C=C1)(=[O:34])=[O:33])=[O:30])([CH3:27])([CH3:26])[CH3:25]>C(#N)C.C(OCC)(=O)C>[C:24]([O:28][C:29]([NH:31][S:32]([NH:1][C@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[O:7][CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1)(=[O:34])=[O:33])=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](N)C1
Reactant: C[N+](C)=c1ccn(S(=O)(=O)[N-]C(=O)OC(C)(C)C)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NS(=O)(=O)N[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
To a solution of tert-butyl (6R,7S)-6-amino-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (300 mg) in acetonitrile (5 mL) was added N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-ylsulfonyl]azanide (375 mg) prepared by the method described in Organic Letters, 3 (14), 2241-2243 (2001), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (200 mg).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([C:20]([NH:22][CH:23]([CH:28]([CH3:30])[CH3:29])[C:24]([O:26][CH3:27])=[O:25])=[O:21])[O:17][N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C1COCC1.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([C:20]([NH:22][CH:23]([CH:28]([CH3:30])[CH3:29])[C:24]([O:26][CH3:27])=[O:25])=[O:21])[O:17][N:16]=2)=[CH:11][CH:10]=1
Reactant: COC(=O)C(NC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)no1)C(C)C
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)C(NC(=O)c1cc(-c2ccc(O)cc2)no1)C(C)C
Reaction time: 3 h

Procedure:
To Methyl 2-(3-(4-(benzyloxy)phenyl)isoxazole-5-carboxamido)-3-methylbutanoate (6 g) in THF (120 ml), 10% Palladium on carbon (Wet, 600 mg) was added and hydrogenated at 50 psi for 3 hours. Reaction mixture was filtered through Celite and filtrate was concentrated to obtain yellow residue. This residue was purified by column chromatography (silica gel, EtOAc—CHCl3) to obtain yellow solid, which was crystallized using DCM—Petroleum ether to obtain the title compound as pale yellow solid. Yield: 2.25 g (48%); MS (ES+): m/z−319 (M+1); 1HNMR (DMSO-d6; 300 MHz): δ 10.01 (bs, 1H), 9.16 (d, 1H), 7.75 (d, 2H), 7.61 (s, 1H), 6.91 (d, 2H), 4.3 (m, 1H), 3.67 (s, 3H), 2.21 (m, 1H), 0.96 (d, 6H);
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[CH3:12][O:13][C:14]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+]>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>[CH3:12][O:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([C:2]2[C:10]([CH3:11])=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=2)=[CH:18][CH:17]=1)=[O:15]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: Cc1ccc(C(=O)O)cc1I
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: [Cs+]
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2cc(C(=O)O)ccc2C)cc1
Yield: 25.3 %

Procedure:
3-Iodo-4-methylbenzoic acid (8.7 g, 33.3 mmol), (4-methoxycarbonylphenyl)boronic acid (6.0 g, 33.3 mmol), caesium carbonate (10.8 g, 33.3 mmol) and tetrakis(triphenylphosphine)palladium (1.92 g, 1.67 mmol) in DME (120 ml) were heated at 90° C. for 6 h. The cooled reaction mixture was filtered and the residue washed with DME. The combined filtrate and washings were absorbed onto silica and chromatographed on a silica flash column eluting with DCM/ethanol/ammonia (40:8:1 then 30:8:1). The product fractions were reduced to dryness under vacuum to give 4′-(methoxycarbonyl)-6-methyl-1,1′-biphenyl-3-carboxylic acid (2.28 g, 25%). LCMS: retention time 3.22 min, [M−H]−269.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)(C)(C)C.Cl.O1CCOCC1>>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCO)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCN(CCO)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 191 (4.02 g, 16.46 mmol) are treated with 4M HCl in dioxane (60 ml, 240 mmol) and the mixture is stirred at room temperature for 1 h. The white precipitate is filtered off, washed with ether and dried under high vacuum. The mother liquor is concentrated and treatred with ether. The white solid is filtered off and dried under high vacuum.