Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[C:18]([C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=1)#N.Cl.[OH2:28]>ClCCl>[CH3:26][C:24]1[CH:23]=[CH:22][N:21]=[C:20]([CH:18]=[O:28])[CH:25]=1
Reactant: Cc1ccnc(C#N)c1
Reactant: O
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1ccnc(C=O)c1
Reaction time: 2 h
Yield: 37 %

Procedure:
Diisobutyl aluminium hydride in toluene (1.5 M, 43.5 ml, 65 mmol) was added dropwise to a solution of 2-cyano-4-methylpyridine (7.0 g, 59 mmol) in dichloromethane (180 ml) at −78° C., and the mixture was stirred at the same temperature for 2 hrs. The reaction mixture was combined with concentrated hydrochloric acid (28 ml) and water (112 ml), and the water layer and the organic layer were separated. The organic layer was extracted with 2 N hydrochloric acid. The water layer was combined, neutralized with sodium hydrogen carbonate and extracted with diethyl ether. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the titled compound (2.7 g, 37%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:52])[CH2:5][CH2:6][NH:7][C:8]([C@:10]12[CH2:48][CH2:47][C@@H:46]([C:49]([CH3:51])=[CH2:50])[C@@H:11]1[C@@H:12]1[C@@:25]([CH3:28])([CH2:26][CH2:27]2)[C@@:24]2([CH3:29])[C@@H:15]([C@:16]3([CH3:45])[C@@H:21]([CH2:22][CH2:23]2)[C:20]([CH3:31])([CH3:30])[C:19]([C:32]2[CH:44]=[CH:43][C:35]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:34][CH:33]=2)=[CH:18][CH2:17]3)[CH2:14][CH2:13]1)=[O:9].[C:53]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])(=[O:60])[CH2:54][CH2:55][C:56](OC)=[O:57].C(Cl)CCl>ClCCl>[C:56]([O:1][CH2:2][CH2:3][N:4]([CH2:5][CH2:6][NH:7][C:8]([C@:10]12[CH2:48][CH2:47][C@@H:46]([C:49]([CH3:51])=[CH2:50])[C@@H:11]1[C@@H:12]1[C@@:25]([CH3:28])([CH2:26][CH2:27]2)[C@@:24]2([CH3:29])[C@@H:15]([C@:16]3([CH3:45])[C@@H:21]([CH2:22][CH2:23]2)[C:20]([CH3:31])([CH3:30])[C:19]([C:32]2[CH:33]=[CH:34][C:35]([C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])=[CH:43][CH:44]=2)=[CH:18][CH2:17]3)[CH2:14][CH2:13]1)=[O:9])[CH3:52])(=[O:57])[CH2:55][CH2:54][C:53]([O:61][C:62]([CH3:64])([CH3:63])[CH3:65])=[O:60]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(C)CCO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: COC(=O)CCC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(C)CCOC(=O)CCC(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 20 °C
Reaction time: 12 h

Procedure:
A mixture of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-((2-hydroxyethyl)(methyl)amino)ethylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (40 mg, 0.056 mmol), tert-butyl methyl succinate (21.06 mg, 0.112 mmol), Hunig'sBase (0.049 mL, 0.280 mmol) and EDC (21.45 mg, 0.112 mmol) in dichloromethane (1 mL) was stirred at 20° C. for 12 hours. LCMS indicated the formation of desired product. The reaction mixture was quenched with distilled water, extracted with DCM (3×4 mL). All the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the crude including the title compound as a white solid (40 mg, 82%). LCMS: m/e 871.43 (M+H)+, 3.93 min (method 1).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29](O)=[O:30])=[CH:23][CH:22]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:24]3[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: COc1ccc(/C=C/C(=O)O)cc1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Product: COc1ccc(/C=C/C(=O)Nc2cnn(Cc3ccc(C(C)=O)o3)n2)cc1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and (E)-3-(4-methoxy-phenyl)-acrylic acid.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=1[NH2:28]>>[F:26][C:24]1[C:23]([F:27])=[CH:22][C:21]2[NH:28][C:15]([CH2:14][C:9]3[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:8]=3)=[N:19][C:20]=2[CH:25]=1
Reactant: Nc1cc(F)c(F)cc1N
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: O=c1cc(N2CCOCC2)nc(Cc2nc3cc(F)c(F)cc3[nH]2)[nH]1
Yield: 43.2 %

Procedure:
The product is prepared according to the procedure described in Stage 3 of Example 1, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 173 mg of 1,2-diamino-4,5-difluorobenzene in place of the 1,2-diamino-4-fluorobenzene. After purification by silica gel column chromatography, elution being carried out with a gradient of pure CH2Cl2 to CH2Cl2/MeOH: 85/15, 150 mg of 2-[(5,6-difluoro-1H-benzimidazol-2-yl)methyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a light pink solid, the characteristics of which are the following:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([Br:12])=[CH:4][C:3]=1[S:13]([NH2:16])(=[O:15])=[O:14].[C:17](Cl)(=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1>>[C:17]([NH:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[C:5]([Br:12])=[CH:4][C:3]=1[S:13]([NH2:16])(=[O:14])=[O:15])(=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Nc1cc(C(F)(F)F)c(Br)cc1S(N)(=O)=O
Product: COc1ccc(C(=O)Nc2cc(C(F)(F)F)c(Br)cc2S(N)(=O)=O)cc1

Procedure:
2-Amino-4-trifluoromethyl-5-bromo-benzenesulfonamide (formula (V): R2 = Br) is first prepared according to the above-described technique. M.p.= 202° C. The 2-amino-4-trifluoromethyl-5-bromobenzenesulfonamide (9.60 g) is then reacted, as in Example 2A, with p-anisic acid chloride (6.8 g), to give 12.2 g 2-p-anisoylamino-4-trifluoromethyl-5-bromo-benzenesulfonamide, M.p.= 321° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][CH3:12])=[O:10])=[N:4][C:5](Br)=[CH:6][CH:7]=1.NC1C(C(OCC)=O)=NC([C:20]2[CH:21]=[N:22][N:23]([CH2:25][CH2:26][CH2:27][CH2:28][OH:29])[CH:24]=2)=CC=1>>[NH2:1][C:2]1[C:3]([C:9]([NH:11][CH3:12])=[O:10])=[N:4][C:5]([C:20]2[CH:21]=[N:22][N:23]([CH2:25][CH2:26][CH2:27][CH2:28][OH:29])[CH:24]=2)=[CH:6][CH:7]=1
Reactant: CNC(=O)c1nc(Br)ccc1N
Reactant: CCOC(=O)c1nc(-c2cnn(CCCCO)c2)ccc1N
Product: CNC(=O)c1nc(-c2cnn(CCCCO)c2)ccc1N
Yield: 98 %

Procedure:
Prepared analogously to Compound 6D using ethyl 3-amino-6-[1-(4-hydroxybutyl)-1H-pyrazol-4-yl]pyridine-2-carboxylate (Compound 15D, 0.211 g, 0.69 mmol) to afford 196 mg of the title compound (98%). 1H NMR (400 MHz, CDCl3) δ 8.12 (br. s., 1H), 7.87 (s, 1H), 7.81 (s, 1H), 7.36 (d, J=8.6 Hz, 1H), 7.03 (d, J=8.6 Hz, 1H), 5.94 (br. s., 2H), 4.23 (t, J=6.9 Hz, 2H), 3.70 (q, J=5.9 Hz, 2H), 3.03 (d, J=5.1 Hz, 3H), 2.03 (quin, J=7.3 Hz, 2H), 1.60-1.67 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][C:27]3[N:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:30][C:31]=3[CH3:32])[CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][C:27]3[N:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:30][C:31]=3[CH3:32])[CH:18]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OC)c(OCc3nc(-c4ccccc4)oc3C)c2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1nn(Cc2ccc(OC)c(OCc3nc(-c4ccccc4)oc3C)c2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
After a mixture of ethyl 3-[3-ethoxy-1-[4-methoxy-3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (572 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, 1N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[4-methoxy-3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (498 mg, yield: 92%). This was recrystallized from ethanol-hexane. Melting point: 136–137° C.
Reaction SMILES: [Cu][C:2]#[N:3].[CH3:4][O:5][C:6]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[C:13](Br)=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9].C(OCC)(=O)C>CN1CCCC1=O>[CH3:4][O:5][C:6]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[C:13]([C:2]#[N:3])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: N#C[Cu]
Reactant: COC(=O)c1cc(Br)c(C(C)C)cc1OC
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COC(=O)c1cc(C#N)c(C(C)C)cc1OC
Temperature: 0 °C
Yield: 74.8 %

Procedure:
Copper (I) cyanide (550 mg, 6 mmol) was added to a solution of methyl 2-methoxy-5-bromo-4-iso-propylbenzoate (861 mg) in N-methyl-2-pyrolidinone (30 ml). The mixture was stirred under argon and boiled under reflux for 4 h. The mixture was cooled, poured into excess ice/water and ethyl acetate and filtered. The organic phase was separated, washed with water, brine and dried(MgSO4). Evaporation gave a crude brown solid which was purified by chromatography on silica gel eluting with ethyl acetate/n-hexane (1:4). The product was obtained as a white solid (523 mg).
Reaction SMILES: [N+]([NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[CH:7][N:6]=1)([O-])=O.[CH3:21][C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH2:27][S:28][CH2:29][CH2:30]N>C(O)C>[CH3:21][C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH2:27][S:28][CH2:29][CH2:30][NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[CH:7][N:6]=1
Reactant: COc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Reactant: Cc1[nH]cnc1CSCCN
Solvent: CCO
Product: COc1ccc(Cc2cnc(NCCSCc3nc[nH]c3C)[nH]c2=O)cn1
Yield: 63 %

Procedure:
An equimolar mixture of 2-nitroamino-5-(6-methoxy-3-pyridylmethyl)-4-pyrimidone and 2-(5-methyl-4-imidazolyl methylthio)-ethylamine was refluxed in ethanol for 18 hours. The solid which crystallised out on cooling was recrystallised from ethanol to give 2-[2-(5-methyl-4-imidazolyl methylthio)ethylamino]-5-(6-methoxy-3-pyridylmethyl)-4-pyrimidone, m.p. 197-198.5° in 63% yield.
Reaction SMILES: [C:1]([NH:9][CH:10]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([OH:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:31]O>>[C:1]([NH:9][CH:10]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]([S:26]([OH:29])(=[O:28])=[O:27])=[CH:24][CH:25]=2)=[CH:16][CH:15]=1)[C:11]([O:13][CH3:31])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC(C(=O)O)c1ccc(-c2ccc(S(=O)(=O)O)cc2)cc1)c1ccccc1
Reactant: CO
Agent: Cl
Product: COC(=O)C(NC(=O)c1ccccc1)c1ccc(-c2ccc(S(=O)(=O)O)cc2)cc1
Reaction time: 2.5 h

Procedure:
To a mixture of 12.46 g (30.31 mmol) of α-(benzoylamino)-4'-sulfo[1,1'-biphenyl]-4-acetic acid in 60 mL of methanol was added 6 g of anhydrous hydrogen chloride. When the addition was complete, the mixture was stirred for 2.5 h. The solvent was removed under reduced pressure.
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10](OC)=[O:11].[H-].[H-].[H-].[H-].[Li+].[Al+3].CO>C1COCC1>[S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][OH:11]
Reactant: COC(=O)c1cc2ncccc2s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1cc2ncccc2s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl thieno[3,2-b]pyridine-2-carboxylate (C-3) (600 mg, 3.1 mmol) in 30 mL of anhydrous THF at 0° C. was added LiAlH4 (472 mg, 12.4 mmol) in anhydrous THF (25 mL) dropwise over 20 mins. The reaction mixture was stirred at 0° C. for 30 mins. MeOH was added and the resulting mixture was purified by chromatography to afford the title compound. MS (m/z): 166 (M+1)+.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][N:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][C:41]=2[C:47]([F:50])([F:49])[F:48])[CH2:36][CH2:35]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:44][C:43]5[CH:45]=[CH:46][C:40]([N:37]6[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]6)=[C:41]([C:47]([F:50])([F:49])[F:48])[CH:42]=5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCN(c2ccc(N)cc2C(F)(F)F)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Product: COc1cc(C(=O)Nc2ccc(N3CCN(C)CC3)c(C(F)(F)F)c2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was prepared in a manner analogous to compound 149 from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid and 4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)aniline with yield 46 mg (34%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43-1.72 (m, 6H) 1.99 (br. s., 2H) 2.23 (s, 3H) 2.47 (br.s., 4H) 2.85 (t, J=4.29 Hz, 4H) 3.99 (s, 3H) 4.07 (t, J=12 Hz, 2H) 4.80 (t, J=7.96 Hz, 1H) 7.46-7.73 (m, 3H) 7.97-8.10 (m, 2H) 8.14 (d, J=2.53 Hz, 1H) 8.29 (s, 1H) 8.38 (d, J=8.34 Hz, 1H) 10.31 (s, 1H). [M+H] calc'd for C33H37F5N8O3, 689. found 689.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][C:5](=[O:27])[CH2:6][C:7]([CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)(O)[CH2:8][CH2:9][C:10]#[C:11][C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([OH:19])=[CH:14][C:13]=1[CH3:20].[OH-].[Na+]>>[CH:22]1([C:7]2([CH2:8][CH2:9][C:10]#[C:11][C:12]3[CH:17]=[C:16]([CH3:18])[C:15]([OH:19])=[CH:14][C:13]=3[CH3:20])[O:28][C:3](=[O:2])[CH2:4][C:5](=[O:27])[CH2:6]2)[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: COC(=O)CC(=O)CC(O)(CCC#Cc1cc(C)c(O)cc1C)C1CCCC1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(C#CCCC2(C3CCCC3)CC(=O)CC(=O)O2)c(C)cc1O
Reaction time: 8 h
Yield: 98.3 %

Procedure:
To 5-cyclopentyl-5-hydroxy-9-(4-hydroxy-2,5-dimethyl-phenyl)-3-oxo-non-8-ynoic acid methyl ester (60 mg, 0.155 mmol) from Step 2 below was added NaOH (0.3 M in MeOH, 1 mL, 0.31 mmol). The solution was stirred overnight, and then quenched with 1 N HCl (5 mL). The solution was extracted with 4×10 mL CH2Cl2. The organic layer was dried over Na2SO4, and then the solids were removed by filtration. After concentrating the mother liquor, the resulting oil was purified by flash chromatography to yield the desired product (54 mg, 98% yield). 1H NMR (CDCl3) δ: 1.35-1.75 (m, 8H), 1.93-1.99 (m, 3H), 2.10 (s, 3H), 2.23 (s, 3H), 2.51 (t, J=7.33 Hz, 2H), 2.69 (d, J=16.17 Hz, 1H), 2.83 (d, J=16.18 Hz, 1H), 3.37 (s, 2H), 4.66 (s, 1H), 6.52 (s, 1H), 7.05 (s, 1H). MS (ESI): 353 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][NH:12][CH2:13]2.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>CC(N(C)C)=O>[C:31]([N:12]1[CH2:11][CH2:10][C:9]2[C:14](=[CH:15][C:16]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])=[CH:17][C:8]=2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:13]1)(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: CC(C)C(=O)Nc1cc2c(c(-c3ccccc3Cl)c1)CCNC2
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CC(=O)N1CCc2c(cc(NC(=O)C(C)C)cc2-c2ccccc2Cl)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67 %

Procedure:
CO-AAW0003 (39 mgs, 0.12 mmoles) was dissolved in anhydrous dimethylacetamide (1 ml) followed by the addition of triethylamine (20 ul, 0.144 mmols) and acetyl chloride (10.3 ul, 0.144 mmoles). The reaction was then left stirring at room temperature for 1.5 hours. The reaction was purified by C18 reverse phase automated HPLC (21 mgs, 67% yield, 100% pure, CO-AAW00024).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:32]([O:36][C:37]([N:39]1[CH2:42][CH2:41][C@H:40]1[CH2:43][OH:44])=[O:38])([CH3:35])([CH3:34])[CH3:33].[Br:45][C:46]1[CH:47]=[N:48][CH:49]=[C:50](O)[CH:51]=1>C1COCC1>[Br:45][C:46]1[CH:51]=[C:50]([O:44][CH2:43][C@@H:40]2[CH2:41][CH2:42][N:39]2[C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[CH:49]=[N:48][CH:47]=1
Reactant: Oc1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Br)c1
Reaction time: 0.17 h

Procedure:
Triphenylphosphine (4.01 g, 15.3 mmol) and DEAD (2.43 mL, 15.3 mmol) were dissolved in 30 mL of THF at 0° C., and the mixture was stirred for 10 minutes. Samples of 1-t-butyloxycarbonyl-2-(S)-azetidinemethanol (2.86 g, 15.3 mmol, Step 7c above) and 3-bromo-5-hydroxypyridine.(1.51 g, 10.2 mmol, Step 10c above) were added, and the mixture was stirred for 40 hours at room temperature. The volatile components were removed under vacuum, and the residue was triturated with hexane. The separated hexane fraction was concentrated, and the residue was chromatographed (silica gel; hexane/ether, 10:1 to 10:2) to afford 5-bromo-3-((1-t-butyloxycarbonyl-(2S)-azetidinyl)methoxy)pyridine as a colorless oil (1.669 g): 1H NMR (CDCl3, 300 MHz) δ1.42 (s, 9H), 2.31 (m, 2H), 3.89 (m, 2H), 4.12 (m, 1H), 4.322 (m, 1H), 4.52 (m, 1H), 7.43 (m, 1H), 8.29 (m, 2H); MS (CI/NH3) m/z 344 (M+H)+. The 5-bromo-3-(2-(1-BOC-2-(S)-azetidinyl)methoxy)pyridine was treated with with 4 M HCl in dioxane to give the free base of the title compound. This was converted to the dihydrochloride salt and recrystallized from methanol/ether to provide the title compound: mp 163-165° C.; [α]25D −5.1 (c 0.57, methanol); 1H NMR (D2O, 300 MHz) δ8.36 (d, J=1.8 Hz, 1H), 8.32 (d, J=2.6 Hz, 1H), 7.84 (dd, J=1.8, 2.6 Hz, 1H), 4.98-4.90 (m, 1H), 4.43 (d, J=4.0 Hz, 2H), 4.20-4.02 (m, 2H), 2.67 (q, J=8.5 Hz, 2H); MS (CI/NH3) m/z 243/246 (M+H)+, 260/262 (M+NH4)+. Anal. calcd for C9H13N2OBrCl2: C, 34.21; H, 4.15; N, 8.86. Found: C, 34.18; H, 4.17; N, 8.89.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.CCN(CC)CC.[O:16]=[C:17]([C:24]1[O:25][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:27][N:28]=1)[CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[CH:23]>C1COCC1.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.[Cu]I>[O:16]=[C:17]([C:24]1[O:25][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:27][N:28]=1)[CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[C:23][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: Clc1cccc(I)c1
Reactant: C#CCCCCC(=O)c1ncc(-c2ccccn2)o1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCCCC#Cc1cccc(Cl)c1)c1ncc(-c2ccccn2)o1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 1-chloro-3-iodobenzene (49 mg, 0.205 mmol) in anhydrous THF (0.5 mL) was treated with PdCl2(PPh3)2 (7 mg, 0.01 mmol). After stirring for 5 min at 25° C., Et3N (0.2 mL, 0.603 mmol) and CuI (10 mg, 0.053 mmol) were added. The suspension was stirred for 35 min and 1-oxo-1-[5-(2-pyridyl)oxazol-2-yl]-hept-6-yne (3b, 30 mg, 0.067 mmol) was added. After stirring for 14 h at 25° C., the reaction mixture was filtered through Celite and concentrated. PTLC (SiO2, 50% EtOAc-hexanes) afforded 1-oxo-1-[5-(2-pyridyl)oxazol-2-yl]-7-(3-chlorophenyl)hept-6-yne (4hh, 24 mg, 0.066 mmol, 56%) as a yellow solid: mp 50-51° C.; 1H NMR (CDCl3, 500 MHz) δ 8.68-8.66 (m, 1H), 7.89-7.86 (m, 2H), 7.82 (td, 1H, J=7.7, 1.8 Hz), 7.38 (m, 1H), 7.34-7.31 (m, 1H), 7.27-7.18 (m, 3H), 3.20 (t, 2H, J=7.4 Hz), 2.49 (t 2H, J=7.0 Hz), 2.00-1.95 (m, 2H), 1.77-1.71 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 187.9, 157.2, 153.3, 150.1, 146.2, 137.1, 133.9, 131.4, 129.6, 129.3, 127.8, 126.8, 125.5, 124.1, 120.3, 90.9, 79.8, 38.5, 27.8, 23.1, 19.1; IR (film) νmax 3061, 2932, 2865, 2230, 1703, 1592, 1575, 1558, 1505, 1471, 1426, 1385, 1283, 1243, 1152, 1081, 1065, 1023, 990, 962, 930, 880, 784, 740, 683 cm−1; ESI-TOF m/z 365.1058 (C21H17ClN2O4+H+ requires 365.1051).
Reaction SMILES: [OH:1][C:2]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[C:4](=[O:19])[C:3]=1[C:20](OCC)=[O:21].Cl.[NH2:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C(N(C(C)C)C(C)C)C>O1CCOCC1>[OH:1][C:2]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[C:4](=[O:19])[C:3]=1[C:20]([NH:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:21]
Reactant: CCOC(=O)C1=C(O)c2cc(OC)ccc2C2(CCOCC2)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ccc2c(c1)C(O)=C(C(=O)NCC(=O)OC(C)(C)C)C(=O)C21CCOCC1
Temperature: 95 °C
Reaction time: 4 h
Yield: 88.6 %

Procedure:
A mixture of ethyl 4-hydroxy-6-methoxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (0.6 g, 2 mmol), tert-butyl 2-aminoacetate hydrochloride (0.5 g, 3 mmol) in 5 mL dioxane was treated with N-ethyl-N-isopropylpropan-2-amine (0.7 g, 5 mmol). The mixture was warmed to 95° C. and stirred for 4 hours, M+1=418. The mixture was then cooled to room temperature and concentrated in vacuo. The crude product was purified by column chromatography eluting with 10-30% EtOAc/hexane to give 0.74 g of the title compound as a white yellow solid. MS (m/z)=418 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][N:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[N:4][N:3]=1.[CH3:32][O:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>CS(C)=O.CO>[CH3:31][O:30][C:26]1[CH:25]=[C:24]2[C:29]([C:20]([S:19][C:16]3[CH:17]=[CH:18][C:13]([NH:12][C:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C:2]([N:37]5[CH2:38][CH2:39][CH:34]([O:33][CH3:32])[CH2:35][CH2:36]5)=[N:3][N:4]=4)=[CH:14][CH:15]=3)=[CH:21][CH:22]=[N:23]2)=[N:28][CH:27]=1
Reactant: COC1CCNCC1
Reactant: COc1cnc2c(Sc3ccc(Nc4nnc(Cl)c5ccccc45)cc3)ccnc2c1
Solvent: CO
Solvent: CS(C)=O
Product: COc1cnc2c(Sc3ccc(Nc4nnc(N5CCC(OC)CC5)c5ccccc45)cc3)ccnc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 15 ml sealed pressure tube was charged with 4-chloro-N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)phthalazin-1-amine (120 mg, 0.269 mmol) and 4-methoxypiperidine (620 mg, 5.382 mmol), in 0.3 ml of DMSO. The sealed tube was placed in a preheated oil bath at 100° C. where it was stirred for 16 hours. The reaction was cooled to ambient temperature, diluted with 2 ml of MeOH, and the solution purified using Gilson Reverse Phase HPLC. The fractions containing the desired product was neutralized with saturated sodium bicarbonate and extracted with 10 ml of DCM (3×). The organics were dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to afford N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)-4-(4-methoxypiperidin-1-yl)phthalazin-1-amine as a yellow solid. MS [M+H]+=525.