Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.CN(C)C(N(C)C)=N.F[C:23]1[N:28]=[C:27]([C:29]2[NH:38][C:37](=[O:39])[C:36]3[C:31](=[CH:32][C:33]([O:42][CH3:43])=[CH:34][C:35]=3[O:40][CH3:41])[N:30]=2)[CH:26]=[CH:25][CH:24]=1>CS(C)=O.C(OCC)(=O)C>[CH3:41][O:40][C:35]1[CH:34]=[C:33]([O:42][CH3:43])[CH:32]=[C:31]2[C:36]=1[C:37](=[O:39])[NH:38][C:29]([C:27]1[N:28]=[C:23]([N:6]3[CH2:7][CH2:8][N:3]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:4][CH2:5]3)[CH:24]=[CH:25][CH:26]=1)=[N:30]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(F)n3)nc2c1
Reactant: COC(=O)CN1CCNCC1
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)CN1CCN(c2cccc(-c3nc4cc(OC)cc(OC)c4c(=O)[nH]3)n2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.1 %

Procedure:
To a stirred suspension of methyl 2-(piperazin-1-yl)acetate dihydrochloride (0.67 g, 2.92 mmol) in dry DMSO (1.5 mL) was added 1,1,3,3-tetramethylguanidine (0.15 g, 1.07 mmol). The resulting mixture was stirred at rt for 10 min. Then 2-(6-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.40 g, 1.33 mmol) was added as a solid. The reaction was heated at 90° C. for 4.5 h. After that time the reaction was cooled to rt and diluted with ethyl acetate (30 mL). The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 98:2 dichloromethane/methanol) followed by trituration with diethyl ether to give methyl 2-(4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperazin-1-yl)acetate (0.357 g, 61%) as a light yellow solid: mp 176-177° C.; 1H NMR (400 MHz, CDCl3) δ 10.30 (br s, 1H), 7.86 (d, J=7.03 Hz, 1H), 7.63-7.71 (m, 1H), 6.80-6.86 (m, 2H), 6.48 (d, J=2.34 Hz, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 3.77 (s, 3H), 3.67-3.73 (m, 4H), 3.34 (s, 2H), 2.73-2.79 (m, 4H); ESI MS m/z 440 [M+H]+.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].Cl[C:6]1[C:19]2[C:10](=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[CH:14][CH:13]=[N:12]3)[N:9]=[C:8]([CH3:20])[CH:7]=1>C(O)C>[CH3:20][C:8]1[CH:7]=[C:6]([O:1][CH2:2][CH3:3])[C:19]2[C:10](=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[CH:14][CH:13]=[N:12]3)[N:9]=1
Reactant: CC[O-]
Reactant: Cc1cc(Cl)c2ccc3cccnc3c2n1
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc(C)nc2c1ccc1cccnc12
Yield: 77.8 %

Procedure:
Solid sodium ethoxide (2.97 g, 48.0 mmol) was added to a 100 mL round-bottomed flask containing a solution of 4-chloro-2-methyl-[1,10]phenanthroline (1.10 g, 4.8 mmol) in ethanol (50 mL). The reaction mixture was refluxed for 18 hours. The solvent was removed in a rotary evaporator and the residue was treated with methylene choride (100 mL) and saturated NaHCO3 (100 mL) and transferred to a separatory funnel. The organic layer was washed with brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo. The solid residue was treated with ethyl ether, filtered, and dried yielding 0.89 g of a brown solid (78%).
Reaction SMILES: [CH3:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][NH-:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][NH2:4]
Reactant: CC(C[NH-])Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(CN)Cc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of commercially available 2-methyl-3-phenylpropylamide (4.32 g, 26.5 mmol) and lithium aluminium hydride (1.3 g, 34.3 mmol) in tetrahydrofuran (184 ml) was stirred at room temperature for 5 h. It was poured into aqu. sat. sodium sulfate and extracted with dichloromethane followed by drying of the organic solution and evaporation to provide the amine as an oil. Other syntheses have been reported, e.g. Dornow and Fust, Chem. Ber. 87, 984 (1954).
Reaction SMILES: C[C@H]1[C@H]2C[C@H]3C(C)(C)[C@@H](CC[C@]2(C)CCC1)[C@H](C)CC3.[CH3:21][C:22]1[C@@H:38]([O:39][C:40]([CH3:42])=[O:41])[CH2:37][C@:33]2([OH:43])[C:34]([CH3:36])([CH3:35])[C:23]=1[C@@H:24]([O:62][C:63]([CH3:65])=[O:64])[C@H:25]([OH:61])[C@@:26]1([CH3:60])[C@H:31]([C@@H:32]2OC(C2C=CC=CC=2)=O)[C@:30]2([O:55][C:56]([CH3:58])=[O:57])[CH2:53][O:54][C@@H:29]2[CH2:28][C@@H:27]1[OH:59]>CO>[CH3:21][C:22]1[C@@H:38]([O:39][C:40]([CH3:42])=[O:41])[CH2:37][C@@:33]2([OH:43])[C:34]([CH3:35])([CH3:36])[C:23]=1[C@@H:24]([O:62][C:63]([CH3:65])=[O:64])[C@H:25]([OH:61])[C@@:26]1([CH3:60])[C@H:31]([CH2:32]2)[C@:30]2([O:55][C:56]([CH3:58])=[O:57])[CH2:53][O:54][C@@H:29]2[CH2:28][C@@H:27]1[OH:59]
Reactant: CC(=O)O[C@H]1C[C@@]2(O)[C@@H](OC(=O)c3ccccc3)[C@@H]3[C@]4(OC(C)=O)CO[C@@H]4C[C@H](O)[C@@]3(C)[C@@H](O)[C@H](OC(C)=O)C(=C1C)C2(C)C
Agent: C[C@@H]1CCC[C@@]2(C)CC[C@H]3[C@H](C)CC[C@@H](C[C@H]12)C3(C)C
Solvent: CO
Product: CC(=O)O[C@H]1C[C@]2(O)C[C@@H]3[C@]4(OC(C)=O)CO[C@@H]4C[C@H](O)[C@@]3(C)[C@@H](O)[C@H](OC(C)=O)C(=C1C)C2(C)C
Reaction time: 1 h

Procedure:
Isolation of A Major Taxane, 9-dihydro-13-acetylbaccatin III: The solid is transferred to a 200 mL erlenmeyer flask and dissolved in 100 mL of methanol. After one hour, crystals of 9-dihydro-13-acetlybaccatin III are observed and the mixture is left at -20° C. for 18 hours to favor crystallization. The solid is filtered in the usual manner and washed with 2×10 mL, of cold methanol. The filtrate and the washings are kept aside for the next step (Filtrate A). The solid is often contaminated with black particles of charcoal which probably passes through the scintered glass during the charcoal filtration. To eliminate these particles, dichloromethane (20 mL) is added to the solid which dissolves rapidly and the insoluble black particles are filtered. The filtrate is evaporated on a rotovap, dichloromethane (2.0 mL) is added to dissolve the residue followed by methanol (80 mL) to induce crystallization. The mixture is left at -20° C. for 18 hours and filtered. The filtrate and washings are combined with Filtrate A. The solid is washed with cold methanol (5×1 mL) and dried under vacuum for 2 hours affording 1.2 g of 9-dihydro-13-acetyl baccatin III as a white product.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[CH:9]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:11])[CH3:10].B(O)O.C(=O)([O-])[O-].[K+].[K+].CCO>C1(C)C=CC=CC=1.O>[NH2:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:19]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:13]([N:12]([CH:9]([CH3:10])[CH3:11])[CH:21]([CH3:22])[CH3:23])=[O:20]
Reactant: Nc1ccncc1Br
Reactant: CC(C)N(C(=O)c1ccccc1)C(C)C
Agent: O=C([O-])[O-]
Agent: OBO
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)N(C(=O)c1ccccc1-c1cnccc1N)C(C)C
Temperature: 80 °C

Procedure:
The bromopyridine 1 (1.4 g, 8.1 mmol), boronic acid 2 (2.0 g, 8.9 mmol) and potassium carbonate (2.2 g, 15.9 mmol) were dissolved in 80 mL toluene, 8 ml EtOH and 8 mL H2O. This mixture was evacuated and refilled with nitrogen several times. Then, tetrakistriphenylphosphine palladium (0) (350 mg, 0.30 mmol) was added to the mixture and the mixture was heated to 80° C. overnight. Water (100 mL) was then added to the reaction and the organic layer was partitioned. The aqueous layer was extracted with EtOAc (2×100 mL) and the combined organics were dried with Na2CO3 and concentrated. The crude reaction product was triturated with diethyl ether (25 mL) and filtered. The resulting solid (2.0 g, 83%) was collected and characterized as the biphenyl amine 3. 1H NMR (CDCl3): δ 8.17 (d, 1H), 8.03 (s, 1H), 7.45 (m, 2H), 7.25 (m, 2H), 6.55 (d, 1H), 4.50 (bs, 2H), 3.61 (m, 1H), 3.31 (m, 1H), 1.49 (d, 3H), 1.16 (d, 3H), 1.03 (d, 3H), 0.83 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:28][C:29]([CH3:35])([CH3:34])[C:30]([O:32]C)=[O:31])=[CH:4][CH:3]=1.[CH:38]1([C:41](Cl)=[O:42])[CH2:40][CH2:39]1.[Na]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([C:41]([CH:38]3[CH2:40][CH2:39]3)=[O:42])=[C:8]2[CH2:28][C:29]([CH3:34])([CH3:35])[C:30]([OH:32])=[O:31])=[CH:36][CH:37]=1
Reactant: O=C(Cl)C1CC1
Reactant: COC(=O)C(C)(C)Cc1cc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Agent: [Na]
Product: CC(C)(Cc1c(C(=O)C2CC2)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1)C(=O)O

Procedure:
The title compound was prepared according to the conditions described in Step B and Step C of Example 47, from methyl 3-[N-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoate (prepared in Step A of Example 47), but using cyclopropanecarbonyl chloride in place of trimethylacetyl chloride in Step B. Anal. C, H, N for sodium salt·1 H2O: Calc. C 67.27; H 5.31; N 4.61 Found C 67.27; H 5.16; N. 4.58.
Reaction SMILES: [NH2:1][C:2](=[O:20])[C@H:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[N:21]1([C:8]2[CH:9]=[CH:10][C:5]([CH2:4][C@@H:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:2]([NH2:1])=[O:20])=[CH:6][CH:7]=2)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(I)cc1)C(N)=O
Reactant: c1c[nH]cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-n2ccnc2)cc1)C(N)=O
Reaction time: 18 h
Yield: 79.8 %

Procedure:
A mixture of (R)-tert-butyl 1-amino-3-(4-iodophenyl)-1-oxopropan-2-ylcarbamate (370 mg, 0.948 mmol), imidazole (85 mg, 1.25 mmol), 8-hydroxyquinoline (30 mg, 0.206 mmol), K2CO3 (150 mg, 1.08 mmol) and CuI (20 mg, 0.105 mmol) in DMSO (4 mL) was degassed with argon, then was stirred at 130 C for 18 h. The mixture was purified by HPLC to give (R)-tert-butyl 3-(4-(1H-imidazol-1-yl)phenyl)-1-amino-1-oxopropan-2-ylcarbamate (250 mg).
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][C@H:8]([OH:24])[CH2:9][NH:10][C:11]([CH3:23])([CH3:22])[CH2:12][CH:13]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[C:4]([F:27])[C:3]=1[F:28].C(#N)CC.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.[C:55]([O:59][CH2:60][CH3:61])(=[O:58])[CH:56]=[CH2:57]>CC([O-])=O.CC([O-])=O.[Pd+2].C(N(CC)CC)C>[CH2:60]([O:59][C:55](=[O:58])/[CH:56]=[CH:57]/[C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][C@H:8]([OH:24])[CH2:9][NH:10][C:11]([CH3:23])([CH3:22])[CH2:12][CH:13]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[C:4]([F:27])[C:3]=1[F:28])[CH3:61]
Reactant: C=CC(=O)OCC
Reactant: CC(C)(CC1Cc2ccccc2C1)NC[C@@H](O)COc1ccc(Br)c(F)c1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CCC#N
Product: CCOC(=O)/C=C/c1ccc(OC[C@H](O)CNC(C)(C)CC2Cc3ccccc3C2)c(F)c1F
Temperature: 25 °C
Yield: 75.3 %

Procedure:
A 150 mL sealed tube was charged with a stirring bar, (R)-1-(4-Bromo-2,3-difluorophenoxy)-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propan-2-ol (3.06 g) 1 and propionitrile (70 mL). To this was added Pd(OAc)2 (0.151 g), P(O-tol)3 (0.82 g), ethyl acrylate (1.35 g), triethylamine (2.73 g) sequentially and deoxygenated the reaction by bubbling nitrogen for 15 minutes. The sealed tube was capped tightly and immersed into a preheated (120° C.) oil bath. The reaction was heated at this temperature for 12 hrs. Cool to ambient temperature and concentrated under reduced pressure. The crude residue was purified by flash column chromatography eluting initially with 50% EtoAc in hexanes and 100% EtOAc. At this time the eluting solvent mixtures were switched to 100% dichloromethane, 5% MeOH in dichloromethane followed by 8% MeOH in dichloromethane. The product was collected and concentrated to get the desired product (2.40 g, 75%) as pale yellow foam. MS (ES) m/z 474 [M+H]+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([OH:8])=O.Cl.[CH3:10][O:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH2:26][CH2:27][O:28][CH3:29])[N:21]=[CH:20][N:19]=[C:18]2[NH:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[C:33]([CH3:44])[CH:32]=1>CN(C)C=O>[CH3:10][O:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH2:26][CH2:27][O:28][CH3:29])[N:21]=[CH:20][N:19]=[C:18]2[NH:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH:38]2[CH2:39][CH2:40][N:41]([C:6]([CH:2]3[CH2:3][CH2:4][CH2:5][O:1]3)=[O:8])[CH2:42][CH2:43]2)=[C:33]([CH3:44])[CH:32]=1
Reactant: COCCOc1cc2ncnc(Nc3ccc(OC4CCNCC4)c(C)c3)c2cc1OCCOC
Reactant: O=C(O)[C@H]1CCCO1
Agent: Cl
Solvent: CN(C)C=O
Product: COCCOc1cc2ncnc(Nc3ccc(OC4CCN(C(=O)C5CCCO5)CC4)c(C)c3)c2cc1OCCOC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,1′-carbonyldiimidizole (35 mg, 0.221 mmol) in N,N-dimethylformamide (2 mL) was added (R)-(+)-tetrahydrofuroic acid (25 mg, 0.221 mmol). The reaction was stirred at room temperature for 30 minutes then [6,7-Bis-(2-methoxy-ethoxy)-quinazolin-4-yl]-[3-methyl-4-(piperidin-4-yloxy)-phenyl]-amine hydrochloride (100 mg, 0.193 mmol) was added. The reaction was then stirred at room temperature overnight. The following day, the reaction was filtered through a 0.45 μm PTFE membrane filter and purified by preparatory HPLC. 1H NMR (300 MHz, DMSO-d6) δ 9.38(bs, 1H), 8.39(s, 1H), 8.15(s, 1H), 7.85(s, 1H), 7.52(d, J=8.39 Hz, 1H), 7.19(s, 1H), 7.04(d, J=8.71 Hz, 1H), 4.70(t, J=7.46, 1.55 Hz, 1H), 4.64(t, J=18.66, 3.42 Hz, 1H), 4.84(t, J=4.97, 3.75 Hz, 2H), 3.77(m, 8H), 3.43(m, 2H), 3.38(s, 3H), 3.36(s, 3H), 2.21(s, 3H), 2.05(m, 4H), 1.90(m, 2H), 1.66(m, 2H), LRMS (M+): 581.1, (M−): 579.2.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([OH:9])[CH2:2]2.[Na].[CH3:11][C:12]1[N:17]2[N:18]=[CH:19][C:20]([C:21](OCC)=[O:22])=[C:16]2[CH:15]=[CH:14][CH:13]=1>C1C=CC=CC=1>[CH3:11][C:12]1[N:17]2[N:18]=[CH:19][C:20]([C:21]([O:9][C@H:3]3[CH:4]4[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]4)[CH2:2]3)=[O:22])=[C:16]2[CH:15]=[CH:14][CH:13]=1
Reactant: O[C@@H]1CN2CCC1CC2
Reactant: CCOC(=O)c1cnn2c(C)cccc12
Agent: [Na]
Solvent: c1ccccc1
Product: Cc1cccc2c(C(=O)O[C@@H]3CN4CCC3CC4)cnn12
Reaction time: 2.5 h
Yield: 236.8 %

Procedure:
After a suspension of 760 mg (0.76 mmol) of (S)-(+)-3-quinuclidinol, which had been prepared in accordance with the procedure disclosed in "Eur. J. Med. Chem.", 14, 111-114 (1979), in 60 ml of benzene was refluxed for 1.5 hours by using a Dean-Stark apparatus, 0.2 g of metal sodium was added and the resultant mixture was refluxed under stirring for further 2.5 hours. Unreacted sodium was removed and 440 mg (2.2 mmol) of ethyl 7-methylpyrazolo[1,5-a]pyridine-3-carboxylate were added, followed by heating under reflux for 24 hours. The solvent of the reaction mixture was distilled off under reduced pressure and the residue was purified by chromatography on a silica gel column (chloroform:methanol=10:1), whereby 500 mg (1.8 mmol) of the title compound were obtained as white crystals (yield: 81%).
Reaction SMILES: CO.[OH-].[K+].[O:5]=[C:6]1[C:15]2[C:10](=[CH:11][C:12]([S:16]C(=O)N(C)C)=[CH:13][CH:14]=2)[CH:9]=[CH:8][NH:7]1>O>[SH:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[C:6](=[O:5])[NH:7][CH:8]=[CH:9]2
Reactant: CN(C)C(=O)Sc1ccc2c(=O)[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=c1[nH]ccc2cc(S)ccc12
Temperature: 80 °C
Yield: 104.1 %

Procedure:
To a solution of 6-hydroxy-2H-isoquinolin-1-one (500 mg, 3.10 mmol), triethyl amine (860 μL, 6.2 mmol) and pyridine (2.5 ml, 31 mmol) in anhydrous tetrahydrofuran (16 ml) was added N, N-dimethylthiocarbamoyl chloride (573 mg, 4.65 mmol) at 0° C. The mixture was heated to 65° C. and stirred for 24 h. The mixture was concentrated in vacuo with the addition of toluene. Saturated aqueous NaHCO3 was added to the residue and the mixture extracted with ethyl acetate (x3), dried (Na2SO4) and concentrated in vacuo to give a residue. Flash chromatography of the residue using ethyl acetate-heptane (5% to 100% ethylacetate) gave an unwanted side product (280 mg), followed by dimethylthiocarbamic acid 1-oxo-1,2-dihydroisoquinolin-6-yl ester (300 mg). A solution of the dimethylthiocarbamic acid 1-oxo-1,2-dihydroisoquinolin-6-yl ester in o-dichlorobenzene (2.5 ml) was heated under microwave conditions at 230° C. for 60 minutes. The mixture was loaded directly onto a column and flash chromatographed using ethyl acetate:heptane (1:9 to 99:1) to give dimethyl-thiocarbamic acid S-(1-oxo-1,2-dihydro-isoquinolin-6-yl) ester (140 mg). Methanol (7 ml) and potassium hydroxide (86 mg) were added to the dimethyl-thiocarbamic acid S-(1-oxo-1,2-dihydro-isoquinolin-6-yl) ester (140 mg) and the mixture refluxed, under nitrogen, for 2 h at 80° C. The mixture was then cooled and concentrated in vacuo to give a residue. Water was added and the mixture extracted with ethyl acetate (x2). The aqueous phase was acidified (pH ˜2) using dilute hydrochloric acid and the mixture extracted with ethyl acetate (x3). The combined organics were dried (Na2SO4) and concentrated in vacuo to give crude 6-mercapto-2H-isoquinolin-1-one (104 mg).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:6]=[CH:5][C:4]=1[C:15]1[S:19][C:18]([N:20]([CH3:31])[CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[NH:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)=[N:17][N:16]=1.C([O-])([O-])=O.[Na+].[Na+].C1(S)C=CC=CC=1>CN1C(=O)CCC1>[CH3:31][N:20]([CH:21]1[CH2:26][C:25]([CH3:28])([CH3:27])[NH:24][C:23]([CH3:30])([CH3:29])[CH2:22]1)[C:18]1[S:19][C:15]([C:4]2[CH:5]=[CH:6][C:7]([C:9]3[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=3)=[CH:8][C:3]=2[OH:2])=[N:16][N:17]=1
Reactant: COc1cc(-c2cnn(C)c2)ccc1-c1nnc(N(C)C2CC(C)(C)NC(C)(C)C2)s1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CN(c1nnc(-c2ccc(-c3cnn(C)c3)cc2O)s1)C1CC(C)(C)NC(C)(C)C1
Temperature: 190 °C

Procedure:
To a stirred solution of 5-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (129 mg, 0.293 mmol) in NMP (3 mL) was added Na2CO3 (47 mg, 0.439 mmol) followed by PhSH (35 μL, 0.337 mmol). The resulting mixture was sealed, evacuated and back filled with nitrogen (×3), then heated at 190° C. for 20 minutes under microwave irradiation. The reaction mixture was diluted with MeOH (10 mL) and filtered through celite. The filtrate was acidified by addition of acetic acid (3 mL) and loaded onto a 2 g SCX cartridge (pre-wet with MeOH). The cartridge was washed with MeOH (15 mL) and flushed with 7M NH3 in MeOH (15 mL). The MeOH/NH3 was removed in vacuo to afford the crude product as a brown solid. The crude material was purified by UV-directed preparative HPLC under basic (5 mM NH4OH) conditions, collecting at 352 nm, to afford the title compound as a pale brown glass-like solid (0.096 g, 77% yield). LC-MS: Rt 0.88 min; MS m/z 427.2 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.13 (s, 1H), 7.86-7.78 (m, 2H), 7.17-7.10 (m, 2H), 4.35-4.25 (m, 1H), 3.87 (s, 3H), 2.99 (s, 3H), 1.62 (dd, J=11.87, 3.28 Hz, 2H), 1.43 (t, J=12.13 Hz, 2H), 1.21 (s, 6H), 1.09 (s, 6H). LC-MS: Rt 1.69 min; MS m/z 427.4 [M+H]+ [Method B]. HR-MS: Rt 1.49 mins; MS m/z 427.2660 [M+H]+ [Method C].
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([NH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)=[O:10].[CH3:21][NH:22][CH2:23][CH2:24][OH:25].C(N(CC)C(C)C)(C)C>CN(C)C=O>[OH:25][CH2:24][CH2:23][N:22]([CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([NH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)=[O:10]
Reactant: CNCCO
Reactant: O=C(CCCCCCCBr)Nc1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCO)CCCCCCCC(=O)Nc1ccc(C(=O)O)cc1
Temperature: 60 °C

Procedure:
To a mixture of 4-[(8-bromooctanoyl)amino]benzoic acid (50 mg, 0.15 mmol, as prepared in Intermediate 36) in N,N-dimethylformamide (2 ml) was added 2-(methylamino)ethanol (24 microliters, 0.3 mmol, 2 equivalents, commercially available e.g. from Aldrich) followed by N,N-diisopropylethylamine (0.13 mL, 0.8 mmol, about 5 equivalents), and the resulting solution was heated at 60° C. for 16 hours. The solvent was removed by evaporation, and the residue was purified by Mass Directed Automated Preparative HPLC (Method A). Fractions containing product were pooled and evaporated to dryness to give the title compound (25.4 mg) as a pale brown solid. LCMS showed MH+=337; TRET=2.03 min.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)([OH:13])[C:9]([F:12])([F:11])[F:10])=[CH:6][N:5]=[C:4]2[N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:24]=[CH:25][C:3]=12.C(=O)(O)[O-].[Na+]>C(O)(=O)C.[Zn]>[F:12][C:9]([F:10])([F:11])[C:8]([C:7]1[CH:2]=[C:3]2[CH:25]=[N:24][N:23]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:4]2=[N:5][CH:6]=1)([C:14]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[OH:13]
Reactant: OC(c1cnc2c(cnn2-c2ccccc2)c1Cl)(c1c[nH]c2ncccc12)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Product: OC(c1cnc2c(cnn2-c2ccccc2)c1)(c1c[nH]c2ncccc12)C(F)(F)F
Yield: 78.7 %

Procedure:
A mixture of 200 mg (0.45 mmol) of 1-(4-chloro-1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-2,2,2-trifluoro-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethanol and 185 mg (2.83 mmol) of zinc powder in acetic acid was warmed at reflux for 30 minutes. The mixture was then cooled and made basic with saturated aqueous sodium bicarbonate and extracted with three 30 mL portions of ethyl acetate. The combined organic layers were washed with two 15 mL portions of saturated aqueous sodium bicarbonate, three 15 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 145 mg (78%) of the title compound. The material from the column was triturated with ether-hexanes to afford 85 mg of the title compound as a white solid. The solid was dried under house vacuum at 90° C. and then 110° C. MS m/z 410.30 (MH+), m.p. 137° C.-141° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[CH2:19][CH2:18][C:17]4([CH3:23])[C:20]([CH3:22])([CH3:21])[CH:13]3[CH2:14][C:15]3[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][C:16]=34)=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH2:30][OH:31]>C(O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[CH2:19][CH2:18][C:17]4([CH3:23])[C:20]([CH3:22])([CH3:21])[CH:13]3[CH2:14][C:15]3[CH:27]=[C:26]([C:28]([NH:30][OH:31])=[NH:29])[CH:25]=[CH:24][C:16]=34)=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: NO
Reactant: CC12CCN(C(=O)c3ccc4[nH]cnc4c3)C(Cc3cc(C#N)ccc31)C2(C)C
Solvent: CCO
Product: CC12CCN(C(=O)c3ccc4[nH]cnc4c3)C(Cc3cc(C(=N)NO)ccc31)C2(C)C
Temperature: 25 °C

Procedure:
A solution of 3-(1H-benzoimidazole-5-carbonyl)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-9-carbonitrile (0.30 g) and hydroxylamine (50% in water, 0.5 ml) in ethanol (5 mL) is stirred at reflux temperature for 2 h. After cooling to room temperature, the mixture is concentrated under reduced pressure to give the title compound as a white foam-like solid.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[C:25][Si](C)(C)C)[CH:19]=2)[CH:8]=1)=[O:6])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[CH:1]([NH:4][C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[CH:25])[CH:19]=2)[CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1cn(-c2cccc(C#C[Si](C)(C)C)c2)c2ncccc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1cccc(-n2cc(C(=O)NC(C)C)c(=O)c3cccnc32)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The crude product from Step 1 was dissolved in methanol (12 mL/mmol) and 1N aqueous sodium hydroxide was added (3 eq), resulting in a suspension. The suspension mixture was stirred at room temperature for 2 hours and the methanol was evaporated. The resulting aqueous suspension was diluted with water and the product was extracted out with ethyl acetate. The crude product was chromatographed on silica gel eluting with 10% ether in methylene chloride to afford the N-isopropyl-1-(3-ethynylphenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide compound as a solid.