Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][N:42]1[CH2:47][C@@H:46]3[CH2:48][C@H:43]1[CH2:44][N:45]3[S:49]([CH3:52])(=[O:51])=[O:50])[CH2:4][CH2:3]2.[C:53]([OH:59])([C:55]([F:58])([F:57])[F:56])=[O:54]>C1COCC1.CO.[OH-].[OH-].[Pd+2]>[CH:36]([C@H:33]1[C@@H:6]2[C@@H:7]3[C@@:2]([CH3:1])([CH2:3][CH2:4][C@@:5]2([NH:39][CH2:40][CH2:41][N:42]2[CH2:47][C@@H:46]4[CH2:48][C@H:43]2[CH2:44][N:45]4[S:49]([CH3:52])(=[O:50])=[O:51])[CH2:35][CH2:34]1)[C@@:19]1([CH3:20])[C@@H:10]([C@:11]2([CH3:32])[C@@H:16]([CH2:17][CH2:18]1)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:30][CH:31]=1)=[CH:13][CH2:12]2)[CH2:9][CH2:8]3)([CH3:38])[CH3:37].[C:53]([OH:59])([C:55]([F:58])([F:57])[F:56])=[O:54]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@@H]4C[C@H]3CN4S(C)(=O)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)[C@@H]1CC[C@]2(NCCN3C[C@@H]4C[C@H]3CN4S(C)(=O)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reaction time: 16 h

Procedure:
To a solution of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-((1S,4S)-5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethyl)amino)-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)benzoic acid, 2 TFA (10 mg, 10.42 μmol) in a mixture of THF (1.5 mL) and MeOH (0.5 mL) was added palladium hydroxide on carbon (14.63 mg, 0.021 mmol). The resulting slurry was purged with H2 (g) and stirred under a H2 (g) atmosphere for 16 h. The mixture was treated with celite (15 mg), filtered, washed with THF and concentrated. A grey residue was dissolved in THF (1 mL) and MeOH (0.5 mL), purified by reverse phase prep-HPLC using HPLC methods 6 and dried under vacuum to give 4-((1S,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3a-((2-((1S,4S)-5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethyl)amino)-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)benzoic acid, 2 TFA (6.2 mg, 60.6% yield) as white solid. LC/MS: m/e 734.6 (M+H)+, 2.25 min (method 3). 1H NMR (400 MHz, 1:1 CDCl3:METHANOL-d4) δ 7.91 (d, J=8.3 Hz, 2H), 7.19 (d, J=8.3 Hz, 2H), 5.29 (d, J=4.6 Hz, 1H), 4.35 (s, 1H), 3.82 (s, 1H), 3.61 (d, J=10.3 Hz, 1H), 3.28 (d, J=1.7 Hz, 1H), 3.15 (d, J=11.7 Hz, 1H), 3.10-3.00 (m, 3H), 2.92 (s, 3H), 2.82 (d, J=10.0 Hz, 1H), 2.14 (dd, J=17.1, 6.4 Hz, 1H), 2.09-2.03 (m, 1H), 2.02-1.86 (m, 5H), 1.85-1.64 (m, 7H), 1.57 (dd, J=17.4, 11.7 Hz, 5H), 1.51-1.40 (m, 4H), 1.39-1.21 (m, 4H), 1.15 (s, 3H), 1.07 (s, 3H), 1.02 (s, 3H), 0.94 (s, 3H), 0.93 (s, 3H), 0.90 (d, J=6.8 Hz, 3H), 0.81 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([B:19]3[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]3)[C:14]=2[CH3:28])=[O:11])=[N:5][CH:6]=[CH:7][CH:8]=1.C1N=CN([C:34](N2C=NC=C2)=[O:35])C=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]2[N:5]([C:34](=[O:35])[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([B:19]4[O:23][C:22]([CH3:24])([CH3:25])[C:21]([CH3:27])([CH3:26])[O:20]4)[C:14]=3[CH3:28])[C:10](=[O:11])[CH:9]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cccnc1CC(=O)Nc1cccc(B2OC(C)(C)C(C)(C)O2)c1C
Solvent: Cc1ccccc1
Product: COc1cccn2c(=O)n(-c3cccc(B4OC(C)(C)C(C)(C)O4)c3C)c(=O)cc12
Temperature: 110 °C
Yield: 37 %

Procedure:
A mixture of 2-(3-methoxypyridin-2-yl)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (1.45 g, 3.78 mmol) and CDI (2.45 g, 15.1 mmol) in toluene (19 mL) was heated at 110° C. for 3 h. The cooled mixture was partitioned between EtOAc and water. The organic layer was washed sequentially with water and brine, dried and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes, to give 5-methoxy-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione as a yellow solid (0.571 g, 37% yield). Mass spectrum m/z 409 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ 7.96 (d, J=7.0 Hz, 1H), 7.91 (dd, J=7.4, 1.2 Hz, 1H), 7.33 (t, J=7.6 Hz, 1H), 7.22 (dd, J=7.8, 1.2 Hz, 1H), 6.39-6.30 (m, 2H), 6.24 (s, 1H), 3.93 (s, 3H), 2.34 (s, 3H), 1.34 (s, 12H).
Reaction SMILES: [C:1]1(=[O:12])[O:7][C:5](=O)[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1.[CH2:13]([C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH3:23])[C:16]=1[NH2:17])[CH3:14]>C(Cl)(Cl)Cl>[CH2:13]([C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH3:23])[C:16]=1[N:17]1[C:5](=[O:7])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2][C:1]1=[O:12])[CH3:14]
Reactant: O=C1Cc2ccccc2C(=O)O1
Reactant: CCc1cccc(CC)c1N
Solvent: ClC(Cl)Cl
Product: CCc1cccc(CC)c1N1C(=O)Cc2ccccc2C1=O
Temperature: 180 °C

Procedure:
162 mg (1.0 mmol) of homophthalic anhydride and 149 mg (1.0 mmol) of 2,6-diethylaniline were charged in an egg-plant type flask of 50 ml, followed by stirring under heating at a temperature of 180° C. for 2 hours. After cooled, the reactant was dissolved in chloroform, purified by silica gel column chromatography (eluent;
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[O:18]1[CH:22]=[C:21]([C:23](OC)=[O:24])[C:20]2[CH:27]=[CH:28][CH:29]=[CH:30][C:19]1=2>O1CCCC1>[OH:24][CH2:23][C:21]1[C:20]2[CH:27]=[CH:28][CH:29]=[CH:30][C:19]=2[O:18][CH:22]=1
Reactant: COC(=O)c1coc2ccccc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCc1coc2ccccc12
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
Diisobutylaluminium hydride in toluene (1.5M, 16.8 ml, 25.2 mmol) was added dropwise to a solution of methyl benzo[b]furan-3-carboxylate (2.02 g, 11.5 mmol) in tetrahydrofuran (50 ml) at -75° C. The resulting solution was stirred at -75° C. for 30 minutes, the cooling bath removed and the mixture allowed to warm to room temperature. The reaction mixture was recooled to -40° C. and quenched by sequential addition of methanol (3 ml), water (1.5 ml) and 2M sodium hydroxide (1.5 ml). The mixture was allowed to warm up to produce a gel, which was filtered off and washed with dichloromethane (6×50 ml). The filtrate was evaporated to dryness, the residue redissolved in ether and the solution dried over magnesium sulphate. The solution was evaporated to afford the title compound (1.66 g, 98%) as an oil which crystallised on standing; δH (CDCl3) 1.61 (1H, br s, OH), 4.85 (2H, s, C H2OH), 7.25-7.35 (2H, m, ArH), 7.49 (1H, dd, J 7.8, 1.0 Hz, ArH), 7.61 (1H, s, 2-H), 7.67 (1H, m, ArH).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][C:9](=O)[NH:8][CH2:7]1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:12]1([C:6]2([CH2:5][CH2:4][OH:3])[CH2:10][CH2:9][NH:8][CH2:7]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)CC1(c2ccccc2)CNC(=O)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCC1(c2ccccc2)CCNC1
Temperature: 5 °C
Reaction time: 18 h

Procedure:
Combine (3-phenyl-5-oxopyrrolidin-3-yl)acetic acid ethyl ester (171 g, 0.69 mol) and tetrahydrofuran (2 L). Cool to about 5° C. Slowly, add over about 15 minutes a solution of lithium aluminum hydride in tetrahydrofuran (2.24 L, 1M, 2.24 mol). After the addition is complete heat to about 60° C. After 18 hours, cool in an ice-bath. Slowly quench by adding a saturated aqueous solution of sodium potassium tartrate (208 mL). After the quench is complete, add Na2SO4 (100 g) and celite (150 g) and stir. After 3 hours, dilute the reaction mixture with tetrahydrofuran (2 L) and filter. Suspend the solids in diethyl ether (2 L) and filter. Combine the filtrates and concentrate the in vacuo to give the title compound: mp; 106°-110° C. Rf =0.12 (silica gel dichloromethane/methanol/ concentrated aqueous ammonia, 9/1/0.1).
Reaction SMILES: Cl([O-])(=O)(=O)=O.[Mg+2].Cl([O-])(=O)(=O)=O.[Br:12][C:13]1[CH:14]=[C:15]([C@@H:19]2[O:21][C@H:20]2[CH2:22][OH:23])[CH:16]=[CH:17][CH:18]=1.[CH2:24]([O:31][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:40]=1[NH:39][CH2:38][CH2:37]2)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(OCC)(=O)C>C(#N)C>[Br:12][C:13]1[CH:14]=[C:15]([C@@H:19]([N:39]2[C:40]3[C:36](=[CH:35][CH:34]=[CH:33][C:32]=3[O:31][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:37][CH2:38]2)[C@H:20]([OH:21])[CH2:22][OH:23])[CH:16]=[CH:17][CH:18]=1
Reactant: OC[C@@H]1O[C@H]1c1cccc(Br)c1
Reactant: c1ccc(COc2cccc3c2NCC3)cc1
Agent: [Mg+2]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: OC[C@@H](O)[C@@H](c1cccc(Br)c1)N1CCc2cccc(OCc3ccccc3)c21
Yield: 84.5 %

Procedure:
Magnesium perchlorate (16.63 g, 74.52 mmol) was added in portions to a magnetically stirred solution of (2S-trans)-3-(3-bromophenyl)oxiranemethanol (16.32 g, 71.26 mmol) in dry acetonitrile (100 ml) at 5° C. under nitrogen. After stirring for 10 min. all of the magnesium salts had dissolved and the resulting intense yellow solution was treated with 7-benzyloxyindoline (16.77 g, 74.52 mmol) in acetonitrile (30.0 ml) dropwise at 0° C. for 20 h, quenched with saturated aqueous NaHCO3 (300 ml), extracted with ethyl acetate (3×200 ml), the combined organic phases were washed with brine (3×200 ml), dried (Na2SO4) and the solvent removed in vacuo to provide a yellow/brown gum. Column chromatography (ethyl acetate--light petroleum (b.p. 40-60° C.), 3:7) provided the title compound (27.37 g, 87%) as a grey/green oil which crystallised on standing. Recrystallised from diethyl ether at -20° C. as white crystals, m.p. 61-66° C. (Found: C, 63.51; H, 5.78; N, 2.84. C24H24BrNO3 requires C, 63.44; H, 5.32; N, 3.08%); [α]D25 -311.1 (c=0.009 gml-1, CHCl3); Vmax (nujol)/cm-1 3353.0 (br. OH), 1584.0, 1565.0; δH (270 MHz) 2.27 (1H, bs, OH); 2.66 (3H, m, OH, 2×indoline 2-H); 3.10 (1H, m, indoline 3-H); 3.30 (1H, m, indoline 3-H); 3.85 (2H, dq, 2×1-H, 2J1,1 =11.5, 3J1,2 =4.0 Hz); 4.22 (1H, m, 2-H); 5.16 (2H, s, CH2Ph); 5.38 (1H, d, 3-H, 3J3,2 =10.2 Hz); 6.65-7.49 (12H, m, 12 ArH). δC (67.8 MHz) 29.2 (indoline 2-C); 46.5 (indoline 3-C); 61.7 (3-C); 64.8 (1-C); 69.9 (C-2); 70.9 (CH2Ph); 112.2 (indoline 6-C); 118.1 (indoline 5-C); 120.3 (indoline 4-C); 122.4 (3'-C); 136.4 (1'-C); 138.5 indoline 7a-C); 139.5 (bensyl ipso-C); 145.0 (indoline 7-C). The remaining signals lie between 127.5-136.4 ppm and could not be assigned with any certainty; m/z 455.3, 453.3 (0.58, 0.74, M+), 394.2, 392.2 (7.81, 7.90), 304.1, 302.1 (4.80, 9.32), 225.2 (8.35), 171.0, 169.0 (5.29, 5.79), 134.1 (34.82), 118.1 (1.35), 59.1 (100).
Reaction SMILES: C(C1[C:16]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22](F)=[CH:21][CH:20]=2)=[N:15]C2[C@H]3N(C(=O)C=2C=1C1C=CC(C(NCC2OC=CC=2)=O)=CC=1)CCC3)(=O)C.[F:41][C:42]1[CH:47]=[CH:46][C:45]([CH:48]2[CH2:57][C:56]3[N:55]=[C:54]4[C@H:58]5[N:62]([C:63](=[O:64])[C:53]4=[C:52]([C:65]4[CH:73]=[CH:72][C:68]([C:69](O)=[O:70])=[CH:67][CH:66]=4)[C:51]=3[C:50](=[O:74])[CH2:49]2)[CH2:61][CH2:60][CH2:59]5)=[CH:44][CH:43]=1.FC1C=CC(C2CC(=O)CC(=O)C2)=CC=1.C(OC(N1CCCC1C(=O)/C(/C(OCC)=O)=C/C1C=CC(C(O)=O)=CC=1)=O)(C)(C)C>>[F:41][C:42]1[CH:47]=[CH:46][C:45]([CH:48]2[CH2:57][C:56]3[N:55]=[C:54]4[C@H:58]5[N:62]([C:63](=[O:64])[C:53]4=[C:52]([C:65]4[CH:73]=[CH:72][C:68]([C:69]([NH:15][C@H:16]6[C:20]7[C:19](=[CH:24][CH:23]=[CH:22][CH:21]=7)[CH2:18][CH2:17]6)=[O:70])=[CH:67][CH:66]=4)[C:51]=3[C:50](=[O:74])[CH2:49]2)[CH2:61][CH2:60][CH2:59]5)=[CH:44][CH:43]=1
Reactant: O=C(O)c1ccc(-c2c3c(nc4c2C(=O)N2CCC[C@@H]42)CC(c2ccc(F)cc2)CC3=O)cc1
Reactant: CC(=O)c1c(CCc2ccc(F)cc2)nc2c(c1-c1ccc(C(=O)NCc3ccco3)cc1)C(=O)N1CCC[C@@H]21
Agent: CCOC(=O)/C(=C\c1ccc(C(=O)O)cc1)C(=O)C1CCCN1C(=O)OC(C)(C)C
Agent: O=C1CC(=O)CC(c2ccc(F)cc2)C1
Product: O=C(N[C@@H]1CCc2ccccc21)c1ccc(-c2c3c(nc4c2C(=O)N2CCC[C@@H]42)CC(c2ccc(F)cc2)CC3=O)cc1
Yield: 52 %

Procedure:
Using the synthetic method described earlier in the synthesis of 4-{(9aS)-3-acetyl-2-[2-(4-fluorophenyl)ethyl]-5-oxo-7,8,9,9a-tetrahydro-5H-pyrido[2,3-α]pyrrolizin-4-yl}-N-(2-furylmethyl)benzamide (Example 29), the title compound was prepared from 4-[(3aS)-6-(4-fluorophenyl)-8,10-dioxo-2,3,3a,5,6,7,8,10-octahydro-1H-pyrrolizino[1,2-b]quinolin-9-yl]benzoic acid (prepared using the enamine of 5-(4-fluorophenyl)-1,3-cyclohexanedione and Knoevenagel product 4-[(1Z)-3-[1-(tert-butoxycarbonyl)-2-pyrrolidinyl]-2-(ethoxy-carbonyl)-3-oxo-1-propenyl]benzoic acid). A portion of the crude material (100 mg) was chromatographed (silica gel/ethyl acetate) to give the title compound as a tan powder (52 mg, 52%). LCMS m/z 572 (MH+) 1H NMR (300 MHz, DMSO-d6) δ 7.90 (d, 2H), 7.40 (m, 2H), 7.10–7.35 (m, 6H), 7.10 (dd, 2H), 6.40 (d, 1H), 5.75 (m, 2H), 4.75 (d, 1H), 3.30–3.75 (m, 2H), 2.80–3.10 (m, 2H), 2.70 (m, 1H), 2.55 (m, 1H), 2.35 (m, 1H), 1.95 (m, 1H), 1.75 (m, 4H), 1.50 (m, 2H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([CH3:7])[S:4][C:3]=1[CH:8]=O.[NH2:10]OS(O)(=O)=O>O>[Br:1][C:2]1[CH:6]=[C:5]([CH3:7])[S:4][C:3]=1[C:8]#[N:10]
Reactant: NOS(=O)(=O)O
Reactant: Cc1cc(Br)c(C=O)s1
Solvent: O
Product: Cc1cc(Br)c(C#N)s1
Temperature: 50 °C
Yield: 83.2 %

Procedure:
To a suspension of 3-bromo-5-methyl-2-thiophenecarboxaldehyde (500 mg) in water (10 ml) was added hydroxylamine-O-sulfonic acid (330 mg). The mixture was heated to 50° C. for 12 h and allowed to cool. The mixture was then extracted with ethyl acetate (3×50 ml). The combined organic layers were washed (brine), dried (MgSO4), filtered and evaporated to leave the sub-title compound (410 mg) as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=O)=[CH:8]2.[NH4+].O[N:28]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH2:28])=[O:14])=[CH:8]2
Reactant: On1nnc2ccccc21
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(=O)O)[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(N)=O)[nH]c12
Temperature: 0 °C
Yield: 94.2 %

Procedure:
To an ice-cooled and stirred mixture of 7-methoxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylic acid (0.78 g) in N,N-dimethylformamide (20 mL) were added 1-hydroxybenzotriazole ammonium salt (0.66 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.83 g). After stirred at room temperature for 7 h, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with aqueous sodium hydrogen carbonate and brine, dried (MgSO4), filtered, and concentrated to give a light yellow amorphous solid, which was crystallized from ethyl acetate-hexane to give the title compound (733 mg, 94%) as pale yellow crystals. MS 361 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[CH:10]=[C:9]2[C:17](N(OC)C)=[O:18])[CH:5]=[CH:6][CH:7]=1.[CH3:23][Mg]Br.CCOCC>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[CH:10]=[C:9]2[C:17](=[O:18])[CH3:23])[CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)c1cc2cccnc2n1-c1cccc(F)c1
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)c1cc2cccnc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a mixture of 1-(3-fluorophenyl)-N-methoxy-N-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (0.35 g, 1.2 mmol) in tetrahydrofuran (10 mL) was added 3.0 M methylmagnesium bromide in ether (3.1 mL, 9.4 mmol). The reaction was stirred at room temperature overnight. The reaction was quenched with saturated NH4Cl solution and then extracted with EtOAc. The combined organic layers were washed with water and brine, dried over MgSO4 and concentrated to give the desired product (0.24 g, 81%). The crude product was used directly in next step. LCMS calculated for C15H12FN2O(M+H)+: m/z=255.1. Found: 255.1.
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl-].[NH4+].CN([CH:16]=[O:17])C>>[CH2:3]([O:17][CH2:16][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCc1ccccc1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Product: c1ccc(COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a slurry of 1.44 g of prewashed sodium hydride (50% dispersion in mineral oil, 27.0 mmole, 1.6 eq.) in 20 ml of dry DMF at 0° C. was added a solution of 3.85 g title E alcohol (27.0 mmole) in 10 ml DMF. The mixture was stirred at 25° C. for 15 minutes, cooled to 0° C. and then 4.3 g of benzylbromide (27.0 mmole, 1.0 eq.) was added. After stirring for 30 minutes at 25° C., the reaction mixture was poured into 300 ml of a saturated aqueous ammonium chloride solution and extracted with three 100 ml of water, dried over anhydrous MgSO4 and concentrated. The residue was purified on an LPS-1 silica gel column, eluting with 10% EtOAc/hexanes to give 4.5 g of title benzylether as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:16](Cl)(=[O:18])[CH3:17].[Al+3].[Cl-].[Cl-].[Cl-]>C(=S)=S>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13]([C:16](=[O:18])[CH3:17])=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CC(=O)Cl
Reactant: COc1ccc(-c2ccccc2)cc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COc1ccc(-c2ccc(C(C)=O)cc2)cc1F
Yield: 82 %

Procedure:
3-Fluoro-4-methoxybiphenyl was acetylated with acetyl chloride/AlCl3 in carbon disulfide in the usual way. The product was twice recrystallized from toluene to obtain 3'-fluoro-4'-methoxy-4-acetylbiphenyl (yield: 82%), m.p. 149°~149.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:16]2[C@@H:15]3[CH2:17][C@@H:14]3[CH2:13][C:12]=2[C:11]([C:18]([OH:20])=O)=[N:10]1.[NH2:21][CH:22]([CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[CH2:23][OH:24]>>[OH:24][CH2:23][CH:22]([NH:21][C:18]([C:11]1[C:12]2[CH2:13][C@H:14]3[CH2:17][C@H:15]3[C:16]=2[N:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[N:10]=1)=[O:20])[CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: NC(CO)C1CCOCC1
Reactant: O=C(O)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Product: O=C(NC(CO)C1CCOCC1)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21

Procedure:
The title compound was prepared in a manner similar to that described in Method G, using Intermediate 1 (see Example 1.1) and 2-amino-2-(tetrahydro-2H-pyran-4-yl)ethanol. LCMS m/z=404.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.46-0.50 (m, 1H), 1.15 (td, J=7.8 and 4.8 Hz, 1H), 1.40-1.53 (m, 2H), 1.70 (d, J=12.6 Hz, 2H), 1.93-2.03 (m, 1H), 2.08-2.15 (m, 1H), 2.24-2.32 (m, 1H), 2.94 (d, J=16.8 Hz, 1H), 3.06 (dd, J=16.8 and 6.2 Hz, 1H), 3.33-3.43 (m, 2H), 3.77-3.85 (m, 3H), 3.95-4.02 (m, 2H), 6.99-7.05 (m, 3H), 7.59-7.66 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:32])=[C:6]([CH:31]=1)[O:7][CH2:8][C:9]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=2[O:26][CH3:27])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:30])=[CH:12][C:13]([CH3:29])([CH3:28])[NH:14]2.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:32])=[C:6]([CH:31]=1)[O:7][CH2:8][C:9]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][S:34]([CH3:33])(=[O:36])=[O:35])=[CH:21][C:20]=2[O:26][CH3:27])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:30])=[CH:12][C:13]([CH3:28])([CH3:29])[NH:14]2
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(OS(C)(=O)=O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
5-(5-Fluoro-2-methylphenoxymethyl)-6-(4-hydroxy-2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 3-1, 61.0 mg, 0.141 mmol) was dissolved in methylene dichloride (2 mL), methanesulfonyl chloride (26 μL, 0.34 mmol) and triethylamine (92 μL, 0.66 mmol) were added thereto, and then the mixture was stirred at room temperature overnight. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (58.0 mg) as a pale pink solid. (Yield 82%)
Reaction SMILES: S(=O)(=O)(O)O.[CH:6]1[CH:7]=[CH:8][C:9]2[C:16](=O)[CH:15]=[CH:14][C:12](=O)[C:10]=2[CH:11]=1.C(O)(=O)C1C(=CC=CC=1)C(O)=O>>[CH:11]1[C:10]2[C:9](=[CH:16][CH:15]=[CH:14][CH:12]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: O=C1C=CC(=O)c2ccccc21
Agent: O=C(O)c1ccccc1C(=O)O
Agent: O=S(=O)(O)O
Product: c1ccc2ccccc2c1
Temperature: 80 °C

Procedure:
As shown in FIG. 2; A curve, when sulfuric acid is present in the aqueous slurry of naphthoquinone and phthalic acid, and the aqueous slurry is heated at higher than 80° C., naphthoquinone is vigorously decomposed. Accordingly, is it clear that when sulfuric acid is present in the aqueous slurry of naphthoquinone in the step of collecting the reaction mixture gas formed by the catalytic vapor phase oxidation of a crude naphthalene with water, the step of dissolving phthalic acid and the step of extracting naphthoquinone, the decomposition of naphthoquinone is remarkably accelerated. The inventors have studied the method of preventing the decomposition of naphthoquinone and have found that the decomposition of naphthoquinone could be prevented by adjusting the pH of the aqueous slurry of naphthoquinone and phthalic acid to 1.2 to 2.5 by neutralizing 1 to 2 equivalents of sulfuric acid and 1 equivalent of maleic acid with a base such as an aqueous solution of sodium hydroxide.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][NH:10][CH2:9][C:8]=3[C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1)#[N:25].Cl.CCOCC>C(Cl)Cl.CCOCC>[ClH:1].[C:24]([C:26]1[CH:27]=[CH:28][C:29]([NH:32][C:33]([N:10]2[CH2:11][CH2:12][C:7]3[NH:6][C:5]4[N:13]=[CH:14][C:2]([Cl:1])=[CH:3][C:4]=4[C:8]=3[CH2:9]2)=[O:34])=[CH:30][CH:31]=1)#[N:25]
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Reactant: N#Cc1ccc(N=C=O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: N#Cc1ccc(NC(=O)N2CCc3[nH]c4ncc(Cl)cc4c3C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 128.8 %

Procedure:
3-Chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg, 0.24 mmol), and DIEA (0.04 mL, 0.24 mmol) were dissolved in DCM (2 mL). 4-Cyanophenyl isocyanate (34 mg, 0.24 mmol) was added and the reaction mixture was stirred overnight at room temperature. The crude reaction mixture was concentrated, and converted to the HCl salt by dissolving the crude material in MeOH (2 ml) and adding 1 M HCl/ether (2 equiv). The resulting solution was refrigerated overnight. Additional ether was added to drive precipitate formation. The resulting precipitate was filtered and dried under vacuum to provide 28 (60 mg, 64% yield) as a yellow solid. LC-MS (M+H=353, obsd.=353).