Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][C@H:17]4[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18]4)[C:14]([CH2:24][O:25][CH2:26][CH3:27])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.B1([C:34]2[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=2)OCCCO1>>[CH3:22][C:19]1([CH3:23])[O:18][C@@H:17]([CH2:16][N:15]2[C:6]3[C:5]4[CH:4]=[CH:3][C:2]([C:34]5[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=5)=[CH:11][C:10]=4[N:9]=[C:8]([NH2:12])[C:7]=3[N:13]=[C:14]2[CH2:24][O:25][CH2:26][CH3:27])[CH2:21][O:20]1
Reactant: c1cncc(B2OCCCO2)c1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1C[C@H]1COC(C)(C)O1
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1C[C@H]1COC(C)(C)O1
Yield: 54.2 %

Procedure:
(S)-7-Bromo-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine (2.65 g, 6.09 mmol) and pyridine-3-boronic acid 1,3-propanediol cyclic ester (1.19 g, 7.30 mmol) were coupled according to the method described in Examples 118-121. The work-up procedure described in Part F of Examples 125-135 was followed. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 80:20) followed by recrystallization from acetonitriled to provide 1.43 g of (S)-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 157-158° C.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:14]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH2:15].C([O-])([O-])=O.[Na+].[Na+].O>C(#N)C>[CH3:19][S:16]([CH2:14][CH2:15][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)(=[O:18])=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C=CS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(CCS(C)(=O)=O)CC1
Temperature: 25 °C
Yield: 93 %

Procedure:
To a solution of 1,1-dimethylethyl 1-piperazinecarboxylate (72.8 g, 390 mmol) in acetonitrile (1.4 L) was added methyl vinyl sulfone (50 g, 470 mmol) and Na2CO3 (124 g, 1170 mmol) and the mixture was refluxed overnight. Then the mixture was cooled to rt, and poured into H2O and extracted with EtOAc. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure to give the title compound (106 g, 93% yield). 1H NMR (400 MHz, CDCl3) δ ppm 1.41-1.57 (m, 9H), 2.39-2.51 (m, 4H), 2.88 (t, J=8.4 Hz, 2H), 3.02 (s, 3H), 3.14 (t, J=8.4 Hz, 2H), 3.35-3.50 (m, 4H).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:11](OC(=O)C)(=O)[CH3:12].C(=O)(O)[O-].[Na+]>>[CH3:11][C:12]1[O:9][C:1](=[O:10])[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[N:4]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1nc2ccccc2c(=O)o1

Procedure:
4-iodo-2-methylbenzenamine (24, 233 mg, 1 mmol) on reaction with ethynyl benzene (25a, 102 mg, 1 mmol) by employing Sonagashira coupling conditions using Pd(PPh3)4 (69.3 mg, 0.06 equiv) as catalyst, CuI (22.8 mg, 0.12 equiv) as cocatalyst, butyl amine (261 mg, 3 equiv) as base and ether as solvent and kept the reaction for 6 h. After completion of the reaction as indicated by TLC and the reaction mixture is extracted into ether (4×25 mL) from the aqueous layer and concentrated in vacuo. The compound was further purified by column chromatography using 60-120 silica gel (ethyl acetate/hexane, 1:9) to obtain 2-methyl-4-(phenylethynyl)benzenamine compound (26a) as pure product. Anthranilic acid (27, 137 mg, 1 mmol) on reaction with acetic anhydride at 150° C. and reflux for 30 min, after completion of reaction aqueous sodium bicarbonate solution is added and extracted in ethyl acetate (4×25 mL) from the aqueous layer and concentrated in vacuo afforded 2-methyl 4H-benzo[d][1,3]oxazin-4-one compound (28) as pure product. To a stirred solution of 2-methyl-4-(phenylethynyl)benzenamine (26a, 207 mg, 1 mmol) with 2-methyl-4H-benzo[α][1,3]oxazin-4-one (28, 161 mg, 1 mmol) in acetic acid and reflux for 8 h. After completion of the reaction as indicated by TLC. The reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4 afforded 2-methyl-3-(2-methyl-4-(phenylethynyl)phenyl)quinazolin-4(3H)-one (29a). Reaction of 2-methyl-3-(2-methyl-4-(phenyl ethynyl)phenyl)quinazolin-4(3H)-one (29a, 350 mg, 1 mmol) with 4-hydroxy benzaldehyde (30b, 122 mg, 1 mmol) was taken in acetic acid Then the resulting mixture was stirred under reflux conditions for 8 h and then the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4. The resulting product (4b) was purified by column chromatography employing EtOAc/Hexane as an eluent.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[C:14]3[C:15]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:16]=4[S:17][C:13]=3[C:12]([C:26]#[N:27])=[CH:11][N:10]=2)=CC=1.O.[OH-].[K+].[O-:33]P([O-])([O-])=O.[K+].[K+].[K+]>OS(O)(=O)=O>[NH2:8][C:9]1[C:14]2[C:15]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:16]=3[S:17][C:13]=2[C:12]([C:26]([NH2:27])=[O:33])=[CH:11][N:10]=1
Reactant: O=P([O-])([O-])[O-]
Reactant: COc1ccc(CNc2ncc(C#N)c3sc4cc(C(F)(F)F)ccc4c23)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1cnc(N)c2c1sc1cc(C(F)(F)F)ccc12

Procedure:
A solution of 1-[(4-methoxybenzyl)amino]-7-(trifluoromethyl)[1]benzothieno[3,2-c]pyridine-4-carbonitrile in conc. H2SO4 (0.1 M) was stirred at room temperature for 2 h. The mixture was poured into H2O, neutralized with KOH and K3PO4 solution to pH 9. The solid was filtered then swished with boiling H2O to give the title compound.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:12]1CCN2C(=NCCC2)CC1>CCOC(C)=O.O>[CH3:12][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: Oc1cccc2ccccc12
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cccc2ccccc12
Temperature: 90 °C

Procedure:
To a solution of 1-naphthol (1.0 g, 6.94 mmol) in DMC (10 mL), DBU (1.06 g, 6.94 mmol) was added and the resulting mixture was heated to reflux (90° C.) for 16 hours. The reaction was cooled to ambient temperature and diluted with EtOAc (50 mL) and H2O (40 mL). The organic layer was separated and washed in sequence with 2M HCl (2×40 mL), 2M NaOH (2×40 mL) and H2O. The organic layer was dried over Na2SO4, filtered and concentrated under vacuum to give 1-methoxynaphthalene as an oil. The yield of 1-methoxynaphthalene as determined by HPLC was 99% conversion.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:22][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[C:11]=1[O:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[Cl:21])[C:5]([O:7][CH3:8])=[O:6].[C:32]([C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]>C1(C)C=CC=CC=1.N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:32]([C:36]1[CH:41]=[CH:40][C:39]([S:42]([NH:1][C:2]2[CH:3]=[C:4]([CH:9]=[C:10]([O:22][CH2:23][CH2:24][O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[C:11]=2[O:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[Cl:21])[C:5]([O:7][CH3:8])=[O:6])(=[O:44])=[O:43])=[CH:38][CH:37]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: COC(=O)c1cc(N)c(Oc2cc(OC)ccc2Cl)c(OCCOC2CCCCO2)c1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c(Oc2cc(OC)ccc2Cl)c(OCCOC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.13 g of methyl 3-amino-4-(2-chloro-5-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate were dissolved in a mixture of toluene/pyridine (20 ml/30 ml) treated dropwise while cooling with ice with a solution of 1.05 g of 4-tert.butyl-benzenesulphonyl chloride in toluene (30 ml) and subsequently stirred at RT for 24 hours. The reaction mixture was poured on to ice/3M HCl, the product was extracted with ethyl acetate and the organic phase was dried over magnesium sulphate. After removing the solvent there was obtained methyl 3-(4-tert-butyl-benzenesulphonylamino)-4-(2-chloro-5-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate as a yellow solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:10])[CH2:7][C:8]#[N:9])[CH3:4].F[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[N+:20]([O-:22])=[O:21].Cl>CN(C=O)C.C(OCC)(=O)C>[CH2:3]([O:5][C:6](=[O:10])[CH:7]([C:8]#[N:9])[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[N+:20]([O-:22])=[O:21])[CH3:4]
Reactant: N#Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C#N)c1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (0.96 g, 60% in mineral oil, 24 mmol) in DMF (6 mL) at 0° C. was added ethylcyanoacetate (2.72 g, 24 mmol) in DMF (2 mL) under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 30 minutes then 4-fluoro-3-nitro-benzonitrile (2.05 g, 22.7 mmol) in DMF (5 mL) was added dropwise. 1M HCl and ethyl acetate were added to the reaction mixture after 1 hour. The organic layer was washed with water and brine, then dried over sodium sulphate and concentrated to give a brown oil which was purified by flash column chromatography to give the title compound. 1H NMR (DMSO-d6) δ 8.79 (1H), 8.38 (1H), 7.95 (1H, d, J=2), 6.38 (1H), 4.21 (2H), 1.19 (3H, t).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]([F:21])[C:14]=3[Cl:22])[CH3:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:23][C:24]1[C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][NH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1>[Cl:22][C:14]1[C:15]([F:21])=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[C:13]=1[C@H:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:28]3[C:24]([CH3:23])=[N:25][NH:26][CH:27]=3)[CH:3]=2)[NH:8][CH:9]=1)[CH3:12]
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(Br)cc12
Reactant: Cc1n[nH]cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3c[nH]nc3C)cc12
Temperature: 100 °C

Procedure:
A mixture of 5-Bromo-3-[(S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (12 mg, 0.031 mmol), 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (13.0 mg, 0.0626 mmol), potassium carbonate (0.0130 g, 0.0938 mmol) and 4:1 Dioxane:water (4:1,1,4-Dioxane:H2O, 0.31 mL, 3.1 mmol) were added to a microwave vessel and the vessel was degassed 3×. The reaction was heated in the microwave at 100° C. for 30 min. Reaction mixture was concentrated in vacuo and purified by HPLC to afford the title compound. 1H NMR (400 MHz, CD3OD): δ=1.82 (d, J=7.3 Hz, 3H), 2.23 (s, 3H), 3.66 (br. s., 3H), 5.12 (d, J=6.8 Hz, 1H), 6.91 (dd, J=9.0, 4.2 Hz, 1H), 7.10 (t, J=9.0 Hz, 1H), 7.36 (d, J=1.3 Hz, 1H), 7.48 (s, 1H), 7.62 (br. s., 1H), 8.18 (d, J=1.8 Hz, 1H). MS (ES+): m/z=384.96/386.94 (100/65) [MH+]. HPLC: tR=3.19 min (ZQ3, polar—5 min).
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[N:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1>CN(C)C=O.C([O-])(=O)C.[Co+2].C([O-])(=O)C>[S:5]1[CH:6]=[CH:7][CH:8]=[C:4]1[C:1](=[O:3])[CH:2]=[CH:15][C:12]1[CH:13]=[CH:14][N:9]=[CH:10][CH:11]=1
Reactant: O=Cc1ccncc1
Reactant: CC(=O)c1cccs1
Agent: [Co+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C(C=Cc1ccncc1)c1cccs1
Reaction time: 0.5 h
Yield: 1.1 %

Procedure:
Dissolve anhydrous cobalt(II) acetate (700 mg, 4 mmol) in dimethylformamide (100 mL) . Add 2,2'-dipyridyl (600 mg, 4 mmol) and stir for 30 minutes. Add 2-acetylthiophene (6.3 g, 50 mmol) and 4-pyridinecarboxaldehyde (5 g, 50 mmol) and heat at 80° C. for 18 hours. Evaporate the solvent and purify the resiude by silica gel chromatography (1:1 toluene/ethyl acetate). Recrystallize (ethyl ether/hexane) to yield 120 mg of the title compound; mp 150.5°-152° C.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[CH:12]=[C:11]([CH2:23][OH:24])[C:10]=2[CH2:25][OH:26])[CH:4]=1.S(C1C=CC(C)=CC=1)(O[CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=O)=O.O>CN(C)P(=O)(N(C)C)N(C)C>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[CH:12]=[C:11]([CH2:23][O:24][CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:10]=2[CH2:25][OH:26])[CH:4]=1
Reactant: COc1cc2cc(CO)c(CO)c(-c3cccnc3)c2cc1OC
Reactant: Cc1ccc(S(=O)(=O)OCC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: COc1cc2cc(COCC(C)(C)C)c(CO)c(-c3cccnc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride in hexamethylphosphoric triamide (40 ml) is added a solution of 1-(3-pyridyl)-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene in hexamethylphosphoramide (10 ml) under ice-cooling. The mixture is warmed to room temperature, and then stirred for 30 minutes. To the reaction solution is added neo-pentyl tosylate (3.67 g), and the mixture is reacted at 100° C. for 30 minutes. The mixture is allowed to cool, and thereto is added water, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried, and concentrated. The resulting residue is subjected to silica gel column chromatography (eluent; chloroform:acetone=5:1), and the desired fractions are concentrated to give 1-(3-pyridyl)-2-hydroxymethyl-3-neo-pentyloxymethyl-6,7-dimethoxynaphthalene (1.5 g) as an oily product.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:8]=2[O:7][CH2:6][C:5]1=[O:20].[C:21]1([C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([SH:29])[CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:30]1([C:27]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([S:29][CH2:2][CH2:3][N:4]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:8]=3[O:7][CH2:6][C:5]2=[O:20])[CH3:28])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COC(=O)COc1cccc2c1OCC(=O)N2CCO
Reactant: CC(S)(c1ccccc1)c1ccccc1
Product: COC(=O)COc1cccc2c1OCC(=O)N2CCSC(C)(c1ccccc1)c1ccccc1
Yield: 42 %

Procedure:
The same process as Example 1 was repeated except that methyl (4-(2-hydroxyethyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate (187 mg) and 1,1-diphenylethanethiol (270 ml) were used to obtain the object compound (172.5 mg, yield 42%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:38]3[CH:39]=[C:34]([CH3:33])[CH:35]=[CH:36][CH:37]=3)[C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:31])(=[O:32])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Reactant: Cc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cccc(-n2c(C(=O)N3CCS(=O)(=O)CC3)cc3cc(C(=O)N4CCN(C5CCCC5)CC4)ccc32)c1
Yield: 76 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone (example 34), 3-methylphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light yellow solid (76%).
Reaction SMILES: N1C2C(=CC=CN=2)C(C(=O)C([O-])=O)=C1.[K+:15].[CH3:16][O:17][C:18]1[CH:26]=[N:25][C:24]([O:27][CH3:28])=[C:23]2[C:19]=1[C:20]([C:29](=[O:35])[C:30]([O:32]CC)=[O:31])=[CH:21][NH:22]2>>[CH3:16][O:17][C:18]1[CH:26]=[N:25][C:24]([O:27][CH3:28])=[C:23]2[C:19]=1[C:20]([C:29](=[O:35])[C:30]([O-:32])=[O:31])=[CH:21][NH:22]2.[K+:15]
Reactant: CCOC(=O)C(=O)c1c[nH]c2c(OC)ncc(OC)c12
Agent: O=C([O-])C(=O)c1c[nH]c2ncccc12
Agent: [K+]
Product: COc1ncc(OC)c2c(C(=O)C(=O)[O-])c[nH]c12

Procedure:
Compound 3ao (Potassium (4,7-dimethoxy-6-azaindol-3-yl)-oxoacetate) was prepared (as a yellow solid), by the same method used to prepare compound 3a except Ethyl (4,7-dimethoxy-6-azaindol-3-yl)-oxoacetate was employed as the starting material. MS m/z: (M+H)+ of the corresponding acid of compound 3ao (M−K+H)+ calcd for C11H11N2O5: 251.07; found 251.09. HPLC retention time: 0.69 minutes (column B).
Reaction SMILES: O=[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[CH2:18][Mg]Cl>>[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[CH2:18][CH:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2=O
Reactant: Cl[Mg]Cc1cccc(Cl)c1
Product: COC(=O)c1cc2c([nH]1)CCC2Cc1cccc(Cl)c1

Procedure:
The title compound was synthesized in two steps. First, methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (447 mg, 2.5 mmol) was reacted with 3-chlorobenzylmagnesium chloride (0.25 M in hexanes, 25 mL, 6.3 mmol) according to General Procedure 3. The resulting products were then converted to the title compound by hydrogenation according to General Procedure 6 (with Pt2O). The crude product was purified by column chromatography eluting with heptane-EtOAc, gradient 0 to 40% EtOAc to afford the title compound. 262 mg. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.04-2.15 (m, J=12.57, 8.03, 6.17, 6.17 Hz, 1H) 2.52-2.64 (m, 1H) 2.64-2.72 (m, 2H) 2.74-2.83 (m, 2H) 3.81 (s, 3H) 6.39 (d, J=1.37 Hz, 1H) 7.07 (d, J=8.25 Hz, 1H) 7.21 (d, J=1.81 Hz, 2H) 7.22-7.26 (m, 1H) 7.28-7.32 (m, 1H) 8.75 (br. s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[CH:11][C:10]1[CH:9]=[CH:8][C:7]([OH:16])=[CH:6][C:5]2=1.[CH:17]1([CH2:20][CH2:21]O)[CH2:19][CH2:18]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>C1COCC1>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]=[CH:11][C:10]3[C:5]([C:4]=2[CH:3]=1)=[CH:6][C:7]([O:16][CH2:21][CH2:20][CH:17]1[CH2:19][CH2:18]1)=[CH:8][CH:9]=3
Reactant: OCCC1CC1
Reactant: Oc1ccc2ccc3ccc(Br)cc3c2c1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Brc1ccc2ccc3ccc(OCCC4CC4)cc3c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 6-bromophenanthren-3-ol (3 g, 11 mmol) from Step 1 of Route A of Example 168, 2-cyclopropylethanol (2.85 g, 33 mmol) and triphenylphosphine (5.78 g, 22 mmol) in THF (50 mL) was added di-tert-butylazodicarboxylate (5.08 g, 22 mmol). The reaction mixture was stirred at room temperature overnight, then quenched with water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The material was purified by flash chromatography on silica (100% hexanes) to afford 3-bromo-6-(2-cyclopropylethoxy)phenanthrene.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:15]1[N:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[CH:17][CH:16]=1.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>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.O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:15]2[N:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]3[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]3)=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(Br)nc2)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
A mixture of [4-(methylsulfonyl)phenyl]boronic acid (540 mg, 2.7 mmol), 1,1-dimethylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (1 g, 2.7 mmol), Pd(PPh3)2Cl2 (190 mg, 0.27 mmol), DME (10 mL) and 2M Na2CO3 (5 mL) was stirred at 80° C. overnight. The mixture was cooled to ambient temperature, charged with water, and extracted with Et2O. The organics were dried over MgSO4, filtered, and the filtrate was concentrated. The aqueous phase was further extracted with CH2Cl2. The CH2Cl2 extracts were combined with the Et2O extracts, dried over MgSO4, filtered, and the filtrate was concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 1.5% MeOH/CH2Cl2, followed by recrystallization from MeOH. The recrystallized material and the mother liquor were combined, then concentrated to give 705 mg (58%) of 1,1-dimethylethyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate as an off-white solid. This material contained a minor impurity which was carried on to the next step. 1H NMR (400 MHz, CDCl3): δ 8.41 (d, 1H, J=2.7 Hz), 8.14 (d, 2H, J=8.4 Hz), 8.01 (d, 2H, J=8.4 Hz), 7.75 (d, 1H, J=8.7 Hz), 7.34 (d, 1H, J=8.2 Hz), 4.26-4.10 (m, 2H), 3.92 (d, 2H, J=6.3 Hz), 3.07 (s, 3H), 2.83-2.66 (m, 2H), 2.10-1.94 (m, 1H), 1.84 (d, 2H, J=12.82 Hz), 1.46 (s, 9H), 1.38-1.21 (m, 2H); LRMS (ESI), m/z 447 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@:10]([CH2:15][CH3:16])([C:13]#[N:14])[C:9]2=[O:17])[CH:5]=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([CH2:31][OH:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(O)(=O)C>C(O)C>[CH2:15]([C@:10]1([C:13]#[N:14])[CH2:11][CH2:12][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4([CH2:31][OH:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:21][CH:20]=3)[N:7]=2)[C:9]1=[O:17])[CH3:16]
Reactant: CC[C@]1(C#N)CCN(c2ccnc(Cl)n2)C1=O
Reactant: Nc1ccc(C2(CO)CCOCC2)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: CC[C@]1(C#N)CCN(c2ccnc(Nc3ccc(C4(CO)CCOCC4)cc3)n2)C1=O
Temperature: 150 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
To a solution of (3R)-1-(2-chloropyrimidin-4-yl)-3-ethyl-2-oxopyrrolidine-3-carbonitrile (100 mg) obtained in Step A of Example 8 in ethanol (3.0 mL) were added (4-(4-aminophenyl)tetrahydro-2H-pyran-4-yl)methanol (83 mg) obtained in Step B of Example 152 and acetic acid (25 μL), and the mixture was stirred in a microwave reactor at 150° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate), and recrystallized (hexane/ethyl acetate) to give the title compound (100 mg).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([S:7]([OH:10])(=[O:9])=[O:8])[CH:4]=[C:3]([NH2:11])[CH:2]=1.[CH2:12]([O:14][C:15](=[O:29])[CH:16]([CH2:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:17](=O)[CH3:18])[CH3:13].[OH-].[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[CH:20]=[C:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:11]([C:3]2[CH:2]=[CH:1][CH:6]=[C:5]([S:7]([OH:10])(=[O:8])=[O:9])[CH:4]=2)[C:17]=1[CH3:18])=[O:29])[CH3:13]
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Reactant: Nc1cccc(S(=O)(=O)O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2cccc(S(=O)(=O)O)c2)c1C

Procedure:
Metanilic acid (5 mmol, 0.9 g), 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (5 mmol, 1.2 g), sodium hydroxide (5 mmol, 0.2 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The unreacted metanilic acid was precipitated on ice and filtered from the reaction mixture. The filtrate was evaporated to yield an oil, which was purified over silica gel. After standing, the named product solidified as purple crystals (m.p. 94° C.-96° C.).