Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])[C@H:2]([C:19]([NH:21][C@H:22]([C:40]([N:42]1[CH2:81][CH2:80][CH2:79][C@H:43]1[C:44]([NH:46][C@H:47]([C:49]([NH:51][C@H:52]([C:69]([O:71]CC1C=CC=CC=1)=[O:70])[CH2:53][CH2:54][CH2:55][CH2:56][NH:57][C:58]([O:60][CH2:61][C:62]1[CH:68]=[CH:67][CH:66]=[CH:65][C:63]=1[Cl:64])=[O:59])=[O:50])[CH3:48])=[O:45])=[O:41])[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[NH:39])[NH:28][S:29]([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30])=[O:20])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[Cl:14])=[O:9].[OH-].[Na+].C(Cl)(Cl)Cl.CO>CO>[NH:1]([C:82]([O:84][C:85]([CH3:86])([CH3:88])[CH3:87])=[O:83])[C@H:2]([C:19]([NH:21][C@H:22]([C:40]([N:42]1[CH2:81][CH2:80][CH2:79][C@H:43]1[C:44]([NH:46][C@H:47]([C:49]([NH:51][C@H:52]([C:69]([OH:71])=[O:70])[CH2:53][CH2:54][CH2:55][CH2:56][NH:57][C:58]([O:60][CH2:61][C:62]1[CH:68]=[CH:67][CH:66]=[CH:65][C:63]=1[Cl:64])=[O:59])=[O:50])[CH3:48])=[O:45])=[O:41])[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[NH:39])[NH:28][S:29]([C:32]1[CH:33]=[CH:34][C:35]([CH3:36])=[CH:37][CH:38]=1)(=[O:31])=[O:30])=[O:20])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[Cl:14])=[O:9]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CCCCNC(=O)OCc2ccccc2Cl)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CCCCNC(=O)OCc2ccccc2Cl)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
At 0° C. to the solution of 250 mg (0196 mmol) of Boc-Lys(ClZ)-Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 15) in 6 ml of methanol 5 ml of the solution of NaOH in methanol (2 mol/L) were added. The reaction mixture was stirred at 0° C. for 2 h and TLC (chloroform/methanol, 15:1) indicated complete disappearance of Boc-Lys(ClZ)-Arg(Tos)-Pro-Ala-Lys(ClZ)-Obzl (SEQ ID NO: 15). The reaction mixture was neutralized to pH 7 and evaporated at room temperature to remove methanol. The residue was acidified to pH 1–2 with hydrochloric acid (2 mol/L) to provide 200 mg (86%) of the title compound as a colorless powder.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)=[O:12])[N:7]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][C:34](O)=[O:35])=[CH:29][CH:28]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].B.S([O-])(OC)=O>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:18][CH:19]=2)=[O:12])[N:7]([C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][OH:35])=[CH:31][CH:32]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccncc3)cc2)n(-c2ccc(CC(=O)O)cc2)n1
Agent: B
Agent: COS(=O)[O-]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccncc3)cc2)n(-c2ccc(CCO)cc2)n1
Temperature: 25 °C
Yield: 51 %

Procedure:
To a solution of (4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}-carbonyl)amino]-1H-pyrazol-1-yl}phenyl)acetic acid (100 mg, 0.21 mmol) in THF (4 mL) was added borane-methyl sulfite complex (0.51 mL, 2M in THF) drop-wise with stirring at room temperature. The resulting reaction mixture was heated at reflux for 2 h, then cooled to room temperature and quenched by the addition of EtOH/1N HCl. The resulting mixture was heated at reflux for 1 h. The mixture was cooled to room temperature and evaporated at reduced pressure, and the residue was dissolved in a mixture of EtOAc and saturated NaHCO3. The organic phase was dried over Na2SO4, concentrated, and purified by MPLC (50:50 hexane/EtOAc). The desired product was obtained as a white solid (50 mg) in 51% yield. 1H-NMR (DMSO-d6) δ 9.12 (s, 1H), 8.39 (m, 3H), 7.48 (d, J=9.0 Hz, 2H), 7.40-7.33 (m, 4H), 7.07 (d, J=8.8 Hz, 2H), 6.85 (m, 2H), 6.34 (s, 1H), 4.69 (t, J=5.1 Hz, 1H), 3.64 (m, 2H), 2.78 (t, J=7.1 Hz, 2H), 1.27 (s, 9H); MS LC-MS [M+H]+=472.2, RT=2.35 min.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=O.[NH2:23][C:24]1[S:25][CH:26]=[C:27]([CH3:29])[N:28]=1>C(OCC)(=O)C>[OH:11][C:10]1[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7](=[O:20])(=[O:21])[N:6]([CH3:22])[C:5]=1[C:3]([NH:23][C:24]1[S:25][CH:26]=[C:27]([CH3:29])[N:28]=1)=[O:2])=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: Cc1csc(N)n1
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Solvent: CCOC(C)=O
Product: Cc1csc(NC(=O)C2=C(O)c3ccc4ccccc4c3S(=O)(=O)N2C)n1
Yield: 39.2 %

Procedure:
5.0 gm (0.016 mol) of 4-hydroxy-2-methyl-2H-naphtho [2,1-e]-1,2-thiazine-3-carboxylic acid methyl ester-1,1-dioxide were reacted with 2.75 gm (0.025 mol) of 2-amino-4-methyl-thiazole in 200 ml ofxylene analogous to Example 1 and yielded 2.52 gm (40% of theory) of 4-hydroxy-2-methyl-N-(4-methyl-2-thiazolyl)-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide, m.p. 177° C (decomp.; from ethyl acetate).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]2[N:13]=[CH:12][CH:11]=[N:10][N:9]2[CH:14]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[N:10]1[N:9]2[CH:14]=[C:6]([CH:4]=[O:3])[N:7]=[C:8]2[N:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1cn2nccnc2n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: O=Cc1cn2nccnc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.2 %

Procedure:
To a solution of imidazo[1,2-b][1,2,4]triazine-6-carboxylic acid ethyl ester (500 mg, 2.6 mmol, from step 1 above) in CH2Cl2 (15 mL) cooled to −78° C. was added diisobutylaluminum hydride (2.6 mL, 1.5 M in toluene). The reaction was stirred for one hour, and then extra diisobutylaluminum hydride (1 mL, 1.5 M) was added. After 20 more minutes, the cold reaction was quenched with EtOAc (10 mL), and then MeOH (10 mL). After the reaction had warmed to room temperature, 30 mL of 0.3 M HCl was added. The layers were separated. The aqueous phase was extracted three times with 10 mL of CH2Cl2. After the organic layers were combined and dried over MgSO4, the solids were removed by filtration. The organic liquid was concentrated by rotary evaporation, and the resulting oil was chromatographed (40 g SiO2, 50 to 100% EtOAc in hexanes) to give the desired product (47 mg, 12%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[O:30][C:31](Cl)=[O:32]>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:31](=[O:32])[O:30][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:20]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)Oc1ccc2ccccc2c1
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)Oc1ccc2ccccc2c1

Procedure:
According to the general method of Example 7, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and chloroformic acid 2-naphthyl ester were combined to provide 2-naphthyl N-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate as a white powder, m.p. 154.0-155.0° C. 1H NMR (300 MHz, DMSO-d6) δ 8.23 (s, 1H), 8.08 (d, J=7.4 Hz, 1H), 7.94-7.86 (m, 4H), 7.64 (dd, J=8.3, 1.0 Hz, 1H), 7.56-7.43 (m, 4H), 7.30 (m, 1H), 7.20 (dd, J=8.8, 2.3 Hz, 1H), 6.61 (broad s, 2H), 4.65 (t, J=6.9 Hz, 2H), 3.14 (q, J=6.4 Hz, 2H), 1.94 (m, 2H), 1.56 (m, 2H); MS (EI) m/e 426.1927 (426.1930 calcd for C25H23N5O2).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.[NH2:23][CH2:24][C@@H:25]([OH:28])[CH2:26][OH:27]>>[Cl:22][C:7]1[C:8]([NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:23][CH2:24][C@@H:25]([OH:28])[CH2:26][OH:27])[CH:11]=[CH:10]2
Reactant: NC[C@@H](O)CO
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Product: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(NC[C@@H](O)CO)ccc12
Yield: 8.6 %

Procedure:
Prepared according to the method of example 2, using N-(2,6-dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1 (a)) (200 mg) and 3-amino-(2R)-1,2-propanediol (655 mg). Purification (SiO2, dichloromethane:methanol 9:1 as eluant) gave the title compound (20 mg).
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1([CH3:22])[C:10](=[O:11])[NH:9][C:8]([C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([O:16][CH3:17])=[O:15])=[N:7]1)([CH3:5])[CH3:4].[N+:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32](Cl)=O)([O-:25])=[O:24]>O1CCCC1>[CH:3]([C:6]1([CH3:22])[C:10](=[O:11])[N:9]([S:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N+:23]([O-:25])=[O:24])[C:8]([C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([O:16][CH3:17])=[O:15])=[N:7]1)([CH3:5])[CH3:4]
Reactant: COC(=O)c1ccccc1C1=NC(C)(C(C)C)C(=O)N1
Reactant: O=[N+]([O-])c1ccccc1S(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1C1=NC(C)(C(C)C)C(=O)N1Sc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A slurry of sodium hydride (0.76 g, 0.019 mol, 60% in mineral oil) and tetrahydrofuran is added dropwise to a 0° C. solution of methyl o-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)benzoate (5.0 g, 0.018 mol) and tetrahydrofuran under a nitrogen atmosphere. After stirring for 1 hour at room temperature, 2-nitrobenzenesulfinyl chloride (3.8 g, 0.020 mol) is added dropwise to the mixture and stirring is continued at room temperature for 72 hours. The reaction mixture is filtered and the filtrate is concentrated in vacuo to give a yellow solid. The solid is chromatographed using silica gel and 10% ethyl acetate in methylene chloride as eluent to yield the title compound as a pale yellow solid (1.08 g, 14%, mp 143°-148° C., identified by IR and NMR spectral analyses.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:7]=[CH:6][C:5]=1[C:14]([O:16]CC)=[O:15])([O-:3])=[O:2].[OH-].[Li+]>C(#N)C.O>[N+:1]([C:4]1[C:13]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:7]=[CH:6][C:5]=1[C:14]([OH:16])=[O:15])([O-:3])=[O:2]
Reactant: CCOC(=O)c1ccc2c(c1[N+](=O)[O-])OCCO2
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: O=C(O)c1ccc2c(c1[N+](=O)[O-])OCCO2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of ethyl 5-nitro-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate (4.30 g, 17.0 mmol) and lithium hydroxide (2.86 g, 68 mmol) in acetonitrile (20 mL) and water (20 mL) was stirred at room temperature for 6 h. The acetonitrile was then removed, and the resulting mixture was extracted with EtOAc (100 mL×2). The extracts were combined and dried, and the solvent removed. The crude product was used in the next step without further purification. ESI MS: m/z 226 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](Cl)=[CH:7][C:6]=1[F:12].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:51][C:52]1[CH:53]=[C:54]([C:68]([C:73]2[CH:78]=[CH:77][C:76](/[CH:79]=[CH:80]/[C:81]([CH2:85][CH3:86])([OH:84])[CH2:82][CH3:83])=[C:75]([CH3:87])[CH:74]=2)([CH2:71][CH3:72])[CH2:69][CH3:70])[CH:55]=[C:56]([CH3:67])[C:57]=1B1OC(C)(C)C(C)(C)O1.[Cl-].[NH4+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:57]2[C:56]([CH3:67])=[CH:55][C:54]([C:68]([CH2:69][CH3:70])([C:73]3[CH:78]=[CH:77][C:76](/[CH:79]=[CH:80]/[C:81]([CH2:85][CH3:86])([OH:84])[CH2:82][CH3:83])=[C:75]([CH3:87])[CH:74]=3)[CH2:71][CH3:72])=[CH:53][C:52]=2[CH3:51])=[CH:7][C:6]=1[F:12]
Reactant: COC(=O)Cc1ccc(Cl)cc1F
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2cc(C)c(B3OC(C)(C)C(C)(C)O3)c(C)c2)cc1C)CC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2cc(C)c(-c3ccc(CC(=O)OC)c(F)c3)c(C)c2)cc1C)CC
Temperature: 100 °C
Reaction time: 1 h
Yield: 60.3 %

Procedure:
(4-Chloro-2-fluoro-phenyl)acetic acid methyl ester (Example 40; 30 mg, 0.149 mmol), palladium acetate (2.2 mg, 0.010 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (8.2 mg, 0.020 mmol), potassium phosphate (63 mg, 0.297 mmol) and water (0.2 mL) were added to a solution of (E)-1-(4-{1-[3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-3-ethyl-1-penten-3-ol (Example 38-(6); 50 mg, 0.099 mmol) in toluene (2 mL). After replacement with nitrogen, the mixture was stirred at 100° C. for one hour. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to give the target compound as a colorless oil (32.5 mg, 60%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([C:12]1[CH:13]=[N:14][C:15]([CH:18]([F:20])[F:19])=[CH:16][CH:17]=1)[OH:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:21][S:22](Cl)(=[O:24])=[O:23].CCN(CC)CC.O>C(Cl)Cl>[CH3:21][S:22]([O:11][C@H:10]([C:12]1[CH:13]=[N:14][C:15]([CH:18]([F:20])[F:19])=[CH:16][CH:17]=1)[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])(=[O:24])=[O:23]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](O)c1ccc(C(F)F)nc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@H](OS(C)(=O)=O)c1ccc(C(F)F)nc1
Temperature: 25 °C
Yield: 59.8 %

Procedure:
To a stirred solution of (R)-2-(tert-butyldimethylsilyloxy)-1-(6-(difluoromethyl)pyridin-3-yl)ethanol (3.0 g, 9.90 mmol) in dry CH2Cl2 at 0° C. was added MeSO2Cl (1.2 g, 10.9 mmol) and Et3N (1.3 g, 12.9 mmol). The resulting reaction mixture was warmed to room temperature over a period of 2 h. After completion of the reaction, the reaction mixture was treated with water and extracted with CH2Cl2. The organic layer was dried over anhydrous Na2SO4 and the solvents were evaporated in vacuo. The residue was purified by column chromatography (SiO2, 10% EtOAc/pet. ether) to afford the title compound (2.26 g, 60% yield). MS: 381 [M+1]+; 1H-NMR (300 MHz, CDCl3): 8.67 (s, 1H), 7.90 (d, 1H, J=8.3 Hz), 7.68 (d, 1H, J=8.3 Hz), 6.65 (t, 1H, J=55.2 Hz), 5.62-5.66 (m, 1H), 3.98 (dd, 1H, J=11.2, 6.8 Hz), 3.87 (dd, 1H, J=11.2, 4.9 Hz), 3.028 (s, 3H), 0.87 (s, 9H), 0.04-0.05 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:21])[O:4][CH:5]([CH:9](O)[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[C:6]=1[O:7][CH3:8].C(N(CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl.CCOC(C)=O.O>[Br:1][C:2]1[C:3](=[O:21])[O:4]/[C:5](=[CH:9]\[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)/[C:6]=1[O:7][CH3:8]
Reactant: COC1=C(Br)C(=O)OC1C(O)c1cccc2ccccc12
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC1=C(Br)C(=O)O/C1=C\c1cccc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A solution of 3-bromo-5-(hydroxynaphthalen-1-ylmethyl)-4-methoxy-5H-furan-2-one (5.3 g, 15.17 mmol) and triethylamine (9.22 g, 12.7 mL, 91.1 mmol) in anhydrous CH2Cl2 at 0° C. is treated dropwise with methane sulfonyl chloride (6.96 g, 4.7 mL, 60.7 mmol), stirred for 0.5 h at 0° C., allowed to warm to room temperature, treated sequentially with additional triethylamine (4.64 g, 6.4 mL, 45.9 mmol) and methane sulfonyl chloride (3.55 g, 2.4 mL, 31 mmol), stirred until the disappearance of starting material and diluted with EtOAc and water. The phases are separated and the organic phase is dried over Na2SO4 and concentrated in vacuo. The resultant residue is flash chromatographed (silica gel, 25% EtOAc in hexanes as eluent) to afford the title product as a yellow solid, 4.0 g (80% yield), mp 143-1481° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6](B(O)O)[CH:7]=1.Br[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:19][C:15]1[CH:14]=[C:13]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[OH:11])[CH:18]=[CH:17][N:16]=1
Reactant: OB(O)c1cc(F)ccc1O
Reactant: Nc1cc(Br)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(-c2cc(F)ccc2O)ccn1
Temperature: 85 °C
Yield: 86.7 %

Procedure:
Argon was bubbled through a suspension of (5-fluoro-2-hydroxyphenyl)boronic acid (55.0 mg, 0.35 mmol), 4-bromopyridin-2-amine (67.1 mg, 0.39 mmol) and sodium carbonate (0.15 g, 1.4 mmol) in 1,4-dioxane (0.9 mL) and water (0.3 mL) for 5 minutes then tetrakis(triphenylphosphine)palladium(0) (41 mg, 0.04 mmol) was added. The resulting mixture was heated at 85° C. for 22 hours then cooled to ambient temperature and diluted with ethyl acetate and water. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by automated silica gel flash chromatography (0% to 100% ethyl acetate in hexanes gradient elution) to afford the title compound as a light tan solid (62 mg).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[CH3:21][C:22]1[NH:23][CH:24]=[CH:25][N:26]=1>>[CH3:21][C:22]1[NH:23][CH:24]=[C:25]([CH2:14][CH:13]([C:3]2[CH:4]=[CH:9][CH:10]=[CH:11][CH:2]=2)[O:1][C:2]2[C:3]([CH2:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]3)[N:26]=1
Reactant: Cc1ncc[nH]1
Reactant: O=C1CCCc2c1ccc(O)c2CCc1ccccc1
Product: Cc1nc(CC(Oc2ccc3c(c2CCc2ccccc2)CCCC3=O)c2ccccc2)c[nH]1

Procedure:
The title compound was prepared using the procedure of Example 20, step 4 using 6-hydroxy-5-(2-phenyl-ethyl)-3,4-dihydro-2H-naphthalen-1-one and 2-methylimidazole.
Reaction SMILES: [OH-].[NH4+:2].[F:3][C:4]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7]/[C:8]/2=[CH:14]\[C:15](Cl)=[O:16]>ClCCl>[F:3][C:4]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7]/[C:8]/2=[CH:14]\[C:15]([NH2:2])=[O:16]
Reactant: [NH4+]
Reactant: O=C(Cl)/C=C1\CCc2c(F)cc(F)cc21
Agent: [OH-]
Solvent: ClCCl
Product: NC(=O)/C=C1\CCc2c(F)cc(F)cc21
Yield: 59.9 %

Procedure:
A 30% aqueous ammonium hydroxide solution (1.7 mL, 0.026 mol) was added dropwise to a stirred, chilled (ice bath) solution of (E)-2-(4,6-difluoro-1-indanylidene)acetyl chloride (2.97 g, 0.013 mol) in dichloromethane (50 mL). After 4.5 h the mixture was concentrated in vacuo and the residue was partitioned between 5% aqueous sodium bicarbonate solution and ethyl acetate. The ethyl acetate solution was washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuo Chromatography on silica gel with ethyl acetate: hexanes (7:3)as eluent and trituration of the resulting solid with pentane gave 1.63 g (60%) of (E)-2-(4,6difluoro-1-indanylidene)acetamide as a white solid: mp 178°-180° C.; NMR (DMSO-d6): d 6.94-7.45 (m, 4H), 6.46 (s, 1H), 2.94-3.00, 3.21-3.27 (2 m's, 4H); steady-state nOe: irradiation at 6.46 d, observed 19% nOe at 7.26 d.
Reaction SMILES: COC1C=C(OC2C=CC(O)=CC=2)C2CC(C3C=CC(OC)=CC=3)CCC=2C=1.Cl.ClCCN1CCCCCC1.C[O:41][C:42]1[CH:43]=[C:44]([O:60][C:61]2[CH:76]=[CH:75][C:64]([O:65][CH2:66][CH2:67][N:68]3[CH2:74][CH2:73][CH2:72][CH2:71][CH2:70][CH2:69]3)=[CH:63][CH:62]=2)[C:45]2[CH2:46][CH:47]([C:52]3[CH:57]=[CH:56][C:55]([O:58]C)=[CH:54][CH:53]=3)[CH2:48][CH2:49][C:50]=2[CH:51]=1>>[N:68]1([CH2:67][CH2:66][O:65][C:64]2[CH:63]=[CH:62][C:61]([O:60][C:44]3[C:45]4[CH2:46][CH:47]([C:52]5[CH:57]=[CH:56][C:55]([OH:58])=[CH:54][CH:53]=5)[CH2:48][CH2:49][C:50]=4[CH:51]=[C:42]([OH:41])[CH:43]=3)=[CH:76][CH:75]=2)[CH2:74][CH2:73][CH2:72][CH2:71][CH2:70][CH2:69]1
Reactant: COc1ccc(C2CCc3cc(OC)cc(Oc4ccc(OCCN5CCCCCC5)cc4)c3C2)cc1
Agent: COc1ccc(C2CCc3cc(OC)cc(Oc4ccc(O)cc4)c3C2)cc1
Agent: Cl
Agent: ClCCN1CCCCCC1
Product: Oc1ccc(C2CCc3cc(O)cc(Oc4ccc(OCCN5CCCCCC5)cc4)c3C2)cc1
Yield: 35.6 %

Procedure:
Synthesized from 4-[3-methoxy-7-(4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-1-yloxy]phenol and 1-(2-chloroethyl)azepane hydrochloride according to an analogous synthetic method to Preparation Example 40, 1-{2-{4-[3-methoxy-7-(4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-1-yloxy]phenoxy}ethyl}azepane (345 mg) was used according to an analogous synthetic method to Example 779 described below to provide the title compound (116 mg).
Reaction SMILES: [CH:1]1[N:9]2[C:4]([CH2:5][O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[N:3][C:2]=1[C:14]([OH:16])=O.S(Cl)([Cl:19])=O>>[CH:1]1[N:9]2[C:4]([CH2:5][O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[N:3][C:2]=1[C:14]([Cl:19])=[O:16]
Reactant: O=C(O)c1cn2c(n1)COc1ccccc1-2
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cn2c(n1)COc1ccccc1-2
Yield: 83 %

Procedure:
5 g (0.023 mole) of 4H-imidazo-[2,1-c][1,4]-benzoxazine-2-carboxylic acid were suspended in 15 ml of thionyl chloride and the mixture obtained was refluxed for two hours during which time the solid material completely dissolved. Excess thionyl chloride was removed by azeotroping with benzene on a rotary evaporator and the product was triturated with ether, filtered off and dried to obtain 4.5 g (83% yield of 4H-imidazo-[2,1-c][1,4]-benzoxazine-2-carbonyl chloride with a melting point of 240° C. (decomp).
Reaction SMILES: Cl[CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].[CH:8]1([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.O>CN(C)C(=O)C>[CH:8]1([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:22]4=[N:27][S:4](=[O:6])(=[O:5])[CH2:3][CH2:2][N:23]4[CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ncccc1-c1ccc(OC2CCCCC2)cc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=S1(=O)CCN2C=CC=C(c3ccc(OC4CCCCC4)cc3)C2=N1
Temperature: 60 °C
Reaction time: 3 h
Yield: 85.1 %

Procedure:
A solution of 2-chloroethanesulfonyl chloride (381 mg) in N,N-dimethylacetoamide (2 mL) was added dropwise to a suspension of 3-[4-(cyclohexyloxy)phenyl]pyridin-2-amine (301 mg) in N,N-dimethylacetoamide (2 mL) and additional N,N-dimethylacetoamide (1 mL) was used to complete the addition of above solution. After being stirred at 60° C. for 3 hr, the mixture was cooled to room temperature. Water (10 mL) was added dropwise to the reaction mixture and the whole was stirred at room temperature for 0.5 hr. The precipitate was collected by filtration, washed with water (10 mL) and diisopropyl ether (3 mL), and dried in vacuo at 60° C. to give the title compound (342 mg) as an off-white powder.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([C:11]([NH2:13])=O)=[CH:4][C:3]=1[Cl:14]>O(Cl)Cl>[NH2:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([C:11]#[N:13])=[CH:4][C:3]=1[Cl:14]
Reactant: NC(=O)c1cc(Cl)c(N)c2c1OCC2
Agent: ClOCl
Product: N#Cc1cc(Cl)c(N)c2c1OCC2
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 62.1 %

Procedure:
Intermediate 7 (0.12 mol) was added to phosporous oxychloride (120 ml) and the reaction mixture was stirred for 45 minutes at 100° C. The mixture was cooled and the solvent evaporated. The residue was added to ice and the mixture was extracted with CH2Cl2 and methanol. The organic layer was dried over MgSO4, filtered and the solvent evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2 /CH3OH 99/1). The pure fractions were collected and the solvent evaporated, yielding 14.5 g (63%) of 4-amino-5-chloro-2,3-dihydro-7-benzofuran-carbonitrile (intermediate 8).