Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1COCC1.[N+:6]([C:9]1[CH:17]=[CH:16][C:12]([CH2:13][C:14]#[N:15])=[CH:11][CH:10]=1)([O-])=O.O.C(=O)=O>CO>[NH2:6][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][C:14]#[N:15])=[CH:11][CH:10]=1
Reactant: N#CCc1ccc([N+](=O)[O-])cc1
Agent: O=C=O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: N#CCc1ccc(N)cc1
Yield: 94.6 %

Procedure:
Under nitrogen, 11.5 g (12.7 mmol) lithium cobalt (I) phthalocyanine×4.5 THF and 324 mg (2 mmol) p-nitrobenzyl cyanide are agitated in 60 ml methanol for 62 hours at 20° C. The green reaction mixture is mixed with 10 ml water; then CO2 and air are passed into it for 5 min., and the blue precipitate is centrifuged which is washed out with ethanol. The centrifugate collected is concentrated, and the residue separated into water and ether. After compression of the ether phase, which is dried via sodium sulfate, 250 mg (95%) p-amino benzyl cyanide is obtained.
Reaction SMILES: C(N(C(=O)CC)CC[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)C.[H-].[Na+].C(O[CH2:23][CH3:24])(=O)C>O1CCCC1>[C:24]1([O:12][C:9]2[CH:8]=[CH:7][CH:6]=[CH:11][CH:10]=2)[CH:23]=[CH:8][CH:7]=[CH:6][CH:11]=1
Reactant: CCC(=O)N(CC)CCc1ccc(O)cc1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(Oc2ccccc2)cc1
Reaction time: 0.17 h
Yield: 32 %

Procedure:
To a stirred solution of N-ethyl,N-propionyl tyramine (2.84 g, 12.83 mmole) in tetrahydrofuran (32.1 ml) was added 60% sodium hydride dispersion (0.56 g, 14.11 mmole). After stirring for 10 minutes, the compound of Example 42(E) (4.70 g, 12.83 mmole) was added. The reaction was allowed to stir at room temperature for 5 hours, poured into ethyl acetate, and extracted with 10% sodium sulfate, then brine. The organic layer was dried over sodium sulfate, evaporated to dryness, and chromatographed on silica gel using a hexane-ethyl acetate gradient. Further chromatography on silica gel using toluene-acetone gradients yielded the intermediate phenyl ether (2.10 g, 32%):
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:28][C:29]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[C:31](=[O:32])[C:30]2[CH:34]=[CH:35][CH:36]=[C:37]([F:38])[C:29]=2[F:28])=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Reactant: O=C(Cl)c1cccc(F)c1F
Product: O=C1OC2(CCN(C(=O)c3cn(C(=O)c4cccc(F)c4F)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure VII as described above, the acylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16) with commercially available 2,3-difluorobenzoyl chloride gave the title compound.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:7][O:6][C:5]2([CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:9][CH2:8]2)[O:4]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>C1(C)C=CC=CC=1>[N:32]1([CH2:2][CH:3]2[CH2:7][O:6][C:5]3([CH2:8][CH2:9][N:10]([CH2:13][CH2:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:11][CH2:12]3)[O:4]2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: C1COCCN1
Reactant: OCC1COC2(CCN(CCc3ccccc3)CC2)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: c1ccc(CCN2CCC3(CC2)OCC(CN2CCOCC2)O3)cc1

Procedure:
2-hydroxymethyl-8-phenethyl-1,4-dioxa-8-azaspiro[4,5]decane (Compound 1.50 gm, 0.18 mole), Para Toluenesulfonic Acid (PTSA, 3.5 gms) was dissolved in toluene (300 ml) at 28° C. To this was added 18.5 gm of morpholine drop wise with continuous stirring, continued the stirring for 13 hrs at reflux temperature. Toluene was distilled under vacuum to get a semi-solid with brick red color. The yield of the product was 90%.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[C:2]#[CH:3].C(N(CC)CC)C.[C:13]([OH:21])(=[S:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[C:13]([S:20]/[CH:3]=[CH:2]\[C:1]([OH:5])=[O:4])(=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OC(=S)c1ccccc1
Reactant: C#CC(=O)O
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(O)/C=C\SC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 35 %

Procedure:
To a stirred, cooled (0° C.) solution of 15.4 ml (0.25 mol) of propiolic acid in 200 ml of absolute ethanol under nitrogen was added 3.48 ml (0.025 mol) of triethylamine. After 5 min, 33 ml (0.28 mol) of thiobenzoic acid was added very cautiously and dropwise. The exothermic reaction led to the ethanol reaching reflux despite the ice-water bath. After 15 min a solid precipitated from the orange solution. After 2 h at 0° C. the reaction mixture was filtered and the solid was washed twice with absolute ethanol and twice with chloroform to afford 18.3 g (35% yield of cis-3-(benzoylthio)propenoic acid as a white powder.
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].[N:14]1([C:25](=[O:26])[C:24]2NC=N[C:20]=2N(C)[C:16]1=[O:17])C.[CH3:27][CH2:28][S:29][C:30]([N:32]([CH2:37][CH:38]([CH3:40])[CH3:39])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:31].C1(N=C=NC2CCCCC2)CCCCC1.ON1C(=O)CCC1=O>C(Cl)Cl>[C:16]1(=[O:17])[N:14]([N:8]2[CH:9]=[N:10][C:11]3[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]2=3)[C:25](=[O:26])[CH2:24][CH2:20]1.[CH3:27][CH2:28][S:29][C:30]([N:32]([CH2:37][CH:38]([CH3:39])[CH3:40])[CH2:33][CH:34]([CH3:35])[CH3:36])=[O:31]
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCSC(=O)N(CC(C)C)CC(C)C
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Product: Cn1c(=O)c2ncn(N3C(=O)CCC3=O)c2n(C)c1=O
Temperature: 25 °C

Procedure:
The activation of theophylline was accomplished by dissolving theophylline-butylate (10 mg; MW 280.29; 3.57×10-5 moles) in methylene chloride (3.0 ml). A three mole excess of dicyclohexyl-carbodiimide (22 mg; MW 206.3) and a three mole excess of N-hydroxysuccinimide (12.3 mg; MW 115.09) were added, and the reaction mixture was stirred over night at room temperature. The mixture was filtered to remove dicyclohexylurea and was rotavaporated to dryness to yield ten milligrams of N-succinimidyl-theophylline-butylate (theophylline-butylate-oSu).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([CH3:20])([N+:17]([O-])=O)[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[NH:8][CH:7]=1>CO>[CH3:1][O:2][C:3](=[O:21])[C:4]([NH2:17])([CH3:20])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[NH:8][CH:7]=1
Reactant: COC(=O)C(C)(Cc1c[nH]c2ccc(OC)cc12)[N+](=O)[O-]
Solvent: CO
Product: COC(=O)C(C)(N)Cc1c[nH]c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
To a solution of (+/−)-3-(5-methoxy-1H-indol-3-yl)-2-methyl-2-nitro-propionic acid methyl ester (4.26 g) in methanol (80 mL) wet Raney nickel (ca 12 g) is added, and the mixture is stirred under hydrogen at atmospheric pressure at room temperature overnight. The solid is filtered through Celite, is washed with methanol, and the filtrate is concentrated. Column chromatography of the residue (dichloromethane-methanol, 98:2→95:5) gives the title compound (3.45 g, 90%). M.p. 131-132° C. (from ethyl acetate-light petroleum).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.O.O.O.[F:23][C:24]([F:32])([F:31])[C:25]([C:27]([F:30])([F:29])[F:28])=[O:26]>C1(C)C=CC=CC=1.O.O.O.FC(F)(F)C(C(F)(F)F)=O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[CH:11]=[C:10]([C:25]([C:27]([F:30])([F:29])[F:28])([C:24]([F:32])([F:31])[F:23])[OH:26])[NH:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:14][CH:15]=1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: Fc1ccc(-c2cc[nH]c2-c2ccc(F)cc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: OC(c1cc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)[nH]1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
A mixture of 20.4 g (0.08 mole) of 2,3-bis(4-fluorophenyl)-1H-pyrrole and 19.8 g (0.09 mole) of hexafluoroacetone trihydrate in 300 ml toluene was heated at reflux for 6 hours. Analysis by tlc indicated a small amount of starting material remained so another 1.0 g of hexafluoroacetone trihydrate was added and the mixture was refluxed another 0.5 hour. After stirring at room temperature overnight, the mixture was concentrated by rotary evaporation. The residue was purified by chromatography on 2 pounds of silica gel, eluting with toluene. The chromatographed product was decolorized with charcoal, then recrystallized from hexane to give 21.5 g (63%) of product, m.p. 112°-113°.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18](/[C:21](=[N:23]/[O:24][CH2:25][C:26]([O:28]C)=O)/[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH3:30]>>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18](/[C:21](=[N:23]/[O:24][CH2:25][C:26]([NH2:30])=[O:28])/[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: COC(=O)CO/N=C(\C)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Product: C/C(=N\OCC(N)=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Yield: 13.4 %

Procedure:
To a solution of (E)-methyl 2-(1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethylideneaminooxy)acetate (example 31) (70 mg, 0.179 mmol) was added ammonia (2 N, 0.268 mL, 0.537 mmol). The reaction was heated at reflux for 12 h. The reaction mixture was concentrated in vacuo to give a crude product which was purified by prep-HPLC to afford 9 mg (16%) of the title compound. 1H-NMR (400 MHz, DMSO-d6+D2O) δ ppm 9.32 (s, 1H), 8.88 (d, 1H), 8.34 (d, 1H), 8.01 (m, 2H), 7.81 (d, 1H), 7.52 (dd, 1H), 7.33 (br, 2H), 6.20 (s, 2H), 4.67 (s, 2H), 2.27 (s, 3H). LCMS (method B): [MH]+=377, tR=1.06 min.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[K+].Cl.Cl[CH2:25][CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH3:32]>CC(N(C)C)=O>[CH3:32][N:28]1[CH2:29][CH2:30][CH2:31][CH:27]1[CH2:26][CH2:25][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cccc(CCc2ccccc2O)c1
Reactant: CN1CCCC1CCCl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cccc(CCc2ccccc2OCCC2CCCN2C)c1
Yield: 9.8 %

Procedure:
Following a procedure similar to that described in Example 35(a), 1.00 g of 2-[2-(3-methylphenyl)ethyl]phenol (prepared as described in Preparation 25), 1.05 g of potassium t-butoxide and 0.870 g of 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride were reacted in 10 ml of dimethylacetamide. The mixture was then worked up as described in Example 35(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 150 mg (yield 11%) of the title compound as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[S:27])[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([N+:24]([O-:26])=[O:25])[CH:18]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]2[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([N+:24]([O-:26])=[O:25])[CH:18]=3)[S:27][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(C(=S)Nc2ccc(OCc3ccccc3)cc2)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=[N+]([O-])c1cc(-c2nc3ccc(OCc4ccccc4)cc3s2)ccc1Cl
Temperature: 130 °C

Procedure:
N-(4-Benzyloxy-phenyl)-4-chloro-3-nitro-thiobenzamide (2 g, 5 mmol) was dissolved in methanol (100 ml). Sodium hydroxide (1.6 g in 5 ml water) was added followed by Triton B (2.1 ml, 5 mmol, commercially available). The mixture was cooled in an ice-bath. Potassium ferri(III)cyanide (13.2 g in 50 ml water) was added drop wise with vigorous stirring. The reaction mixture was allowed to warm up overnight and was further warmed to 130° C. for 1 hour. The reaction mixture was cooled and extracted with ethyl acetate/water. The organic phase dried and the solvent removed under reduced pressure. The product, compound was purified by flash chromatography with Hexane/Ethyl acetate as eluent.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=O.[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=1.C([O-])(O)=O.[Na+].O>CN(C)C=O>[CH3:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=3)[N:19]=2)[CH:18]=1
Reactant: Cc1ccc(N)nc1
Reactant: Cc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2cn3cc(C)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.4 %

Procedure:
A solution of 2-bromo-1-p-tolyl-ethanone (500 mg, 2.3 mmol) in dimethylformamide (2 mL) was added slowly to a solution of 5-methyl-pyridin-2-yl-amine (249 mg, 2.3 mmol) in dimethylformamide (2 mL). NaHCO3 (386 mg, 4.6 mmol) was added in portions and the mixture was stirred at room temperature for 15 minutes, then at reflux for 1.5 hours. The mixture was cooled and poured into water (5 mL). The solid was collected, washed with water (2 mL) and recrystallized from dimethylformamide (5 mL) to yield the desired product 6-methyl-2-p-tolyl-imidazo[1,2-a]pyridine (360 mg, 70%). 1H NMR (300 MHz, DMSO-d6) δ 2.27 (s, 3H), 2.32 (s, 3H), 7.08 (d, 1H), 7.21 (d, 2H), 7.46 (d, 1H), 7.83 (d, 2H), 8.24 (s, 1H), 8.29 (s, 1H); ESI-MS (MH+), 223.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:11]=2)[C:6](=[O:33])[C:5]([CH2:34]O)=[N:4]1)[CH3:2].CS(Cl)(=O)=O.[NH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>ClCCl>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)=[C:10]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH:11]=2)[C:6](=[O:33])[C:5]([CH2:34][N:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)=[N:4]1)[CH3:2]
Reactant: C1CCNCC1
Reactant: CCn1nc(CO)c(=O)c2cc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCn1nc(CN2CCCCC2)c(=O)c2cc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Reaction time: 2 h
Yield: 57 %

Procedure:
To a suspension of 1-ethyl-3-(hydroxymethyl)-6,7-bis((4-methoxybenzyl)oxy)cinnolin-4(1H)-one (Example 8d) (2.13 g, 4.47 mmol) in Dichloromethane (DCM) (40 mL) in an ice bath under N2 was added TEA (1.495 mL, 10.73 mmol) followed by methanesulfonyl chloride (0.627 mL, 8.05 mmol) (white suspension turned into a light yellow clear solution). The mixture was stirred in an ice bath for 2 h, and then the above reaction mixture was added dropwise into a stirred solution of piperidine (1.195 mL, 12.07 mmol) in dichloromethane (DCM) (40.0 mL) at room temperature overnight. The reaction mixture was concentrated and purified through column chromatography eluting with dichloromethane and methanol/dichloromethane/ammonium hydroxide (from 0% to 100%) over 15 mins twice to afford 1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-3-(piperidin-1-ylmethyl)cinnolin-4(1H)-one (1.54 g, 2.55 mmol, 57.0% yield). LCMS (M+H)+: 544.0
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>CCO.C1COCC1>[CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccccc2C)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccccc1C1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(2-methylphenyl)-2-naphthalenyl)ethynyl]-benzoate (Compound 3) 80.0 mg (0.190 mmol) in 3 ml of EtOH and 2 ml of THF was added 60.0 mg (1.50 mmol, 1.50 ml) of NaOH (1.0 M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (DMSO): δ 7.89(2H, d, J=8.4 Hz), 7.57 (2H, d, J=8.4 Hz), 7.46 (2H, s), 7.29-7.14 (4H, m), 6.59 (1H, s), 5.90 (1H, t, J=4.7 Hz), 2.39 (2H, m), 2.60 (3H, s), 1.39 (3H, s), 1.29 (3H, s).
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7](=[O:31])[CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([N:15]2[C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:25])[C:19]=3[C:18]3=[N:26][O:27][C:28]([CH3:29])=[C:17]3[C:16]2=[O:30])[CH2:10]1)C>O.O1CCOCC1.C(Cl)(Cl)Cl>[Cl:25][C:20]1[C:19]2[C:18]3[C:17](=[C:28]([CH3:29])[O:27][N:26]=3)[C:16](=[O:30])[N:15]([CH:11]3[CH2:12][CH2:13][CH2:14][N:9]([CH2:8][C:7]([OH:31])=[O:6])[CH2:10]3)[C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)CN1CCCC(n2c(=O)c3c(C)onc3c3c(Cl)cccc32)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: Cc1onc2c1c(=O)n(C1CCCN(CC(=O)O)C1)c1cccc(Cl)c21
Yield: 122.2 %

Procedure:
Add a solution of lithium hydroxide monohydrate (7 mg, 0.17 mmol) in water (2 mL) to a solution of [3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-piperidin-1-yl]-acetic acid ethyl ester (45.7 mg, 0.11 mmol) in dioxane (3 mL). Stir the reaction at room temperature for 1 hour. Concentrate the reaction. Dissolve in chloroform and concentrate (×3) to assist in removal of solvents to yield the resulting 50.5 mg of the title compound as a white solid, quantitative yield. MS (ion spray) 376 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.OS(O)(=O)=O.[CH3:17]O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:17])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Cl)cc1C
Yield: 92 %

Procedure:
4-Chloro-2-methylbenzoic acid (3 g, 17.6 mmol) was suspended in 12 ml of MeOH with 1 ml of concentrated H2SO4. The mixture was refluxed overnight, MeOH was evaporated and the residue was extracted with EtOAc, dried over MgSO4 filtered and evaporated to give methyl 4-chloro-2-methylbenzoate as a colorless viscous liquid (2.96 g, 92%) that was used in the next step without further purification. The ester (2.96 g, 16 mmol) was, under inert atmosphere, dissolved in THF (100 mL) and NMP (9 mL) and Iron (III) acetylacetonate (318 mg, 0.9 mmol) was added giving a red solution. Then EtMgBr (7 ml of 1M solution in ether) was added dropwise under vigorous stirring. The mixture turned dark brown and then violet and then was stirred for 15 more min. The reaction was diluted with ether and quenched upon the addition of aq. HCl (1M, 10 ml). The crude product was extracted with ether. The combined organic layers were washed with water and brine, dried over MgSO4 and evaporated. The residue was purified on silica gel (30% EtOAc/hexanes) to give methyl 4-ethyl-2-methylbenzoate as an oil (2.37 g, 83%). (1H NMR (500 MHz, CDCl3): δ 1.26 (t, 3H), 2.63 (dd, 2H), 3.9 (s, 3H), 7.1 (b, 2H), 7.85 (d, 1H)).
Reaction SMILES: [I:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[CH3:13][O:14][C:15](=[O:18])[CH2:16]Br.CI>>[I:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[N:9]2[CH2:16][C:15]([O:14][CH3:13])=[O:18])=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(I)cc2N1
Reactant: COC(=O)CBr
Solvent: CI
Product: COC(=O)CN1C(=O)CCc2ccc(I)cc21

Procedure:
According to the Step 8-1 in synthetic method for EXAMPLE aa8, 3,4-dihydro-7-iodo-2(1H)-quinolinone (2.12 g) and bromoacetic acid methyl ester (1.10 mL) were used instead of aa7-1 and MeI to obtain compound aa21-1 (2.24 g) as a white amorphous solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15](F)=[C:16]([Cl:19])[CH:17]=2)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[NH2:23][CH:24]1[CH2:31][CH2:30][CH2:29][CH:28]([OH:32])[CH2:27][CH2:26][CH2:25]1.C(OC1C2C(=CC(OC3CC(N)C3)=C(Cl)C=2)C=CN=1)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:32][CH:28]3[CH2:29][CH2:30][CH2:31][CH:24]([NH2:23])[CH2:25][CH2:26][CH2:27]3)=[C:16]([Cl:19])[CH:17]=2)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cc2ccnc(OCc3ccccc3)c2cc1Cl
Reactant: NC1CCCC(O)CCC1
Agent: NC1CC(Oc2cc3ccnc(OCc4ccccc4)c3cc2Cl)C1
Agent: [H-]
Agent: [Na+]
Product: NC1CCCC(Oc2cc3ccnc(OCc4ccccc4)c3cc2Cl)CCC1
Yield: 30.6 %

Procedure:
1.3 g of the title compound were synthesized starting from 0.8 g (2.78 mmol) of 1-benzyloxy-7-chloro-6-fluoro-isoquinoline (11), 417 mg (14.4 mmol) of sodium hydride (60%), and 0.63 g (3.5 mmol) of 5-amino-cyclooctanol (60), following the protocol described for 3-(1-benzyloxy-7-chloro-isoquinolin-6-yloxy)-cyclobutylamine (51). Purification by silica gel chromatography (dichloromethane methanol:aq. ammonia—100:7:0.75) gave 0.35 g of the desired product as a mixture of diastereoisomers. Rt=1.41 min (Method C). Detected mass: 413.1 (M+H+).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH3:23])[C:12](=[O:22])[C:13]1[CH:18]=[CH:17][C:16](F)=[C:15]([Cl:20])[C:14]=1F)(C(C)(C)C)(C)C.[OH:24][C:25]1[CH:26]=[C:27]([CH:37]=[C:38]([O:40][CH:41]([CH3:43])[CH3:42])[CH:39]=1)[C:28]([NH:30][C:31]1[CH:35]=[CH:34][N:33]([CH3:36])[N:32]=1)=[O:29].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[Cl:20][C:15]1[C:14]2[O:8][CH2:9][CH2:10][N:11]([CH3:23])[C:12](=[O:22])[C:13]=2[CH:18]=[CH:17][C:16]=1[O:24][C:25]1[CH:26]=[C:27]([CH:37]=[C:38]([O:40][CH:41]([CH3:43])[CH3:42])[CH:39]=1)[C:28]([NH:30][C:31]1[CH:35]=[CH:34][N:33]([CH3:36])[N:32]=1)=[O:29]
Reactant: CC(C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1ccc(F)c(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)Oc1cc(Oc2ccc3c(c2Cl)OCCN(C)C3=O)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 135 °C
Yield: 33.3 %

Procedure:
N-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-3-chloro-2,4-difluoro-N-methylbenzamide (705 mg, 1.94 mmol) was added to 3-hydroxy-5-[(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (512 mg, 1.86 mmol) and potassium carbonate (536 mg, 3.88 mmol) in DMA (25 mL) and the mixture was heated at 135° C. for 5 hours. Water (100 mL) was added and the reaction mixture extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with water (2×30 mL), brine (2×30 mL), dried (MgSO4), filtered and evaporated. Purification by column chromatography on silica, eluting with 40-100% ethyl acetate in hexanes, afforded the desired compound as a pale yellow oil (300 mg). 1H NMR δ (CDCl3): 1.28 (d, 6H), 3.17 (s, 3H), 3.53 (t, 2H), 3.73 (s, 3H), 4.48 (t, 2H), 4.48-4.55 (m, 1H), 6.63 (t, 1H), 6.71 (d, 1H), 6.73 (d, 1H), 6.95 (t, 1H), 7.12 (t, 1H), 7.22 (d, 1H), 7.61 (d, 1H), 8.52 (s, 1H), m/z 485 (M+H)+ 483 (M−H)−