Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[C:4](=[O:18])[CH:3]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][O:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[C:4](=[O:18])[CH:3]=1
Reactant: O=c1cc(O)ccn1CCc1ccc(CO)cc1
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccccc2F)ccn1CCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 400 mg (1.63 mmol) 4-hydroxy-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 2b) in 20 mL DMF is added 216 μL (1.79 mmol) 1-bromomethyl-2-fluoro-benzene and 0.45 g (3.26 mmol) potassium carbonate. The reaction mixture is stirred overnight at RT, diluted with 60 mL of EtOAc and is washed twice with water. The combined organic phase is dried over MgSO4, filtered and the solvent is evaporated. The residue is purified via reverse HPLC chromatography (Waters symmetry C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[C:4]([C:13]([O:15]CC)=[O:14])[CH:3]=1>Cl>[Br:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([C:9]([F:11])([F:12])[F:10])=[C:4]([C:13]([OH:15])=[O:14])[CH:3]=1
Reactant: CCOC(=O)c1cc(Br)c(=O)[nH]c1C(F)(F)F
Agent: Cl
Product: O=C(O)c1cc(Br)c(=O)[nH]c1C(F)(F)F
Yield: 92.2 %

Procedure:
Ethyl 5-bromo-6-oxo-2-(trifluoromethyl)-1,6-dihydropyridine-3-carboxylate (0.25 g) was suspended in 30% aqueous hydrochloric acid and heated at reflux for 4 days. Cooling and filtration gave the subtitle compound (0.210 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[CH:19]=3)[N:9]=2)=[CH:4][CH:3]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:15])[F:16])[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:27]4[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=4)[CH:19]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: OB(O)c1cccnc1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-c2ccnc(Cl)c2)n1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-c2ccnc(-c3cccnc3)c2)n1

Procedure:
The title compound was prepared from 4-(4-chloro-phenyl)-2-(2-chloro-pyridin-4-yl)-6-trifluoromethyl-pyrimidine (example E.5) (0.185 g, 0.5 mmol) and commercially available 3-pyridineboronic acid (0.08 g, 0.65 mmol) according to the general procedure VI. Obtained as a white solid (0.018 g, 9%). MS (ISP) 413.1 [(M+H)+]; mp 226° C.
Reaction SMILES: [Cl:1][C:2]1[CH2:3][CH:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[CH:5]2[CH2:11][CH:12]=1.ClCl>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1
Reactant: O=C1OC(=O)C2CC(Cl)=CCC12
Agent: ClCl
Product: O=C1OC(=O)c2cc(Cl)ccc21
Temperature: 200 °C
Reaction time: 8 h
Yield: 12 %

Procedure:
To a three necked 50 ml round bottom flask, fitted with a stirrer, gas inlet tube and connected to a trap system, for recovery of products, was placed 20.38 g of 4-chloro-1,2,3,6-tetrahydrophthalic anhydride. The reactor was heated to 200° C. and illuminated with a 15 watt black, blue bulb (GE F15T8-BLB) with a transmission range of 300-400 nm and a maximum at 375 nm. An excess flow of chlorine was begun and the reaction continued for 8 hours. The reactor was purged with nitrogen and sampled. A 12% yield of 4-chlorophthalic anhydride was obtained.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[P:11]([O-:16])([O:14]C)[O:12][CH3:13].C(N(CC)CC)C>C(#N)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>[PH:11](=[O:14])([O:16][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1)[O:12][CH3:13]
Reactant: O=[N+]([O-])c1cccc(I)c1
Reactant: COP([O-])OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CO[PH](=O)Oc1cccc([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 102.2 %

Procedure:
1-Iodo-3-nitrobenzene (249 mg, 1 mmol) was dissolved in 10 mL of acetonitrile. Tetrakis(triphenylphosphine)palladium (58 mg, 3 mol %), dimethyl phosphite (0.138 ml, 1.5 mmol) and triethylamine (0.28 ml, 2 mmol) were added thereto and stirred at 70° C. overnight. After removing a solvent, the mixture was purified in accordance with the purification process A to obtain a mixture (0.222 g) of monomethyl (3-nitrophenyl) phosphonate and dimethyl ester. The obtained monomethyl phosphonate was dissolved in 10 mL of methanol. Pd/C in catalyst quantity was added thereto and stirred under hydrogen atmosphere overnight. After filtering out the catalyst, a solvent was removed to obtain a mixture of monomethyl (3-aminophenyl) phosphonate and dimethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH:14]=[CH:13][C:12]3=[N:15][C:16]([CH2:18][O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:17][N:11]3[C:10]2=[O:26])=[N:6][C:7]=1[CH3:8].[H][H]>CN(C=O)C.CO.[Ni]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][C:12]3=[N:15][C:16]([CH2:18][O:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:17][N:11]3[C:10]2=[O:26])=[N:6][C:7]=1[CH3:8]
Reactant: [H][H]
Reactant: Cc1nc(-n2ccc3nc(COc4ccccc4)cn3c2=O)ccc1F
Agent: [Ni]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1nc(N2CCc3nc(COc4ccccc4)cn3C2=O)ccc1F
Yield: 40.8 %

Procedure:
A solution of 6-(5-fluoro-6-methyl-pyridin-2-yl)-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one (20 mg, 0.057 mmol) in a mixture of DMF (0.6 mL) and MeOH (0.6 mL) was hydrogenated in a H-cube reactor (1 mL/min, 30 mm Raney nickel cartridge, 80° C., full hydrogen mode, 1 cycle). The solvents were evaporated in vacuo and the crude product was purified by RP HPLC (C18 XBridge 19×100 5 um, gradient from 80% of 0.1% solution of ammonium formate/ammonium hydroxide buffer pH 9 solution in water and 20% CH3CN to 0% of 0.1% solution of ammonium formate/ammonium hydroxide buffer pH 9 solution in water and 100% ACN) to yield 6-(5-fluoro-6-methyl-pyridin-2-yl)-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one (8.2 mg, 41% yield). 1H NMR (400 MHz, CDCl3) δ ppm 2.49 (d, J=3.0 Hz, 3H), 3.24 (t, J=6.7 Hz, 2H), 4.35 (t, J=6.7 Hz, 2H), 5.02 (s, 2H), 6.97 (br. t, J=7.4, 7.4 Hz, 1H), 7.00-7.05 (m, 2H), 7.27-7.33 (m, 2H), 7.39 (t, J=8.6 Hz, 1H), 7.59 (s, 1H), 7.65 (dd, J=8.8, 3.2 Hz, 1H).
Reaction SMILES: O.[CH2:2]([OH:6])[CH2:3][CH2:4][CH3:5].C([O:10][CH2:11][CH2:12][CH2:13]C)(=O)C>>[C:11]([O:6][CH2:2][CH2:3][CH2:4][CH3:5])(=[O:10])[CH:12]=[CH2:13]
Reactant: CCCCOC(C)=O
Reactant: CCCCO
Solvent: O
Product: C=CC(=O)OCCCC

Procedure:
At the top of the column, a mixture of water, butanol, butyl acetate and butyl acrylate was obtained which separated into an aqueous phase and an organic phase; after the addition of 300 ppm of phenothiazine, the organic phase was supplied as reflux to the column.
Reaction SMILES: [CH3:1][C:2]([CH:4]=[CH:5][CH3:6])=[CH2:3].[CH3:7][C:8]1([CH3:15])[C:13](=[O:14])[CH:12]=[CH:11][CH2:10][CH2:9]1>>[CH3:7][C:8]1([CH3:15])[CH2:9][CH2:10][CH:11]2[CH:12]([CH:5]([CH3:6])[CH:4]=[C:2]([CH3:3])[CH2:1]2)[C:13]1=[O:14]
Reactant: CC1(C)CCC=CC1=O
Reactant: C=C(C)C=CC
Product: CC1=CC(C)C2C(=O)C(C)(C)CCC2C1

Procedure:
adding 2-methyl-penta-1,3-diene to 6,6-dimethyl-cyclohex-2-en-1-one under the conditions of a Diels-Alder type reaction to give 3,4,4a,5,8,8a-hexahydro-2,2,6,8-tetramethyl-1(2H)-naphthalenone, and
Reaction SMILES: C[O:2][C:3](=[O:46])[CH2:4][C:5]([CH3:45])([CH3:44])[CH2:6][CH2:7][N:8]1[C:21]2[C:13](=[CH:14][C:15]3[CH2:16][O:17][CH2:18][C:19]=3[CH:20]=2)[C@@H:12]([N:22]([CH2:29][C:30]2[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=2)[C:23]2[N:24]=[N:25][N:26]([CH3:28])[N:27]=2)[CH2:11][CH2:10][CH2:9]1.[OH-].[Na+].Cl>CO.O>[F:39][C:36]([F:37])([F:38])[C:34]1[CH:35]=[C:30]([CH:31]=[C:32]([C:40]([F:41])([F:42])[F:43])[CH:33]=1)[CH2:29][N:22]([C:23]1[N:24]=[N:25][N:26]([CH3:28])[N:27]=1)[C@@H:12]1[C:13]2=[CH:14][C:15]3[CH2:16][O:17][CH2:18][C:19]=3[CH:20]=[C:21]2[N:8]([CH2:7][CH2:6][C:5]([CH3:45])([CH3:44])[CH2:4][C:3]([OH:46])=[O:2])[CH2:9][CH2:10][CH2:11]1
Reactant: COC(=O)CC(C)(C)CCN1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2cc3c(cc21)COC3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCN(CCC(C)(C)CC(=O)O)c3cc4c(cc32)COC4)n1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a solution of (S)-5-{9-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-yl}-3,3-dimethyl-pentanoic acid methyl ester (0.113 mmol) in methanol (3 mL), add 5 N NaOH (2 mL) and heat to 60° C. After stirring for 6 h, cool the reaction to room temperature, dilute with water (10 mL) and neutralize with 5 M HCl. Extract the organics with ethyl acetate (2×20 mL). Combine the organic portions, dry over sodium sulfate, filter, and remove the solvent under vacuum. Chromatograph the product over silica gel, eluting with ethyl acetate/hexane (20-60%) to afford the title compound as a colorless foam. MS (ES+): 641.3 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[OH:17])[CH:7]([C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])[C:6]=2[CH:5]=[CH:4][CH:3]=1>C(OC(=O)C)(=O)C>[C:2]([O:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[O:17][C:14](=[O:16])[CH3:13])[CH:7]([C:18]([CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]3)=[O:19])[C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:1])[CH3:3]
Reactant: O=C1c2c(O)cccc2C(C(=O)C2CCCCC2)c2cccc(O)c21
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1cccc2c1C(=O)c1c(OC(C)=O)cccc1C2C(=O)C1CCCCC1
Yield: 195.6 %

Procedure:
This compound was obtained by using the same procedure as that described in Example 8(b), by treating 9 g of 1,8-dihydroxy-10-cyclohexylcarbonylanthrone with 150 cm3 of acetic anhydride. After 3 hours the mixture was concentrated, and the oil obtained crystallized out by agitation in hexane. After the solvents had been sucked off, the 11 g of product obtained was dissolved in 150 cm3 of toluene heated to 100° C. and stirred in the presence of 10 g of silica gel. After a few minutes, the solution was filtered and the filtrate was cooled to 0° C. In this way 6 g of light-beige crystals of 1,8-diacetoxy-10-cyclohexylcarbonylanthrone having a melting point of 188° C. was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][C:8](=[O:13])[CH:7]=[C:6]1[CH3:14])=[O:4].C(OCC)(OCC)O[CH2:17][CH3:18].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH3:11])([CH3:12])[CH2:9][C:8]([O:13][CH2:17][CH3:18])=[CH:7][C:6]=1[CH3:14])=[O:4]
Reactant: CCOC(OCC)OCC
Reactant: COC(=O)C1C(C)=CC(=O)CC1(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CCOC1=CC(C)=C(C(=O)OC)C(C)(C)C1
Reaction time: 4 h

Procedure:
800 g. of crude 3,5,5-trimethyl-2-cyclohexen-1-on-4-carboxylic acid methyl ester prepared in Example 1, and 720 g. of triethyl orthoformate were mixed with 1.5 l. of anhydrous ethanol containing 4 ml. of sulfuric acid. After standing for 4 hours at room temperature, the dark blue solution was poured onto petroleum ether over a sodium bicarbonate solution. The ether layer was washed twice with water, dried over sodium sulfate, and concentrated by removing all of the ether solvent. The resulting dark residue was distilled over a vigreux column under high vacuum to yield 2,6,6-trimethyl-4-ethoxy-1,3-cyclohexadien-1-carboxylic acid methyl ester.
Reaction SMILES: [CH2:1]([NH:5][CH3:6])[CH2:2][CH2:3][CH3:4].[CH:7]([N:10]=[C:11]=[N:12][CH:13]([CH3:15])[CH3:14])([CH3:9])[CH3:8]>>[CH2:1]([N:5]([CH3:6])[C:11]([NH:12][CH:13]([CH3:15])[CH3:14])=[N:10][CH:7]([CH3:9])[CH3:8])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)N=C=NC(C)C
Reactant: CCCCNC
Product: CCCCN(C)C(=NC(C)C)NC(C)C
Yield: 100 %

Procedure:
A mixture of 32.68 g of N-butyl-N-methylamine (0.375 mol) and 23.66 g of diisopropylcarbodiimide (0.1875 mol) is heated at reflux for 3 hours. GC analysis then shows a conversion of more than 99.5% of the diisopropylcarbodiimide. The final mixture, which is colorless, is concentrated at 60° C. under 5 mbar for 2 hours, to give 40 g of a colorless and virtually odorless liquid of low viscosity, which corresponds to the expected guanidine (100% yield).
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[Li]CCCC.[Cl-].[C:24]1([PH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[NH4+].[Cl-]>C1COCC1>[C:31]1([P:30]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:2]2[C:15]3[C:16]4=[C:17]5[C:12](=[CH:13][CH:14]=3)[CH:11]=[CH:10][CH:9]=[C:8]5[CH:7]=[CH:6][C:5]4=[CH:4][CH:3]=2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: Brc1ccc2ccc3cccc4ccc1c2c34
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: c1ccc(P(c2ccccc2)c2ccc3ccc4cccc5ccc2c3c45)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
Bromopyrene (5 mmol, 1.41 g) was charged and dissolved in THF (25 ml). After the solution was cooled to −78° C., n-BuLi (5.5 mmol, 2.08 ml, 2.64 M, 1.1 eq) was slowly added dropwise to the solution and the mixture was stirred for 2 hours. Then, diphenylphosphine chloride (5 mmol, 0.92 ml, 1 eq) was slowly added dropwise to the mixture, followed by stirring overnight. Saturated NH4Cl (10 mL) was added to the mixture. The THF layer was separated from the aqueous layer. The aqueous layer was extracted with dichloromethane (50 mL×3). The organic layer and the THF layer were combined. The resulting mixture was dried over sodium sulfate and concentrated on an evaporator. The residue was purified by silica gel column chromatography (developing solvent: dichloromethane:hexane=1:3). Thus, diphenylpyrenylphosphine (DPPP) was obtained (yield 39%) as white yellow crystals. The crystals were identified by 1H-NMR and 31P-NMR.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:37])[CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]([OH:36])([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[OH-].[K+].[BH4-].[Na+]>CO>[C:2]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([OH:37])[CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]([OH:36])([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)=[CH:10][CH:11]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(C(=O)CCCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)c1ccc(C(O)CCCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 25 °C

Procedure:
To 62.3 g (0.12 mole) of 4'-tert-butyl-5-[4-(α-hydroxy-α-phenylbenzyl)piperidino]valerophenone hydrochloride dissolved in about 1200 ml of methanol is added methanolic potassium hydroxide until the solution is basic. The solution is cooled in an ice bath with stirring and 5 g (0.13 mole) of sodium borohydride is added portionwise. The mixture is stirred an additional half hour, allowed to warm to room temperature then heated on a steam bath for half an hour. The solvent is removed at reduced pressure and the remaining residue is washed with water and recrystallized from acetone to give α-(p-tert-butylphenyl)-4-(α-hydroxy-α-phenylbenzyl)-1-piperidine-pentanol.
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([CH2:13][C:14]([O:16]C)=[O:15])=[C:7]([CH2:18][N:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]([CH3:22])=[O:21])[CH:6]=1>CO>[CH3:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([CH2:13][C:14]([OH:16])=[O:15])=[C:7]([CH2:18][N:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]([CH3:22])=[O:21])[CH:6]=1
Reactant: COC(=O)Cc1cc(OC)c(OC)cc1CN(C(C)=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(CC(=O)O)c(CN(C(C)=O)c2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 78 %

Procedure:
An aqueous solution of lithium hydroxide (0.5 M, 56 ml, 28 mmol) was added to a solution of methyl 4,5-dimethoxy-2-[(phenylacetamino)methyl]phenylacetate 6 (2 g, 5.6 mmol) in methanol (50 ml). The reaction mixture was stirred at ambient temperature for 12 hours, then neutralized with an aqueous solution of HCl (2N) and precipitation of the product was observed. Filtration gave the 4,5-dimethoxy-2-[(phenylacetamino)methyl]-phenylacetic acid 7 (1.5 g, 78%) in the form of a white powder. M.p.=186° C. 1H NMR ((CD3)2SO, 300 MHz) δ 8.40 (br s, 1H), 7.30-7.20 (m, 6H), 6.80 (s, 1H), 6.73 (s, 1H), 4.18 (d, J=5.6 Hz, 2H), 3.70 (s, 3H), 3.59 (s, 3H), 3.55 (s, 2H), 3.44 (s, 2H). 13C NMR ((CD3)2SO, 75 MHz) δ 172.8, 170.0, 147.4, 147.3, 136.6, 129.9, 129.0 (2C), 128.3 (2C), 126.4, 125.2, 114.6, 111.9, 55.6, 55.4, 42.5, 39.6, 37.5. Analysis calculated for C19H21NO5: C=66.46, H=6.16 and N=4.08. Analysis measured: C=66.52, H=5.92 and N=4.06.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[N:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Clc1ncccn1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4ncccn4)cc3CC[C@@H]12
Yield: 23.3 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloropyrimidine (53 mg, 0.46 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 30 mg (23%) of the title compound as an oil. FDMS: m/e=339
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][F:19]>[I-].[K+].CS(C)=O>[F:19][CH2:18][CH2:17][O:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:1]#[N:2]
Reactant: N#Cc1cccc(O)c1
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1cccc(OCCF)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To a flame dried 50 mL round bottom flask was added 3-cyanophenol (1.0 g, 8.39 mmol) followed by 10 mL dimethyl sulfoxide. Potassium iodide (7.0 mg, 0.042 mmol) and potassium carbonate (1.74 g, 12.6 mmol) were added. The flask was immersed in an oil bath at 85° C. and 1-bromo-2-fluoroethane (1.17 g, 0.686 mL, 9.23 mmol) was added. The reaction was stirred at this temperature for 30 min, cooled to room temperature, filtered, and the filtrate was diluted with water (100 mL). The resulting solution was extracted with dichloromethane (3×30 mL). The organic layer was then washed with water (5×20 mL) and brine, and dried over magnesium sulfate. The solution was filtered and concentrated in vacuo to obtain 1.31 g (94%) of an oil as the product. 1H NMR (600 MHz, CDCl3): δ 7.37 (m, 1H), 7.26 (m, 1H), 7.15 (m, 2H), 4.75 (t of d, 2H, J=4.2, 46.8 Hz), 4.22 (t of d, 2H, J=4.2, 27.6 Hz). 13C NMR (75 MHz, CDCl3): δ 158.4, 130.4, 125, 119.8, 117.9, 117.5, 113.3, 81 (d, J=171 Hz), 67.4 (d, J=10.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([F:21])[CH:20]=1)[CH2:5][CH:6]1[C:13]2[CH:12]=[C:11]([C:14]([O:16]C)=[O:15])[NH:10][C:9]=2[CH2:8][CH2:7]1.[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([F:21])[CH:20]=1)[CH2:5][CH:6]1[C:13]2[CH:12]=[C:11]([C:14]([OH:16])=[O:15])[NH:10][C:9]=2[CH2:8][CH2:7]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1cc(F)cc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2c([nH]1)CCC2Cc1cc(F)cc(Cl)c1

Procedure:
The title compound was synthesized from methyl 4-(3-chloro-5-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.045 g, 0.15 mmol) and lithium hydroxide (0.063 g, 1.5 mmol in 2 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (2 mL) was used. The resulting product was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-100% EtOAc/heptane followed by reverse phase chromatography from MeOH and water (0.1% formic acid) to afford the title compound: 3.7 mg, 8.4% yield. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.03-2.16 (m, 1H) 2.46-2.60 (m, 1H) 2.60-2.73 (m, 2H) 2.79 (dd, J=7.35, 2.03 Hz, 2H) 3.26 (m, 1H) 6.32 (s, 1H) 6.91 (dd, J=9.57, 1.51 Hz, 1H) 7.02 (dt, J=8.63, 2.13 Hz, 1H) 7.06 (s, 1H); 19F NMR δ ppm −114.32 (t, J=0.8 Hz); LCMS-MS (ESI−) 292.0 (M−H); HPLC (UV=100%), (ELSD=100%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:38]=[CH:37][C:8]2[N:9]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[C:17]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=3Br)[CH:16]=[CH:15]4)=[N:11][C:7]=2[CH:6]=1)=[O:4].[F:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][C:41]=1[Cl:49].C(=O)(O)[O-].[Na+].[OH-].[K+]>C1(C)C=CC=CC=1.CO.O.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>[Cl:49][C:41]1[CH:42]=[C:43]([CH:44]=[CH:45][C:40]=1[F:39])[C:23]1[C:22]([C:17]2[CH:16]=[CH:15][C:14]3[C:19](=[CH:20][CH:21]=[C:12]([C:10]4[N:9]([CH:31]5[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]5)[C:8]5[CH:37]=[CH:38][C:5]([C:3]([OH:2])=[O:4])=[CH:6][C:7]=5[N:11]=4)[CH:13]=3)[N:18]=2)=[CH:27][C:26]([O:28][CH3:29])=[CH:25][CH:24]=1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(OC)ccc4Br)ccc3c1)n2C1CCCCC1
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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: COc1ccc(-c2ccc(F)c(Cl)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 6.6 %

Procedure:
In dried vial with a Teflon lined screw cap, a solution of Compound 365b (100 mg, 0.175 mmol), 4-fluoro-3-chlorophenylboronic acid (61 mg, 0.2625 mmol), and Palladium Tetrakis (20 mg, 0.0175 mmol) in toluene (6.5 mL), methanol (1.6 mL), and saturated sodium bicarbonate in water (800 ul) was degassed, flushed with argon, and sealed. The reaction was stirred for 16 hours at 90° C. The vial was then cooled to room temperature and 10% w/v KOH in methanol (2 mL, 3.5 mmol) was added. The reaction was resealed and stirred at 70° C. for 1 hour. The completed reaction was then evaporated to dryness, purified via HPLC, and converted to the HCl salt using the standard procedure (as described for Compound 516) to produce the title compound (7 mg, 7% yield).