Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1.Br[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC>[F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:6][CH:5]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Brc1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: FC(F)(F)Oc1ccc(-c2cccnc2)cc1
Temperature: 85 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
4-(Trifluoromethoxy) phenyl boronic acid (1.3 g, 6.31 mmol) was dissolved in ethylene glycol dimethyl ether (50 ml). 3-Bromopyridine (1 ml, 9.5 mmol), aqueous sodium carbonate (2M, 30 ml), and Pd(dppb)Cl2 (100 mg) were added and the reaction mixture was stirred at 85° C. for 3 hours. The mixture was allowed to cool to room temperature, then water (200 ml) was added and the mixture was extracted with ethyl acetate (3×100 ml). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/ether (60:40) to give the title compound as an oil (1.26 g, 84%). 1H NMR (250 MHz, CDCl3) δ 8.84 (1H, s), 8.60 (1H, br d), 7.87 (1H, m), 7.61 (2H, m), and 7.36 (3H, m). m/z (ES+) 240 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[C:4](S(C)=O)[N:3]=1.[CH2:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]([C:9]#[N:10])=[C:6]([Cl:8])[N:7]=1
Reactant: OCc1ccccc1
Reactant: CS(=O)c1nc(N)nc(Cl)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(Cl)nc(N)nc1OCc1ccccc1

Procedure:
From 2-amino-4-chloro-6-methanesulfinyl-pyrimidine-5-carbonitrile, benzyl alcohol and DBU in DME. EI-MS m/e (%): 262 (M{37Cl}+, 22), 260 (M{35Cl}+,60), 91 (100).
Reaction SMILES: Br.[C:2]([C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26]C)[N:21]=2)=[CH:13]\[C@@H:14]2[NH:18][C:17](=[O:19])[CH2:16][CH2:15]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].O>O1CCOCC1>[C:2]([C:6]1[CH:7]=[CH:8][C:9](/[C:12](/[C:20]2[NH:21][C:22](=[O:26])[CH:23]=[CH:24][CH:25]=2)=[CH:13]\[C@H:14]2[CH2:15][CH2:16][C:17](=[O:19])[NH:18]2)=[CH:10][CH:11]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: COc1cccc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(C(C)(C)C)cc2)n1
Agent: Br
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)c1ccc(/C(=C\[C@H]2CCC(=O)N2)c2cccc(=O)[nH]2)cc1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 13.9 %

Procedure:
48% hydrobromic acid (0.5 mL) was added to a solution of the crude product of (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(6-methoxypyridin-2-yl)ethenyl]pyrrolidin-2-one obtained in Example 4-185(2) (15 mg) in 1,4-dioxane (1 mL), and the mixture was stirred at 65° C. for 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=10:0→4:1). This was powdered with ethyl acetate-hexane to give the title compound as an orange powder (2 mg).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5](=O)[CH3:6].[F:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][NH2:17])=[CH:12][CH:11]=1>C(O)(=O)C>[F:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:3](=[O:2])[CH2:4][C:5]([CH3:6])=[N:17]2)=[CH:12][CH:11]=1
Reactant: COC(=O)CC(C)=O
Reactant: NNc1ccc(F)cc1
Solvent: CC(=O)O
Product: CC1=NN(c2ccc(F)cc2)C(=O)C1
Temperature: 120 °C
Yield: 69 %

Procedure:
To a solution of 3-oxo-butyric acid methyl ester (2.8 g) in acetic acid (6.5 mL) in a round bottom flask under argon was added 4-fluorophenylhydrazine (3.05 g). The mixture was immersed into an oil bath and heated to 120° C. overnight. The reaction vessel was then cooled and the acetic acid was evaporated in vacuo and the remaining solid was dissolved in EtOAc and water. The phases were separated and the aqueous phase was extracted with further EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo and azeotroped with toluene (2×). The crude residue was then purified via ISCO Combiflash chromatography using EtOAc/heptane as eluent to afford the desired 2-(4-fluoro-phenyl)-5-methyl-2,4-dihydro-pyrazol-3-one (3.2 g) as a beige solid. MS (ESI+): 193.3 ([M+H]+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:22][C:23](=[O:35])[C@@H:24]([O:33][CH3:34])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[CH3:21].[Br:36][CH2:37][CH2:38][CH2:39]O>C1(C)C=CC=CC=1.C1COCC1>[CH2:20]([O:22][C:23](=[O:35])[C@@H:24]([O:33][CH3:34])[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH2:39][CH2:38][CH2:37][Br:36])=[CH:30][CH:31]=1)[CH3:21]
Reactant: OCCCBr
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reaction time: 0.33 h

Procedure:
A solution of triphenylphosphine (4.77 mmol, 1250 mg) in 50 mL of dry toluene was treated at 0° C. with diisopropilazodicarboxylate (4.77 mmol, 964.5 mg) and stirred for about 20 minutes. A solution of (2S)-3-(4-hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester (Example 283, Step 1) (4.46 mmol, 1000 mg) and 3-bromo-propan-1-ol (4.77 mmol, 663 mg) in 10 mL of dry THF was added, and the mixture was stirred at room temperature overnight. The mixture was concentrated to dryness under vacuum and purified by silica gel chromatography (silica gel, hexanes/ethyl acetate 6:1). The fraction with Rf 0.4 corresponding to the coupled compound was combined and concentrated to dryness to afford a yellow oil. MS (ES) for C15H21BrO4 [M+Na]+: 367.2.
Reaction SMILES: C1([NH:4][S:5]([NH2:8])(=[O:7])=[O:6])CC1.[CH:9]1[N:13]=[C:12]([NH2:14])[S:11][CH:10]=1>>[S:11]1[CH:10]=[CH:9][N:13]=[C:12]1[NH:14][NH:4][S:5]([NH2:8])(=[O:6])=[O:7]
Reactant: NS(=O)(=O)NC1CC1
Reactant: Nc1nccs1
Product: NS(=O)(=O)NNc1nccs1

Procedure:
The titled compound was prepared according to the same procedures described for the synthesis of N-cyclopropylsulfamide above, substituting cyclopropyl amine with 2-amino thiozol. However, the Boc-protected intermediate was never isolated due to loss of the protection group during reaction work-up and the following recrystallization steps. The titled product was isolated after silica gel column chromatography (Biotage 40 M, eluent=5-10% MeOH in DCM). 1H NMR (d6-DMSO, 400 MHz) 6.52 (br s, 2H), 6.75 (d, 1H), 7.19 (d, 1H), 12.1 (br s, 1H). MS m/z 180 (ESI+, MH+).
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([OH:14])[CH2:6][CH2:5]1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[N:26]2[CH:27]=[C:28](F)[CH:29]=[CH:30][C:25]2=[N:24][N:23]=1>CN(C=O)C>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[N:26]2[CH:27]=[C:28]([O:14][C@H:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C@@H:4]([NH2:3])[CH2:5][CH2:6]3)[CH:29]=[CH:30][C:25]2=[N:24][N:23]=1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: Fc1ccc2nnc(-c3ccccc3Cl)n2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N[C@H]1CC[C@@H](Oc2ccc3nnc(-c4ccccc4Cl)n3c2)c2ccccc21
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 51.8 %

Procedure:
Sodium hydride (60% in mineral oil, 840 mg, 21.9 mmol) was added portionwise to a stirred solution of Intermediate 1d (1.19 g, 7.31 mmol) in anhydrous DMF (30 mL) at RT under an argon atmosphere. Intermediate 31b (1.81 g, 7.31 mmol) was then added, and stirring at 60° C. was continued for 1.5 h. After cooling, the reaction mixture was quenched by careful addition of a saturated aqueous solution of NH4Cl and extracted with EtOAc (×2). The combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC, using 0-10% MeOH in DCM to afford the title compound (1.48 g, 52%) as a brown foam. LCMS (Method 3): Rt 0.42 and 2.33 min, m/z 391. [MH+].
Reaction SMILES: [C:1]([CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)#[N:2].[Li+].[CH3:16][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1>[C:1]([C:3]1([CH3:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)#[N:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)C1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1(C#N)CCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
To a solution of tert-butyl 3-cyanopyrrolidine-1-carboxylate (1.0 g, 5.1 mmol) in THF (20 mL) at −78° C. was slowly added LiHMDS (1.0 M in THF, 5.6 mL, 5.6 mmol). The reaction mixture was stirred at −78° C. for 30 min then iodomethane (0.48 mL, 7.64 mmol) was slowly added. The reaction mixture was stirred at −78° C. for 30 min then warmed to room temperature and quenched with saturated aqueous NH4Cl. Diluted with H2O and extracted with EtOAc (2×) then dried over MgSO4 and concentrated. The residue was purified by SiO2 chromatography (20% to 40% EtOAc/hexanes) to afford 0.95 g (89%) of tert-butyl 3-cyano-3-methylpyrrolidine-1-carboxylate as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]=[C:13]([CH3:21])[N:14]([CH:15]4[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]4)[C:5]=3[C:4]=2[N:3]=1.CCN(CC)CC.[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1>C1COCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]=[C:13]([CH3:21])[N:14]([CH:15]4[CH2:20][CH2:19][N:18]([C:32]([CH:29]5[CH2:31][CH2:30]5)=[O:33])[CH2:17][CH2:16]4)[C:5]=3[C:4]=2[N:3]=1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1nc2cnc3ccc(Cl)nc3c2n1C1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc2cnc3ccc(Cl)nc3c2n1C1CCN(C(=O)C2CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To a solution of 8-chloro-2-methyl-1-(piperidin-4-yl)-1H-imidazo[4,5-c][1,5]naphthyridine (110 mg, 0.364 mmol) and Et3N (101 μL, 0.728 mmol) in THF (15 mL) was added cyclopropanecarbonyl chloride (36 μL, 0.401 mmol) while cooling with an ice-water bath. The reaction mixture was stirred at r.t. for 3 h, and was then concentrated under vacuum. The residue was dissolved in a mixture of CH2Cl2 (10 mL) and H2O (10 mL). The resulting solution was then extracted with EA (2×10 mL). The combined organic layers were concentrated to give crude (4-(8-chloro-2-methyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl) piperidin-1-yl)(cyclopropyl)methanone as a yellow solid (105 mg, yield 80%) which was used in the next step without further purification. MS (m/z): 370 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([O:17][CH3:18])=[CH:11][CH:10]=3)[CH3:2].[OH:19][CH:20]1[CH2:25][CH2:24][CH:23]([CH2:26][NH2:27])[CH2:22][CH2:21]1>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:27][CH2:26][CH:23]4[CH2:24][CH2:25][CH:20]([OH:19])[CH2:21][CH2:22]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([O:17][CH3:18])=[CH:11][CH:10]=3)[CH3:2]
Reactant: NCC1CCC(O)CC1
Reactant: CCn1ncc2c(Cl)c3cc(OC)ccc3nc21
Solvent: CS(C)=O
Product: CCn1ncc2c(NCC3CCC(O)CC3)c3cc(OC)ccc3nc21
Temperature: 110 °C
Yield: 32.8 %

Procedure:
A mixture of 1-ethyl-4-chloro-6-methoxy-1H-pyrazolo[3,4-b]quinoline (2.02 g, 15.5 mmol), DMSO (6 ml) and 4-hydroxy cyclohexylmethylamine (2 g, 15.5 mmol) is heated at 110° C. overnight. The reaction mixture is partitioned between CH2Cl2 /water/NaHCO3, and the CH2Cl2 layer is separated, dried over MgSO4 and evaporated. The residue is purified by column chromatography on silica gel eluting with ethyl acetate to afford 1.8 g of 1-ethyl-6-methoxy-N-(4-hydroxycyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][CH2:6][CH2:7][P:8]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])C.O.[OH-].[Li+]>C1COCC1.O>[CH2:19]([O:18][P:8]([CH2:7][CH2:6][CH2:5][C:4]([OH:26])=[O:3])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)CCCP(=O)(OCc1ccccc1)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCP(=O)(OCc1ccccc1)OCc1ccccc1
Reaction time: 1 h

Procedure:
A solution of the compound of example 73 (8.66 g, 23.02 mmol) in THF (150 mL) was treated drop wise with a solution of lithium hydroxide-mono hydrate (1.97 g, 46.04 mmol) in water (150 mL). The reaction was complete after about 1 h, according to TLC analysis. Most of the solvent was evaporated. The residue was partitioned between water and ether. The organic phase was separated and the alkaline phase was extracted again with ether. It was next acidified with HCl (6M) to pH˜1 followed by several extractions with ethyl acetate. The recombined organic layer was dried over sodium sulfate, filtered, and evaporated to give the product as colorless oil. 1H-NMR(CDCl3, 400 MHz: 1.88(m, 4H); 2.40(t, J=6.9 Hz, 2H); 4.97, 4.96, 5.05(2dd, J1=11.8 Hz. J2=8.11 Hz, 4H); 7.35(m, 10H). 31P-NMR(CDCl3, 400 MHz): 33.15.
Reaction SMILES: [Br:1][C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13](I)=[CH:14][C:5]=3[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH:40]=[CH:39][C:27]([CH2:28][N:29]3[CH2:34][CH2:33][CH:32]([C:35]([F:38])([F:37])[F:36])[CH2:31][CH2:30]3)=[CH:26][CH:25]=2)O1>C(=O)([O-])[O-].[Na+].[Na+]>[Br:1][C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13]([C:24]4[CH:25]=[CH:26][C:27]([CH2:28][N:29]5[CH2:30][CH2:31][CH:32]([C:35]([F:38])([F:36])[F:37])[CH2:33][CH2:34]5)=[CH:39][CH:40]=4)=[CH:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: Brc1cc2c(cn1)[nH]c1ncc(I)cc12
Reactant: CC1(C)OB(c2ccc(CN3CCC(C(F)(F)F)CC3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: FC(F)(F)C1CCN(Cc2ccc(-c3cnc4[nH]c5cnc(Br)cc5c4c3)cc2)CC1
Temperature: 85 °C
Yield: 6.9 %

Procedure:
A degassed mixture of 6-bromo-3-iodo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (0.64 g, 1.7 mmol), 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-4-trifluoromethyl piperidine (1.14 g, 3.1 mmol) and 1,1′-[bis(diphenyl phosphino)ferrocene]dichloropalladium(II) (0.21 g, 0.26 mmol) in 2-methyl-THF (26 mL) and saturated aqueous sodium carbonate solution (12 mL) was heated at 85° C. for 16 h. The cooled reaction mixture was filtered through celite and partitioned between DCM and water and the phases were separated. The organic phase was dried over sodium sulfate, filtered and evaporated then the residue was purified by flash chromatography (silica, 40 g column, ISCO, 0-15% methanol in DCM). Trituration of the resultant residue with acetonitrile afforded the title compound as a tan solid (57 mg, 7%). NMR (CD3OD, 300 MHz): 8.84 (d, J=2.2 Hz, 1H), 8.70-8.67 (m, 2H), 8.27 (d, J=1.0 Hz, 1H), 7.67 (d, J=8.0 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H), 3.63 (s, 2H), 3.11-3.02 (m, 2H), 2.14-2.02 (m, 3H), 1.94-1.84 (m, 2H), 1.76-1.59 (m, 2H. LCMS (Method B): RT=2.55 min, M+H+=489.
Reaction SMILES: C([N:3]1[C:15]2[C:14]([O:16][CH3:17])=[CH:13][CH:12]=[C:11]([S:18]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)(=[O:20])=[O:19])[C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)=O.[BH4-].[Na+]>C1COCC1>[CH3:17][O:16][C:14]1[C:15]2[NH:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]=2[C:11]([S:18]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=2)(=[O:19])=[O:20])=[CH:12][CH:13]=1
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(C)cc2)c2c3ccccc3n(C=O)c12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)Nc2ccc(C)cc2)c2c1[nH]c1ccccc12
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 99 %

Procedure:
N-Formyl-1-methoxy-4-[4-methylphenylaminosulphonyl]-9H-carbazole (example 72) (0.14 g, 0.35 mM) was dissolved in 15 mL of 20% aqueous THF solution. The reaction mixture was cooled to 0° C. in an ice bath. To it was added NaBH4 (0.08 g, 2.1 mM) portion wise. The reaction mixture was stirred for 4-5 hrs. Solvent was evaporated and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine and dried over anh. Na2SO4. It was filtered and concentrated to yield the desired compound as a white solid with a yield of 99% (0.13 g). mp 199-203° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]1.[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[CH:5][C:4]=1[O:9][CH3:10]
Reactant: COc1ccccc1OC
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)CCC(=O)O)cc1OC

Procedure:
The naphthalenes of formulas A and B are known to the art. Moreover, they can be prepared by conventional means. For example, 1,2-dimethoxybenzene is treated with succinic anhydride and aluminum chloride in a hydrocarbon solvent to afford 4-(3', 4'-dimethoxyphenyl)-4-oxobutanoic acid. This is reduced by treatment with sodium borohydride, hydrogenolyzed by treating with palladium charcoal catalyst and hydrogen to furnish 4-(3', 4'-dimethoxyphenyl) butanoic acid. The corresponding acid chloride is prepared such as by treatment with thionyl chloride, and the acid chloride is treated with aluminum chloride to afford 6,7-dimethoxy-1-tetralone. The tetralone is reduced and hydrogenolyzed by the means described above to furnish 6,7-dimethoxytetralin which is dehydrogenated by treating with palladium charcoal catalyst to afford 2,3-dimethoxy naphthalene. By utilizing 1-methyl-3-fluorobenzene in the above process, 6-methyl-8-fluoro-4-tetralone and 6-fluoro-8-methyl-4-tetralone (as intermediates) and 1-methyl-3-fluoro naphthalene and 1-fluoro-3-methyl naphthalene are prepared. The mixture of naphthalenes are separated by conventional means, such as vacuum distillation.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].C(N(CC)CC)C.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=1)=[O:28]>ClCCl>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][N:13]([C:27]([O:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:28])[CH2:12][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCc1ccc(C2CNCC(C(=O)OC)C2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccc(C2CC(C(=O)OC)CN(C(=O)Oc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 0 °C

Procedure:
10.0 g (40.4 mmol) of the compound from Example 2A were initially charged in 135 ml of dichloromethane and cooled to 0° C., and 11.2 ml (8.2 g, 80.9 mmol) of triethylamine and 8.5 g (40.4 mmol) of 4-nitrophenyl chloroformate were added. The reaction mixture was allowed to warm to room temperature over a period of 2 h. For work-up, the mixture was twice washed with water, and the organic phase was dried over sodium sulphate. The solvent was removed under reduced pressure and the residue was dried under high vacuum. Yield: 16.5 g (83% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(#N)C.C([O-])(O)=O.[Na+]>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][N:14]1[CH2:15][CH2:16][CH:11]([C:9](=[O:10])[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:12][CH2:13]1)[CH3:30]
Reactant: COc1ccc(C(=O)C2CCNCC2)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCC(C(=O)c2ccc(OC)cc2)CC1
Temperature: 85 °C
Reaction time: 18 h
Yield: 49.1 %

Procedure:
To a solution of 4-methoxy-phenyl-piperidin-4-yl-methanone (20 g, 78 mmol, 1 eq.) in 313 mL of acetonitrile was added triethylamine (22 mL, 156 mmol, 2 eq.), followed by ethyl 2-bromoacetate (9.5 mL, 86 mmol, 1.1 eq.) dropwise. The resulting mixture was heated at 85° C. overnight. After 18 h, the reaction mixture was diluted with saturated NaHCO3 (150 mL) and extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give an oil. This oil was purified by silica gel column chromatography (10-20% acetone/heptane) to give the title compound as a white solid (11.7 g, 49% yield). Exact mass calculated for C17H24N1O4 306.2. MS (ESI) m/z 306.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:3]=1.C(N(CC)CC)C.Cl[C:22]([O:24][CH3:25])=[O:23]>ClCCl>[C:22](=[O:23])([O:24][CH3:25])[O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)Cl
Reactant: Oc1ccc(Cl)cc1C1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Oc1ccc(Cl)cc1C1CCCC1
Temperature: 0 °C

Procedure:
4-Chloro-2-cyclopentylphenol (2.366 g, 7.94 mmol) was dissolved in dichloromethane (20 mL) and triethylamine (2.2 mL, 15.9 mmol). The solution was cooled to 0° C. and treated with methyl chloroformate (920 μL, 11.91 mmol) and allowed to warm to room temperature over 16 h. The reaction was quenched with 3 mL saturated NaHCO3, washed with 50% saturated NaHCO3 (1×50 mL) and brine (1×50 mL), then dried over Na2SO4. Filtration, followed by concentration in vacuo yielded an oil that was purified by silica gel chromatography (20% ethyl acetate/hexane) to yield 4-chloro-2-cyclopentylphenyl methyl carbonate as a colorless oil. 1H NMR (400.0 MHz, DMSO-d6) δ 7.31-7.28 (m, 1H), 7.20-7.13 (m, 1H), 7.06 (d, J=8.6 Hz, 1H), 3.93 (d, J=3.1 Hz, 3H), 3.18-3.09 (m, 1H), 2.08-2.01 (m, 2H), 1.87-1.78 (m, 2H), 1.75-1.65 (m, 2H), 1.61-1.51 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[OH-].[Na+]>CO.CCOC(C)=O.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][CH2:18][CH2:17][CH2:16][CH2:15][Br:14]
Reactant: BrCCCCBr
Reactant: COC(=O)Cc1ccc(O)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)Cc1ccc(OCCCCBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-chloro-4-hydroxyphenylacetate and 1,4-dibromobutane (0.021 g, 0.044 mmol) in 0.5 mL of methanol was added 5N NaOH soln (0.04 mL, 5 eq) at rt. The reaction mixture was heated initially with a heat gun to reflux in order to dissolve the starting material. After heating, the reaction mixture stirred at ambient temperature for 1 h. The reaction mixture was diluted with EtOAc and 0.1N HCl (5 mL). The organic layer was separated from the aqueous portion, and washed with 0.1N HCl (5 mL) followed by 10 mL brine. The organic layer was dried (MgSO4), filtered, and evaporated in vacuo to afford the title compound. This compound was taken forward without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:16])[C:5]([CH3:15])=[C:6]2[C:10]=1[C:9](=O)[C:8]([CH3:13])([CH3:12])[C:7]2=O.C1C=CC=CC=1>Cl.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:16])[C:5]([CH3:15])=[C:6]2[C:10]=1[CH2:9][C:8]([CH3:12])([CH3:13])[CH2:7]2
Reactant: Cc1cc(Cl)c2c(c1C)C(=O)C(C)(C)C2=O
Agent: Cl
Solvent: CCO
Solvent: c1ccccc1
Product: Cc1cc(Cl)c2c(c1C)CC(C)(C)C2
Temperature: 25 °C
Yield: 50.2 %

Procedure:
To a mixture of 100 g of 7% Zn/Hg in 200 ml of 20% hydrochloric acid and 70 ml of ethanol was added 38.42 g of the 7-chloro-2,2,4,5-tetramethylindan-1,3-dione with stirring. After refluxing for 6 hours, the reaction mixture was added 100 ml of benzene and refluxed for 1 hour. The reaction mixture was cooled to room temperature and extracted with diethyl ether. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography to afford 17.0 g of the title compound as yellow oil.