Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[O:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:31](O)=[O:32])=[CH:25]2.Cl.C(N=C=N)C.ON1C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O1CCCC1.C(OCC)(=O)C>[C:17]([O:16][C:14](=[O:15])[CH2:13][O:12][C@H:3]1[C@H:2]([NH:1][C:31]([C:26]2[NH:27][C:28]3[C:24]([CH:25]=2)=[CH:23][C:22]([Cl:21])=[CH:30][CH:29]=3)=[O:32])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)CO[C@@H]1Cc2ccccc2C[C@H]1N
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CO[C@@H]1Cc2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 1 h
Yield: 72.5 %

Procedure:
To a stirred solution of trans 3-amino-2-carbo-t-butoxymethoxy-1,2,3,4-tetrahydronaphthalene (550 mg, 1.98 mmol) and 5-chloroindole-2-carboxylic acid (466 mg, 2.39 mmol) in tetrahydrofuran (12 mL) at room temperature under nitrogen was added 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (760 mg, 2.39 mmol), 1-hydroxy-7-azabenzotriazole (540, 2.39 mmol), and diisopropylethylamine (0.4 mL). After 1 h, the reaction mixture was diluted with ethyl acetate. The organic layer was washed with 1.0 M aqueous hydrochloric acid solution, 1.0 M aqueous sodium hydroxide solution and brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel chromatography (20% ethyl acetate in hexane was used) to obtain the title compound (653 mg, 72%). 13C NMR (400 MHz, CDCl3) δ 172.31, 162.11, 134.72, 133.82, 132.8, 132.7, 128.8, 128.7, 126.6, 126.3, 125.7, 124.3, 121.0, 113.2, 102.6, 83.3, 77.6, 66.1, 51.7, 35.8, 34.4, 28.2. 1H NMR (400 MHz, CDCl3) δ 9.22 (s, 1H), 8.92 (d, J=4.0 Hz, 1H), 7.60 (s, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.22 (dd, J=2.2, 7.8 Hz, 1H), 7.07-7.19 (m, 3H), 4.27 (d, J=17.6 Hz, 1H), 4.20 (m, 1H), 4.12 (d, J=17.6 Hz, 1H), 3.91 (dd, J=4.5, 16.8 Hz, 1H), 3.76 (dt, J=5.3, 8.0 Hz, 1H), 3.24 (dd, J=5.2, 16.8 Hz, 1H), 2.92 (dd, J=9.5, 15.0 Hz, 1H), 2.77 (dd, J=9.5, 15.0 Hz, 1H). MS [M+H]+, 455; [M−H]−, 453.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([SH:20])=[N:9]2)=[CH:4][CH:3]=1.ClC(Cl)(Cl)S(O[CH2:27][C:28]([F:31])([F:30])[F:29])(=O)=O>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([S:20][CH2:27][C:28]([F:31])([F:30])[F:29])=[N:9]2)=[CH:6][CH:7]=1
Reactant: SC1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Product: Cl
Product: FC(F)(F)CSC1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1

Procedure:
By the procedure described in Example 1, 2.0 g of 4,5-bis-(4-chlorophenyl)-4,5-dihydro-1H-imidazole-2-thiol was reacted with 2,2,2-trifluoroethyl trichloromethanesulfonate to give the title compound. Recrystallization from nitromethane afforded 850 mg of colorless crystals, m.p. 230° dec. The NMR and infrared spectra were consistent with this structure.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8](=[O:14])[C:9]2[S:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:15](=O)C.[S].N1C[CH2:23][O:22]CC1.Cl.[OH2:26]>C(Cl)(Cl)Cl>[C:9]1([C:8]([C:7]2[C:2]([CH2:1][C:23]([OH:22])=[O:26])=[C:3]([CH3:15])[CH:4]=[CH:5][CH:6]=2)=[O:14])[S:13][CH:12]=[CH:11][CH:10]=1
Reactant: C1COCCN1
Reactant: CC(=O)c1cccc(C(=O)c2cccs2)c1C
Reactant: O
Agent: Cl
Agent: [S]
Solvent: ClC(Cl)Cl
Product: Cc1cccc(C(=O)c2cccs2)c1CC(=O)O

Procedure:
A mixture of 14.7 parts of 2'-methyl-3'-(2-thenoyl)acetophenone, 4.3 parts of sulfur and 33 parts of morpholine is stirred and refluxed for 3 hours. The reaction mixture is cooled, diluted with 450 parts of chloroform and shaken successively twice with diluted hydrochloric acid solution and twice with water. The organic layer is dried and evaporated. The oily residue is boiled in a mixture of 200 parts of glacial acetic acid and 150 parts of a 50% sulfuric acid solution for 2 hours. After cooling, the mixture is poured onto 700 parts of ice-water and the product is extracted twice with ether. The combined extracts are washed with water, dried, stirred with activated charcoal, filtered and evaporated. The residue is taken up in 200 parts of water, alkalized with diluted sodium hydroxide solution and washed twice with ether. The aqueous phase is acidified with concentrated hydrochloric acid solution and the product is extracted twice with ether. The extracts are dried and evaporated. The residue is purified by column-chromatography over silica gel, using a mixture of chloroform and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is dissolved in ether and the solution is stirred with activated charcoal. The latter is filtered off and the filtrate is evaporated. The residue is crystallized from acetonitrile at -20° C, yielding a 2-[3-(2-thenoyl)-o-tolyl]acetic acid; m.p. 136° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH: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]=[C:7]1[CH2:20][O:21][CH2:22][CH3:23].C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>C(Cl)Cl>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][O:21][CH2:22][CH3:23])[N:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][C:31](=[O:33])[CH3:32])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CC(=O)Cl
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1NCCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1NCCCNC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.2 %

Procedure:
A solution of N1-(3-aminopropyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (1.00 g, 3.18 mmol) in 15 mL of CH2Cl2 was placed under an atmosphere of nitrogen. The solution was chilled in an ice water bath and treated first with triethylamine (0.89 mL, 6.7 mmol) and then slowly with acetyl chloride (0.89 mL, 3.3 mmol). After 2 h, the reaction was warmed to ambient temperature, quenched with 15 mL of saturated NaHCO3 solution and diluted with 30 mL of CHCl3. The phases were separated and the organic portion was washed with H2O (15 mL) and brine (15 mL). The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure to yield a light yellow foam. The foam was crystallized from MeCN to give light yellow crystals. The crystals were pulverized and then triturated with Et2O for 18 h and filtered off to yield N-(3-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]amino}propyl)acetamide (0.728 g) as a white solid. mp 178–181° C.; 1H NMR (500 MHz, DMSO-d6) δ 8.44 (d, J=8.1 Hz, 1H), 7.82 (t, J=5.1 Hz, 1H), 7.59 (d, J=8.2 Hz, 1H), 7.45–7.42 (m, 1H), 7.26–7.22 (m, 1H), 6.96 (t, J=5.6 Hz, 1H), 6.59 (s, 2H), 4.75 (s, 2H), 3.61 (q, J=7.0 Hz, 2H), 3.20–3.14 (m, 4H), 1.77 (s, 3H), 1.71 (p, J=7.0 Hz, 2H), 1.17 (t, J=7.0Hz, 3H);
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[CH:21][C:22]([C:25]([OH:27])=O)=[N:23][CH:24]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[CH3:18][CH:17]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:19]3[CH:24]=[N:23][C:22]([C:25]([N:39]4[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]4)=[O:27])=[CH:21][CH:20]=3)=[CH:13][CH:14]=2)[CH2:9][N:8]1[C:6]1[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: CN1CCNCC1
Reactant: CC1Cc2ccc(-c3ccc(C(=O)O)nc3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Product: CC1Cc2ccc(-c3ccc(C(=O)N4CCN(C)CC4)nc3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 50A starting from 5-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid (Example 50A, Step 1) and 1-methylpiperazine (Aldrich, Cat. No. 130001). LCMS (M+H)+: m/z=542.3.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH2:7][CH2:6][CH2:5]2.[C:15]([O-])([O-])=O.[K+].[K+].BrC[CH2:23][CH2:24][Cl:25]>CC(C)=O>[Cl:25][CH2:24][CH2:23][CH2:13][O:12][C:11]1[CH:10]=[C:9]2[C:4](=[CH:3][C:2]=1[O:1][CH3:15])[CH2:5][CH2:6][CH2:7][C:8]2=[O:14]
Reactant: COc1cc2c(cc1O)CCCC2=O
Reactant: ClCCCBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc2c(cc1OCCCCl)C(=O)CCC2
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A mixture of 6-hydroxy-7-methoxy-1-tetralone q. Org. Chem., 1985, aQ, 4937) (1.5 g, 7.8 mmol), K2CO3 (1.7 g, 12.3 mmol), and acetone (30 ml) was stirred at reflux under nitrogen for 45 minutes. The reaction was cooled to ambient temperature and a solution of 1-bromo-3-chloropropane (1.9 g, 12.1 mmol) dissolved in 8 ml acetone was dripped into the mixture. After total addition, the reaction was heated to reflux and stirred under nitrogen for 21 hours. The reaction was cooled to ambient temperature and filtered. The filter cake was washed well with acetone and the filtrate was concentrated to yield 2.0 g 6-(3-chloropropoxy)7-methoxy4--tetralone as an amber oil.
Reaction SMILES: Cl[C:2]1[C:11]([C@@H:12]([N:14]2C(=O)[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH3:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:25])=[CH:7][CH:8]=2)[N:3]=1.[F:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.[C:36](=[O:39])([O-])[O-:37].[Na+].[Na+].N#N>CC#N.O.CCOC(C)=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>[F:25][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[C:11]([C@@H:12]([NH:14][C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:36]([OH:37])=[O:39])=[O:24])[CH3:13])[C:2]([C:31]3[CH:30]=[CH:29][CH:28]=[C:27]([F:26])[CH:32]=3)=[N:3]2)=[CH:8][CH:7]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: C[C@@H](c1cc2ccc(F)cc2nc1Cl)N1C(=O)c2ccccc2C1=O
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: C[C@H](NC(=O)c1ccccc1C(=O)O)c1cc2ccc(F)cc2nc1-c1cccc(F)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 65.6 %

Procedure:
To a solution of (S)-2-(1-(2-chloro-7-fluoroquinolin-3-yl)ethyl)isoindoline-1,3-dione (150 mg, 423 μmol), 3-fluorophenylboronic acid (65 mg, 465 μmol) and sodium carbonate (90 mg, 846 μmol) in MeCN (8 mL) and water (2 mL) was purged with N2 followed by the addition of Pd(PPh3)4 (24 mg, 21 μmol) and the resulting mixture was stirred at 90° C. overnight. The reaction mixture was diluted with EtOAc washed with water, brine and dried over Na2SO4. Purification using preparatory TLC eluted with 100% EtOAc afforded 2-(((S)-1-(7-fluoro-2-(3-fluorophenyl)quinolin-3-yl)ethyl)carbamoyl)benzoic acid (120 mg, 66%). Mass Spectrum (ESI) m/e=433 (M+1). 2-(((S)-1-(7-Fluoro-2-(3-fluorophenyl)-quinolin-3-yl)ethyl)carbamoyl)benzoic acid was dissolved in EtOH (2 mL) and cond HCl (0.1 mL) was added. The resulting solution was heated to 80° C. for 4 h. Solvent was removed and satd NaHCO3 was added to the reaction mixture and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, concentrated and purified via preparatory TLC using 3% MeOH/DCM saturated with NH3 gas to afford a white solid of 2-((S)-1-(7-fluoro-2-(3-fluorophenyl)quinolin-3-yl)ethyl)isoindoline-1,3-dione (85 mg, 49%). Mass Spectrum (ESI) m/e=415 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[N:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[CH3:19][NH2:20]>C1COCC1.O>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[N:10]=[C:9]([CH2:11][NH:20][CH3:19])[S:8][C:6]=2[N:7]=1
Reactant: O=Cc1nc2c(N3CCOCC3)nc(Cl)nc2s1
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Product: CNCc1nc2c(N3CCOCC3)nc(Cl)nc2s1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Also, to a solution of 5-chloro-7-morpholinothiazolo[5,4-d]pyrimidine-2-carbaldehyde 44 in 50 mL THF was added 20 mL of 40% methylamine in water. The reaction mixture was stirred at room temperature under N2 for 24 hours. The solvents were removed in vacuo and the residue was dissolved in 50 mL MeOH and 50 mL THF and the NaBH4 added portion-wise. This reaction mixture was stirred at room temperature under N2 for 24 hours and complete reaction was confirmed by LCMS. The solvents were removed in vacuo and the crude product purified by flash chromatography (EtOAc/EtOH) to give of 1-(5-chloro-7-morpholinothiazolo[5,4-d]pyrimidin-2-yl)-N-methylmethanamine 61.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([C:18]1([OH:42])[CH2:23][CH2:22][N:21]([CH2:24][CH:25]([OH:41])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])=[CH:29][CH:28]=2)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.[NH4+].[Cl-]>C(Cl)Cl>[CH2:11]([C:18]1([OH:42])[CH2:19][CH2:20][N:21]([CH2:24][C:25](=[O:41])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][Si:34]([C:37]([CH3:38])([CH3:39])[CH3:40])([CH3:35])[CH3:36])=[CH:29][CH:28]=2)[CH2:22][CH2:23]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(O)CN2CCC(O)(Cc3ccccc3)CC2)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)CN2CCC(O)(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.4 %

Procedure:
To a solution of oxalylchloride (0.28 ml, 3.3 mmol) in CH2Cl2 (4 ml) at -78° C. was added dropwise dimethyl sulfoxide (DMSO) (0.47 ml, 6.6 mmol). After 30 min., a solution of (RS)-4-Benzyl-1-{3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-2-hydroxy-propyl}-piperidin-4-ol (0.75 g, 1.65 mmol) in CH2Cl2 (4 ml) was added. After another hour at -78° C., triethylamine (1.8 ml, 13.2 mmol) was added and reaction mixture was allowed to warm up slowly to room temperature. After 1 hour, 20% NH4Cl (15 ml) was added, the resulting aqueous phase was extracted with CH2Cl2 (3×30 ml). Combined organic phases were dried over Na2SO4 and concentrated. The residue was chromatographed over silica gel (hexane-ethylacetate 1:1 then ethyl acetate) to provide 1-(4-Benzyl-4-hydroxy-piperidin-1-yl)-3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-propan-2-one (0.4 g, 54%) as a yellow oil, and MS: m/e=454.5 (M+H+).
Reaction SMILES: O[C:2]([CH3:6])([CH3:5])[C:3]#[N:4].[NH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>>[NH2:4][CH2:3][C:2]([N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:6])[CH3:5]
Reactant: C1CCNCC1
Reactant: CC(C)(O)C#N
Product: CC(C)(CN)N1CCCCC1

Procedure:
The starting material 1-(2-amino-1,1-dimethylethyl)piperidine was prepared in a route similar to that in Example 39 from 2-hydroxy-2-methyl-propionitrile and piperidine.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[O:19][CH:18]=[CH:17][C:16]=12)=[O:10].[F:20][C:21]1[CH:22]=[C:23]([C:27]2[S:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33](O)=[O:34])[CH:24]=[CH:25][CH:26]=1>>[F:20][C:21]1[CH:22]=[C:23]([C:27]2[S:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[O:19][CH:18]=[CH:17][C:16]=23)=[O:10])=[O:34])[CH:24]=[CH:25][CH:26]=1
Reactant: O=C(NC[C@H]1NC[C@@H]2C[C@@H]21)c1cccc2occc12
Reactant: Cc1nc(C(=O)O)c(-c2cccc(F)c2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3occc23)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of Benzofuran-4-carboxylic acid[(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 5-(3-Fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=0.90 min; [M+H]+=476.0.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)O.[CH3:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH2:20][CH2:21][CH2:22][CH:23]([CH2:25][CH2:26][CH2:27][C:28]([OH:32])([CH:30]=[CH2:31])[CH3:29])[CH3:24])[CH3:19])[CH3:14].[C:33](OC(=O)C)(=[O:35])[CH3:34].B([O-])([O-])[O-]>>[CH3:9][C:5]1[C:6]2[O:32][C@@:28]([CH2:27][CH2:26][CH2:25][C@@H:23]([CH2:22][CH2:21][CH2:20][C@@H:18]([CH2:17][CH2:16][CH2:15][CH:13]([CH3:12])[CH3:14])[CH3:19])[CH3:24])([CH3:29])[CH2:30][CH2:31][C:8]=2[C:2]([CH3:1])=[C:3]([O:11][C:33]([CH3:34])=[O:35])[C:4]=1[CH3:10]
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: CC(=O)OC(C)=O
Reactant: C=CC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Agent: [O-]B([O-])[O-]
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Yield: 92 %

Procedure:
EP 0 784 042 claimed hydrogen bis(oxalato)borate as protic acid catalyst for the Friedel-Crafts condensation of trimethylhydroquinone with isophytol and the acylation of phenols, for example tocopherol. In an example the acylation of tocopherol is described. For this, tocopherol was charged into a flask together with acetic anhydride and hydrogen bis(oxalato)borate and the reaction mixture was heated to reflux for one hour under an argon atmosphere. The initial molar ratio of acetic anhydride/tocopherol was greater than 1.1 mol/mol and the borate concentration was approximately 0.5 mol %, based on tocopherol. After concentration on a rotary evaporator, tocopherol acetate was obtained in a purity of 87% at a yield of 92%. This batch process has the disadvantage that both yield and purity are still not satisfactorily high. In addition, carrying out the reaction in an argon atmosphere is associated with high costs for industrial production.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH:19]=[C:20]([CH3:22])[CH3:21])[CH2:15][C@H:14]1[CH2:13][S:12][C:11]([NH:23][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[N:10]2.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:15][C@H:14]1[CH2:13][S:12][C:11]([NH:23][C:24](=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[N:10]2
Reactant: CC(C)=C[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1

Procedure:
A solution of N-[(4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(2-methylprop-1-en-1-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C28) (42 mg, 95 μmol) in methanol (28 mL) was treated with palladium on activated carbon [10% by weight (dry), 50% water, 224 mg, 105 μmol] and hydrogenated (35 pounds per square inch of hydrogen) for 20 hours. The reaction mixture was filtered through Celite®, and the filter pad was rinsed with methanol (30 mL). The combined filtrates were concentrated in vacuo and purified via silica gel chromatography (Gradient: 0% to 30% ethyl acetate in heptane) to provide the product as an opaque semi-solid. Yield: 10.9 mg, 24.5 μmol, 26%. LCMS m/z 445.2 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 8.24 (br d, J=8 Hz, 2H), 7.48-7.54 (m, 1H), 7.37-7.48 (m, 3H), 6.84-6.96 (m, 2H), 4.11 (dd, J=12.2, 1.5 Hz, 1H), 3.77 (d, J=12.1 Hz, 1H), 3.64-3.72 (m, 1H), 3.09-3.17 (m, 1H), 3.01 (dd, J=12.7, 4.1 Hz, 1H), 2.63 (dd, J=12.7, 2.7 Hz, 1H), 1.86-1.97 (m, 1H), 1.76-1.87 (m, 1H), 1.55-1.65 (m, 2H), 1.23-1.31 (m, 1H), 0.93 (d, J=6.5 Hz, 3H), 0.92 (d, J=6.6 Hz, 3H).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-].Cl>O>[CH3:7][C:8]1[CH:9]=[C:10]([C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[CH:11]=[CH:12][C:13]=1[CH3:14]
Reactant: CC(C)C(=O)Cl
Reactant: Cc1ccccc1C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: Cc1ccc(C(=O)C(C)C)cc1C
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
In a nitrogen atmosphere, 213.1 g (2.0 mol) of isobutyryl chloride and 400 g of o-xylene are introduced into a 1.5 litre reaction flask. The solution is cooled to 5-0° C. Then, over about three hours, 293.3 g (2.2 mol) of aluminium chloride are added in small portions at 0-5° C. After the evolution of HCl gas has ceased, the reaction is checked using GC. The dark-red reaction solution is then poured into ice and water and stirred to complete the reaction. The two phases are separated in a separating funnel. The organic phase is washed with water and is then concentrated using a vacuum rotary evaporator. The last remnants of solvent are removed under a high vacuum. 329.1 g of faintly yellowish oil remain behind. The product is checked using GC and a 1H NMR spectrum. The product, 1-(3,4-dimethyl-phenyl)-2-methyl-propan-1-one, is used directly in the next reaction.
Reaction SMILES: [Mg].II.[C:4]1([CH:10]2[O:14][C:13]3[CH:15]=[CH:16][CH:17]=[C:18](CCBr)[C:12]=3[O:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:22](=[O:24])=[O:23].[CH:25]1C=CC=CC=1>CCOCC>[C:4]1([C:10]2([CH2:25][C:22]([OH:24])=[O:23])[O:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[O:14]2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C=O
Reactant: BrCCc1cccc2c1OC(c1ccccc1)O2
Reactant: c1ccccc1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: O=C(O)CC1(c2ccccc2)Oc2ccccc2O1

Procedure:
To a mixture of 0.61 g. of magnesium, in chips, 10 cc. of anhydrous ether and one crystal of iodine, one cc. of a solution of 7.3 g. of 2-phenyl-2-bromoethyl-1,3-benzodioxole in 25 cc. of anhydrous ether is added. When the reaction has begun, the mixture is stirred and the rest of the mixture is then added dropwise. The mixture is then refluxed for 2 hours. After cooling CO2 is bubbled into the reaction mixture for 2 hours. The mixture is then cooled with ice and hydrolysed with 25% H2SO4. The ether phase is then separated and dried with Na2SO4. After evaporation, the product obtained has the m.p. 152°-53°C. (from benzene).
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7][C:6]=2[N:5]=[CH:4][N:3]=1.Cl>C(Cl)Cl.O1CCOCC1>[Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ncnc(Cl)c2CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Clc1ncnc2c1CCNCC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 4-chloro-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepine-7-carboxylate (2.0 g, 7.1 mmol) in DCM, a solution of 4N HCl in dioxane (10 mL) is added. The mixture is stirred for 4 hr at rt. The solvent is removed under vacuum to give the title compound (dichloride salt) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]1([CH3:19])[O:18][C:16](=[O:17])[CH2:15][C:13](=[O:14])[O:12]1>O>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:15]2[C:16](=[O:17])[O:18][C:11]([CH3:19])([CH3:10])[O:12][C:13]2=[O:14])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: O
Product: CC1(C)OC(=O)C(=Cc2ccc(O)cc2)C(=O)O1
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxybenzaldehyde (20 g, 163 mmol) in water (250 mL) is added Meldrum's acid (2,2-dimethyl-1,3-dioxane-4,6-dione) (24.78 g, 171 mmol) as a slurry in water (250 mL) at 75° C. The reaction mixture is agitated for 2 hours, cooled in an ice bath, and extracted with EtOAc (2×400 mL). The combined extracts are washed with saturated brine, dried over sodium sulfate, filtered, and concentrated to a yellow solid (39 g, 97%). ESI/MS m/z 247.1 (M−H)−.