Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:18])[N:4]([CH2:10][C:11]2[CH:16]=[N:15][C:14]([CH3:17])=[CH:13][N:12]=2)[C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:27]=1[CH2:28]Br>CC(N(C)C)=O>[Br:1][C:2]1[C:3](=[O:18])[N:4]([CH2:10][C:11]2[CH:16]=[N:15][C:14]([CH3:17])=[CH:13][N:12]=2)[C:5]([CH3:9])=[CH:6][C:7]=1[O:8][CH2:28][C:27]1[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:26]=1[F:25]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: Cc1cnc(Cn2c(C)cc(O)c(Br)c2=O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cnc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.2 %

Procedure:
To a mixture of 3-Bromo-4-hydroxy-6-methyl-1-[(5-methylpyrazin-2-yl)methyl]pyridin-2(1H)-one (0.45 g, 0.0015 mol), and potassium carbonate (0.25 g, 0.0018 mol) in dimethylacetamide (5.0 mL) was added 2,4-difluorobenzyl bromide (0.25 mL. 0.0019 mol) and stirred at room temperature under argon for 1 h. Dimethylacetamide was distilled in vacuo and the residue was partitioned between CH2Cl2 (20 mL) and water (20 mL). The organic phase was washed with water, dried (Na2SO4) and concentrated under reduced pressure. The resulting material was purified by flash chromatography (EtOAc/hexane 4:1 v/v) as the eluent. The appropriate fractions (m/z=451/453) were combined and concentrated under reduced pressure to give a white (0.25 g, 38%)solid. 1H NMR (CD3OD/400 MHz) δ8.49 (s, 1H), 8.40 (s, 1H), 7.60 (m, 1H), 6.99 (m, 2H), 6.51 (s, 1H), 5.42 (s, 2H), 5.29 (s, 2H), 2.54 (s, 3H), and 2.50 (s, 3H); 19F NMR (CD3OD/400 MHz) δ −117.70 (m), and −116.09 (m); ES-HRMS m/z 436.0439 (M+H C19H17N3O2BrF2 requires 436.0467).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.C[Si]([C:17]#[CH:18])(C)C>N1C=CC=CC=1.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:17]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2)#[CH:18]
Reactant: O=C1CCc2cc(Br)ccc2N1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: C#Cc1ccc2c(c1)CCC(=O)N2
Reaction time: 18 h

Procedure:
A mixture of 8.0 g of 6-bromo-3,4-dihydrocarbostyril, 6.95 g of trimethylsilylacetylene, 460 mg of bis(triphenylphosphine)palladium dichloride and 62 mg of cuprous iodide in 53 ml of pyridine and 11 ml of triethylamine was refluxed for 3 days. The solvent was removed under reduced pressure, 50 ml of methanol added along with 300 mg of potassium carbonate, and the mixture stirred under nitrogen for 18 hours. The solvent was removed under reduced pressure and the residue chromatographed on silica gel, eluting with 3% methanol in methylene chloride, giving a product of 6-ethynyl-3,4-dihydrocarbostyril, m.p. 182°-184° C.
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1>C(O)C.[Ni]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=3)[CH2:13][CH2:14]2)=[O:7])=[CH:25][CH:26]=1
Reactant: Cc1ccc(C(=O)OC2CCN(Cc3ccc([N+](=O)[O-])cc3)CC2)cc1
Agent: [Ni]
Solvent: CCO
Product: Cc1ccc(C(=O)OC2CCN(Cc3ccc(N)cc3)CC2)cc1
Reaction time: 3 h
Yield: 92.5 %

Procedure:
0.48 g (0.00135 mol) of 1-(4-nitro-benzyl)-piperidin-4-yl 4-methyl-benzoate was dissolved in 27 ml of ethanol and treated with 0.48 g of Raney-nickel. The mixture was hydrogenated at room temperature and under normal pressure for 3 hrs. The catalyst was filtered off and, after concentration, the residue was chromatographed on silica gel with ethyl acetate/hexane (1:1→5:2) as the eluent. 0.405 g (92.5%) of 1-(4-amino-benzyl)-piperidin-4-yl 4-methyl-benzoate was obtained as a yellowish oil. MS: me/e=325 (C20H25N2O2+).
Reaction SMILES: Cl.[CH3:2]O.[C:4]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=[O:16])(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Na].Cl>CC(C)=O>[OH:11][CH:4]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:12]1[CH:20]=[CH:19][CH:18]=[C:14]([C:15]([O:17][CH3:2])=[O:16])[CH:13]=1
Reactant: O=C(O)c1cccc(C(=O)c2ccccc2)c1
Reactant: CO
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(C(O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
25 ml of 10% hydrogen chloride-methanol was added to 1.95 g (8.62 mmol) of 3-benzoylbenzoic acid and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with a sodium hydrogencarbonate aqueous solution and brine, and dried (MgSO4). The solvent was distilled off and the residue was dissolved in 20 ml of methanol. Under ice-cooling, 0.32 g (8,41 mmol) of sodium boronhydride was added thereto and the mixture was stirred for 30 minutes. After acetone and 1N hydrochloric acid were added, the reaction mixture was extracted twice with chloroform, the extract was washed with a sodium hydrogencarbonate aqueous solution, and dried (MgSO4). The solvent was distilled off to obtain 2.04 g (8.42 mmol) of methyl a-hydroxy-a-phenyl-m-toluate as a colorless oily substance. Its spectroscopic data are as follows:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.[C:12]1([S:18]([O-:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Na+]>CN(C)C(=O)C>[C:12]1([S:18]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(S(=O)(=O)c2ccccc2)ccc1[N+](=O)[O-]
Yield: 75.3 %

Procedure:
4-Fluoro-2-methyl-1-nitrobenzene (2.6 g) (available from Aldrich) and sodium benzenesulfinate (3.0 g) (available from Aldrich) were heated in N,N-dimethylacetamide (40 ml) at 50° C. for 16 h. After cooling the mixture was filtered, the filtrate collected and the solvent removed in vacuo. The residue was triturated with cyclohexane and the resultant precipitate collected by filtration to give the title compound as a white solid (3.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH2:14]([N:16]([CH2:28][CH3:29])[C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]([CH3:27])[NH:22][CH2:21][CH2:20]2)[CH3:15]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:22]3[CH2:21][CH2:20][C:19]4[C:24](=[CH:25][CH:26]=[C:17]([N:16]([CH2:28][CH3:29])[CH2:14][CH3:15])[CH:18]=4)[CH:23]3[CH3:27])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CCN(CC)c1ccc2c(c1)CCNC2C
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CCN(CC)c1ccc2c(c1)CCN(C(=O)c1cc3ncc(Br)cn3n1)C2C

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with Diethyl-(1-methyl-1,2,3,4-tetrahydro-isoquinolin-6-yl)-amine to provide the title compound in moderate yield.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][CH2:11][CH:12]2[O:14][CH2:13]2)[CH2:4][C:3]1([CH3:16])[CH3:15].[OH-:17].[Na+]>>[OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][CH2:11][CH:12]([OH:14])[CH2:13][OH:17])[CH2:4][C:3]1([CH3:16])[CH3:15]
Reactant: [OH-]
Reactant: CC1(C)CC(OCC2CO2)CC(C)(C)N1O
Agent: [Na+]
Product: CC1(C)CC(OCC(O)CO)CC(C)(C)N1O

Procedure:
1.0 g of the compound of Example 3 is heated at 110° C. in 50 mL of 5% aqueous sodium hydroxide for six hours. The mixture is extracted with ethyl acetate, and the organic extract is dried and concentrated. The title compound is isolated as a red oil after column chromatography.
Reaction SMILES: [CH:1]1[S:5][CH:4]=[C:3]2[C:6](=[O:14])[C:7]3[C:8]([C:12](=[O:13])[C:2]=12)=[CH:9][S:10][CH:11]=3.S(=O)(=O)(O)O.[N-:20]=[N+]=[N-].[Na+]>C(Cl)Cl>[CH:1]1[S:5][CH:4]=[C:3]2[C:2]=1[C:12](=[O:13])[C:8]1=[CH:9][S:10][CH:11]=[C:7]1[C:6](=[O:14])[NH:20]2
Reactant: O=C1c2cscc2C(=O)c2cscc21
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1[nH]c2cscc2c(=O)c2cscc12
Temperature: 0 °C

Procedure:
30.4 g (138 mmoles) of 4,8-dihydro-benzo[1,2-c:4,5-c']dithiophene-4,8-dione are suspended in 200 ml of methylene chloride; 280 ml of concentrated sulfuric acid are then added dropwise, with ice-cooling and stirring. A total of 13.0 g (200 mmoles) of sodium azide is then introduced a little at a time into the well stirred reaction mixture at 0° C. over a period of 2 hours. The mixture is then stirred at room temperature for 8 to 10 hours. The reaction mixture is poured carefully into 3 l of ice-water, with thorough stirring, and the solid which precipitates after a short time is filtered off with suction. The crude product is washed with a large amount of water until it gives a neutral reaction, and is dried at 50° C. under reduced pressure.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Br:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:21][C:22]1[N:23]=[CH:24][N:25](COCC[Si](C)(C)C)[C:26]=1[C:27](O)=[O:28].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Br:19][C:17]1[CH:18]=[C:11]([O:10][C:5]2[C:4]([F:20])=[C:3]([CH2:2][NH:1][C:27]([C:26]3[NH:25][CH:24]=[N:23][C:22]=3[Cl:21])=[O:28])[CH:8]=[CH:7][C:6]=2[Cl:9])[CH:12]=[C:13]([C:14]#[N:15])[CH:16]=1
Reactant: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 74.4 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-bromobenzonitrile (0.193 g, 0.542 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.150 g, 0.542 mmol) and DIPEA (0.189 mL, 1.084 mmol) were combined in THF (2 mL) and treated with HATU (0.227 g, 0.596 mmol) at 25° C. overnight with stirring. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with water, dried over MgSO4, filtered and concentrated to dryness. The residue was dissolved in DCM (2.5 mL) and treated with TFA (2.5 mL) at 25° C. overnight. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to dryness. The resultant solid was recrystallized from EtOH, cooled in an ice bath and filtered to give N-({3-[(3-bromo-5-cyanophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1H-imidazole-5-carboxamide (0.195 g, 0.403 mmol, 74.3% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.18 (br. s., 1H), 8.26 (s, 1H), 7.93 (s, 1H), 7.78 (s, 1H), 7.46-7.60 (m, 3H), 7.37 (t, J=7.69 Hz, 1H), 4.53 (d, J=2.47 Hz, 2H). LC-MS (ES−) m/z 481.04, 483.07 [M−1]. LC-MS (ES+) m/z 482.94, 484.92 [M+H].
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8]COC)=[CH:6][N:5]=[C:4]([CH3:12])[CH:3]=1.Cl>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH3:12])[N:5]=[CH:6][C:7]=1[OH:8]
Reactant: COCOc1cnc(C)cc1Br
Agent: Cl
Solvent: CO
Product: Cc1cc(Br)c(O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
920 mg (3.05 mmol) 4-bromo-5-methoxymethoxy-2-methyl-pyridine (Stage 40.5) were dissolved in 5 mL MeOH, HCl conc. (1 mL, 12 mmol) was added and the reaction mixture was stirred for 2 h at rt. While concentrating the mixture in vacuo, the title compound (as hydrochloride) crystallized. Filtration afforded 570 mg white crystals. 1H-NMR (d6-DMSO, 400 MHz): 8.19 (s, 1H), 8.04 (s, 1H), 2.53 (s, 3H).
Reaction SMILES: [OH:1][C:2]1([C:29]2[S:33][C:32](S(C)(=O)=O)=[N:31][CH:30]=2)[CH2:7][CH2:6][CH:5]([N:8]2[CH2:11][CH:10]([NH:12][C:13]([CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[O:14])[CH2:9]2)[CH2:4][CH2:3]1.[CH3:38][C:39]([O-:42])([CH3:41])[CH3:40].[K+]>>[C:39]([O:42][C:32]1[S:33][C:29]([C:2]2([OH:1])[CH2:7][CH2:6][CH:5]([N:8]3[CH2:11][CH:10]([NH:12][C:13]([CH2:15][NH:16][C:17](=[O:28])[C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=4)=[O:14])[CH2:9]3)[CH2:4][CH2:3]2)=[CH:30][N:31]=1)([CH3:41])([CH3:40])[CH3:38]
Reactant: CC(C)(C)[O-]
Reactant: CS(=O)(=O)c1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1
Agent: [K+]
Product: CC(C)(C)Oc1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1

Procedure:
The title compound was prepared as a white solid from N-({1-[4-hydroxy-4-(2-methanesulfonyl-thiazol-5-yl)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide (less polar isomer, 47a), and t-BuOK (Aldrich, 1.0 N in THF) using the procedure described in Example 52.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH:10]1[CH:14](C(OCC)=O)[C:13](=[O:20])[C:12](=[O:21])[N:11]1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1.Cl.C(Cl)Cl.C([O-])(O)=O.[Na+]>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH:10]1[N:11]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:27][CH:28]=2)[C:12](=[O:21])[C:13](=[O:20])[CH2:14]1
Reactant: CCOC(=O)C1C(=O)C(=O)N(Cc2ccc(OC(F)(F)F)cc2)C1c1c(F)cccc1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cccc(F)c1C1CC(=O)C(=O)N1Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C

Procedure:
A solution of ethyl 2-(2-fluoro-6-methoxyphenyl)-4,5-dioxo-1-(4-(trifluoromethoxy)benzyl)pyrrolidine-3-carboxylate (2.937 g; 6.26 mmol) in dioxane (13 ml) was treated with 25% hydrochloric acid (13 ml). The resulting mixture was then refluxed, under nitrogen, for 11 h. After cooling to rt, DCM and aq. sat. NaHCO3 were added. The separated aqueous layer was further extracted with DCM. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 5-(2-fluoro-6-methoxyphenyl)-1-(4-(trifluoromethoxy)benzyl)pyrrolidine-2,3-dione which was used for the next step without additional purification. LC-MS (conditions A): tR=0.85 min.; [M+H]+: 397.99 g/mol.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=[O:11].[OH:12][CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15].[OH-].[Na+].OO.Cl>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[O:11][C:17]2[C:16]([C:14](=[O:15])[C:13]=1[OH:12])=[CH:21][CH:20]=[CH:19][CH:18]=2
Reactant: O=Cc1cc2ccccc2o1
Reactant: O=C(CO)c1ccccc1
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CO
Product: O=c1c(O)c(-c2cc3ccccc3o2)oc2ccccc12
Temperature: 12.5 °C
Reaction time: 24 h

Procedure:
To a three necked round bottomed flask, equipped with reflux condenser, calcium chloride guard tube and nitrogen inlet and magnetic stirrer, was charged methanol (200 ml), 2-benzofuranaldehyde (1.46 g) and 2-hydroxy acetophenone (1.36 g). The reaction mixture was cooled to 10-15° C. and sodium hydroxide (4 g) was added slowly and the reaction was stirred at room temperature (˜25° C.) for 24 hrs. Then methanol (200 ml) was added to the reaction and the reaction mixture was cooled below 15° C. and sodium hydroxide (4 g) and hydrogen peroxide (10 ml) were added to the reaction mixture and the reaction mixture was stirred for 6-8 hrs at room temperature. After this the reaction mixture was cooled to 10° C., neutralized using hydrochloric acid and the solid product that precipitated was filtered. The solid was washed with water till the filtrate is free of acid. The solid product was dried in oven at 70° C.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:13][CH:14]([C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][N:22]=[CH:23]2)[C:15](O)=[O:16].C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:15](=[O:16])[CH:14]([OH:13])[C:18]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:19]=2[CH:20]=[CH:21][N:22]=[CH:23]3)=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: O=C(O)C(O)c1cccc2cnccc12
Agent: O=C(O)Cc1cccc2cnccc12
Solvent: CO
Product: CC(C)(C)c1ccc(CNC(=O)C(O)c2cccc3cnccc23)cc1

Procedure:
The title compound was prepared using the procedure described in Example 222B using 4-(tert-butyl)benzylamine and hydroxy(5-isoquinolinyl)acetic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. [α]22D-47.2 (c 0.7, MeOH); MS (ESI+) m/z 349 (M+H)+; MS (ESI−) m/z 347 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.26 (s, 9H), 3.69 (s, 1H), 4.27 (d, J 6.1, 2H), 5.62 (s, 1H), 6.52 (br s, 1H), 7.17 (d, J 8.1, 2H), 7.29 (m, 3H), 7.67 (t, J 8.1, 1H), 7.82 (d, J 7.1, 1H), 8.10 (m, 2H), 8.44 (d, J 5.8, 1H), 8.71 (t, J 6.1, 1H), 9.30 (s, 1H); Anal. Calcd for C22H24N2O2+0.25 H2O: C, 74.87; H, 7.00; N, 7.94. Found: C, 75.22; H, 7.40; N, 7.80.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[CH3:6][O:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10]Cl>>[CH3:6][O:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][NH:1][CH2:2][CH2:3][CH2:4][OH:5]
Reactant: COc1ccccc1CCl
Reactant: NCCCO
Product: COc1ccccc1CNCCCO
Yield: 55.8 %

Procedure:
In a similar manner to Reference Example 23, 3-amino-1-propanol (27.0 g) was reacted with 2-methoxybenzylchloride (5.00 g) to obtain 3-(2-methoxybenzylamino)-1-propanol (3.48 g, 50%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[N:16]1([C:22]2[CH:23]=[C:24]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=2)[C:25](O)=[O:26])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[CH3:1][N:2]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[C:25](=[O:26])[C:24]1[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=[C:22]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:23]=1
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: O=C(O)c1cc(N2CCOCC2)cc(C(F)(F)F)c1
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(N2CCOCC2)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 3-morpholin-4-yl-5-trifluoromethyl-benzoic acid (CAS RN 250682-08-7) after a reaction time of 5 days. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 20:80). Colorless solid (12%). MS (ESI): m/z=456.188 [M+H]+.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][NH:7][C:8](=[O:17])[C:9]([CH2:14][O:15][CH3:16])([CH3:13])[CH2:10][O:11][CH3:12])C.CC1C=CC(S(O)(=O)=O)=CC=1.O>CC(C)=O>[CH3:16][O:15][CH2:14][C:9]([CH2:10][O:11][CH3:12])([CH3:13])[C:8]([NH:7][CH2:6][CH2:5][CH:4]=[O:3])=[O:17]
Reactant: CCOC(CCNC(=O)C(C)(COC)COC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: COCC(C)(COC)C(=O)NCCC=O
Temperature: 25 °C
Yield: 97.9 %

Procedure:
To a solution of 3 g of N-(3,3-diethoxy-propyl)-3-methoxy-2-methoxymethyl-2-methyl-propionamide in 71 mL of acetone was added 3.91 g of TsOH.H2O. The mixture was stirred over night at rt, quenched with sat.-NaHCO3 and extracted with DCM. The organic phase was washed with brine, dried over anh. Na2SO4 and concentrated in vacuo. The resulting crude material was purified by CC using heptane/EtOAc from 100/0 to 0/100 as eluant to yield 2.19 g of 3-methoxy-2-methoxymethyl-2-methyl-N-(3-oxo-propyl)-propionamide
Reaction SMILES: [Na].[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6][OH:7])[CH3:3].[C:10]([NH:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25](Cl)=[O:26])[CH2:21][CH2:20]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C1(C)C=CC=CC=1>[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6][O:7][C:25]([N:22]1[CH2:21][CH2:20][CH:19]([NH:18][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:24][CH2:23]1)=[O:26])[CH3:3]
Reactant: CCN(CC)CCO
Reactant: O=C(NC1CCN(C(=O)Cl)CC1)c1ccccc1
Agent: [Na]
Solvent: O
Solvent: Cc1ccccc1
Product: CCN(CC)CCOC(=O)N1CCC(NC(=O)c2ccccc2)CC1
Yield: 59.8 %

Procedure:
Sodium (0.432 g., 0.0188 mole) was added to β-diethylaminoethanol (2.23 g., 0.0190 mole) in dry toluene (80 ml) and the mixture was refluxed to give a complete solution. 4-Benzamidopiperidine-1-carbonyl chloride (4.2 g., 0.01575 mole) in suspension in dry toluene (150 ml.) was added in portions and the mixture refluxed for 21/2 hours. Water was added to the mixture, the toluene layer was collected, dried and evaporated to give the title compound (3.27 g. 37%), melting point 78°-82° C.
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]2[C:9](=[O:18])[C:10]3[C:15]([C:16](=[O:17])[C:6]=2[CH:5]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3)(=[O:3])[CH3:2].[C:19]([O:23][C:24]([NH:26][CH2:27][C:28](O)=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2C=CC=CC=2N=N1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.[Zn].C(OCC)(=O)C>[C:1]([C:4]1[O:8][C:7]2[C:9]([O:18][C:28](=[O:29])[CH2:27][NH:26][C:24]([O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:25])=[C:10]3[C:15](=[C:16]([OH:17])[C:6]=2[CH:5]=1)[CH:14]=[CH:13][CH:12]=[CH:11]3)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC(=O)c1cc2c(o1)C(=O)c1ccccc1C2=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1cc2c(O)c3ccccc3c(OC(=O)CNC(=O)OC(C)(C)C)c2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.4 %

Procedure:
In a 250 ml round-bottom flask, 2 grams (8.3 mmoles) of 2-acetyl-naphtho[2,3-b]furan-4,9-dione (prepared in example 2 or 3) was dissolved in 50 ml of DMF with heating. To the solution, added 3.5 ml of TEA, 2 grams of zinc powder, 0.3 gram of tetrabutylammonium bromide, 2.33 grams (13.3 mmoles) of [(tert-butoxycarbonyl)amino]acetic acid, 5.04 grams (13.3 mmoles) of N,N,N′,N′-Tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU) and 7.25 grams (41.7 mmoles) of sodium hydrosulfite. The mixture was sealed or isolated from air, and then had been stirred vigorously at room temperature overnight. After addition of 100 ml of ethyl acetate, the reaction mixture was filtered, and the solid was washed with 50 ml of ethyl acetate. The filtrates were combined, extracted with 100 ml of ice-cooled aqueous 3% citric acid solution twice, and dried with anhydrous sodium sulfate. The organic phase was evaporated to dryness. Product was purified by silica gel chromatograph using dichloromethane/ethyl acetate (4:1) as elution solvent. 1.64 gram (4.1 mmoles) of product was obtained with yield of 49.4% and characterized by 1H NMR and mass spectrum. 1H NMR (in DMSO) δ 1.44 (s, 9H), 2.59 (s, 3H), 4.28 (d, J=6, 2H), 7.49-7.65 (m, 3H), 7.97 (m, 1H), 8.20-8.35 (m, 2H), 11.4 (s, 1H). Mass (M+H) is 400, Mass [M-(tert-butyl)+2H] is 344.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:10])=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:11](O)(=O)[CH2:12][CH3:13].Cl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:11]([CH2:12][CH3:13])=[N:9][C:4]=2[C:3]=1[Cl:10]
Reactant: CCC(=O)O
Reactant: Nc1ccc(Br)c(Cl)c1N
Agent: Cl
Product: CCc1nc2c(Cl)c(Br)ccc2[nH]1
Temperature: 140 °C
Yield: 89 %

Procedure:
4-Bromo-3-chloro-1,2-benzenediamine (0.17 g, 0.766 mmol), propionic acid (0.17 g, 2.298 mmol), and 4 N HCl (1.724 ml, 6.894 mmol) were combined and heated to 140° C. for 3 h. Treatment with 1 N NaOH was followed by extraction with EtOAc (×3), and washing with brine. The dried (Na2SO4) organic portions were filtered, concentrated, and chromatographed (SiO2, MeOH/CH2Cl2) to obtain 0.177 g of the title compound: 1HNMR (400 MHz, CDCl3) δ 9.50 (broad s, 1H), 7.43 (d, J=8.31 Hz, 1H), 7.35 (broad s, 1H), 2.96 (q, J=7.5 Hz, 2H), 1.43 (t, J=7.5 Hz, 3H); MS (ESI) m/z 261 (M+1).