Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.Br[CH2:25][CH2:26][O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1>CN(C=O)C>[F:3][C:4]1[CH:9]=[C:8]([O:10][CH2:25][CH2:26][O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[CH:7]=[CH:6][C:5]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(O)cc2F)CC1
Reactant: BrCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(OCCOC3CCCCO3)cc2F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of NaH (21.3 mmol) in DMF (50 ml), 4-(2-fluoro-4-hydroxy-phenyl)-piperazine-1-carboxylic acid, tert.-butyl ester (17.8 mmol) is successively added at 0° C. To the mixture, 2-(2-bromoethoxy)-tetrahydro-2H-pyrane (24.9 mmol) is added at 0° C. and the mixture is stirred for 2 h at ambient temperature. The reaction mixture is quenched with ice-water and extracted with AcOEt. The combined extracts are washed with H2O, brine and dried over magnesium sulfate. Chromatography on silica gel using n-hexane, n-hexane:AcOEt=6:1, n-hexane:AcOEt=4:1 gives the desired 4-{2-fluoro-4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-piperazine-1-carboxylic acid, tert-butyl ester.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=3)[CH:12]=[CH:11][CH:10]=2)(O)[CH2:4][CH2:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[CH3:1][N:2]1[CH2:3][CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: CN1CCC(O)(c2cccc3ccc(O)cc23)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: CN1CC=C(c2cccc3ccc(O)cc23)CC1

Procedure:
A mixture of 1-(1-methyl-4-hydroxypiperidin-4-yl)-7-hydroxynaphthalene (7.64 g, 29.7 mmol) and p-toluenesulfonic acid (6.78 g, 35.7 mmol) in dioxane (250 mL) was refluxed overnight. The solvent was removed at reduced pressure and the residue was taken up in methylene chloride. The naphthol product was extracted from this organic phase with 1 N sodium hydroxide, 4 N sodium hydroxide and then 1 N sodium hydroxide. The combined basic aqueous phase was neutralized to pH 8 with saturated aqueous sodium bicarbonate and extracted with warm chloroform (3×, two phase mixture vigorously magnetically stirred while heat was applied by means of a hot plate.) The combined organic phase (still warm) was washed with brine, dried over calcium sulfate and concentrated to afford 5.01 g (83% for this step) of 1-(1-methyl-1,2,3,6-tetrahydropyrid-4-yl)-7-hydroxynaphthalene as a tan solid. A sample recrystallized from ethyl acetate had: mp 182.5-184° C.; 1HNMR (250 MHz, CDCl3) δ 9.15 (s, 1 H), 7.98 (d, J=2.5 Hz, 1 H), 7.69 (d, J=9 Hz, 1H), 7.65 (d, J=8 Hz, 1 H), 7.25-7.12 (m, 2 H), 7.03 (dd, J=2.5, 9 Hz, 1 H), 5.70 (sym m, 1 H), 3.32 (sym m, 2 H), 2.92 (t, J=6 Hz, 2 H), 2.70-2.60 (m, 2 H), 2.66 (s, 3 H). Analysis calculated for C16H17NO.0.25 H2O: C, 78.82; H, 7.23; N, 5.74. Found: C, 78.81; H, 7.21; N, 5.83.
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:19][F:20])[CH:8]=[C:7]([C:9](O)=[O:10])[C:6]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:5]=2[O:4]1.[C:21](N1C=CN=C1)([N:23]1C=CN=C1)=O.CN.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[F:1][CH2:2][C:3]1([CH2:19][F:20])[CH:8]=[C:7]([C:9]([NH:23][CH3:21])=[O:10])[C:6]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:5]=2[O:4]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)C1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Agent: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)C1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Reaction time: 14 h
Yield: 15.9 %

Procedure:
To a mixture of 0.78 g of 2,2-bis(fluoromethyl)-6-nitro-2H-1-benzopyran-4-carboxylic acid and 5 ml of tetrahydrofuran was added 0.67 g of 1,1'-carbonyldiimidazole with stirring under ice-cooling and the mixture was stirred for 1 hour. Then, 6.3 ml of 40% methylamine (methanol solution) was added therein. The resultant mixture was stirred under ice-cooling for 1 hour and then at room temperature for 14 hours. An aqueous potassium carbonate solution was added therein and the mixture was extracted with ether. An organic layer was washed with water and dried, and the solvent was distilled. The obtained residue was purified according to silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 0.13 g of 2,2-bis(fluoromethyl)-N-methyl-6-nitro-2H-1-benzopyran-4-carboxamide with a melting point of 178°-179° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][O:16][CH2:17][CH2:18][NH2:19]>CN(C=O)C>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([NH:19][CH2:18][CH2:17][O:16][CH3:15])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: COCCN
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: COCCNc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Yield: 81.4 %

Procedure:
4-(2-Methoxy-ethylamino)-3-nitro-benzoic acid methyl ester (960.0 mg) was prepared by following General Procedure A starting from methyl 4-chloro-3-nitrobenzoate (1.0 g) and 2-methoxy-ethylamine (413.0 mg) in DMF (10.0 mL). The crude product was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])[CH:14]=[CH:13][CH:12]=3)=O)C.[C:40]1([Li])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.CCOCC>O1CCCC1>[C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])[CH:14]=[CH:13][CH:12]=3)(=[O:3])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CCOC(=O)c1ncc2c(c1COC)c1c(Cc3ccccc3Cl)cccc1n2S(=O)(=O)c1ccc(C)cc1
Reactant: [Li]c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COCc1c(C(=O)c2ccccc2)ncc2[nH]c3cccc(Cc4ccccc4Cl)c3c12
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 16 %

Procedure:
To a solution of 1.2 g (0.0021 mol) of 5-(2-chlorobenzyl)-4-methoxymethyl-9-tosyl-β-carboline-3-carboxylic acid ethyl ester in 60 ml of absolute tetrahydrofuran is slowly added 2.4 ml of a 2-molar solution of phenyllithium in bezene/ether at -70° C. under argon protection. The reaction mixture is stirred for another 15 minutes at -70° C. then for 3 hours at room temperature and finally for one hour at 35° C. The it is concentrated by evaporation. The residue is taken up in 150 ml of ethyl acetate. The solution in succession is washed with citric acid solution, water, sodium bicarbonate solution, water, saturated common salt solution and once more with water, dried and concentrated by evaporation. After chromatography on silica gel with equal parts of toluene and ethyl acetate and recrystallization from ethanol, 0.15 g (16% of theory) of 3-benzoyl-5-(2-chlorobenzyl)-4-methoxymethyl-β-carboline is obtained, melting point 147°-148° C.
Reaction SMILES: CCN=C=NCCCN(C)C.OC(C(F)(F)F)=O.[NH2:19][CH2:20][C:21]([NH:23][CH:24]1[CH2:27][N:26]([CH:28]2[CH2:33][CH2:32][CH:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:30][CH2:29]2)[CH2:25]1)=[O:22].[F:40][C:41]1[CH:49]=[CH:48][C:47]([C:50]([F:53])([F:52])[F:51])=[CH:46][C:42]=1[C:43](O)=[O:44]>>[F:40][C:41]1[CH:49]=[CH:48][C:47]([C:50]([F:51])([F:52])[F:53])=[CH:46][C:42]=1[C:43]([NH:19][CH2:20][C:21](=[O:22])[NH:23][CH:24]1[CH2:27][N:26]([CH:28]2[CH2:33][CH2:32][CH:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:30][CH2:29]2)[CH2:25]1)=[O:44]
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1F
Reactant: NCC(=O)NC1CN(C2CCC(c3ccccc3)CC2)C1
Agent: CCN=C=NCCCN(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNC(=O)c1cc(C(F)(F)F)ccc1F)NC1CN(C2CCC(c3ccccc3)CC2)C1

Procedure:
The title compound was prepared as a white solid from the EDCI coupling of 2-amino-N-[1-(4-phenyl-cyclohexyl)-azetidin-3-yl]-acetamide TFA salt (as prepared in the previous step) and 2-fluoro-5-trifluoromethyl-benzoic acid (Aldrich) using the procedure described in Step F of Example 1.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([O:27][CH3:28])[CH:18]=2)=[C:11]([NH:29][C:30](=O)[C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][N:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)=[CH:33][CH:32]=2)[CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CC1C=CC=CC=1C>[Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]2[N:15]([CH2:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([O:27][CH3:28])[CH:18]=3)[C:30]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][N:40]4[CH2:41][CH2:42][CH2:43][CH2:44]4)=[CH:33][CH:32]=3)=[N:29][C:11]=2[CH:10]=1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(CNc2ccc(O[Si](C)(C)C(C)(C)C)cc2NC(=O)c2ccc(OCCN3CCCC3)cc2)cc1OC
Solvent: Cc1ccccc1C
Product: COC(=O)c1ccc(Cn2c(-c3ccc(OCCN4CCCC4)cc3)nc3cc(O[Si](C)(C)C(C)(C)C)ccc32)cc1OC
Yield: 80.8 %

Procedure:
To the above amide (Example 1, Part E; 3.95, 6.23 mmol) was added o-xylene (50 mL) and the mixture heated at reflux overnight. After concentrating under reduced pressure the resulting residue was purified by flash chromatography (SiO2, 5% MeOH in CHCl3 with 1% Et3N v/v added); yielding 3.1 g (82%) of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]2[NH:8][CH2:9][C:10]3([CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.Cl[C:17]1[C:26]2[C:21](=[C:22]([CH3:27])[CH:23]=[CH:24][CH:25]=2)[N:20]=[C:19]([CH3:28])[C:18]=1[CH3:29]>>[Br:1][C:2]1[CH:7]=[C:6]2[N:8]([C:17]3[C:26]4[C:21](=[C:22]([CH3:27])[CH:23]=[CH:24][CH:25]=4)[N:20]=[C:19]([CH3:28])[C:18]=3[CH3:29])[CH2:9][C:10]3([CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(c1)NCC21CCOCC1
Reactant: Cc1nc2c(C)cccc2c(Cl)c1C
Product: Cc1nc2c(C)cccc2c(N2CC3(CCOCC3)c3ccc(Br)cc32)c1C

Procedure:
Prepared according to procedure M using 6-bromo-2′,3′,5′,6′-tetrahydrospiro-[indoline-3,4′-pyran] (0.5 g, 1.86 mmol) and 4-chloro-2,3,8-trimethylquinoline (0.4219 g, 2.05 mmol) to give 6-bromo-1-(2,3,8-trimethylquinolin-4-yl)-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.52 (2H, dd, J=17.2, 7.4 Hz), 7.37 (1H, dd, J=8.2, 7.0 Hz), 7.20 (1H, d, J=7.8 Hz), 6.78 (1H, dd, J=7.8, 1.6 Hz), 5.82 (1H, d, J=2.0 Hz), 3.83-4.00 (4H, m), 3.39-3.54 (2H, m), 2.73 (3H, s), 2.71 (3H, s), 2.24 (3H, s), 1.92-2.10 (2H, m), 1.66-1.90 (2H, m); Mass Spectrum (ESI) m/e=437.0 [M+1 (79Br)] and 439.1 [M+1 (81Br)].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[CH2:11][C:10]([C:20]([C:26]([F:29])([F:28])[F:27])([C:22]([F:25])([F:24])[F:23])[OH:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][S:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.C(OCC)(=O)C.C(O)C>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:12]1[N:8]([C:4]2[CH:3]=[C:2]([C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([S:31][CH3:30])[CH:37]=3)[CH:7]=[CH:6][CH:5]=2)[N:9]=[C:10]([C:20]([C:26]([F:27])([F:29])[F:28])([C:22]([F:24])([F:25])[F:23])[OH:21])[CH2:11]1
Reactant: CSc1cccc(B(O)O)c1
Reactant: OC(C1=NN(c2cccc(Br)c2)C(c2ccccc2Cl)C1)(C(F)(F)F)C(F)(F)F
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: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CSc1cccc(-c2cccc(N3N=C(C(O)(C(F)(F)F)C(F)(F)F)CC3c3ccccc3Cl)c2)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 9.7 %

Procedure:
1-(3-Bromo-phenyl)-5-(2-chloro-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (50.0 mg, 0.10 mmol) prepared in Step 2 of Preparation 25, 3-methylthiophenylboronic acid (20.0 mg, 0.15 mmol), Pd(PPh3)4 (11.5 mg, 0.01 mmol), and a 2N sodium carbonate solution (0.5 mL) were added to a mixed solvent of 1,2-dimethoxyethane (2.0 mL) and ethanol (0.5 mL). The reaction mixture was stirred at 90° C. for 2 hours and then ethyl acetate was added thereto. The reaction mixture was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10) to give 5.3 mg of the titled compound as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:22]=[CH:21][C:14]([C:15]([NH:17][CH2:18][CH2:19][CH3:20])=[O:16])=[CH:13][C:12]=1[O:23][CH3:24].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:22]=[CH:21][C:14]([C:15]([NH:17][CH2:18][CH2:19][CH3:20])=[O:16])=[CH:13][C:12]=2[O:23][CH3:24])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: CCCNC(=O)c1ccc(N)c(OC)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCCNC(=O)c1ccc(Nc2nc(Cl)ncc2Cl)c(OC)c1

Procedure:
2,4,5-Trichloropyrimidine (1.0 g, 5.4 mmol), 4-amino-3-methoxy-N-propylbenzamide (778 mg, 3.74 mmol), and N,N-diisopropylethylamine (1.19 g, 9.21 mmol) were combined in isopropanol (40 mL) and reacted in a microwave (120° C.) for 5½ hours. The 4-(2,5-dichloropyrimidin-4-ylamino)-3-methoxy-N-propylbenzamide that formed as a yellow solid (1.33 g, 71%) was isolated by filtration. A small amount of this material (50 mg, 0.10 mmol) was combined with 7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (35 mg, 0.14 mmol) and 10-camphorsulfonic acid (36 mg, 0.15 mmol) in isopropanol (3 mL) to which had been added 0.05 mL water. The mixture was heated in a microwave (130° C.) for 3 hours and on cooling was concentrated. The organics were extracted into dichloromethane which was washed with saturated sodium bicarbonate solution and subsequently dried (sodium sulfate). Concentration followed by ISCO chromatography (gradient elution: 1 to 10% MeOH:dichloromethane) afforded 4-[5-Chloro-2-(7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-3-methoxy-N-propyl-benzamide as a white solid (58 mg, 70%). Mp: 193-7° C. (dec). LCMS (m/e) 565 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.58 (d, J=8 Hz, 1H), 8.11 (s, 1H), 8.05 (s, 1H), 7.50 (s, 1H), 7.35 (s, 1H), 7.31 (m, 1H), 7.25 (m, 1H), 7.10 (d, J=8 Hz, 1H), 6.96 (s, 1H), 6.11 (m, 1H), 4.03 (s, 3H), 3.72 (m, 4H), 3.48 (m, 2H), 2.86 (m, 2H), 2.70 (m, 2H), 2.57 (s, 4H), 2.10 (m, 2H), 1.68 (m, 3H), 1.47 (m, 2H), 1.03 (t. J=7 Hz, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][CH2:9][C:10]2[C:15]3=[N:16][CH:17]=[C:18]([C:21]#[N:22])[C:19](=[O:20])[N:14]3[CH:13]=[CH:12][CH:11]=2)=[C:6]([CH2:25][CH2:26][CH3:27])[C:5]=1[OH:28])(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[N-:33]=[N+:34]=[N-:35].[Na+].Cl>O1CCCC1>[C:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][CH2:9][C:10]2[C:15]3=[N:16][CH:17]=[C:18]([C:21]4[NH:35][N:34]=[N:33][N:22]=4)[C:19](=[O:20])[N:14]3[CH:13]=[CH:12][CH:11]=2)=[C:6]([CH2:25][CH2:26][CH3:27])[C:5]=1[OH:28])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1c(OCc2cccn3c(=O)c(C#N)cnc23)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCCc1c(OCc2cccn3c(=O)c(-c4nnn[nH]4)cnc23)ccc(C(C)=O)c1O
Temperature: 0 °C
Yield: 64.6 %

Procedure:
A mixture of l.00 g (2.65 mmoles) of 9-[(4-acetyl-3-hydroxy-2-n-propylphenoxy)methyl]-3-cyano-4H-pyrido[1,2-a]pyrimidin-4-one, 0.97 g (7.27 mmoles) of aluminum chloride, 1.43 g (21.99 mmoles) of sodium azide and 20 ml of tetrahydrofuran was heated under reflux for 2 hours. After cooling, the resulting reaction solution was diluted with ice water and then acidified with dilute hydrochloric acid. The precipitate so formed was collected by filtration and recrystallized from dimethyformamide to obtain 0.72 g (65% yield) of 9-[(4-acetyl-3-hydroxy-2-n-propylphenoxy)methyl]-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]-pyrimidin-4-one in the form of white crystals. These crystals had a melting point of 269°-271° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[O:9])=[CH:6][CH:5]=[C:4]([NH:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:3]=1.[C:24](Cl)(=[O:26])[CH3:25]>>[NH2:1][C:2]1[N:3]=[C:4]([NH:17][CH:18]2[CH2:19][CH2:20][N:21]([C:24](=[O:26])[CH3:25])[CH2:22][CH2:23]2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16]
Reactant: CC(=O)Cl
Reactant: Nc1nc(NC2CCNCC2)ccc1C(=O)c1ccccc1F
Product: CC(=O)N1CCC(Nc2ccc(C(=O)c3ccccc3F)c(N)n2)CC1

Procedure:
The title compound was prepared from [2-Amino-6-(piperidin-4-ylamino)-pyridin-3-yl]-(2-fluoro-phenyl)-methanone (Example 9) and acetyl chloride (Aldrich 98.5%) using the procedure described in Example 12. HRMS, observed: 356.1655, Calcd for M+: 356.1649.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][N:14]3C(=O)C4C(=CC=CC=4)C3=O)=[C:11]([CH3:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.FC1C=C(C2C(CN3C(=O)C4C(=CC=CC=4)C3=O)=C(C)ON=2)C=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][NH2:14])=[C:11]([CH3:25])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2ccc(F)cc2)c1CN1C(=O)c2ccccc2C1=O
Agent: Cc1onc(-c2cccc(F)c2)c1CN1C(=O)c2ccccc2C1=O
Product: Cc1onc(-c2ccc(F)cc2)c1CN
Yield: 53.9 %

Procedure:
As described for example 167b, 2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-isoindole-1,3-dione (5.9 mg, 18 mmol), instead of 2-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-isoindole-1,3-dione, was converted to the title compound (2.0 g, 54%) which was obtained as a light yellow oil. MS: m/e=190.3 [M+H]+.
Reaction SMILES: CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.Br[C:20]1[CH:21]=[N:22][CH:23]=[C:24]([C:27]#[C:28][CH3:29])[C:25]=1[CH3:26].C([O-])(=O)C.[K+].CC1C(B2OC(C)(C)C(C)(C)O2)=CN=CC=1C#CC.CC([PH+](C(C)(C)C)CCCS([O-])(=O)=O)(C)C.Br[C:71]1[CH:92]=[C:91]2[C:74]([CH2:75][C:76]3([C:84]42[N:88]=[C:87]([NH2:89])[C:86]([CH3:90])=[N:85]4)[CH2:81][CH2:80][CH:79]([O:82][CH3:83])[CH2:78][CH2:77]3)=[CH:73][CH:72]=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.[Na+].[Na+].Cl[Pd+2](Cl)(Cl)Cl.C(#N)C>[CH3:83][O:82][CH:79]1[CH2:80][CH2:81][C:76]2([C:84]3([N:88]=[C:87]([NH2:89])[C:86]([CH3:90])=[N:85]3)[C:91]3[C:74](=[CH:73][CH:72]=[C:71]([C:20]4[CH:21]=[N:22][CH:23]=[C:24]([C:27]#[C:28][CH3:29])[C:25]=4[CH3:26])[CH:92]=3)[CH2:75]2)[CH2:77][CH2:78]1
Reactant: COC1CCC2(CC1)Cc1ccc(Br)cc1C21N=C(C)C(N)=N1
Reactant: CC#Cc1cncc(Br)c1C
Agent: Cl[Pd]Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CC#N
Product: CC#Cc1cncc(-c2ccc3c(c2)C2(N=C(C)C(N)=N2)C2(CCC(OC)CC2)C3)c1C
Yield: 14.7 %

Procedure:
A suspension of 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (160 mg, 0.63 mmol), 3-bromo-4-methyl-5-(prop-1-ynyl)pyridine (Intermediate 45, 66 mg, 0.31 mmol) and potassium acetate (93 mg, 0.94 mmol) in dioxane (3 mL) was degassed with a stream of argon for a couple of min. PdCl2(dppf) CH2Cl2 (13 mg, 0.02 mmol) was added and the mixture was heated at reflux under N2 for 4 h. The mixture was allowed to cool, filtered and concentrated in vacuo. The obtained residue (80 mg, 4-methyl-3-(prop-1-ynyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine) was mixed with sodium tetrachloropalladate(II) (4 mg, 0.01 mmol), 3-(di-tert-butylphosphonium)propane sulfonate (6 mg, 0.02 mmol), and (1r,4r)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine (Example 19, 90 mg, 0.24 mmol) in dioxane (3 mL). The mixture was degassed with a stream of argon for a couple of min. and then heated at reflux. The reaction mixture was allowed to cool and the solvent was removed in vacuo. The residue was partitioned between water and EtOAc. The organic phase was dried (Na2SO4) and evaporated to give a crude product which was purified by flash chromatography (4 g SiO2, heptane-(EtOAc/MeOH/NH3 90:10:1) gradient. The obtained material was purified by preparative chromatography. Fractions containing the product were pooled and the organic solvent was removed in vacuo. The residue was partitioned between 1 M NaOH and EtOAc. The organic phase was dried (Na2SO4) and evaporated to give an oily residue which was solidified by co-evaporation with acetonitrile to give the title compound (15 mg, 15% yield) after drying in vacuo at 40° C.: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.98 (t, 1 H), 1.11-1.34 (m, 2 H), 1.34-1.57 (m, 3 H), 1.83 (d, 2 H), 2.13 (m, 9 H), 2.87-3.13 (m, 3 H), 3.20 (s, 3 H), 6.50 (d, 3 H), 7.18 (d, 1 H), 7.39 (d, 1 H), 8.16 (br. s., 1 H), 8.46 (br. s., 1 H); MS (APCI+) m/z 427 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[CH3:13][C:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[CH3:20][C:14]([O:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=3)[N:3]=2)=[CH:26][CH:27]=1)([CH3:13])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Product: CCOC(=O)C(C)(C)Oc1ccc(Oc2ccc3cc(Cl)ccc3n2)cc1

Procedure:
Ethyl 2-methyl-2-[4-(6-chloroquinolin-2-yloxy)phenoxy]-propionate (36) was prepared from 2,6-dichloroquinoline and ethyl 2-methyl-2-(4-hydroxyphenoxy)propionate following essentially the same procedure as that described in Example 1. The product was isolated after chromatography as a low melting point solid. Mass spectrum (m/e): 385 (parent ion; 30%); 312 (35%); 271 (100%); 270 (100).
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[CH:4][CH:3]=1.[CH3:7][C:8]([CH3:14])([CH3:13])[CH2:9][C:10](Cl)=[O:11].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[N+](C)([O-])=O>[Br:1][C:2]1[S:6][C:5]([C:10](=[O:11])[CH2:9][C:8]([CH3:14])([CH3:13])[CH3:7])=[CH:4][CH:3]=1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Brc1cccs1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C[N+](=O)[O-]
Product: CC(C)(C)CC(=O)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
Stir overnight at room temperature a mixture of 5-bromothiophene (1 g, 6.1 mmol), 3,3-dimethylbutyryl chloride (1.3 mL, 9.1 mmol) and ytterbium(III) trifluoromethanesulfonate (378 mg, 0.6 mmol) in nitromethane (15 mL). Wash the mixture sequentially with water, saturated aqueous NaHCO3 and water. Extract with chloroform, dry over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane to obtain the desired intermediate (1.3 g, 80%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)Br)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=1[O:23][CH2:24][C:25]([NH2:27])=[S:26]>C(#N)C.CO>[Cl:20][C:21]1[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=1[O:23][CH2:24][C:25]1[S:26][C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:27]=1
Reactant: NC(=S)COc1ccccc1Cl
Reactant: CSc1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Solvent: CC#N
Solvent: CO
Product: CSc1ccc(-c2sc(COc3ccccc3Cl)nc2-c2ccc(F)cc2)cc1
Temperature: 0 °C

Procedure:
A solution of 1-(4-fluorophenyl)-2-(4-methylthiophenyl)-2-bromo-ethanone (2.05 g, 6.04 mmol) (Example 1, Step 3) and 2-chlorophenoxy thioacetamide (1.21 g, 6.0 mmol) in 30 mL of acetonitrile was heated to reflux for 3 hours. The solution was diluted with methanol, cooled to 0° C. in an ice bath and a precipitate formed that was removed by filtration. The crude solid was further purified by flash chromatography over silica gel and the appropriate fractions were combined, concentrated in vacuo and crystallized from methanol to provide 2.60 g (98%) of pure 4-2- ((2 -chlorophenoxy) methyl)-4-(4-fluorophenyl)-5-(4-methylthiophenyl) thiazole: mp 126°-129° C., 1H NMR (CDCl3) 300 MHz 7.55-7.39 (m, 4H), 7.28-6.90 (m, 8H), 5.44 (s, 2H), 2.49 (s, 3H). 19F NMR (CDCl3) -114.00 (m). Mass spectrum M+H+ =442.