Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30].[OH-].[Na+]>O1CCCC1>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:27](=[O:28])[NH:26][C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[C:21]([C:29]([F:30])([F:31])[F:32])[CH:22]=3)=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc2c(c1)CCCN2Cc1ccccc1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Oc1ccc2c(c1)CCCN2Cc1ccccc1
Temperature: 35 °C
Reaction time: 14 h

Procedure:
A mixture of 1-benzyl-1, 2, 3, 4-tetrahydro-quinolin-6-ol (0.24 g., 1 mmol), 4-chloro-3-trifluoromethyl-phenyl isocyanate (0.265 g., 1 mmol), pulverized sodium hydroxide (0.044 g., 1 mmol) in dry tetrahydrofuran (20 ml) was stirred for 14 hours at room temperature (35° C.). The reaction mixture was concentrated under vaccum, diluted with water, extracted with chloroform and concentrated under vaccum. The residue was then chromatographed on silica gel using chloroform-hexane (30.70) as eluant to give 2k; yield: 0.20 g. (43.4%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][C:37]1[C:38]([CH:46]2[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH2:48][CH2:47]2)=[CH:39][C:40]([O:44][CH3:45])=[C:41]([CH:43]=1)[NH2:42].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C(F)(F)F.C[O-].[Na+]>C(Cl)Cl>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:41]3[CH:43]=[C:37]([CH3:36])[C:38]([CH:46]4[CH2:47][CH2:48][N:49]([CH2:52][CH2:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH2:50][CH2:51]4)=[CH:39][C:40]=3[O:44][CH3:45])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1cc(C2CCN(CCS(C)(=O)=O)CC2)c(C)cc1N
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: OCC(F)(F)F
Solvent: ClCCl
Product: COc1cc(C2CCN(CCS(C)(=O)=O)CC2)c(C)cc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 150 °C
Yield: 39.7 %

Procedure:
5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (200 mg, 0.41 mmol), 5-methyl-2-(methyloxy)-4-{1-[2-(methylsulfonyl)ethyl]-4-piperidinyl}aniline (120 mg, 0.37 mmol), and p-toluenesulfonic acid (186 mg, 0.98 mmol) were weighed into a 20 mL microwave vial. 7 mL of trifluoroethanol was added and the mixture was heated in the microwave to 150° C. for 2 h. The mixture was transferred to a 50 mL round bottom and neutralized with 2.5 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 2 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (115 mg, 0.147 mmol, 40%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.79 (s, 1H), 9.40 (d, J=6.97 Hz, 1H), 8.47 (s, 1H), 8.26 (d, J=5.13 Hz, 1H), 8.11 (d, J=2.57 Hz, 1H), 7.78 (dd, J=8.43, 2.20 Hz, 1H), 7.71 (d, J=8.80 Hz, 1H), 7.56 (s, 1H), 7.42-7.49 (m, 1H), 7.34-7.42 (m, 1H), 7.28 (d, J=8.80 Hz, 1H), 7.18 (t, J=8.07 Hz, 2H), 6.97 (t, J=6.97 Hz, 1H), 6.89 (s, 1H), 6.59 (d, J=5.13 Hz, 1H), 3.99 (s, 3H), 3.81 (s, 3H), 3.28-3.32 (m, 2H), 3.06 (s, 3H), 3.02 (d, J=11.36 Hz, 2H), 2.74 (t, J=6.97 Hz, 2H), 2.60-2.70 (m, 1H), 2.20 (s, 3H), 2.04-2.15 (m, 2H), 1.65-1.76 (m, 4H). MS (ESI): 782 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:7][C:8]=1[F:9].Br[CH2:19][CH2:20][OH:21]>C(O)CCC>[F:17][C:2]([F:16])([F:1])[C:3]1[CH:4]=[C:5]([N:10]2[CH2:11][CH2:12][N:13]([CH2:19][CH2:20][OH:21])[CH2:14][CH2:15]2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Fc1ccc(N2CCNCC2)cc1C(F)(F)F
Reactant: OCCBr
Solvent: CCCCO
Product: OCCN1CCN(c2ccc(F)c(C(F)(F)F)c2)CC1

Procedure:
10 g (0.04 mole) 4-(3-Trifluoromethyl-4-fluorophenyl)piperazine and 7 g (0.056 mole) 2-bromoethanol are heated under reflux for 4 hours in 60 ml n-butanol. The mixture is left to cool, filtered and then recrystallised from ethanol.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:17](=[O:19])[CH3:18])[C:12]([CH3:21])([CH3:20])[CH2:11][C:10]2([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22])=[O:6].O>O1CCOCC1.O>[C:17]([N:13]1[C:14]2[C:9](=[CH:8][C:7]([C:5]([OH:6])=[O:4])=[CH:16][CH:15]=2)[C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH3:22])[CH2:11][C:12]1([CH3:21])[CH3:20])(=[O:19])[CH3:18]
Reactant: COC(=O)c1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(C(=O)O)cc2C(C)(c2ccccc2)CC1(C)C
Reaction time: 18 h

Procedure:
A 2 M NaOH solution was added dropwise to a stirred solution of 1-acetyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline-6-carboxylic acid methyl ester (1.2 g) in dioxane/water 4:1 (v/v) (50 ml) until pH 12. After stirring for 18 h, the reaction mixture was poured into water and extracted with ethyl acetate at pH 2. The organic layer was washed with water and brine, dried (MgSO4) and concentrated in vacuo.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[C:30]([C:39]([F:42])([F:41])[F:40])[CH:29]=1>CC(N(C)C)=O>[CH:34]1([C:31]2[CH:32]=[CH:33][C:28]([CH2:27][O:1][C:2]3[CH:10]=[CH:9][C:8]4[NH:7][C:6]5[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=5[C:4]=4[CH:3]=3)=[CH:29][C:30]=2[C:39]([F:40])([F:41])[F:42])[CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(O)cc21
Reactant: FC(F)(F)c1cc(CCl)ccc1C1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 124.2 %

Procedure:
In a 2 L, 3-necked, round-bottomed flask under nitrogen atmosphere were placed ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (55.85 g, 215 mmol), cesium carbonate (84.2 g, 258 mmol), 4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (68 g, 259 mmol) in DMA (670 mL). The mixture was stirred 15 minutes at room temperature and heated at 50° C. overnight. The mixture was cooled down to room temperature and filtered. The filtrate was concentrated under vacuum. The residue was added hexanes (400 mL) and heated to 40° C. to give a dark solution. The solution was cooled down to room temperature over the weekend. The mixture was concentrated in vacuo and dried under vacuum to give the title compound (129.7 g). LCMS m/z=486.2.
Reaction SMILES: [CH:1]([C:3]1[CH2:4][CH2:5][CH2:6][O:7][CH:8]=1)=[CH2:2].[CH:9]([CH:11]=[CH2:12])=[O:10].O>C(Cl)Cl>[O:7]1[C@H:8]2[C:3](=[CH:1][CH2:2][CH2:12][C@H:11]2[CH:9]=[O:10])[CH2:4][CH2:5][CH2:6]1
Reactant: C=CC=O
Reactant: C=CC1=COCCC1
Solvent: ClCCl
Solvent: O
Product: O=C[C@@H]1CCC=C2CCCO[C@@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2.613 g 5-ethenyl-3,4-dihydro-2H-pyran and 8.9 mL acrolein (90% pure) was dissolved in 39 mL CH2Cl2 and stirred overnight at RT. The reaction was added to water and extracted with CH2Cl2. The crude extract was filtered, concentrated using a rotovap, then purified on silica gel to provide the title compound. 1H NMR (500 MHz, CDCl3) δ=1.64-1.98 (m, 5H), 2.04-2.16 (m, 1H), 2.23-2.29 (m, 1H), 2.34-2.38 (m, 1H), 2.60-2.64 (m, 1H), 3.55-3.61 in, 1H), 3.99-4.04 (m, 1H), 4.21 (d, J=5.6 Hz, 1H), 5.55 (s, 1H), 9.88 (s, 1H) ppm.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>O1CCCC1>[CH3:20][S:21]([O:1][CH:2]1[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 98.6 %

Procedure:
A mixture of tert-butyl 3-hydroxyazetidine-1-carboxylate (4.98 g, 28.7 mmol) and triethylamine (4.82 mL, 62.3 mmol) in tetrahydrofuran (75 mL) was cooled to 0° C. using an ice bath. Methanesulfonyl chloride (2.46 mL, 31.8 mmol) in tetrahydrofuran (12.5 mL) was added slowly to the reaction. Once the addition was complete, the ice bath was removed and the reaction was stirred at room temperature for 4 hours. Water (100 mL) was added to the reaction, and the mixture extracted with ethyl acetate (2×150 mL). The combined organic phase was washed with brine (2×100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a pale yellow oil (7.11 g, 98%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:14][N:5]2[C:6]3[C:11]([NH:12][CH2:13][C@@H:4]2[CH2:3]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[C:15]1([CH3:39])[CH:20]=[CH:19][C:18]([C:21]2[CH:38]=[CH:37][CH:36]=[CH:35][C:22]=2[C:23]([NH:25][C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)=[O:24])=[CH:17][CH:16]=1>>[OH:1][C@H:2]1[CH2:14][N:5]2[C:6]3[C:11]([N:12]([C:30](=[O:31])[C:29]4[CH:28]=[CH:27][C:26]([NH:25][C:23](=[O:24])[C:22]5[CH:35]=[CH:36][CH:37]=[CH:38][C:21]=5[C:18]5[CH:17]=[CH:16][C:15]([CH3:39])=[CH:20][CH:19]=5)=[CH:34][CH:33]=4)[CH2:13][C@@H:4]2[CH2:3]1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)O)cc2)cc1
Reactant: O[C@@H]1C[C@H]2CNc3ccccc3N2C1
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N3C[C@@H]4C[C@@H](O)CN4c4ccccc43)cc2)cc1
Yield: 55 %

Procedure:
The same procedures used in Example 1 were repeated using (2R, 3aS)-2-hydroxy-1,2,3,3a,4,5-hexahydro-pyrrolo[1,2-a]quinoxaline prepared in Reference Example 16 and 4-[[2-(4-tolyl)benzoyl]amino]benzoic acid to give the title compound after recrystallization from ethyl acetate-hexane. m.p.: 163-164.5° C.; Yield 55.0%.
Reaction SMILES: [C:1]([C:4]1[NH:8][N:7]=[C:6]([O:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:5]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26])(=O)[CH3:2].[F:27][C:28]1[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=1[C:30]([NH:32][NH2:33])=O>C1(C)C(C)=CC=CC=1>[F:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:5]1[C:6]([O:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[N:7][N:8]2[C:4]=1[C:1]([CH3:2])=[N:33][N:32]=[C:30]2[C:29]1[CH:34]=[CH:35][CH:36]=[CH:37][C:28]=1[F:27]
Reactant: NNC(=O)c1ccccc1F
Reactant: CC(=O)c1[nH]nc(OS(=O)(=O)c2ccc(C)cc2)c1-c1ccccc1F
Solvent: Cc1ccccc1C
Product: Cc1ccc(S(=O)(=O)Oc2nn3c(-c4ccccc4F)nnc(C)c3c2-c2ccccc2F)cc1
Temperature: 180 °C

Procedure:
Toluene-4-sulfonic acid 5-acetyl-4-(2-fluorophenyl)-1H-pyrazol-3-yl ester (8.26 g, 22.1 mmol) and 2-fluorobenzhydrazide (3.86 g, 25.0 mmol) were stirred together in xylene (250 ml) at reflux overnight. The solvent was removed in vacuo, and the residue was heated in Dowtherm A at 180° C. for 2 h. The mixture was poured directly onto a column of silica gel, and the Dowtherm was eluted off with dichloromethane before eluting the product off with 10% ethyl acetate in dichloromethane (UV detection). Toluene-4-sulfonic acid 3,7-bis(2-fluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester was obtained as a yellow solid (6.62 g). 1H NMR (400 MHz, CDCl3) δ 2.43 (3H, s), 2.53 (3H, s), 7.17-7.37 (6H, m), 7.41-7.51 (2H, m), 7.63 (1H, m), 7.69 (3H, m); MS (ES+) m/e 493 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([C:13](O)=[O:14])[CH:7]=[CH:8][CH:9]=2)[O:4][C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[N:35]1([CH:41]([CH3:44])[CH2:42][NH2:43])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>O1CCCC1>[N:35]1([CH:41]([CH3:44])[CH2:42][NH:43][C:13]([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[O:4][C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:2]([CH3:1])[C:11]3=[O:12])=[O:14])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: Cc1c(-c2ccccc2)oc2c(C(=O)O)cccc2c1=O
Reactant: CC(CN)N1CCCCC1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)oc2c(C(=O)NCC(C)N3CCCCC3)cccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To a solution of 4.00 g of 3-methylflavone-8-carboxylic acid and 1.98 ml of triethylamine in 74 ml of anhydrous tetrahydrofuran was added a solution of 1.50 ml of ethyl chlorocarbonate in 15 ml of anhydrous tetrahydrofuran under ice-cooling and the mixture was stirred for 1 hour. To the mixture, a solution of 2.03 g of 2-piperidinopropylamine in 20 ml of anhydrous tetrahydrofuran was added and the mixture was stirred for 1.5 hours under ice-cooling and further at room temperature for 16 hours. The reaction mixture was treated by the same procedure as in Examples 3(b) to give 4.15 g of colorless crystals, which were recrystallized from ethyl acetate as colorless needles, m.p. 106.5°-108.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21]Br)[CH:7]=1)[CH3:2].[CH3:24][C@H:25]1[C@@H:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:28][C:27](=[O:36])[NH:26]1>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][N:26]2[C@H:25]([CH3:24])[C@@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:28][C:27]2=[O:36])[CH:7]=1)[CH3:2]
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1
Reactant: CCOC(=O)Cc1ccc(Cl)c(Oc2ccc(Br)cc2CBr)c1
Product: CCOC(=O)Cc1ccc(Cl)c(Oc2ccc(Br)cc2CN2C(=O)O[C@H](c3ccccc3)[C@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 24, Step 7, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-4-chloro-phenyl]-acetic acid ethyl ester and (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N:9]([CH2:13][CH2:14][OH:15])[CH2:10][CH2:11]O)[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N:9]2[CH2:10][CH2:11][O:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: OCCN(CCO)c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Oc1ccc(Br)cc1N1CCOCC1
Temperature: 160 °C

Procedure:
4-Bromo-2-bis(2-hydroxyethyl)aminophenol (2.5g) was dissolved in 70% sulphuric acid (25 ml) and the solution heated to 160° C for three hours, allowed to cool, then neutralised with saturated sodium carbonate solution. Extraction with ether and evaporation of the extracts gave crude 4-bromo-2-morpholinophenol which was crystallised from ether gave the pure phenol (1.4g, 60%, m.p. 128° C).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([N:20]3[CH2:25][CH2:24][CH:23]([N:26]4[C:35](=[O:36])[C:34]5[C:29](=[CH:30][CH:31]=[C:32]([CH3:37])[CH:33]=5)[N:28]([CH3:38])[C:27]4=[O:39])[CH2:22][CH2:21]3)=[N:9][C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:11]2)=[CH:6][C:5]=1[OH:40])[CH3:2].Br[CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44]>>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([N:20]3[CH2:25][CH2:24][CH:23]([N:26]4[C:35](=[O:36])[C:34]5[C:29](=[CH:30][CH:31]=[C:32]([CH3:37])[CH:33]=5)[N:28]([CH3:38])[C:27]4=[O:39])[CH2:22][CH2:21]3)=[N:9][C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:11]2)=[CH:6][C:5]=1[O:40][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH3:2]
Reactant: CCOc1cc2nc(N3CCOCC3)nc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1O
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)nc(N3CCOCC3)nc2cc1OCC
Yield: 64 %

Procedure:
The same procedure as in Example 48 was repeated, except that 290 mg (0.53 mmol) of Compound 59 obtained in Example 59 was used in place of Compound 47 obtained in Example 47, and ethyl bromoacetate was used in place of methyl iodide, to give 216 mg (yield: 64%) of Compound 60 as white crystals.
Reaction SMILES: Cl.O1CCOCC1.C(O[C:13](=O)[N:14](C)[CH2:15][C:16]#[C:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1)(C)(C)C>ClCCl>[CH3:13][NH:14][CH2:15][C:16]#[C:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:20][CH:19]=1
Reactant: CN(CC#Cc1ccc(OC(F)(F)F)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNCC#Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
A 4 M solution of HCl in dioxane (330 μl, 1 mmol) was added at ambient temperature to a solution of methyl-[3-(4-trifluoromethoxy-phenyl)-prop-2-ynyl]-carbamic acid tert-butyl ester (50 mg, 0.15 mmol) in dichloromethane (0.5 ml). The reaction mixture was stirred for 3 h at ambient temperature. The solvent was removed under reduced pressure and the residue crystallized from dichloromethane/heptane to yield 20 mg (90 μmol, 57%) of the title compound as brown crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([C:29]3[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=3)[C:22]3[C:17](=[CH:18][C:19]([OH:43])=[C:20]([O:41][CH3:42])[CH:21]=3)[C:16]2=[O:44])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu](I)I>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([C:29]3[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=3)[C:22]3[C:17](=[CH:18][C:19]([O:43][C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=4)=[C:20]([O:41][CH3:42])[CH:21]=3)[C:16]2=[O:44])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2cc(OC)c(O)cc2c(=O)n1-c1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: Brc1ccccn1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2cc(OC)c(Oc3ccccn3)cc2c(=O)n1-c1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A suspension of the compound obtained in Example 5 (300 mg), 2-bromopyridine (57 μl), copper iodide (113 mg) and potassium carbonate (82 mg) in dimethylformamide (5 μl) is heated with stirring at 80° C. for five hours. After the reaction is complete, the reaction mixture is extracted with ethyl acetate. The extract is washed with aqueous ammonia, and further washed with water, dried, and concentrated under reduced pressure. The residue is purified by Chromatotron (solvent; hexane:ethyl acetate=1:1) to give 2-[4-(tert-butoxycarbonylamino)phenyl]-6-methoxy-3-methoxycarbonyl-7-(2-pyridyloxy)-4-(3,4,5-trimethoxyphenyl)-1(2H)-isoquinolinone (40 rag) as listed in Table 20.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:8][NH:7][C@H:6]([C:9]([OH:11])=O)[C@@H:5]([C:12]([O:14][CH3:15])=[O:13])[CH2:4]1.[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[CH3:1][O:2][C@@H:3]1[CH2:8][NH:7][C@H:6]([C:9]([N:25]2[CH2:26][CH2:27][N:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][CH2:24]2)=[O:11])[C@@H:5]([C:12]([O:14][CH3:15])=[O:13])[CH2:4]1
Reactant: COC(=O)[C@H]1C[C@H](OC)CN[C@@H]1C(=O)O
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1C[C@H](OC)CN[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (2S,3S,5S)-5-methoxy-3-(methoxycarbonyl)piperidine-2-carboxylic acid (14.0 mg, 0.0000644 mol), 1-phenyl-piperazine (0.01231 mL, 8.056E-5 mol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (35.63 mg, 8.056E-5 mol) in N,N-dimethylformamide (0.20 mL, 0.0026 mol)was added N,N-diisopropylethylamine (0.01403 mL, 8.056E-5 mol). The mixture was stirred at rt for 2 h. After quenched with water, the mixture was extracted with ethyl acetate. The combine organic layers were washed with brine, dried and concentrated to dry. The residue was used directly in next step without further purification. MS (ESI): (M+H)+=362.1.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[CH3:12][C:13]1([CH3:29])[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15](OS(C(F)(F)F)(=O)=O)=[CH:14]1>>[CH3:12][C:13]1([CH3:29])[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][CH:15]([C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)[CH2:14]1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC1(C)C=C(OS(=O)(=O)C(F)(F)F)CC(C)(C)C1
Product: CC1(C)CC(c2ccc(O)cc2)CC(C)(C)C1

Procedure:
The title compound was prepared from 4-methoxy-benzeneboronic acid and trifluoro-methanesulfonic acid 3,3,5,5-tetramethyl-cyclohex-1-enyl ester in accordance with the procedure described in Step 1, Example 86.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9].C(N(CC)C(C)C)(C)C.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH2:38][CH:37]([C:41](O)=[O:42])[CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].ON1C2C=CC=CC=2N=N1>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:41]([CH:37]3[CH2:38][CH2:39][CH2:40][N:35]([C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])[CH2:36]3)=[O:42])[CH2:15][CH2:14]2)=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCNCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a mixture of N-(3,4-dichlorophenyl)piperazine-1-carboxamide hydrochloride (1.0 g) in dichloromethane (100 mL) was added N,N-di-iso-propylethylamine (0.56 mL) at room temperature. After 10 minutes N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide (617 mg) was added followed by 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (671 mg) and 1-hydroxybenzotriazole (435 mg). The reaction was stirred overnight at room temperature. The reaction mixture was partitioned between dichloromethane and water and the organic layer was washed with brine. The organic extract was dried over magnesium sulfate and evaporated. The residue was purified by silica column chromatography, eluting with a gradient of 0 to 15% ethyl acetate in hexane to give the title compound as a white foam (1.4 g, 99%).
Reaction SMILES: Cl[C:2]1[C:3]([C:11]([OH:13])=[O:12])=[CH:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].[Cl:14][C:15]1[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][C:16]=1[NH2:17]>>[Cl:14][C:15]1[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][C:16]=1[NH:17][C:2]1[C:3]([C:11]([OH:13])=[O:12])=[CH:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)c(C(=O)O)cn(C)c1=O
Reactant: Nc1ccc(I)cc1Cl
Product: Cc1c(Nc2ccc(I)cc2Cl)c(C(=O)O)cn(C)c1=O

Procedure:
The title compound is prepared from 4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid by the procedure described in step e for Example 5, using 2-chloro-4-iodoaniline instead of 2-fluoro-4-iodoaniline. The title compound is used for the next reaction without further purification.