Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=4)(O)[C:20]4[N:21]([CH3:25])[CH:22]=[N:23][CH:24]=4)[CH:17]=3)[N:12]([CH3:34])[C:11](=[O:35])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH:42]1([NH2:45])[CH2:44][CH2:43]1>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=4)([NH:45][CH:42]4[CH2:44][CH2:43]4)[C:20]4[N:21]([CH3:25])[CH:22]=[N:23][CH:24]=4)[CH:17]=3)[N:12]([CH3:34])[C:11](=[O:35])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Cn1cncc1C(O)(c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C)c1ccc(Cl)cn1
Reactant: NC1CC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cncc1C(NC1CC1)(c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C)c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 32.1 %

Procedure:
For the formation of the correspondent chloride, the same procedure was used as that in example 2, except that 4-(3-chloro-phenyl)-6-[(5-chloro-pyridin-2-yl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-methyl-1H-quinolin-2-one (55 mg, 0.112 mmol) was used in the place of 4-(3-chloro-phenyl)-6-[(6-chloro-pyridin-3-yl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1H-quinolin-2-one. The obtained chloride was dissolved in DMF (8 ml). To this solution were added potassium carbonate (K2CO3) and cyclopropylamine (0.049 ml, 0.786 mmol). The reaction mixture was stirred at ambient temperature for 15 hours after which time it was partitioned between CHCl3 and water. The organic layer was washed with brine, dried over MgSO4 and concentrated under vacuum to give the crude product. It was chromatographed on silica gel with MeOH-CHCl3—NH4OH (2:98:0.2 to 5:95:0.5) as eluents to afford the title compound as a white solid (19 mg, 0.036 mmol, 32% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)[CH:5]=[CH:4][C:3]=1[OH:17].Cl[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([B:8]2[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH3:16])([CH3:15])[O:9]2)[CH:5]=[CH:4][C:3]=1[O:17][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: ClCc1ccccn1
Reactant: CC1(C)OB(c2ccc(O)c(F)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)OB(c2ccc(OCc3ccccn3)c(F)c2)OC1(C)C

Procedure:
2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1 equivalent), 2-(chloromethyl)pyridine (1.1 equivalent), K2CO3 (3 equivalents), and KI (0.1 equivalents) are refluxed in acetone overnight. The mixture is cooled, filtered, the filtrate is concentrated and purified by column chromatography.
Reaction SMILES: Br[CH2:2][C:3]#[C:4][CH2:5][CH3:6].[O:7]=[CH:8][C:9]1[CH:17]=[CH:16][C:14]([OH:15])=[C:11]([O:12][CH3:13])[CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:13][O:12][C:11]1[CH:10]=[C:9]([CH:17]=[CH:16][C:14]=1[O:15][CH2:2][C:3]#[C:4][CH2:5][CH3:6])[CH:8]=[O:7]
Reactant: CCC#CCBr
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC#CCOc1ccc(C=O)cc1OC
Yield: 83.3 %

Procedure:
1-Bromopent-2-yne (0.67 mL, 6.6 mmol) was added to a suspension of vanillin (0.50 g, 3.3 mmol) and potassium carbonate (1.37 g, 9.85 mmol) in acetone (5.0 mL) and treated according to Procedure 3. 3-Methoxy-4-(pent-2-ynyloxy)benzaldehyde (0.60 g, 84%) was obtained as a yellow crystalline solid; mp 47-50° C.; δH (400 MHz, CDCl3) 1.11 (t, J=7.6 Hz, 2H, CH2CH3), 2.20 (tq, J=7.6, 2.4 Hz, 3H, CH2CH3), 3.93 (s, 3H, OCH3), 4.83 (t, J=2.4 Hz, 2H, OCH2), 7.13 (d, J5,6=8.0 Hz, 1H, H5), 7.42 (s, 1H, H2), 7.45 (d, J5,6=8.0 Hz, H6), 9.86 (s, 1H, CHO); δC (100 MHz, CDCl3) 12.5, 13.4, 56.0, 57.3, 73.1, 90.7, 109.2, 112.3, 126.4, 130.5, 149.9, 152.5, 190.9; vmax 997, 1136, 1263, 1508, 1586, 1682, 2230, 2298, 2845, 2932 cm−1.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+]>[Fe].C(O)C.O>[N:15]1([CH2:14][CH2:13][N:10]2[C:11]3[C:7](=[CH:6][CH:5]=[C:4]([NH2:1])[CH:12]=3)[CH:8]=[N:9]2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1ccc2cnn(CCN3CCCC3)c2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc2cnn(CCN3CCCC3)c2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 6-nitro-1-(2-pyrrolidin-1-yl-ethyl)-1H-indazole (1.60 g, 6.15 mmol), iron powder (3.40 g, 60.8 mmol), and ammonium chloride (166 mg, 3.13 mmol) in a 4:1 solution of ethanol/H2O was heated to reflux for 3 hours, cooled to room temperature, concentrated under reduced pressure. The residue was stirred in triethylamine/ethyl acetate (1/4, 30 mL) for 15 minutes, filtered through a plug of silica gel which was rinsed with triethylamine/ethyl acetate (1/4), and the filtrate was concentrated under reduced pressure to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.66 (m, 4H), 2.50 (m, 4H), 2.85 (t, 2H, J=6.78), 4.27 (t, 2H, J=6.78), 5.30 (s, 2H), 6.49 (m, 2H), 7.35 (m, 1H), 7.70 (m, 1H); MS (DCI/NH3) m/z 231 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[C:6]([N:12]3[CH2:16][CH2:15][CH2:14][C:13]3=[O:17])[CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[C:3]1=[O:24].[C:25]([O:29][C:30]([NH:32][C@H:33]([CH2:37][C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]([CH2:47][CH2:48][CH3:49])[CH:39]=1)[C:34](O)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[O:35]=[C:34]([NH:1][CH:2]1[CH2:11][C:10]2[C:5](=[C:6]([N:12]3[CH2:16][CH2:15][CH2:14][C:13]3=[O:17])[CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[C:3]1=[O:24])[C@H:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:37][C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]([CH2:47][CH2:48][CH3:49])[CH:39]=1
Reactant: NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Reactant: CCCn1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)c2ccccc21
Product: CCCn1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)NC2Cc3cccc(N4CCCC4=O)c3N(Cc3ccsc3)C2=O)c2ccccc21
Yield: 107 %

Procedure:
The procedure of Example 14(a) was repeated, except that (−)-3-amino-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-3,4-dihydroquinolin-2(1H)-one (500 mg) and (R)-2-(tert-butoxycarbonylamino)-3-(1-propyl-1H-indol-3-yl)propanoic acid (641 mg) synthesized in Referential Example 1(d) were used, whereby the title compound (1.05 g) was yielded.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([C:15]([CH2:26][CH3:27])([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH3:25])[CH:19]=3)[CH2:16][CH3:17])[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2].Br[CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:20]([CH3:25])[CH:19]=3)([CH2:26][CH3:27])[CH2:16][CH3:17])[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(C(CC)(CC)c3ccc(O)c(C)c3)cc2s1
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc2ccc(C(CC)(CC)c3ccc(OCC(=O)C(C)(C)C)c(C)c3)cc2s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.8 %

Procedure:
A solution of 6-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-benzo[b]thiophene-2-carboxylic acid ethyl ester (0.780 g, 2.04 mmol) and 1-bromopinacolone (0.731 g, 4.08 mmol) in acetone (30 mL) is treated with K2CO3 (0.563 g, 4.08 mmol) and stirred at RT for 4 h. The mixture is filtered, and the filtrate is concentrated. The residue is purified using silica gel column chromatography (10-15% EtOAc/Hex) to provide the title compound (0.89 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([OH:16])=[O:15].[C:20]([CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:25]=1)O)#[CH:21]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([O:16][CH:22]([C:20]#[CH:21])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:25]=1)=[O:15]
Reactant: C#CC(O)c1cccc(Oc2ccccc2)n1
Reactant: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O
Product: C#CC(OC(=O)C(Nc1ccc(C(F)(F)F)cc1Cl)C(C)C)c1cccc(Oc2ccccc2)n1

Procedure:
Following the procedure of Example 11, 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoic acid is reacted with α-ethynyl(6-phenoxy-2-pyridyl)methanol to yield the ester, α-ethynyl(6-phenoxy-2-pyridyl)methyl 2-(2-chloro-4-trifluoromethylphenyl-amino)-3-methylbutanoate, MS m/e 502 (M+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[C:4]([Cl:11])[N:3]=1.[CH2:12]([NH2:14])[CH3:13]>CC(C)=O>[Cl:11][C:4]1[C:5]([C:9]#[N:10])=[C:6]([Cl:8])[N:7]=[C:2]([NH:14][CH2:12][CH3:13])[N:3]=1
Reactant: CCN
Reactant: N#Cc1c(Cl)nc(Cl)nc1Cl
Solvent: CC(C)=O
Product: CCNc1nc(Cl)c(C#N)c(Cl)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred solution of 12.9 grams of 2,4,6-trichloro-5-pyrimidinecarbonitrile in 150 ml of acetone was cooled to -10°, and 7.7 grams of an aqueous 70% ethylamine solution was added dropwise during 2 hours. The temperature of the reaction mixture was maintained at -10° throughout the addition. Following complete addition, the reaction mixture was allowed to warm to room temperature, where it stood for 16 hours. Then most of the acetone was removed by evaporation under reduced pressure. The residue was extracted with a mixture of water and diethyl ether. The ether layer was separated and dried over magnesium sulfate. The dried ether layer was filtered, and the ether was removed under reduced pressure. The residue was recrystallized from a mixture of methylcyclohexane and benzene, then from carbon tetrachloride, to give 4.2 grams of 4,6-dichloro-2-ethylamino-5-pyrimidinecarbonitrile; mp, 145-150°.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[C:11]([C:12]3[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=3)=[N:10][CH:9]=[CH:8][N:7]=2)[CH2:3]1.Cl[C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[C:14]1([CH3:18])[CH:15]=[CH:16][CH:17]=[C:12]([C:11]2[C:6]([CH:4]3[CH2:5][N:2]([C:20]4[CH:29]=[CH:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]=4)[CH2:3]3)=[N:7][CH:8]=[CH:9][N:10]=2)[CH:13]=1
Reactant: Cc1cccc(-c2nccnc2C2CNC2)c1
Reactant: Clc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(-c2nccnc2C2CN(c3ccc4ccccc4n3)C2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 260 %

Procedure:
To a solution of 2-azetidin-3-yl-3-m-tolyl-pyrazine hydrochloride (131 mg, 0.05 mmol) and 2-chloro-quinoline (82 mg, 0.05 mmol) in DMF (10 mL) was added Cs2CO3 (325 mg, 1.0 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was diluted with water, extracted with EtOAc (30 mL×2). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 40% EtOAc in petroleum ether) to give 2-[3-(3-m-tolyl-pyrazin-2-yl)-azetidin-1-yl]-quinoline (44 mg, 0.13 mmol, 25%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][C:17]=1[CH:18]=[O:19].[CH2:29]([Mg]Br)[CH3:30].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:27])([F:28])[F:26])=[CH:20][C:17]=1[CH:18]([OH:19])[CH2:29][CH3:30]
Reactant: CC[Mg]Br
Reactant: COc1cc2nccc(Oc3ccc(OC(F)(F)F)cc3C=O)c2cc1OC
Solvent: C1CCOC1
Solvent: O
Product: CCC(O)c1cc(OC(F)(F)F)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-trifluoromethoxybenz-aldehyde was dissolved in anhydrous tetrahydrofuran (1 ml) to prepare a solution. A 1 M tetrahydrofuran solution (0.5 ml) of ethylmagnesium bromide was added to the solution at 0° C., and the mixture was stirred at 0° C. for one hr. Water (1 ml) was added dropwise to the reaction solution to stop the reaction. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure to give 1-{2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-(trifluoromethoxy)phenyl}-1-propanol.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11]3[C:12]4[CH:32]=[CH:31][NH:30][C:13]=4[N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)=[CH:20][CH:19]=4)[N:16]=3)[CH:8]=2)[CH:3]=[N:2]1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11]3[C:12]4[CH:32]=[CH:31][NH:30][C:13]=4[N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH2:25][CH2:26][N:27]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:28][CH2:29]5)=[CH:20][CH:19]=4)[N:16]=3)[CH:8]=2)[CH:3]=[N:2]1
Reactant: c1cc2c(Nc3ccc4cn[nH]c4c3)nc(Nc3ccc(N4CCNCC4)cc3)nc2[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2ccc(Nc3nc(Nc4ccc5cn[nH]c5c4)c4cc[nH]c4n3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.9 %

Procedure:
To a suspension of N4-(1H-indazol-6-yl)-N2-(4-(piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (9 mg, 0.021 mmol) and triethylamine (TEA) (0.010 mL, 0.072 mmol) in CH2Cl2 (1 mL) at room temperature, methanesulfonyl chloride (MeSO2Cl) (0.006 mL, 0.077 mmol) was added. After being stirred at room temperature for 3 h, the mixture was concentrated in vacuo. The residue was purified by HPLC to give N4-(1H-indazol-6-yl)-N2-(4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (2 mg), MS 504.3 (M+H) (Compound 8-1); and N4-(1-(methylsulfonyl)-1H-indazol-6-yl)-N2-(4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (1 mg), MS 582.4 (M+H) (Compound 8-2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]([CH3:25])[C:12]([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=1)([OH:17])[C:13]([F:16])([F:15])[F:14])[C:5](O)=[O:6].[CH2:26]([O:28][C:29]([C:31]1[N:32]=[C:33]([NH2:36])[O:34][CH:35]=1)=[O:30])[CH3:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH2:26]([O:28][C:29]([C:31]1[N:32]=[C:33]([NH:36][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][C:10]([CH:11]([CH3:25])[C:12]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=3)([OH:17])[C:13]([F:14])([F:15])[F:16])=[C:2]([Cl:1])[CH:3]=2)[O:34][CH:35]=1)=[O:30])[CH3:27]
Reactant: CCOC(=O)c1coc(N)n1
Reactant: CC(c1ccc(C(=O)O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CCOC(=O)c1coc(NC(=O)c2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)n1

Procedure:
In analogy to Example 26, step 4, 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-benzoic acid (Example 26, step 3), was reacted with 2-aminooxazol-4-carboxylic acid ethylester and HBTU at r.t. 17 h to give the title compound as a white solid. MS (m/e)=532.3 [M+H+].
Reaction SMILES: [Br:1][C:2]#[C:3][CH2:4][C@@:5]12[C@@H:22]3[C@H:13]([C@H:14]4[C@@:18]([CH2:20][CH2:21]3)([CH3:19])[C:17](=[O:23])[CH2:16][CH2:15]4)[CH2:12][CH2:11][C:10]1=[CH:9][C:8](=[O:24])[CH2:7][CH2:6]2>O1CCOCC1.C(OCC)C>[Br:1][C:2]#[C:3][CH2:4][C@@:5]12[C@@H:22]3[C@H:13]([C@H:14]4[C@@:18]([CH2:20][CH2:21]3)([CH3:19])[C:17](=[O:23])[CH2:16][CH2:15]4)[CH2:12][CH2:11][C:10]1=[CH:9][C:8](=[O:24])[CH:7]=[CH:6]2
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CC#CBr)[C@@H]1CCC2=O
Solvent: C1COCCO1
Solvent: CCOCC
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43CC#CBr)[C@@H]1CCC2=O

Procedure:
A mixture of 188 mg of 10β-(3-bromo-2-propynyl)estr-4-ene-3,17-dione and 376 mg of dichlorodicyanoquinone in 12.5 ml of dioxane is refluxed for 20 hours. The mixture is cooled and diluted with diethyl ether, then washed with aqueous sodium carbonate solution and dried. The solvent is evaporated and the residue is purified by flash chromatography on silica gel eluting with ethyl acetate:n-hexane 30:70 to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])[O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[H-].[Na+].[CH2:16](I)[CH:17]=[CH2:18]>CN(C=O)C.O>[F:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])[O:7][C:8](=[O:10])[N:9]([CH2:18][CH:17]=[CH2:16])[C:4]=2[CH:3]=1
Reactant: C=CCI
Reactant: O=c1[nH]c2cc(F)ccc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1c(=O)oc(=O)c2ccc(F)cc21
Reaction time: 2 h
Yield: 73.9 %

Procedure:
To a solution of 7-fluoro-2H-3,1-benzoxazine-2,4(1H)-dione (5.01 g, 27.7 mmol) in DMF (100 ml) at 0° C. was added sodium hydride (1.11 g, 27.7 mmol, 60% in paraffin) over 15 min. Allyl iodide (2.6 ml, 27.7 mmol) was added and the solution stirred for 2 h, then poured onto ice (100 g) in water (200 ml). The precipitate was collected, washed with water, then hexane and dried under vacuum at 40° C. to yield the title compound (4.53 g, 74%) as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]([CH3:11])[CH:3]=1.[Br:12]Br>C(O)(=O)C>[Br:12][C:3]1[C:2](=[O:1])[C:7]([C:8]([OH:10])=[O:9])=[CH:6][NH:5][C:4]=1[CH3:11]
Reactant: BrBr
Reactant: Cc1cc(O)c(C(=O)O)cn1
Solvent: CC(=O)O
Product: Cc1[nH]cc(C(=O)O)c(=O)c1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-hydroxy-6-methyl-nicotinic acid (10.00 g, 65.3 mmol) in glacial acetic acid (35 mL) is added bromine (4.00 mL, 78.1 mmol). After stirring for 18 h at room temperature, additional bromine (0.5 mL) is added and the reaction mixture is stirred for an additional 24 h. The reaction mixture is evaporated under reduced pressure and the remaining residue is co-evaporated with toluene. The remaining residue is treated with a small amount of MeOH and then triturated with water. The precipitate is filtered off and dried. Yield: 13.8 g (92% of theory); ESI mass spectrum: [M+H]+=232 (bromine isotope pattern); Retention time HPLC: 0.61 min (Z002—002).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[CH:11][C:12]([NH2:14])=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[Cl:15][CH:16](Cl)[C:17](=O)[CH3:18]>C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[CH:11][C:12]3[O:13][CH:18]=[C:17]([CH2:16][Cl:15])[N:14]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NC(=O)C=Cc1ccc2c(c1)OCO2
Reactant: CC(=O)C(Cl)Cl
Solvent: Cc1ccccc1
Product: ClCc1coc(C=Cc2ccc3c(c2)OCO3)n1
Yield: 75.9 %

Procedure:
49.0 g (256 mmol) 3-Benzo[1,3]dioxol-5-yl-acrylamide, 44.4 g (350 mmol) dichloro acetone and 300 ml toluene were kept at reflux temperature for 48 h with continuous removal of water by applying a Dean-Stark trap. After removal of solvents in vacuo, the residue was treated with 600 ml of a 1:1 mixture of water/isopropanol. After filtration the precipitate was washed first with isopropanol, then with heptane. Drying at 40° C. in vacuo gave 51.2 g (76%) 2-(2-Benzo[1,3]dioxol-5-yl-vinyl)-4-chloromethyl-oxazole.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:6][CH:7]=1.Cl.[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[N:25]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[N:25]1[CH2:31][CH2:30][CH2:29][N:28]([CH2:2][C:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[S:6][CH:7]=2)[CH2:27][CH2:26]1
Reactant: COc1ccc(N2CCCNCC2)c(OC)c1
Reactant: ClCc1csc(-c2ccccc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(N2CCCN(Cc3csc(-c4ccccc4)n3)CC2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
A mixture of 4-chloromethyl-2-phenylthiazole (80 mg, 0.38 mmol, 1 equiv), 1-(2,4-dimethoxyphenyl)-[1,4]diazepane HCl salt (117 mg, 0.38 mmol, 1 equiv) and Cs2CO3 (619 mg, 5 equiv) in 1 mL of DMF was stirred at room temperature overnight. The mixture was diluted with EtOAc (˜30 mL), washed with saturated aqueous NaHCO3 (20 mL) and brine (20 mL) sequentially and then dried over magnesium sulfate. The residue was purified by flash column chromatograph using 30 to 100% EtOAc in hexane to afford the title compound as light tan solid (50 mg) after evaporation and drying in vacuo. 1H NMR (400 MHz, CDCl3) δ 7.90 (d, 2H, J=8.0 Hz), 7.39 (m, 3H), 7.15 (s, 1H), 6.88 (d, 1H, J=8.8 Hz), 6.42 (s, 1H), 6.39 (d, 1H, J=8.8 Hz), 3.91 (s, 2H), 3.79 (s, 3H), 3.74 (s, 3H), 3.25 (m, 4H), 2.92 (m, 4H), 1.98 (m, 2H). MS (ES) m/z 410.2 (M+H+).
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO>[Cl:17][C:14]1[CH:15]=[CH:16][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH3:12])[C:9]=2[CH:13]=1
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1CNCCc2ccc(Cl)cc21
Reaction time: 3.5 h
Yield: 81.3 %

Procedure:
A solution of N-trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (65 mg, 0.22 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH (2 mL), and stirred for 3.5 hours at 60 C. The product mixture was concentrated, extracted 3 times with CH2Cl2 (5 mL), dried with Na2SO4 and concentrated to give 35 mg of a clear oil. 1H NMR (400 MHz, CDCl3) d 7.11 (s, 1H), 7.05 (d, J=8 Hz, 1H), 6.98 (d, J=8 Hz, 1H), 3.1-2.9 (m, 6H), 2.71 (m, 1H), 2.68 (bs, 1H), 1.32 (d, J=8 Hz, 3H). MS calculated for C11H14ClN+H: 196, observed: 196.
Reaction SMILES: Cl[C:2]1[C:10]2OC[CH:7](OC)[C:6]=2[C:5]([CH:13]2[C@H:18]([O:19]CC3C=CC=CC=3)[C@@H:17]([O:27]CC3C=CC=CC=3)[C@H:16]([O:35]CC3C=CC=CC=3)[C@@H:15]([CH2:43][O:44]CC3C=CC=CC=3)[O:14]2)=[CH:4][C:3]=1[CH2:52][C:53]1[CH:58]=[CH:57][C:56]([O:59][CH2:60][CH3:61])=[CH:55][CH:54]=1.[CH2:62]1[CH2:66][O:65][CH2:64][CH2:63]1.CO>[Pd]>[CH:10]1([C:2]2[C:66]3[O:65][CH2:64][CH2:63][C:62]=3[C:5]([C@H:13]3[C@H:18]([OH:19])[C@@H:17]([OH:27])[C@H:16]([OH:35])[C@@H:15]([CH2:43][OH:44])[O:14]3)=[CH:4][C:3]=2[CH2:52][C:53]2[CH:54]=[CH:55][C:56]([O:59][CH2:60][CH3:61])=[CH:57][CH:58]=2)[CH2:6][CH2:7]1
Reactant: C1CCOC1
Reactant: CCOc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)OCC3OC)cc1
Agent: [Pd]
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3c(c2C2CC2)OCC3)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 29 %

Procedure:
To a solution of 7-chloro-6-(4-ethoxybenzyl)-3-methoxy-4-((3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)-2,3-dihydrobenzofuran (102 mg, 0.125 mmol) in THF/MeOH (4 mL/2 mL) was added 10% Pd/C (10 mg) at rt. The reaction mixture was stirred at r.t. for 15 hours under hydrogen and filtered off. The filtrate was concentrated in vacuo and the residue was purified using reverse phase preparative HPLC to provide the title compound (17 mg, 29%) as a white solid.