Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)NC1CC(=O)OC1OCC)C=C.NC1C=CC(C(NC(C)C(N2CCCC2C(O)=O)=O)=O)=CC=1Cl.[O:40]=[C:41]1[O:45][CH:44]([O:46][CH2:47][CH2:48]C2C=CC=CC=2)[CH:43]([NH:55][C:56]([CH:58]2[CH2:62][CH2:61][CH2:60][N:59]2[C:63](=[O:77])[CH:64]([NH:66][C:67](=[O:76])[C:68]2[CH:73]=[CH:72][C:71]([NH2:74])=[C:70]([Cl:75])[CH:69]=2)[CH3:65])=[O:57])[CH2:42]1>>[CH2:47]([O:46][CH:44]1[CH:43]([NH:55][C:56]([CH:58]2[CH2:62][CH2:61][CH2:60][N:59]2[C:63](=[O:77])[CH:64]([NH:66][C:67](=[O:76])[C:68]2[CH:73]=[CH:72][C:71]([NH2:74])=[C:70]([Cl:75])[CH:69]=2)[CH3:65])=[O:57])[CH2:42][C:41](=[O:40])[O:45]1)[CH3:48]
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Agent: C=CCOC(=O)NC1CC(=O)OC1OCC
Agent: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)O
Product: CCOC1OC(=O)CC1NC(=O)C1CCCN1C(=O)C(C)NC(=O)c1ccc(N)c(Cl)c1

Procedure:
Prepared from (2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester and 97a following the method used for 98a. The title compound was isolated as a white solid (175 mg, 77% yield). 1H-NMR (500 MHz, CD3OD) δ 1.13 (t, 0.5H), 1.23 (t, 2.5H), 1.36 (d, 0.5H), 1.44 (d, 2.5H), 1.75-2.38 (m, 4H), 2.56 (dd, 1H), 2.76 (dd, 1H), 3.45-3.97 (m, 5H), 4.47 (dd, 1H), 4.59-4.67 (m, 1H), 4.74 (q, 1H), 5.55 (d, 0.2H), 5.56 (d, 0.8H), 6.75-6.82 (m, 1H), 7.56 (dd, 1H), 7.77 (d, 1H), 8.39 (d, 1H). Analytical HPLC 8.17 min. LC-MS (ES+) m/e=467.4 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[Cl:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[C:18]([C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])[NH:19]2)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.[N+](C1C=CC=CC=1)([O-])=O.[Cu]Br>[Cl:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[C:18]([C:22]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)=[O:23])[N:19]2[C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=2)=[CH:15][CH:14]=1
Reactant: O=C(c1cc2ccc(Cl)cc2[nH]1)N1CCOCC1
Reactant: COc1ccc(Br)cc1OC
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(-n2c(C(=O)N3CCOCC3)cc3ccc(Cl)cc32)cc1OC
Temperature: 140 °C
Reaction time: 14 h

Procedure:
4-Bromoveratrole (5.7 g, 26 mmol), 6-chloroindole-2-carboxylic acid morpholide (1.7 g, 6.5 mmol), potassium carbonate (1.7 g), copper(I) bromide (0.2 g) in a mixture of pyridine (2 ml) and nitrobenzene was stirred at 140° C. for 14 hours. After cooling to room temperature, the reaction mixture was applied onto a flash chromatography column (silica gel, 140 g), Elution with toluene, toluene/acetone [9:1] and toluene/acetone [8:2] (500 ml each) gave 6-chloro-1-(3,4-dimethoxyphenyl)indole-2-carboxylic acid morpholide as brown oil. Yield: 2.1 g (81% of theoretical) Rf : 0.54 (toluene/acetone, 7:3). The H-NMR spectra was consistent with the assigned structure.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][CH2:10][CH2:11][NH:12]C(=O)OC(C)(C)C)=[C:4]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:12][CH2:11][CH2:10][CH2:9][C:5]1[C:4]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[N:3][C:2]([NH2:1])=[N:7][C:6]=1[CH3:8]
Reactant: CCCCCNc1nc(N)nc(C)c1CCCNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCNc1nc(N)nc(C)c1CCCN
Yield: 84.6 %

Procedure:
The product from step (iv) (3.8 g) was dissolved in DCM (100 mL) and TFA (35 mL) and the reaction mixture stirred at rt for 16 h. The solvent was evaporated and the residue taken up in MeOH. The product was purified via SCX resin to give the subtitle compound 2.3 g.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=1B(O)O)[CH3:13]>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([C:16]3[CH:17]=[C:18]([C:21]([F:24])([F:23])[F:22])[CH:19]=[CH:20][C:15]=3[O:14][CH2:12][CH3:13])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: CCOc1ccc(C(F)(F)F)cc1B(O)O
Reactant: Clc1nc2c(Br)cccn2n1
Product: CCOc1ccc(C(F)(F)F)cc1-c1cccn2nc(Cl)nc12

Procedure:
2-Chloro-8-(2-ethoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (0.500 g, 2.15 mmol) and 2-ethoxy-5-trifluoromethylbenzeneboronic acid (0.755 g, 3.23 mmol) in a manner analogous to Example 311a to give product (0.645 g, 88%). MS=342 (MH)+. 318b) 7-[8-(2-Ethoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(2-ethoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.640 g, 1.87 mmol) and 7-amino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.590 g, 2.25 mmol) in a manner analogous to Example 311b to give product (1.06 g, 99%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.55 (s, 1H), 8.78 (d, 1H), 7.98 (s, 1H), 7.78 (d, 1H), 7.72 (d, 1H), 7.42 (m, 2H), 7.35 (d, 1H), 7.08 (t, 1H), 7.00 (d, 1H), 4.15 (q, 2H), 3.42 (m, 4H), 2.78 (m, 4H), 1.41 (s, 9H), 1.22 (t, 3H): MS=568 (MH)+.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:28][C:29]1[N:34]=[C:33]([NH2:35])[CH:32]=[CH:31][C:30]=1I.[CH3:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1B(O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:28][C:29]1[N:34]=[C:33]([NH2:35])[C:32]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[O:38][CH3:37])=[CH:31][CH:30]=1
Reactant: COc1ccccc1B(O)O
Reactant: Nc1ccc(I)c(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Product: COc1ccccc1-c1ccc(Cl)nc1N
Temperature: 75 °C
Yield: 71.9 %

Procedure:
Potassium phosphate (12.72 g, 60 mmol), triphenyl phosphine (0.682 g, 2.40 mmol), 6-chloro-5-iodo-2-aminopyridine (6.1 g, 24 mmol), 2-methoxybenzeneboronic acid (5.10 g, 33.5 mmol) and palladium acetate (0.27 g, 1.20 mmol) were sequentially added to degassed acetonitrile (200 mL) and water (60 mL) under nitrogen. The reaction mixture was heated at 75° C. for overnight, then cooled to room temperature. The organic layer was separated and aqueous layer and was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, concentrated and purified by silica column using hexanes and ethyl acetate as eluent furnishing 4.05 g of title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5](=[O:7])[O:4][C:3]=1[CH2:8][O:9][C:10](=[O:31])[C@H:11]([OH:30])[CH2:12][C@H:13]([NH2:29])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[F:28])=[CH:17][CH:16]=1.[OH:32][N:33]1[CH:37]=[C:36]([C:38](O)=[O:39])[N:35]=[N:34]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.CCN(C(C)C)C(C)C>>[CH3:1][C:2]1[O:6][C:5](=[O:7])[O:4][C:3]=1[CH2:8][O:9][C:10](=[O:31])[C@H:11]([OH:30])[CH2:12][C@H:13]([NH:29][C:38]([C:36]1[N:35]=[N:34][N:33]([OH:32])[CH:37]=1)=[O:39])[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[F:28])=[CH:19][CH:20]=1
Reactant: O=C(O)c1cn(O)nn1
Reactant: Cc1oc(=O)oc1COC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2cc(Cl)ccc2F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1oc(=O)oc1COC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cn(O)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
(2R,4R)-4-Amino-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxypentanoic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester (30.7 mg, 68.3 μmol), 1-hydroxy-1H-[1,2,3]triazole-4-carboxylic acid (10.6 mg, 82 μmol) and HATU (39.0 mg, 102 μmol) were stirred in DMF (1.0 mL, 12.9 mmol) for 10 minutes. DIPEA (35.7 μL, 205 μmol) was added dropwise and the resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated and to yield a clear yellow liquids, which was purified using preparative scale C18 column chromatography (small column; 30-90% MeCN in water with 0.05% TFA) to yield the title compound as a white solid (27.1 mg). MS m/z [M+H]+ calc'd for C25H22ClFN4O8, 561.11. found 561.1.
Reaction SMILES: [OH:1][C:2]([CH3:30])([CH3:29])[C:3]#[C:4][C:5]1[C:26]([O:27][CH3:28])=[CH:25][C:8]2[C:9]([CH3:24])([CH3:23])[C:10]3[NH:11][C:12]4[C:17]([C:18]=3[C:19](=[O:20])[C:7]=2[CH:6]=1)=[CH:16][CH:15]=[C:14]([C:21]#[N:22])[CH:13]=4>C(O)C.CN(C)C(=O)C.[Pd]>[OH:1][C:2]([CH3:30])([CH3:29])[CH2:3][CH2:4][C:5]1[C:26]([O:27][CH3:28])=[CH:25][C:8]2[C:9]([CH3:23])([CH3:24])[C:10]3[NH:11][C:12]4[C:17]([C:18]=3[C:19](=[O:20])[C:7]=2[CH:6]=1)=[CH:16][CH:15]=[C:14]([C:21]#[N:22])[CH:13]=4
Reactant: COc1cc2c(cc1C#CC(C)(C)O)C(=O)c1c([nH]c3cc(C#N)ccc13)C2(C)C
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)N(C)C
Product: COc1cc2c(cc1CCC(C)(C)O)C(=O)c1c([nH]c3cc(C#N)ccc13)C2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
9-(3-Hydroxy-3-methyl-but-1-ynyl)-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound E4-2-1, 21.0 mg, 0.0527 mmol) was dissolved in ethanol (15 mL) and N,N-dimethylacetamide (2 mL), added with 10% Pd/C (6.7 mg), and then stirred at room temperature overnight under hydrogen atmosphere. The reaction solution was filtered and concentrated under reduced pressure. The resulting residues were diluted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was washed with dichloromethane to obtain the title compound (yellow powder, 16.9 mg, 80%).
Reaction SMILES: Cl[CH:2](Cl)[C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:6]=[C:5]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:4]=1.ClC(Cl)C1N=C(N2CCCC2)N(CC2C=CC([O:42]C)=CC=2)N=1.C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:7]2[C:3]([CH:2]=[O:42])=[N:4][C:5]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:6]2)=[CH:10][CH:11]=1
Reactant: COc1ccc(Cn2nc(C(Cl)Cl)nc2N2CCCC2)cc1
Reactant: COc1ccc(Cn2nc(N3CCCC3)nc2C(Cl)Cl)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(Cn2nc(N3CCCC3)nc2C=O)cc1
Temperature: 60 °C
Yield: 29 %

Procedure:
The mixture of 5-(dichloromethyl)-1-(4-methoxybenzyl)-3-(pyrrolidin-1-yl)-1H-1,2,4-triazole and 3-(dichloromethyl)-1-(4-methoxybenzyl)-5-(pyrrolidin-1-yl)-1H-1,2,4-triazole from the previous step (299 mg, 0.876 mmol, Eq: 1) was suspended in ethanol (5 ml) and water (5 ml). Sodium acetate (180 mg, 2.2 mmol, Eq: 5) was added. The reaction mixture was heated for 16 h at 60° C. The mixture was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate. The product (74 mg, 29%) was obtained as a yellow solid by column chromatography (SiO2, ethyl acetate n-heptane). MS: m/z=287.3 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[O:12]1[CH2:17][CH2:16][N:15]([S:18]([C:21]2[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=2)[C:24]([NH:26][NH2:27])=[O:25])(=[O:20])=[O:19])[CH2:14][CH2:13]1>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6](/[C:8](=[N:27]/[NH:26][C:24](=[O:25])[C:23]2[CH:28]=[CH:29][CH:30]=[C:21]([S:18]([N:15]3[CH2:16][CH2:17][O:12][CH2:13][CH2:14]3)(=[O:19])=[O:20])[CH:22]=2)/[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)ccc1F
Reactant: NNC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\NC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1)c1cc(Cl)ccc1F
Temperature: 120 °C
Yield: 19 %

Procedure:
1-(5-chloro-2-fluorophenyl)ethanone (20 mg, 0.116 mmol) and 3-(morpholinosulfonyl)benzohydrazide (33.1 mg, 0.116 mmol) was dissolved in Methanol (Volume: 4 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) afforded the title compound (E)-N′-(1-(5-chloro-2-fluorophenyl)ethylidene)-3-(morpholinosulfonyl)benzohydrazide (10 mg, 0.022 mmol, 19.22% yield) as a solid. 1H NMR (CDCl3, 400 MHz): δ 8.26 (m, 1H), 8.09 (m, 1H), 7.80 (d, 1H, J=7.6 Hz), 7.58 (t, 1H, J=7.6 Hz), 7.37 (m, 1H), 7.21 (m, 1H), 6.95 (m, 1H), 3.61 (m, 4H), 2.90 (m, 4H), 2.29 (s, 3H). Mass [M+H]+:440.1
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[N:18]=[N:17][C:16]=2[CH2:29][CH2:30][CH2:31][CH3:32])=[CH:11][C:10]=1[O:33][CH3:34])C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[CH2:29]([C:16]1[N:17]=[N:18][C:19]([O:21][CH:22]2[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]2)=[CH:20][C:15]=1[C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([O:33][CH3:34])[CH:11]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OCc2ccccc2)c(OC)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(O)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of 4-(4-benzyloxy-3-methoxy-phenyl)-3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazine (1.0 mmol, 462 mg) in methanol/ethyl acetate (10 mL, 1/1) was added 10% palladium on activated carbon (70 mg). The mixture was repeatedly de-gassed under vacuum, filled with hydrogen for 3 times. Then hydrogen balloons were attached to the reaction, which was stirred at room temperature for 2 hours. TLC/LCMS monitored to completion. The mixture was then filtered through celite, the celite cake was washed with 1/1 methanol/ethyl acetate for 3 times, and the organic layers were combined and condensed under reduced pressure to give 4-[3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-2-methoxy-phenol as a white powder (327 mg), which was used directly in the next step.
Reaction SMILES: [CH:1]([O:14][CH2:15][CH2:16][C:17]1[CH2:18][CH2:19][N:20](CC2C=CC=CC=2)[CH2:21][CH:22]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:31]([O:33][CH3:34])=[O:32]>C1C=CC=CC=1>[CH:1]([O:14][CH2:15][CH2:16][C:17]1[CH2:22][CH2:21][N:20]([C:31]([O:33][CH3:34])=[O:32])[CH2:19][CH:18]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1=C(CCOC(c2ccccc2)c2ccccc2)CCN(Cc2ccccc2)C1
Reactant: COC(=O)Cl
Solvent: c1ccccc1
Product: COC(=O)N1CC=C(CCOC(c2ccccc2)c2ccccc2)CC1

Procedure:
With reference to FIG. 7, a solution of 4-(2-(benz-hydryloxy)ethyl)-1-benzyl-1,2,3,6-tetrahydropyridine 4 (12.44 g, 0.0324 mol) and methyl chloroformate (5.0 ml, 0.0648 mol) in benzene (40 ml) was refluxed for 6 hrs. After completion of reaction (monitored by TLC), the solvent was removed in vacuo to yield methyl 4-(2-(benzhydryloxy)ethyl)-5,6-dihydropyridine-1(2H)-carboxylate in the form of viscous oil. It was purified by column chromatography (hexane: EtOAc 9:1) to get 6.7 g (59%) of pure product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([OH:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[K+].[K+].[CH2:29](Br)[CH:30]=[CH2:31]>CC(C)=O>[CH2:31]([O:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[O:21][CH3:22])[N:13]=[CH:12][N:11]=[C:10]2[NH:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1)[CH:30]=[CH2:29]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OC
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-ol (0.70 g, 2.18 mmol) (from Example 18, Step B, supra) in acetone (140 mL) was added K2CO3 (0.61 g, 10.9 mmol) and allyl bromide (0.94 mL, 10.9 mmol) (Aldrich). The reaction mixture was heated with stirring at 90° C. for 4 hours. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was purified by chromatography using EtOAc/CH2C2/Et3N (1:1:0.02) as eluent to give the desired (6-allyloxy-7-methoxy-quinazolin-4-yl)-(3-chloro-4-fluoro-phenyl)-amine as an off white solid. (Yield 0.64 g, 82%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][C@@H:13]([C:16]1[CH:17]=[C:18]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:19]=[C:20]([F:23])[C:21]=1[F:22])[CH2:14][OH:15]>N1C=CC=CC=1>[F:23][C:20]1[CH:19]=[C:18]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:17]=[C:16]([C@H:13]([OH:12])[CH2:14][O:15][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[C:21]=1[F:22]
Reactant: CCOC(=O)CCc1cc(F)c(F)c([C@H](O)CO)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCOC(=O)CCc1cc(F)c(F)c([C@H](O)COS(=O)(=O)c2ccc(C)cc2)c1
Temperature: -15 °C
Reaction time: 4.5 h
Yield: 81 %

Procedure:
p-Toluenesulfonyl chloride (12.4 g, 64.8 mmol) in pyridine (35 mL) was added dropwise over 7 min to a cooled (−10 to −20° C.) solution of ethyl 3-{3-[(1S)-1,2-dihydroxyethyl]-4,5-difluorophenyl}propanoate (17.7 g, 64.8 mmol) in pyridine (70 mL) under N2. The reaction was stirred at −10 to −20° C. for ˜4.5 h. The reaction was quenched with ice H2O and stirred overnight. The reaction mixture was diluted with H2O and extracted three times with ethyl ether. The combined organic layers were washed with 1N HCl, aq. CuSO4, and brine. The organic layer was dried over MgSO4, filtered, and concentrated. Purification by column chromatography (0-80% ethyl acetate:hexane) afforded the desired product (22.5 g, 81%) along with some recovered starting material (2.13 g).
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[N:33]=[C:32]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:30][CH:29]=2)[CH2:24][CH2:23]1>>[C:35]([NH:34][C:32]1[N:33]=[C:28]([CH:25]2[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][CH2:19][NH:18][C:8](=[O:10])[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH3:11])[CH2:23][CH2:24]2)[CH:29]=[CH:30][CH:31]=1)(=[O:39])[CH:36]([CH3:38])[CH3:37]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)n1
Reactant: CC(C(=O)O)(c1ccccc1)c1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(C)(c3ccccc3)c3ccccc3)CC2)n1

Procedure:
Example 83 was prepared from 2,2-diphenylpropanoic acid and N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.05 (d, 1H, J=8.0 Hz), 7.80 (s, 1H), 7.63 (t, 1H, J=7.6 Hz), 7.35–7.24 (m, 10H), 6.85 (d, 1H, J=8.0 Hz), 6.26 (t, 1H, J=4.8 Hz), 3.38 (dd, 2H, J=6.4, 12.4 Hz), 2.92–2.89 (m, 2H), 2.55–2.48 (m, 2H), 2.32 (t, 2H, J=6.8 Hz), 2.00 (s, 3H), 1.96 (t, 2H, J=11.2 Hz), 1.79 (d, 2H, J=11.6 Hz), 1.72–1.61 (m, 4H), 1.27 (d, 6H, 6.8 Hz); ESMS m/e: 513.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)=[O:5].[NH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+].C(OC(=O)C)C>C1(C)C(C)=CC=CC=1>[CH2:25]([N:22]1[CH2:23][CH2:24][CH:19]([NH:18][C:2]2[N:17]=[CH:16][CH:15]=[CH:14][C:3]=2[C:4]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)=[O:5])[CH2:20][CH2:21]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(Nc1cccc(Cl)c1)c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: O=C(Nc1cccc(Cl)c1)c1cccnc1NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.5 %

Procedure:
A solution of 2-chloro-(N-3-chlorophenyl)nicotinamide (280 mg, 1.05 mmol, 1.05 eq) prepared in Preparation Example 5, 4-amino-1-benzylpiperidine (1.0 mmol), and anhydrous potassium carbonate (1.3 mmol) in ortho-xylene was stirred for 24 hrs under reflux. The reaction mixture was cooled to a room temperature, added with ethylacetate, and extracted twice with 1N HCl. The aqueous layer thus formed was washed with 30 ml of ethylacetate, adjusted to a pH of about 9-10 by adding 2 N sodium hydroxide, and extracted two or three times with 20 ml of methylene chloride. The organic layer was dried over a desiccant, and concentrated in a reduced pressure. A desired fraction obtained by purification through silica gel chromatography was concentrated in a reduced pressure and dried in a vacuum to afford the title compound. Yield: 66.5% 1H NMR (DMSO-d6) δ8.15˜8.30 (m, 2H), 8.03 (d, 1H), 7.90 (s, 1H), 7.66 (d, 1H), 7.60 (d, 1H), 7.30˜7.60 (m, 6H), 7.19 (d, 1H), 6.70 (m, 1H), 4.10 (bs, 1H), 3.95 (s, 1H), 2.85˜3.15 (m, 2H), 2.70˜2.85 (m, 2H), 1.90˜2.15 (m, 2H), 1.60˜1.85 (m, 2H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C@H:5]([CH3:21])[N:6](C=O)[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[NH:15][CH:16]=[CH:17][N:18]=2)=[CH:9][CH:8]=1)[CH3:2].[ClH:23]>C(O)C>[ClH:23].[ClH:23].[CH2:1]([O:3][C:4](=[O:22])[C@H:5]([CH3:21])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][C:14]2[NH:15][CH:16]=[CH:17][N:18]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](C)N(C=O)c1ccc(Cc2ncc[nH]2)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)[C@H](C)Nc1ccc(Cc2ncc[nH]2)cc1

Procedure:
In a 200 ml round-bottom flask is placed a solution of 8.0 g of p-(1-imidazolylmethyl)aniline prepared as described in Reference Example 3, and 30 ml of formic acid in 80 ml of toluene. The flask was fitted with a water separator, and the solution was refluxed for 4 hours. After concentration under reduced pressure, the residual solid was recrystallized from ethanol-diethyl ether to give 6.4 g of p-(1-imidazolylmethyl)-N-formylaniline as colorless prisms. M.P.: 121°-123° C. To a suspension of 0.48 g of 50% sodium hydride in 50 ml of dry dimethylformamide was added 2.01 g of the formylaniline and mixture was heated to 100° C. A solution of 1.81 g of ethyl α-bromopropionate in 30 ml of dry dimethylformamide was added to the mixture and the reaction mixture was heated at 100° C. for 16 hours. After removal of the solvent under reduced pressure, 50 ml of dichloromethane was added to the residue, and the solution was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was chromatographed on silica gel using dichloromethane-ethanol (20:1 by volume) to give 1.58 g of N-formyl-N-[p-(1-imidazolylmethyl)phenyl]alanine ethyl ester as a pale brown oil. Then, a solution of 1.58 g of the resulting ester and 5 ml of concentrated hydrochloric acid in 50 ml of ethanol was stirred for 40 hours at room temperature. After concentration under reduced pressure, the residual solid was recrystallized from ethanol-diethyl ether to give 1.18 g of N-[p-(1-imidazolylmethyl)phenyl]alanine ethyl ester dihydrochloride as pale yellow crystals. M.P.: 154°-159° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:10])=[C:4]([CH2:8][OH:9])[CH:5]=[CH:6][CH:7]=1.FC(F)(F)[C:13]([O-])=[O:14].[Tl+].C(O)(C(F)(F)F)=O.[O-2].[Mg+2].[Cl-].[Li+]>C(Cl)Cl.[Pd](Cl)Cl.C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:13](=[O:14])[O:9][CH2:8][C:4]=2[C:3]=1[Cl:10]
Reactant: OCc1cccc(Br)c1Cl
Reactant: O=C([O-])C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: O=C1OCc2c1ccc(Br)c2Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a flask charged with (3-bromo-2-chlorophenyl)methanol (1.1 g, 4.8 mmol) and a stir bar was added thallium trifluoroacetate (2.9 g, 5.3 mmol) and TFA (6 mL). The mixture was allowed to stir at RT for 16 hours. The volatiles were removed under reduced pressure. The residue was pumped under high vacuum for 15 minutes before palladium (II) chloride (0.085 g, 0.48 mmol), magnesium oxide (0.39 g, 9.6 mmol), lithium chloride (0.20 g, 4.8 mmol), and ethanol (30 mL) were added. The mixture was stirred under an atmosphere of carbon mono-oxide until the reaction turned black. The reaction was diluted with DCM. The suspension was filtered through a pad of celite to remove the solids. The filtrate was adsorbed onto silica gel, and purified by MPLC to afford the title compound.