Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]2)=[O:8])=[CH:4][CH:3]=1.[CH2:22]([O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)[C:23]#[C:24][CH3:25]>>[CH2:22]([O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([N:12]2[CH2:13][CH2:14][N:9]([C:7]([NH:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:21][CH:20]=3)=[O:8])[CH2:10][CH:11]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:35])=[O:34])=[CH:29][CH:28]=1)[C:23]#[C:24][CH3:25]
Reactant: CCOC(=O)C1CN(C(=O)Nc2ccc(F)cc2)CCN1
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Product: CC#CCOc1ccc(S(=O)(=O)N2CCN(C(=O)Nc3ccc(F)cc3)CC2C(=O)OCC)cc1
Yield: 70 %

Procedure:
In the same manner as described in Step 2 of Example 215, ethyl 4-[(4-fluoroanilino)carbonyl]-2-piperazinecarboxylate (0.41 g, 1.4 mmol) and 4-but-2-ynyloxy-benzenesulfonyl chloride provided 0.49 g (70%) of ethyl 1-{[4-(2-butynyloxy)phenyl]sulfonyl}-4-[(4-fluoroanilino)carbonyl]-2-piperazinecarboxylate as a white powder. Electrospray Mass Spec 504.4 (M+H)+.
Reaction SMILES: Cl.C(=N)(OCC)C.[C:8]([NH2:12])([CH3:11])([CH3:10])[CH3:9].C1(N2[C:20]([CH:21]=[O:22])=[CH:19][N:18]=[C:17]2[CH3:23])CC1>>[C:8]([N:12]1[C:20]([CH:21]=[O:22])=[CH:19][N:18]=[C:17]1[CH3:23])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)N
Reactant: Cc1ncc(C=O)n1C1CC1
Agent: CCOC(C)=N
Agent: Cl
Product: Cc1ncc(C=O)n1C(C)(C)C

Procedure:
3-tert-Butyl-2-methyl-3H-imidazole-4-carbaldehyde was prepared from ethyl acetimidate hydrochloride and tert-butylamine in the same manner as 3-cyclopropyl-2-methyl-3H-imidazole-4-carbaldehyde (Example 45).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.[I:22]N1C(=O)CCC1=O.[NH4+].[OH-]>CC(O)=O>[CH2:1]([C:8]1[CH:9]=[C:10]([I:22])[C:11]([OH:14])=[N:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1ccc(Cc2ccccc2)cn1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: Oc1ncc(Cc2ccccc2)cc1I
Reaction time: 8 h

Procedure:
To a yellow solution of 5-benzylpyridin-2-ol (1.10 g, 5.94 mmol) in 22 mL AcOH under Ar was added 1.5 mL TFA, followed by N-iodosuccinimide (1.34 g, 5.94 mmol). The red homogeneous solution was allowed to stir overnight, poured onto ice and neutralized with conc. NH4OH. The solids were collected by filtration, rinsed with water, treated with MeOH/DCM, dried over sodium sulfate, and evaporated. The resulting brown solid was purified by silica gel chromatography (ISCO, 80 g, 0-70% 90/10 DCM/MeOH in DCM) to give 5-benzyl-3-iodopyridin-2-ol as a yellow/brown solid. MS (ESI) m/z: Calculated: 311.0; Observed: 311.9 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].Cl>C(Cl)Cl.O>[OH:12][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(N)ccc1O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc(NS(C)(=O)=O)ccc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.5 %

Procedure:
To a solution of methyl 5-amino-2-hydroxybenzoate (9.58 g, 57.3 mmol) in DCM (150 ml), pyridine (9.27 ml, 115 mmol) was added followed by methanesulfonyl chloride (4.47 ml, 57.3 mmol). The reaction mixture was stirred at RT for 4 hours. Water (50 ml) and HCl 6M (15 ml) were added, and the resulting precipitate was collected by filtration, washed with water and dried to give methyl 2-hydroxy-5-(methylsulfonamido)benzoate (13 g, 53.0 mmol, 92% yield, MS/ESI+ 246.0 [MH]+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([NH2:14])=[O:13])[CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>[N:37]1([CH2:36][CH2:35][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[C:10]([C:12]([NH2:14])=[O:13])[CH:11]=2)[N:8]=[CH:7][N:6]=[C:5]3[NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:19][CH:18]=2)[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1
Reactant: NC(=O)c1cc(O)cc2c(NCc3ccc(C(F)(F)F)cc3)ncnc12
Reactant: ClCCN1CCOCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: NC(=O)c1cc(OCCN2CCOCC2)cc2c(NCc3ccc(C(F)(F)F)cc3)ncnc12
Temperature: 55 °C
Reaction time: 0.21 h
Yield: 87.8 %

Procedure:
To a solution of 6-Hydroxy-4-(4-trifluoromethyl-benzylamino)-quinazoline-8-carboxylic acid amide (85 mg, 0.2 mmol) in N,N-dimethylformamide (3.0 mL) was added cesium carbonate (229 mg, 0.6 mmol). The mixture was stirred vigorously for 10-15 minutes and 4-(2-Chloro-ethyl)-morpholine hydrochloride (48 mg, 0.26 mmol) was added followed by tetrabutylammonium iodide (10 mol %). The reaction was heated to 55° C. for 16 hours and then cooled to room temperature and diluted with water (15 mL) and ethyl acetate (10 mL). The phases were separated and the aqueous phase was extracted further with ethyl acetate (3×10 mL). The combined organic phases were then washed with water, dried over sodium sulfate and concentrated to a residue that was purified by column chromatography (dichloromethane to 90% dichloromethane/9% methanol/1% ammonium hydroxide) to afford the title compound as an off-white solid (83.5 mg, 75%). LCMS (ESI) 476 (M+H)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[NH2:14])[CH3:2].N1C=CC=CC=1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.Cl>ClCCl>[CH2:1]([O:3][C:4](=[O:15])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[NH:14][S:28]([C:25]1[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=1)(=[O:30])=[O:29])[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(Cl)cc1N
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C=Cc1ccc(Cl)cc1NS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.4 %

Procedure:
To 3-(2-amino-4-chloro-phenyl)-acrylic acid ethyl ester (18.0g, 79.8 mmol) in dichloromethane (144 ml) was added pyridine (9.04 ml, 112 mmol) and p-toluenesulfonyl chloride (16.0g, 83.9 mmol). The reaction was stirred at room temperature for 18 hours and poured into 1N hydrochloric acid (150 ml). The layers were separated and the organic layer was dried over magnesium sulfate, filtered, and concentrated. The resulting solid was slurried in hexanes and filtered to afford 3-[4-chloro-2-(toluene-4-sulfonylamino)-phenyl]-acrylic acid ethyl ester (28.3g, 93%). mp=124-127° C. 1H NMR (300 MHz, CDCl3) d 1.35 (t, 3, J=7.2), 2.40 (s, 3), 4.27 (q, 2, J=7.2), 6.12 (dd, 1, J=15.9, 0.9), 7.20-7.39 (m, 4), 7.39 (d, 1, J=8.6), 7.48-7.53 (m, 2), 7.62 (d, 2, J=8.3). 13C NMR (75 MHz, CDCl3) d 15.50, 22.79, 62.24, 122.48, 127.98, 128.49, 129.34, 129.50, 131.05, 136.82, 137.00, 137.73, 138.93, 145.55, 167.59. IR 3214, 1694, 1631, 1318, 1167 cm−1. Analysis calculated for C18H18ClNO4S: C, 56.91; H, 4.78; N, 3.69. Found: C, 57.10; H, 5.08; N, 3.70.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][O:19][C:20]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[C:22]([F:36])[CH:21]=2)[CH2:15]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.[OH-].[K+]>CS(C)=O>[CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][O:19][C:20]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[C:22]([F:36])[CH:21]=2)[CH2:15]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
Reactant: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(O)c1cc(C2CC2)c(OCC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of tert-butyl 4-((1-benzhydrylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate (203 mg) and potassium hydroxide (187 mg) in DMSO (1.7 mL) was stirred at rt for 16 hr. The contents were acidified with 1M NaH2PO4. Solid was collected with filtration, washed with water, and dried under vacuum (171 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]([OH:13])=[O:12])[CH2:7][CH:6]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)=[O:4]>CC(OC)(C)C>[CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=[O:12])[CH2:7][C@@H:6]1[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=1)=[O:4]
Reactant: COC(=O)N1CCC(C(=O)O)CC1Cc1ccc(C(F)(F)F)cc1
Solvent: COC(C)(C)C
Product: COC(=O)N1CC[C@H](C(=O)O)C[C@@H]1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 63.5 %

Procedure:
1-(Methoxycarbonyl)-2-(4-(trifluoromethyl)benzyl)piperidine-4-carboxylic acid (14.65 g, 42.43 mmol) was suspended in MTBE (150 mL) and heated under reflux for 1 min, then stirred at room temperature for 3 days. The solids were isolated and dried under vacuum. Cis-1-(methoxycarbonyl)-2-(4-(trifluoromethyl)benzyl)piperidine-4-carboxylic acid (9.3 g, 63.5%) was isolated. 1H NMR (600 MHz, cd3od) δ 1.68-1.77 (m, 1H), 1.90-1.97 (m, 1H), 1.99-2.10 (m, 2H), 2.58-2.64 (m, 1H), 2.83-2.89 (m, 1H), 2.93-3.00 (m, 1H), 3.16-3.31 (m, 1H), 3.43 (s, 3H), 3.86-3.92 (m, 1H), 4.31-4.36 (m, 1H), 7.36 (d, 2H), 7.53 (d, 2H).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH3:12][C@@H:13]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:23]([CH3:25])=[CH2:24])[CH:20]=2)[C:15](=[O:26])[O:14]1>ClCCCl>[CH3:12][C@@H:13]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:23]3([CH3:25])[CH2:24][O:9]3)[CH:20]=2)[C:15](=[O:26])[O:14]1
Reactant: C=C(C)c1ccc2c(c1)C[C@@H](C)OC2=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCCl
Product: C[C@@H]1Cc2cc(C3(C)CO3)ccc2C(=O)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
mCPBA (774 mg, 4.49 mmol) was added to a solution of (3R)-3-methyl-6-(prop-1-en-2-yl)-3,4-dihydro-1H-isochromen-1-one (605 mg, 2.99 mmol) in DCE (15 mL). The reaction was stirred at room temp for 3 h before it was complete by TLC. The reaction was then partitioned between saturated sodium bicarbonate solution and DCM. The aq. layer was further extracted with DCM (2×75 mL) the combined organic layers were dried over magnesium sulfate, filtered, and purified via MPLC (10-50% EtOAc/Hex) to give the title compound: LC-MS: (M+H)+219;
Reaction SMILES: C(N(C(C)C)C(C)C)C.Cl.[OH:11][C:12]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:13]=1[NH2:14].[C:20]12([CH2:30][C:31](O)=[O:32])[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2.CCCP(=O)=O>ClCCl>[C:20]12([CH2:30][C:31]([NH:14][C:13]3[CH:15]=[CH:16][C:17]([OH:19])=[CH:18][C:12]=3[OH:11])=[O:32])[CH2:27][CH:26]3[CH2:25][CH:24]([CH2:23][CH:22]([CH2:28]3)[CH2:21]1)[CH2:29]2
Reactant: O=C(O)CC12CC3CC(CC(C3)C1)C2
Reactant: Nc1ccc(O)cc1O
Agent: CCCP(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nc1ccc(O)cc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.05 ml of N-ethyl-diisopropylamine is added to a solution of 323 mg 2,4-dihydroxyaniline hydrochloride (formula V), 388 mg (adamantan-1-yl)acetic acid (formula R3COOH) and 1.2 ml of propylphosphonic anhydride (50% in ethyl acetate) in 20 ml of dry dichloromethane at 0°. The mixture obtained is stirred for about 18 hours at room temperature and the solvent is evaporated off. The residue is dissolved in 50 ml of ethyl acetate and extracted with 1 M aqueous hydrochloric acid, saturated aqueous NaHCO3 solution and brine. The organic layer is dried and the solvent is evaporated off. The title compound is obtained (m.p. 195-197°).
Reaction SMILES: C(C(C1C=CC(F)=CC=1)C([O:7][C:8](=O)[CH:9]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH:10]([CH3:12])[CH3:11])=O)(C)C.[C:28]1([CH2:34][CH:35]=[C:36]([CH3:41])[CH:37]([OH:40])[C:38]#[CH:39])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>N1C=CC=CC=1>[CH:10]([CH:9]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:8]([O:40][CH:37]([C:36]([CH3:41])=[CH:35][CH2:34][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:38]#[CH:39])=[O:7])([CH3:12])[CH3:11]
Reactant: C#CC(O)C(C)=CCc1ccccc1
Reactant: CC(C)C(C(=O)OC(=O)C(c1ccc(F)cc1)C(C)C)c1ccc(F)cc1
Solvent: c1ccncc1
Product: C#CC(OC(=O)C(c1ccc(F)cc1)C(C)C)C(C)=CCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.11 Grams (20 millimoles) of α-isopropyl-4-fluorophenylacetic anhydride and 1.86 g (10 millimoles) of 6-phenyl-4-methylhexa-4-ene-1-yne-3-ol are dissolved in 30 ml of a dry pyridine. The resulting solution is stirred overnight at room temperature. Next day, the reaction solution is poured into 100 g of ice water and extracted with three 30-ml portions of ether. The ether layers obtained are combined and extracted twice with an aqueous saturated sodium hydrogen carbonate. Thereafter, the ether layer is further washed once with a 10% aqueous hydrochloric acid and three times with water, followed by drying over anhydrous sodium sulfate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([NH2:16])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:17][C:18]1[N:22]([CH:23]([CH3:27])[C:24](O)=[O:25])[N:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[N:19]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH:13]([CH3:14])[CH3:15])=[C:11]([NH:16][C:24](=[O:25])[CH:23]([N:22]3[C:18]([CH3:17])=[N:19][C:20]([C:28]([F:29])([F:30])[F:31])=[N:21]3)[CH3:27])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1nc(C(F)(F)F)nn1C(C)C(=O)O
Reactant: CC(C)c1c(N)cnn1-c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(F)(F)F)nn1C(C)C(=O)Nc1cnn(-c2ccc(Cl)cc2)c1C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.8 %

Procedure:
To a solution of 1-(4-chlorophenyl)-5-isopropylpyrazol-4-amine (0.054 g, 0.23 mmol) in DMF (1.0 mL) was added 2-[5-methyl-3-(trifluoromethyl)-1,2,4-triazol-1-yl]propanoic acid (0.051 g, 0.23 mmol), followed by diisopropylethylamine (0.059 g, 0.46 mmol) and HATU (0.105 g, 0.28 mmol). After stirring at room temperature for 1 h, the reaction was diluted with water and the aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude product was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.025 g, 0.057 mmol, 25%). 1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 8.03 (d, J=0.6 Hz, 1H), 7.49-7.41 (m, 2H), 7.32-7.23 (m, 2H), 5.12 (q, J=7.2 Hz, 1H), 3.02 (m, 1H), 2.61 (s, 3H), 1.92 (d, J=7.2 Hz, 3H), 1.27 (d, J=7.2 Hz, 3H), 1.10 (d, J=7.2 Hz, 3H); MS: (ES) m/z calculated for C19H20ClF3N6O [M+H]+ 441.1, found 440.9.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:68]=[N:69][C:70]([N:73]3[CH2:77][CH2:76][CH2:75][CH2:74]3)=[CH:71][CH:72]=2)[C:56]=1[CH3:78].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH:47][C:55]3[C:64]4[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=4[F:65])[N:58]=[C:57]([C:67]4[CH:68]=[N:69][C:70]([N:73]5[CH2:74][CH2:75][CH2:76][CH2:77]5)=[CH:71][CH:72]=4)[C:56]=3[CH3:78])=[CH:45][C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2ccc(N3CCCC3)nc2)nc2cc(F)cc(F)c2c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(N3CCCC3)nc2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
The Buchwald coupled product was prepared according to Procedure S using of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.018 g, 0.037 mmol), 2,5-dimorpholinopyridin-3-amine (0.074 g, 0.28 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(6-(pyrrolidin-1-yl)pyridin-3-yl)quinoline (0.084 g, 0.23 mmol) and Pd2dba3 (0.009 g, 0.009 mmol) and sodium tert-butoxide (0.056 g, 0.58 mmol) in toluene (2.3 mL) at 100° C. for 2.5 h. The crude product was purified by column chromatography on alumina (0-60% EtOAc/hexanes) to give the desired product N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(6-(pyrrolidin-1-yl)-pyridin-3-yl)quinolin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.42 (1H, dd, J=2.4, 0.5 Hz), 7.84 (1H, dd, J=8.7, 2.4 Hz), 7.73 (1H, d, J=5.7 Hz), 7.56-7.62 (1H, m), 7.55 (1H, d, J=2.5 Hz), 7.39 (1H, ddd, J=13.2, 9.4, 2.4 Hz), 6.58 (1H, d, J=8.6 Hz), 6.39 (1H, d, J=2.7 Hz), 3.61-3.82 (8H, m), 3.47 (4H, t, J=6.6 Hz), 3.15 (2H, br. s.), 2.94-3.05 (4H, m), 2.84 (2H, br. s.), 2.13 (3H, s), 1.95-2.03 (4H, m). Mass Spectrum (ESI) m/e=588.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][NH:14][CH:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:29]([O:31][CH3:32])=[O:30]>O1CCCC1>[CH3:32][O:31][C:29](=[O:30])[N:14]([CH2:13][CH2:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([F:10])([F:11])[F:9])=[CH:7][C:2]=1[Br:1])[CH:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18]
Reactant: COC(=O)Cl
Reactant: CCCC(CCC)NCCc1ccc(C(F)(F)F)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCC(CCC)N(CCc1ccc(C(F)(F)F)cc1Br)C(=O)OC

Procedure:
770 mg of N-[2-(2-bromo-4-trifluoromethylphenyl)ethyl]heptan-4-amine in solution in 15 cm3 of anhydrous tetrahydrofuran and 500 mg of potassium carbonate are stirred under an inert atmosphere at a temperature in the vicinity of 5° C. 0.19 cm3 of methyl chloroformate is introduced over 5 minutes into the reaction mixture. The reaction mixture is brought to reflux over 15 h, the insoluble material is separated by filtration and the filtrate is concentrated using a rotary evaporator under reduced pressure (5 kPa). The residual oil is purified by filtration through a silica pellet using a mixture of 10% ethyl acetate and 90% cyclohexane as eluent. The organic phase is then concentrated to dryness using a rotary evaporator under reduced pressure (5 kPa) in order to result in 666 mg of methyl[2-(2-bromo-4-trifluoromethylphenyl)ethyl](1-propylbutyl)carbamate in the form of a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[OH-].[K+].[CH2:13]([CH:15]1[O:17][CH2:16]1)Cl>CS(C)=O.[NH4+].[Cl-]>[NH:6]1[C:7]2[C:3](=[C:2]([O:1][CH2:13][CH:15]3[O:17][CH2:16]3)[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: Oc1cccc2[nH]ccc12
Reactant: ClCC1CO1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CS(C)=O
Product: c1cc(OCC2CO2)c2cc[nH]c2c1
Temperature: 45 °C
Reaction time: 4 h
Yield: 104.3 %

Procedure:
To a solution of 4-hydroxyindole (0.50 g, 3.8 mmol) in dimethylsulfoxide (10 mL) at 45° C. were added potassium hydroxide (0.43 g, 7.6 mmol) and then epichlorohydrin (1.4 g, 15.2 mmol). After being stirred at 45° C. for 4 h, the reaction mixture was diluted with a saturated solution of NH4Cl and extracted with diethyl ether (3×50 mL). The combined organic layers were dried with Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel with benzene/acetone mixtures to give the glycidyl 4-indolyl ether (compound 1a) (0.75 g, quant) as a colorless oil. See FIG. 18.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:8]([CH2:12][O:13][CH2:14][CH:15]=[N:16]O)[NH:9][C:10]=1[CH3:11])=[O:4].C([O-])=O.[NH4+]>CO.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]([C:5]1[CH:6]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:8]([CH2:12][O:13][CH2:14][CH2:15][NH2:16])[NH:9][C:10]=1[CH3:11])=[O:4]
Reactant: CCOC(=O)C1=C(COCC=NO)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Yield: 60.7 %

Procedure:
A mixture of 4-(2-chlorophenyl)-2-(2-hydroxyimino-ethoxymethyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid 3-ethyl 5-methyl ester (IBa, 150 mg), palladium hydroxide on carbon (10 mg) and ammonium formate (224 mg) in methanol (10 mL) was refluxed for 5 h under a nitrogen atmosphere. On cooling to room temperature, the mixture was filtered through a pad of celite. The filtrate was concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (grade 9385, Merck, 230-400 mesh, 60 Å) using a solvent mixture of dichloromethane and methanol (9:1; 100 mL), and dichloromethane, methanol and ammonium hydroxide (90:10:1; 500 mL) as eluent afforded the title compound (IAa 88 mg).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH2:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[BH4-].[Na+].C(O)(=[O:24])C>O1CCCC1.O.[OH-].[Na+]>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:11][C:12]([OH:24])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: C=C(COC1CCN(C(C)=O)CC1)c1ccccc1
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N1CCC(OCC(C)(O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-Acetyl-4-(2-phenylallyloxy)piperidine (4.0 g.) in dry tetrahydrofuran (60 ml.) was added dropwise to a stirred solution of mercuric acetate (6.35 g.) in water (60 ml.) and the solution stirred at room temperature for one hour. Sodium hydroxide solution (40 ml., 3 N) and sodium borohydride (0.75 g.) in sodium hydroxide solution (40 ml., 3 N) were then added dropwise to the stirred solution at 0° C. The grey suspension was stirred at 0° C. for one hour, glacial acetic acid was added to pH 6, then the suspension filtered and the filtrate extracted with chloroform (3×150 ml.). The combined chloroform extracts were dried (Na2SO4) and evaporated in vacuo to give N-acetyl-4-(2-hydroxy-2-phenyl-n-propoxy)piperidine (2.1 g.). This product in methanol (30 ml.) and sodium hydroxide solution (20 ml., 5 N) was heated under reflux for 4 hours. The organic solvent was evaporated and the aqueous solution extracted with chloroform (3×20 ml.), dried (Na2SO4) and the solvent evaporated in vacuo to give 4-(2-hydroxy-2-phenyl-n-propoxy)piperidine (1.8 g.) as an oil. A sample was characterized as the oxalate salt which recrystallized from ethyl acetate and had an m.p. of 132°-134° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=2[O:23]CC2C=CC(OC)=CC=2)[CH:12]=[CH:11][C:10]=1[N:33]1[S:37](=[O:39])(=[O:38])[N:36]([CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[C:35](=[O:46])[CH2:34]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=2[OH:23])[CH:12]=[CH:11][C:10]=1[N:33]1[S:37](=[O:39])(=[O:38])[N:36]([CH2:40][CH2:41][Si:42]([CH3:43])([CH3:45])[CH3:44])[C:35](=[O:46])[CH2:34]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(COc2ccc(C)cc2Cc2ccc(N3CC(=O)N(CC[Si](C)(C)C)S3(=O)=O)c(OCc3ccccc3)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(O)c(Cc2ccc(N3CC(=O)N(CC[Si](C)(C)C)S3(=O)=O)c(OCc3ccccc3)c2)c1

Procedure:
A solution of 5-{2-benzyloxy-4-[2-(4-methoxybenzyloxy)-5-methylbenzyl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (50 mg) in 10% TFA/methylene chloride (1 mL) is stirred at RT for 2 h. The solvent is removed under reduced pressure to give the title compound.