Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7](Cl)[S:8][C:4]=2[CH:3]=1.Cl.[NH:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([OH:19])[CH2:14]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([N:13]3[CH2:18][CH2:17][CH2:16][C@H:15]([OH:19])[CH2:14]3)[S:8][C:4]=2[CH:3]=1
Reactant: O[C@H]1CCCNC1
Reactant: Clc1nc2ccc(Br)cc2s1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O[C@H]1CCCN(c2nc3ccc(Br)cc3s2)C1
Temperature: 150 °C

Procedure:
A mixture of 6-bromo-2-chlorobenzo[d]thiazole (1.0 g, 4.0 mmol) and (S)-piperidin-3-ol hydrochloride (0.609 g, 4.43 mmol), and N,N-diisopropylethylamine (3.51 mL, 0.02012 mole) in N,N-dimethylformamide (2.0 mL) was heated to 150° C. under microwave irradiation for 15 minutes. The reaction mixture was transferred to a 100 mL round bottom flask (methanol rinse) and volatiles were removed under reduced pressure. The residue was partitioned between CHCl3 and saturated aqueous sodium carbonate. The organic layer was dried over MgSO4. Drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography on an Analogix IntelliFlash-280 (Analogix SF15-12g, 100% CHCl3 to 60:40 CHCl3/ethyl acetate). Fractions containing product were combined and concentrated under reduced pressure to provide (S)-1-(6-bromobenzo[d]thiazol-2-yl)piperidin-3-ol.
Reaction SMILES: [Li].[O:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH:6]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=O)[C:5]=2[CH:4]=[CH:3]1.O.[OH-].[Na+]>O1CCCC1>[N:13]1([CH2:11][CH:6]2[C:5]3[CH:4]=[CH:3][O:2][C:10]=3[CH2:9][CH2:8][NH:7]2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(C1NCCc2occc21)N1CCCC1
Agent: [Li]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: c1cc2c(o1)CCNC2CN1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a suspension of lithium alumimium hydride (0.2 g) in dry tetrahydrofuran (30 ml) was added a solution of the product of stage (i) (0.58 g) in tetrahydrofuran (10 ml) and the mixture was stirred at ambient temperature for 1 h. Water (0.2 ml), aqueous sodium hydroxide (2M; 0.6 ml) and water (0.2 ml) were cautiously added and the mixture was filtered. The filtrate was evaporated, the residue was dissolved in dichloromethane (20 ml), dried and evaporated in vacuo to give the title compound as an oil (0.54 g). T.l.c. SiO2 dichloromethane/methanol/ammonia (75:10:2) Rf 0.5.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]=C)[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[O:14]=[O+][O-].CSC>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]=[O:14])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: C=Cc1cccc(Cl)c1C(=O)OC
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CSC
Product: COC(=O)c1c(Cl)cccc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
Into a solution of methyl 2-chloro-6-vinylbenzoate (6.7 g, 34 mmol) in dry DCM (100 mL) was bubbled O3 at −78° C. over a 30 minute period. Next, nitrogen gas was bubbled into the solution until the solution was colorless. Dimethylsulfane (4.3 g, 68 mmol) was added dropwise and the resulting mixture was warmed to RT and stirred for 2 hours. The reaction mixture was subsequently washed with water (30 mL) and extracted with DCM (3×100 mL). The organic layers were combined, dried over Na2SO4, and concentrated. The crude product was purified by column chromatography eluting with a gradient of EtOAc (0-90%) and PE to give the title compound (3.8 g, 56%). 1H NMR (400 MHz, CDCl3) δ ppm 9.89 (s, 1H), 7.728 (d, J=7.2 Hz, 1H), 7.606 (d, J=8.0 Hz, 1H), 7.489 (t, J=8.0 Hz, 1H), 3.95 (s, 3H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[C:9](OS(C(F)(F)F)(=O)=O)=[N:10][C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=2.[NH:30]1[C:38]2[C:33](=[CH:34][C:35](B(O)O)=[CH:36][CH:37]=2)[CH:32]=[CH:31]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:30]1[C:38]2[C:33](=[CH:34][C:35]([C:9]3[C:8]([N:3]4[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]4[CH3:1])=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=4)[N:10]=3)=[CH:36][CH:37]=2)[CH:32]=[CH:31]1
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCC[C@@H]3C)nc2c1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc4[nH]ccc4c3)c(N3CCCC[C@@H]3C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 34.2 %

Procedure:
To a solution of (S)-methyl 3-(2-methylpiperidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (250 mg, crude) in dioxane (5 mL) was added Pd(PPh3)4 (33 mg, 0.03 mmol), 1H-indol-5-ylboronic acid (234 mg, 1.45 mmol), K3PO4 (367 mg, 1.74 mmol) and water (5 drops). The resulting solution was stirred for 1 h at 90° C. with an inert atmosphere of nitrogen and then concentrated in vacuo to give a residue, which was purified by silica gel column chromatography eluting with 1%-10% ethyl acetate in petroleum ether to afford (S)-methyl 2-(1H-indol-5-yl)-3-(2-methylpiperidin-1-yl)quinoxaline-6-carboxylate as a yellow solid (79 mg).
Reaction SMILES: [C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]4[NH:21][C:20]5[CH:22]=[CH:23][C:24]([C:26]([OH:28])=O)=[CH:25][C:19]=5[N:18]=4)=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:31]([NH2:37])[C:32]1[O:36][CH:35]=[CH:34][CH:33]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[O:36]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH2:31][NH:37][C:26]([C:24]1[CH:23]=[CH:22][C:20]2[NH:21][C:17]([CH2:16][O:15][C:14]3[CH:29]=[CH:30][C:11]([C:1]45[CH2:10][CH:5]6[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]6)[CH2:2]4)[CH2:8]5)=[CH:12][CH:13]=3)=[N:18][C:19]=2[CH:25]=1)=[O:28]
Reactant: O=C(O)c1ccc2[nH]c(COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)nc2c1
Reactant: NCc1ccco1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccco1)c1ccc2[nH]c(COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.3 %

Procedure:
To a solution of 2-(4-adamantan-1-yl-phenoxymethyl)-1H-benzoimidazole-5-carboxylic acid (50 mg, 0.124 mmol), furfuryl amine (18 mg, 0.186 mmol) and DMAP (22.78 mg, 0.186 mmol) in DMF (1 mL) was added PyBOP (97 mg, 0.186 mmol) at room temperature. The mixture was stirred for 16 h at room temperature and then poured into water (150 mL). The resulting solid was extracted with a mixture of methanol:MC (10%), washed with brine, aqueous sodium bicarbonate and water, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The resulted crude product was purified by PLC (methanol: MC=0.5:9.5) to afford 2-(4-adamantan-1-yl-phenoxymethyl)-1H-benzoimidazole-5-carboxylic acid (furan-2-ylmethyl)-amide as a colorless solid (43.2 mg, 72% yield).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[C:19](\[CH3:25])/[C:20]([O:22]CC)=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:26]3[CH:31]=[CH:30][C:29]([O:32]C)=[CH:28][CH:27]=3)[S:8][C:7]=2[CH:34]=1.B(Br)(Br)Br>C(Cl)Cl.CO>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:13]=[CH:14][C:15](/[CH:18]=[C:19](\[CH3:25])/[C:20]([OH:22])=[O:21])=[CH:16][CH:17]=3)=[C:9]([C:26]3[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=3)[S:8][C:7]=2[CH:34]=1
Reactant: CCOC(=O)/C(C)=C/c1ccc(Oc2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: C/C(=C\c1ccc(Oc2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 1.67 h
Yield: 34.7 %

Procedure:
To a solution of (E)-ethyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)-benzo[b]thiophen-3-yl)oxy)phenyl)-2-methylacrylate (107 mg, 0.225 mmol) in DCM (5.0 mL) at 0° C. was added BBr3 (1.0 M in DCM, 0.902 mL, 0.902 mmol) dropwise. The resulting mixture was stirred at 0° C. for 100 min after which the reaction was quenched by addition of sat. aq. NaHCO3 (4 mL) and acidified to pH 3 by addition of concentrated HCl. The aqueous layer was then extracted with 5% MeOH/EtOAc (4×12 mL) and the combined organic layers were passed through a phase separator to remove water and concentrated in vacuo to afford the crude product which was dissolved in MeOH and purified by reverse phase HPLC (neutral condition, 3% 1-propanol in 1-100% CH3CN/H2O) to afford (E)-3-(4-((6-hydroxy-2-(4-hydroxyphenyl)-benzo[b]thiophen-3-yl)oxy)phenyl)-2-methylacrylic acid (32.4 mg, 0.078 mmol, 34% yield). HRMS (m/z, MH+): 419.0872.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19](=[NH:23])[NH:20][O:21][CH3:22])[C:3]=1[S:24]([CH3:26])=[O:25].[CH3:27]C(C)([O-])C.[K+].IC>C1COCC1>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19](=[N:23][CH3:27])[NH:20][O:21][CH3:22])[C:3]=1[S:24]([CH3:26])=[O:25]
Reactant: CC(C)(C)[O-]
Reactant: CONC(=N)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CN=C(NOC)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Reaction time: 16 h
Yield: 25.2 %

Procedure:
A solution of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-N-methoxy-4-methylsulfinyl-1H-pyrazole-3-carboximidamide (0.5 g) in anhydrous THF was stirred at 0-5° C. and potassium tert-butoxide (0. 13 g) and iodomethane (0.081 ml) added. After three hours further potassium tert-butoxide (0.068 g) and iodomethane (0.08 ml) were added at 0-5° C. The mixture was stirred at this temperature for 16 hours, evaporated and the residue purified by chromatography on silica gel eluting with 3:1 dichloromethane/ethyl acetate to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-N-methoxy-N′-methyl-4-methylsulfinyl-1H-pyrazole-3-carboximidamide (0.13 g), m.p.139-142° C. Compound 50.
Reaction SMILES: [C:1]1([C@H:7]([CH2:11][CH3:12])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.CC[N+](CCCN(C)C)=C=N.[CH2:34]([N:41]1[CH2:45][C@H:44]2[C@H:46]([NH2:49])[CH2:47][CH2:48][C@H:43]2[CH2:42]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl>[CH2:34]([N:41]1[CH2:45][C@H:44]2[C@H:46]([NH:49][C:8](=[O:10])[C@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:11][CH3:12])[CH2:47][CH2:48][C@H:43]2[CH2:42]1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC[C@H](C(=O)O)c1ccccc1
Reactant: N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Agent: CC[N+](=C=N)CCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC[C@H](C(=O)N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(S)-2-Phenylbutanoic acid (41.7 mg, 0.254 mmol), 1-hydroxybenzotriazole (38.9 mg, 0.254 mmol), and N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (0.045 mL, 0.254 mmol) were combined in dichloromethane (1 mL). The reaction was stirred at room temperature for 10 minutes, and then (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine (50 mg, 0.231 mmol) from Step E was added in 0.5 mL of dichloromethane. The reaction was stirred at room temperature for 20 hours, and then quenched with 0.5 mL of water. The organic layer was separated. The crude material was chromatographed using a silica gel cartridge (Analogix®, Burlington, Wis., RS-4) eluting with 1-10% methanol(ammonia)/dichloromethane to give the title compound: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.47 (d, J=7.0, 1H), 7.59 (m, 2H), 7.42 (d, J=7.1, 2H), 7.34 (dd, J=7.6, 16.5, 4H), 7.25 (dt, J=5.0, 10.1, 2H), 4.45-4.29 (m, 1H), 3.62-3.51 (m, 2H), 3.44 (d, J=13.2, 1H), 2.85 (dd, J=2.7, 9.0, 1H), 2.58-2.50 (m, 1H), 2.50-2.42 (m, 2H), 2.40-2.31 (m, 1H), 2.31-2.22 (m, 2H), 1.97 (dq, J=6.1, 12.1, 1H), 1.85 (td, J=6.9, 13.6, 1H), 1.74 (dt, J=6.4, 14.3, 1H), 1.46 (dt, J=7.1, 19.2, 1H), 1.31 (dt, J=6.2, 20.5, 1H), 0.96 (dd, J=5.5, 9.1, 3H); MS (ESI+) m/z 363 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][CH3:25])[CH:11]=1)[CH3:2].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34][C:35]([OH:37])=O)[CH:28]=1>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[CH2:22][N:23]([CH2:24][CH3:25])[C:35](=[O:37])[CH2:34][CH2:33][C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)[CH:11]=1)[CH3:2]
Reactant: O=C(O)CCc1cccnc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OCC)c1
Product: CCOC(=O)Cc1cncc(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)CCc2cccnc2)c1

Procedure:
[5-(2-Ethylaminomethyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester and 3-pyridinepropionic acid were reacted as described in Example 8, Step 6 to provide [5-(2-{[N-ethyl-N-(3-pyridin-3-yl-propionyl)-amino]-methyl}-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester. The ester was hydrolyzed to the acid as described in Example 30, Step 2.
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9]([CH3:11])C)[CH2:3]C1.[F:13][C:14]1[CH:21]=[C:20](F)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17].C(=O)([O-])[O-].[Li+].[Li+]>>[CH2:9]([C@H:5]1[C@@:4]([CH2:1][CH3:3])([OH:12])[CH2:8][CH2:7][N:6]1[C:20]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([F:13])[CH:21]=1)[CH3:11]
Reactant: N#Cc1ccc(F)cc1F
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@@H]1N(c2ccc(C#N)c(F)c2)CC[C@@]1(O)CC

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2,3-diethylpyrrolidin-3-ol 0.5 oxalate (196 mg), 2,4-difluorobenzonitrile (284 mg) and lithium carbonate (202 mg), the title compound was obtained as pale-yellow oil (yield: 208 mg, yield: 76%).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[CH:32]1([NH2:36])[CH2:35][CH2:34][CH2:33]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH:32]1([NH:36][C:3](=[O:5])[CH:2]([OH:1])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[N:16]=[C:15]([C:17]4[O:21][N:20]=[C:19]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[C:18]=4[C:28]([F:30])([F:31])[F:29])[O:14][N:13]=3)=[CH:10][CH:11]=2)[CH2:35][CH2:34][CH2:33]1
Reactant: NC1CCC1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NC1CCC1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 23.9 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol), cyclobutanamine (4.95 mg, 0.070 mmol), HATU (22.92 mg, 0.060 mmol), and 4-methylmorpholine (18.76 mg, 0.185 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 12 min, 20 mL/min, 220 nM, product retention=14.17 min) to provide (R/S)-N-cyclobutyl-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (7 mg, 0.011 mmol, 23.93% yield): LCMS=485.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.12-8.23 (2 H, m), 7.53-7.73 (7 H, m), 5.09 (1 H, s), 4.15-4.42 (1 H, m), 2.28 (2 H, dddd, J=10.07, 4.90, 4.62, 2.86 Hz), 1.98-2.13 (2 H, m), 1.70-1.79 (2 H, m); HPLC peak RT=10.4 min (Method A).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[C:13]1(=[O:23])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[N:15][NH:14]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:23]=[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[N:15][N:14]1[CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1
Reactant: O=Cc1ccc(OCCBr)cc1
Reactant: O=c1[nH]ncc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCCn2ncc3ccccc3c2=O)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 83.9 %

Procedure:
A mixture of 4-(2-bromoethoxy)benzaldehyde (4.97 g), 1(2H)-phthalazinone (3.27 g), potassium carbonate (6.20 g) and N,N-dimethylformamide (50 ml) was stirred at 80° C. for 5 hours. After cooling, the reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated to obtain 4-[2-[1-oxo-2(1H)-phthalazinyl]ethoxy]benzaldehyde (5.36 g, yield 84%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 126–127° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.[C:16](=O)([O-])[O-].[K+].[K+].COP(C(=[N+]=[N-])C(=O)C)(=O)OC.C(=O)([O-])[O-].[Na+].[Na+]>CO>[C:14]([C:9]1[N:10]([CH3:13])[N:11]=[N:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)#[CH:16]
Reactant: O=C([O-])[O-]
Reactant: Cn1nnc(-c2ccc(F)cc2)c1C=O
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: C#Cc1c(-c2ccc(F)cc2)nnn1C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
To a mixture of 5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazole-4-carbaldehyde (616 mg, 3.0 mmol) in MeOH (13 mL) was added potassium carbonate (829 mg, 6.0 mmol) followed by a solution of (1-diazo-2-oxo-propyl)-phosphonic acid dimethyl ester (634 mg, 3.3 mmol) in MeOH (4 mL) at room temperature and the resulting mixture stirred for 1 h. The mixture was then poured into sodium carbonate solution (1 M) and extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 50% ethyl acetate in heptane) afforded the title compound (556 mg, 92%) as a light red solid. MS: m/e=202.2 [M]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([Cl:20])[CH:15]=3)[N:12]=[C:11]([C:21](O)=[O:22])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=C(C2N(C3C=NC=CC=3)N=C(C([N:45]3[CH2:50][CH2:49][NH:48][C:47](=[O:51])[CH2:46]3)=O)C=2)C=C(F)C=1.O=C1CNCCN1>>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([Cl:20])[CH:15]=3)[N:12]=[C:11]([C:21]([N:45]3[CH2:50][CH2:49][NH:48][C:47](=[O:51])[CH2:46]3)=[O:22])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3cccnc3)n2)CCN1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Br)c2)n(-c2ccnc(Cl)c2)n1
Agent: O=C1CNCCN1
Product: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Br)c3)n(-c3ccnc(Cl)c3)n2)CCN1

Procedure:
50 mg (0.13 mmol) of the compound of Example 33A is reacted analogously to the synthesis of the compound of Example 4 with 14 mg (0.14 mmol) of 2-oxopiperazine. 49 mg (81% of theory) of the title compound is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[CH3:21])=[CH:7][C:6]=2[C:5]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:4]=2[N:3]=1.Br[CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:16][C:15]=3[CH3:21])=[CH:7][C:6]=2[C:5]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:4]=2[N:3]=1
Reactant: CCOC(=O)CCCCBr
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3C)cc12
Product: CCOC(=O)CCCCOc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1

Procedure:
Ethyl 5-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)pentanoate was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenol (from Example 50) following the procedure described for Example 139, but using ethyl 5-bromopentanoate 1H NMR (CDCl3): δ 8.64 (s, 1H), 8.27 (s, 1H), 8.02 (d, 1H), 7.66 (s, 1H), 7.32 (d, 1H), 6.91 (d, 1H), 6.66 (s, 1H), 6.63 (d, 1H), 4.13 (q, 2H), 3.93 (t, 2H), 3.14 (t, 2H), 2.99 (t, 2H), 2.54 (s, 3H), 2.38 (t, 2H), 2.25 (s, 3H), 1.79-1.83 (m, 4H), 1.26 (t, 3H). LRMS [M+H]=472.3
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([O:13][C:14]2[CH:25]=[CH:24][C:17]([O:18][CH:19]([CH3:23])[C:20](Cl)=[O:21])=[CH:16][CH:15]=2)=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1.C(N(CC)CC)C>O1CCCC1>[Cl:2][C:3]1[C:4]([O:13][C:14]2[CH:25]=[CH:24][C:17]([O:18][CH:19]([CH3:23])[C:20]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:34])=[O:35])=[CH:29][CH:28]=3)=[O:21])=[CH:16][CH:15]=2)=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)Nc1ccc(S(N)(=O)=O)cc1
Yield: 80.8 %

Procedure:
(2-(4-(3-Chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy)propionic acid chloride hydrochloride (0.8 g) and 4-aminobenzene sulfonamide (0.5 g) were dissolved in dry tetrahydrofuran (20 ml), and the solution was stirred, with an addition of triethylamine (0.6 ml) at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated under a reduced pressure, the residue was dissolved in methylene chloride and washed with 1 N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water and saturated aqueous sodium chloride After drying over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under a reduced pressure was purified by medium pressure column chromatography by using silica gel, to obtain the title compound (0.8 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[CH2:27](P(CCCC)CCCC)[CH2:28][CH2:29]C.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.CC(O)C>O1CCCC1>[CH3:27][CH:28]([O:1][C:2]1[CH:3]=[C:4]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2)[CH3:29]
Reactant: CCCCP(CCCC)CCCC
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(O)c2[nH]1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OC(C)C)c2[nH]1
Temperature: 70 °C
Reaction time: 5.5 h
Yield: 84 %

Procedure:
A mixture of ethyl 7-hydroxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (2.0 g), tributylphosphine (2.6 mL), 1,1′-(azodicarbonyl)dipiperidine (2.69 g), 2-propanol (0.81 mL) and tetrahydrofuran (50 mL) was stirred at 70° C. for 5.5 h. Furthermore, tributylphosphine (0.7 mL) and 1,1′-(azodicarbonyl)dipiperidine (0.7 g) were added to the mixture. After stirring at 70° C. for 2 h, the mixture was cooled to 0° C. and a precipitate was removed by filtration. The filtrate was concentrated and the residue was purified by basic silica gel column chromatography (ethyl acetate/hexane 1/99 to 40/60), followed by silica gel column chromatography (ethyl acetate/hexane=1/99 to 35/65, volume ratio) to give the title compound (1.87 g, 84%) as a white amorphous solid. MS 418 (MH+).