Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:6]2[CH:7]=[C:8]([CH:11]=O)[CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:33](Br)(Br)([Br:35])[Br:34]>C1COCC1>[Br:34][C:33]([Br:35])=[CH:11][C:8]1[CH:9]=[CH:10][C:5]2[O:4][CH2:3][C:2]([CH3:13])([CH3:1])[C:6]=2[CH:7]=1
Reactant: CC1(C)COc2ccc(C=O)cc21
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)COc2ccc(C=C(Br)Br)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
To a solution of 3,3-dimethyl-2,3-dihydro-1-benzofuran-5-carbaldehyde (4.18 g, 23.7 mmol) and triphenylphosphine (15.5 g, 59.3 mmol) in THF (40 mL) was added carbon tetrabromide, and the mixture was stirred at room temperature for 15 min. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=49:1 to 7:3) to give the title compound (5.75 g, yield 73%) as an oil.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH3:14].[O:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([N:18]1[C:19](=[O:21])[CH2:20][O:16][C:17]1=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH3:14]
Reactant: CC/C=C\CCCCCCCCCCO
Reactant: O=C1COC(=O)N1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC/C=C\CCCCCCCCCCN1C(=O)COC1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
420 mg (1.98 mmol) of (11Z)-tetradec-11-en-1-ol, in solution in 2 ml of tetrahydrofuran, are added to a solution of 200 mg (1.98 mmol) of 1,3-oxazolidine-2,4-dione and of 571 mg (2.18 mmol) of triphenylphosphine in 4 ml of tetrahydrofuran. 0.99 ml (2.2 mmol) of a 40% solution of diethyl azodicarboxylate in toluene is subsequently added dropwise. The mixture is stirred at ambient temperature for 5 h.
Reaction SMILES: CC1C=C[C:5]([CH2:6][S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=CC=1.ICC.CC[O-].[Na+].SCC(OCC)=O>C(O)C>[CH2:6]([S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:5]
Reactant: CCOC(=O)CSCc1ccc(C)cc1
Agent: CCOC(=O)CS
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCI
Product: CCOC(=O)CSCC

Procedure:
The procedure is as in Example 29 for the preparation of ethyl (4-methylbenzylthio)acetate, starting with iodoethane (10.5 g), a 2M ethanolic solution of sodium ethylate (37 cc) and ethyl 2-mercaptoacetate (8.1 g) in ethanol (100 cc). Ethyl (ethylthio)acetate (6.9 g) is thereby obtained, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [Br-].[CH2:2]([Zn+])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.I[C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([C:18]2[N:19]=[C:20]([NH:23][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[S:21][CH:22]=2)=[C:13]([CH3:32])[CH:12]=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:2]([C:11]1[CH:12]=[C:13]([CH3:32])[C:14]([C:18]2[N:19]=[C:20]([NH:23][C:24](=[O:31])[C:25]3[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=3)[S:21][CH:22]=2)=[C:15]([CH3:17])[CH:16]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cc(I)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Reactant: [Zn+]Cc1ccccc1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Cc2ccccc2)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1

Procedure:
A THF solution of benzylzinc(II) bromide (4.0 mL, 2.0 mmol) was added to a degassed solution of N-(4-(4-iodo-2,6-dimethylphenyl)thiazol-2-yl)isonicotinamide (435 mg, 1.0 mmol) and tetrakistriphenylphosphine palladium (57.8 mg, 0.10 mmol) in THF (5.0 mL). The reaction mixture was heated at reflux for 16 h under N2 and then poured into saturated aqueous NaHCO3. The mixture was extracted with ethyl acetate, washed with brine, dried MgSO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give N-(4-(4-benzyl-2,6-dimethylphenyl)thiazol-2-yl)isonicotinamide: 1H NMR (500 MHz, CDCl3 δ 8.70 (d, J=4.9 Hz, 2 H), 7.67 (d, J=4.9 Hz, 2 H), 7.33 (d, J=8.6 Hz, 2 H), 7.10-7.26 (m, 3 H), 6.80 (s, 1 H), 6.24 (s, 1 H), 3.86 (s, 2 H), 2.04 (s, 6 H); ESI-MS: m/z 399.9 (M+H)+.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][C:16]=1[NH:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[N:28]([O-])=O.[Na+].[F:32][P-:33]([F:38])([F:37])([F:36])([F:35])[F:34].[K+]>CO.Cl.O>[F:32][P-:33]([F:38])([F:37])([F:36])([F:35])[F:34].[CH2:1]([O:9][C:10]1[CH:11]=[C:12]([N+:13]#[N:28])[CH:14]=[CH:15][C:16]=1[NH:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:19])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1cc(N)ccc1NS(=O)(=O)c1ccc(C)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCCCCCCCOc1cc([N+]#N)ccc1NS(=O)(=O)c1ccc(C)cc1
Reaction time: 0.17 h
Yield: 88.5 %

Procedure:
Then, 39 g of 3-(n-octyloxy)-4-(p-toluenesulfonyl)aminoaniline was dissolved in a mixed solution of 300 ml of methanol and 25.3 ml of concentrated hydrochloric acid. The solution was cooled to -10° to -5° C., and a solution of 6.9 g of sodium nitrite in 14 ml of water was added thereto in several seconds and, after 10 minutes, 18.5 g of powdery potassium hexafluorophosphate was added thereto. Thereafter, 150 ml of water was dropwise added thereto over about 30 minutes, and the resulting mixture was stirred for about one hour while keeping the internal temperature at about 5° C. 3-(n-Octyloxy)-4-(p-toluene-sulfonyl)aminobenzenediazonium hexafluorophosphate precipitated as crystals was filtered out, and washed with a mixed solvent of methanol-water to obtain 48.4 g of 3-(n-octyloxy)-4-(p-toluenesulfonyl)aminobenzenediazonium hexafluorophosphate.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][N:27]=1>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]3)=[CH:19][C:18]=1[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][N:27]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Reactant: OB(O)c1ccc(F)c(-c2ccncn2)c1
Product: Fc1ccc(-c2ccnc3nc(C(F)(F)F)ccc23)cc1-c1ccncn1
Yield: 24.5 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (50 mg, 0.22 mmol) was coupled to 4-fluoro-3-pyrimidin-4-yl-phenylboronic acid (61 mg, 0.28 mmol) as described in Example 7 part g), affording 5-(4-fluoro-3-pyrimidin-4-ylphenyl)-2-trifluoromethyl[1,8]naphthyridine (20 mg, 25%). δH (360 MHz, CDCl3) 7.46 (1H, dd, J 8.4 and 11.2), 7.60-7.64 (2H, m), 7.85 (1H, d, J 8.8), 7.96-7.98 (1H, m), 8.42 (1H, dd, J 2.5 and 7.4), 8.53 (1H, d, J 8.4), 8.87 (1H, d, J 5.3), 9.30 (1H, s), 9.31 (1H, s). m/z (ES+) 371 [MH]+.
Reaction SMILES: [NH:1]1[C:5]2[N:6]=[CH:7][CH:8]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1.C1N2CN3CN(C2)CN1C3.[C:24](O)(=[O:26])C>O>[CH:24]([C:3]1[C:4]2[C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=[N:6][C:5]=2[NH:1][CH:2]=1)=[O:26]
Reactant: CC(=O)O
Reactant: COC(=O)c1ccnc2[nH]ccc12
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: COC(=O)c1ccnc2[nH]cc(C=O)c12
Temperature: 25 °C

Procedure:
Methyl 1H-pyrrolo[2,3-b]pyridine-4-carboxylate (500 mg, 2.84 mmol) and hexamethylenetetramine (796 mg, 5.68 mmol) were combined in water (8 mL) and glacial acetic acid (16 mL) and heated at 100° C. overnight then cooled to room temperature. The reaction mixture was extracted with ethyl acetate and the organics were dried over MgSO4 and concentrated in vacuo to give a residue. Purification of the residue by silica gel chromatography (50% EtOAc/Hexanes) gave the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 8.57 (s, 1H), 8.48 (d, 1H, J=4.8 Hz), 7.48 (d, 1H, J=4.8 Hz), 5.74 (d, 1H, J=6.8 Hz), 3.91 (s, 3H), 2.78 (s, 3H). [M+H] found 205.
Reaction SMILES: [CH2:1]([N:3]([CH2:40][CH3:41])[C:4]1[CH:5]=[CH:6][C:7]([NH:30][C:31](=[O:39])[C:32]2[CH:37]=[CH:36][CH:35]=[C:34](I)[CH:33]=2)=[C:8]([C:10]2[CH:11]=[C:12]([CH:27]=[CH:28][N:29]=2)[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[O:14])[CH:9]=1)[CH3:2].[CH2:42]([OH:57])[CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][C:55]#[CH:56].CCN(CC)CC>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C1COCC1>[CH2:1]([N:3]([CH2:40][CH3:41])[C:4]1[CH:5]=[CH:6][C:7]([NH:30][C:31](=[O:39])[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:56]#[C:55][CH2:54][O:53][CH2:52][CH2:51][O:50][CH2:49][CH2:48][O:47][CH2:46][CH2:45][O:44][CH2:43][CH2:42][OH:57])[CH:33]=2)=[C:8]([C:10]2[CH:11]=[C:12]([CH:27]=[CH:28][N:29]=2)[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[O:14])[CH:9]=1)[CH3:2]
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(I)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: C#CCOCCOCCOCCOCCO
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CC)c1ccc(NC(=O)c2cccc(C#CCOCCOCCOCCOCCO)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reaction time: 13 h
Yield: 78.8 %

Procedure:
To a slurry of 2-(5-(diethylamino)-2-(3-iodobenzamido)phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide (385 mg, 0.57 mmol), 3,6,9,12-tetraoxapentadec-14-yn-1-ol (175 mg, 0.75 mmol), Et3N (3 mL) and THF (2 mL) was added bis(triphenylphosphine)palladium(II)dichloride (12 mg, 0.017 mmol) and CuI (10 mg, 0.053 mmol) and purged well with nitrogen. The reaction mixture was stirred for 13 hours, then concentrated under vacuum and combined with the crude product from another run (0.15 mmol scale). Purification by flash chromatography on silica gel eluting (1% to 5% MeOH in DCM) gave the title compound (349 mg). 1H NMR (400 MHz, CDCl3, ppm) δ□ 12.51 (s, 1H), 8.83 (d, J=5.3 Hz, 1H), 8.42 (d, J=9.0 Hz, 1H), 8.21 (s, 1H), 7.99 (t, J=1.6 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.75-7.68 (m, 2H), 7.65 (s, 1H), 7.60 (d, J=7.3 Hz, 1H), 7.58-7.54 (m, 2H), 7.48 (t, J=7.6 Hz, 1H), 7.42 (t, J=7.9 Hz, 1H), 6.98 (d, J=2.6 Hz, 1H), 6.76 (d, J=8.8 Hz, 1H), 4.76 (d, J=5.9 Hz, 2H), 4.48 (s, 2H), 3.82-3.80 (m, 2H), 3.72-3.70 (m, 2H), 3.67-3.63 (m, 4H), 3.60 (s, 4H), 3.53-3.51 (m, 2H), 3.32 (quar, J=7.2 Hz, 4H), 2.90 (s, 1H), 1.13 (t, J=6.8 Hz, 6H). MS (ES, m/z): 777.4 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:22])[C@@H:9]([C:13]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1>ClCCl.O>[CH3:22][N:8]([C@H:9]([C:10]([N:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1)=[O:12])[C:13]([CH3:21])([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH3:14])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C(C)(C)c1ccccc1
Reactant: C1COCCN1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CN(C(=O)OC(C)(C)C)[C@H](C(=O)N1CCOCC1)C(C)(C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.12 h

Procedure:
To a cooled (0°C., ice bath) solution of (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-methyl-3-phenylbutanoic acid (1.0 g, 3.30 mmol, WO 99/32509) and benzotriazole-1-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate (1.46 g, 3.30 mmol) in anhydrous dichloromethane (5 ml) is added diisopropylethylamine (1.15 ml, 6.60 mmol) under an inert atmosphere. To this solution is added a solution of morpholine (0.313 ml, 3.60 mmol) in dichloromethane (2.5 ml). After stirring at 0° C. for 5-10 minutes, the cooling bath is removed, and the resulting reaction mixture is stirred at room temperature for 15-20 hours. The mixture is diluted with water, and the aqueous layer is extracted with ethyl acetate (3 times). The combined extracts are washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is chromatographed (silica gel, flash column), to give a dark yellow oil. (0.943 g, 76%) MS [M+H] 377.2
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:32]=[CH:31][CH:30]=[CH:29][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([N+:26]([O-:28])=[O:27])[CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:34]([C:37]1[CH:45]=[CH:44][C:40]([C:41]([OH:43])=[O:42])=[C:39]([OH:46])[CH:38]=1)(=[O:36])=[O:35]>>[CH2:1]([C:8]1[O:9][C:10]2[CH:32]=[CH:31][CH:30]=[CH:29][C:11]=2[C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][S:34]([C:37]3[CH:45]=[CH:44][C:40]([C:41]([OH:43])=[O:42])=[C:39]([OH:46])[CH:38]=3)(=[O:36])=[O:35])=[C:21]([N+:26]([O-:28])=[O:27])[CH:20]=2)=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: O=[N+]([O-])c1cc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)ccc1O
Product: O=C(O)c1ccc(S(=O)(=O)Oc2ccc(-c3ccc(-c4c(Cc5ccccc5)oc5ccccc45)cc3)cc2[N+](=O)[O-])cc1O

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzofuran-3-yl)-3-nitro-biphenyl-4-ol and 4-chlorosulfonyl-2-hydroxy-benzoic acid, in substantially the same manner, as described in Example 1 step g, and was obtained as a yellow solid, mp 200° C.; MS m/e 620 (M-H)+;
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:13]1[N:14]=[N+:15]([O-:26])[C:16]2[CH:25]=[C:24]3[C:20]([CH2:21][CH2:22][CH2:23]3)=[CH:19][C:17]=2[N:18]=1.CCN(CC)CC>COCCOC>[N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:13]2[N:14]=[N+:15]([O-:26])[C:16]3[CH:25]=[C:24]4[C:20]([CH2:21][CH2:22][CH2:23]4)=[CH:19][C:17]=3[N:18]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCC3
Reactant: NCCCCN1CCOCC1
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: [O-][n+]1nc(NCCCCN2CCOCC2)nc2cc3c(cc21)CCC3
Yield: 88 %

Procedure:
4-(4-Morpholinyl)butylamine (306) (2.02 g, 12.8 mmol) was added to a stirred solution of chloride 21 (1.89 g, 8.5 mmol) and Et3N (1.8 mL, 12.8 mmol) in DME (80 mL) and the solution stirred at reflux temperature for 16 h. The solvent was evaporated and the residue was partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 62 (2.57 g, 88%) as pale yellow solid: mp (MeOH/EtOAc) 151-152° C.; 1H NMR δ 8.07 (s, 1H, H-9), 7.38 (s, 1H, H-5), 5.78 (br s, 1H, NH), 3.78 (br t, J=4.6 Hz, 4H, 2×CH2O), 3.50 (br dd, J=6.6, 5.9 Hz, 2H, CH2N), 2.95-3.02 (m, 4H, H-6, H-8), 2.45 (br t, J=4.4 Hz, 4H, 2×CH2N), 2.40 (t, J=7.0 Hz, 2H, CH2N), 2.15 (p, J=7.5 Hz, 2H, H-7), 1.67-1.74 (m, 2H, CH2), 1.58-1.64 (m, 2H, CH2); 13C NMR δ 158.8, 154.5, 148.8, 143.2, 129.8, 120.5, 114.7, 66.9 (2), 58.5, 53.7 (2), 41.3, 33.1, 32.3, 27.4, 25.7, 24.0. Anal. Calcd for C18H25N5O2: C, 63.0; H, 7.3; N, 20.4. Found: C, 62.9; H, 7.2; N, 20.5%.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:10]=1[O:11][CH2:12][CH:13]1[CH2:16][N:15](C(C2C=CC=CC=2)C)[CH2:14]1.[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]\[C:33]([OH:35])=[O:34]>C(O)C.[Pd]>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]\[C:33]([OH:35])=[O:34].[CH3:8][C:9]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:10]=1[O:11][CH2:12][CH:13]1[CH2:16][NH:15][CH2:14]1
Reactant: Cc1cccc(C)c1OCC1CN(C(C)c2ccccc2)C1
Agent: [Pd]
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cccc(C)c1OCC1CNC1
Yield: 95.8 %

Procedure:
Triethylamine (2 mL) was added to a solution of 3-[(2,6-dimethylphenoxy)methyl]-1-(1-phenylethyl)azetidine (6.01 g, 21.3 mmol) in absolute ethanol (100 mL). The solution was hydrogenated on a Parr apparatus with approximately 1 g of 10% Pd on carbon as a catalyst at 55° C. and 60 psi (initial pressure) overnight. The mixture was cooled, filtered, and concentrated in vacuo. The residue was dissolved in 2-propanol and added to a solution of maleic acid (2.1 g, 18 mmol). The solid which formed was collected by filtration and recrystallized from 2-propanol to give 5.3 g (81%) of white solid; mp 150°-151.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[NH2:12][CH:13]1[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]1.CCN(C(C)C)C(C)C>CS(C)=O.O.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:12][CH:13]2[CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16]2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(Nc2cc(Br)ccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.1 %

Procedure:
To a solution of 4-bromo-2-fluoro-1-nitrobenzene (500 mg, 2.27 mmol) and tert-butyl 3-aminoazetidine-1-carboxylate (390 mg, 2.27 mmol) in DMSO (5 mL) was added DIPEA (351 mg, 2.72 mmol). The solution was stirred in sealed tube at room temperature for 16 h after which time, LCMS showed the completion of the reaction. The solution was diluted with water (100 mL) and DCM (100 mL) and the organic layer washed with water (30 mL×2) and brine (30 mL) and dried over anhydrous Na2SO4, then filtered and concentrated to give desired crude product (660 mg, Yield 80%). LCMS (m/z): 372.1 (M+1) which was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1([C@H:10]2[CH2:14][N:13]([C@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[C:12](=[O:23])[C@H:11]2[F:24])[CH2:9][CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>CO>[C:4]([C:6]1([C@H:10]2[CH2:14][N:13]([C@H:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH3:16])[C:12](=[O:23])[C@H:11]2[F:24])[CH2:7][CH2:8][CH2:9]1)([OH:5])=[O:3]
Reactant: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C(=O)[C@H]2F)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H](c1ccccc1)N1C[C@H](C2(C(=O)O)CCC2)[C@H](F)C1=O
Temperature: 40 °C
Reaction time: 18 h

Procedure:
Cis 4-(1-ethoxycarbonylcyclobutyl)-3-fluoro-1-[1-(S)-phenylethyl]-2-pyrrolidone (optical isomer B; 1.79 g, 5.37 mmol) was dissolved in methanol (10 ml) to which was subsequently added dropwise a 1 N sodium hydroxide aqueous solution (10 ml). The reaction solution was stirred at 40° C. for 18 hours and then methanol was evaporated under reduced pressure. The thus obtained residue was mixed with water (50 ml) and washed with chloroform (100 ml). The thus separated aqueous layer was acidified by dropwise addition of 1 N hydrochloric acid and extracted with chloroform (100 ml×2). The organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound quantitatively as a crude product.
Reaction SMILES: [Na].[C:2]([O:8]C)(=O)[CH2:3][C:4]([CH3:6])=[O:5].[F:10][C:11]([F:22])([F:21])[C:12]([CH3:20])=[CH:13]C(OC(C)C)=O>C(O)C>[CH3:13][C:12]1([C:11]([F:22])([F:21])[F:10])[CH2:20][C:2](=[O:8])[CH2:3][C:4](=[O:5])[CH2:6]1
Reactant: COC(=O)CC(C)=O
Reactant: CC(=CC(=O)OC(C)C)C(F)(F)F
Agent: [Na]
Solvent: CCO
Product: CC1(C(F)(F)F)CC(=O)CC(=O)C1

Procedure:
0.64 g of sodium were introduced into 40 ml of ethanol, and 3.23 ml of methyl acetoacetate and 4.9 g of isopropyl 4,4,4-trifluoro-3-methylbut-2-enoate were introduced, and the mixture was heated at the boil for 18 hours. After the mixture has been partitioned between dilute hydrochloric acid and ethyl acetate, the mixture is evaporated. The remaining unpurified methyl 2-methyl-4,6-dioxo-2-trifluoromethylcyclohexanecarboxylate is hydrolysed in a mixture of methanol and water at boiling point in the presence of 9.1 g of sodium hydroxide. The mixture is subsequently acidified with hydrochloric acid and extracted with fresh ethyl acetate. After recrystallization (ethyl acetate), pure 5-methyl-5-trifluoromethylcyclohexane-1,3-dione of melting point 150-152° C. is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[CH3:1][C:2]1[CH:10]=[C:6]([C:7]([O:9][CH2:17][CH3:18])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1
Reactant: Cc1ccc(O)c(C(=O)O)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(C)ccc1O

Procedure:
To a solution of 5-methyl salicylic acid (9.90 g) in ethanol (100 ml) was added concentrated sulfuric acid (1.0 g) and the mixture was refluxed under heating for 21 hr. The reaction mixture was concentrated to give an oil mainly containing the objective compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[N:23]([CH3:28])[N:24]=[C:25]([CH3:27])[CH:26]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:29](OCC)=[O:30].[O-]CC.[Na+].Cl>C(O)C>[OH:30][CH:29]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[N:23]([CH3:28])[N:24]=[C:25]([CH3:27])[CH:26]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)n(C)n1
Reactant: CCOC=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Temperature: 78 °C
Yield: 68.8 %

Procedure:
2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (1.2 g, 3.205 mmol) and ethyl formate (0.800 mL, 9.903 mmol) were dissolved in anhydrous ethanol (10 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (3.6 mL, 9.643 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a pale orange precipitate. The suspension was filtered yielding an orange solid as the pure 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.887 g, 2.204 mmol, 69%).
Reaction SMILES: [OH-].[Na+].CO.[CH:5]1([C:8]2[CH:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][CH2:29][C:28]5[N:27]=[C:26]([CH3:31])[C:25]([C:32]([O:34]C)=[O:33])=[CH:24][C:23]=5[C:22]4=[O:36])[CH2:17][CH2:16]3)[CH:11]=[C:10]([O:37][CH2:38][CH3:39])[C:9]=2[C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)[CH2:7][CH2:6]1.Cl>C(OCC)(=O)C.C1COCC1>[CH:5]1([C:8]2[CH:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][CH2:29][C:28]5[N:27]=[C:26]([CH3:31])[C:25]([C:32]([OH:34])=[O:33])=[CH:24][C:23]=5[C:22]4=[O:36])[CH2:17][CH2:16]3)[CH:11]=[C:10]([O:37][CH2:38][CH3:39])[C:9]=2[C:40]2[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=2)[CH2:6][CH2:7]1
Reactant: CCOc1cc(CN2CCC(N3CCc4nc(C)c(C(=O)OC)cc4C3=O)CC2)cc(C2CC2)c1-c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOc1cc(CN2CCC(N3CCc4nc(C)c(C(=O)O)cc4C3=O)CC2)cc(C2CC2)c1-c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 29.4 %

Procedure:
A 2 M aqueous sodium hydroxide solution (1.50 mL) was added at room temperature to a methanol (2 mL)-THF (2 mL) solution of methyl 6-(1-((2-cyclopropyl-6-ethoxy-4′-fluorobiphenyl-4-yl)methyl)piperidin-4-yl)-2-methyl-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate (770 mg), and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was neutralized with hydrochloric acid at room temperature. Then, ethyl acetate was added thereto, and the solvent was distilled off under reduced pressure. The deposited solid was collected by filtration and washed with diethyl ether. The obtained solid was recrystallized (DMSO/ethanol/hexane) to obtain the title compound (221 mg).