Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([N:13]2[CH:17]([C:18]3[CH:23]=[CH:22][C:21](F)=[C:20]([F:25])[CH:19]=3)[CH2:16][O:15][C:14]2=[O:26])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:27]C1C=C(C=C(F)C=1)C=O>>[F:27][C:22]1[CH:23]=[C:18]([C@H:17]2[CH2:16][O:15][C:14](=[O:26])[N:13]2[C:11]([O:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[O:12])[CH:19]=[C:20]([F:25])[CH:21]=1
Reactant: O=Cc1cc(F)cc(F)c1
Reactant: O=C1OCC(c2ccc(F)c(F)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Product: O=C1OC[C@H](c2cc(F)cc(F)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1

Procedure:
Following the procedure for the synthesis of 4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid-4-nitro-phenyl ester, 3,5-diflourobenzaldehyde yielded the desired product. 1H NMR (400 MHz, CDCl3) δ 8.26 (d, 2H, J=9.3 Hz), 7.33–6.81 (m, 5H), 5.41 (dd, 1H, J=4.1, 8.7 Hz), 4.81 (t, 1H, J=9.3 Hz), 4.33 (dd, 1H, J=4.1, 9.3 Hz); Anal. Calc. for C16H10F2N2O6+0.2EtOAc: C, 52.84; H, 3.06; N, 7.34. Found: C, 53.26; H, 2.83; N, 7.73.
Reaction SMILES: C(O[C:6]([N:8]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:10]([CH2:11][C@@H:12]([C:14]([NH:16][CH2:17][CH2:18][C:19]2[CH:26]=[CH:25][C:23]([OH:24])=[C:21]([OH:22])[CH:20]=2)=[O:15])[NH2:13])=[CH:9]1)=[O:7])(C)(C)C.C(O)(=O)/[CH:34]=[CH:35]/[C:36]1[CH:43]=[CH:42][C:40]([OH:41])=[C:38]([OH:39])[CH:37]=1>>[C:6]([N:8]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:10]([CH2:11][C@@H:12]([C:14]([NH:16][CH2:17][CH2:18][C:19]2[CH:26]=[CH:25][C:23]([OH:24])=[C:21]([OH:22])[CH:20]=2)=[O:15])[NH2:13])=[CH:9]1)(=[O:7])/[CH:34]=[CH:35]/[C:36]1[CH:43]=[CH:42][C:40]([OH:41])=[C:38]([OH:39])[CH:37]=1
Reactant: CC(C)(C)OC(=O)n1cc(C[C@H](N)C(=O)NCCc2ccc(O)c(O)c2)c2ccccc21
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Product: N[C@@H](Cc1cn(C(=O)/C=C/c2ccc(O)c(O)c2)c2ccccc12)C(=O)NCCc1ccc(O)c(O)c1
Yield: 63 %

Procedure:
The title compound was prepared from N-(N′-tert-butoxycarbonyl-L-tryptophanyl)dopamine obtained in step A of example no. 29 (1.3 g, 2.8 mmol) according to the indications of example 3, for 2 h. The crude intermediate was coupled with caffeic acid (770 mg, 4.3 mmol) according to the indications of example 4. The crude product was purified by flash chromatography using 30% AcOEt/CH2Cl2/1% AcOH and 5-10% MeOH/CH2Cl2/1% AcOH to yield the desired product (899 mg, 63%).
Reaction SMILES: CO[C:3]([C:5]1[C:18]2[C:17](=O)[C:16]3[C:11](=[CH:12][CH:13]=[C:14](C)[CH:15]=3)[O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=O.[NH2:21][NH2:22]>>[N:21]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[O:10][C:9]3[C:18]=2[C:5]([CH:6]=[CH:7][CH:8]=3)=[CH:3][N:22]=1
Reactant: NN
Reactant: COC(=O)c1cccc2oc3ccc(C)cc3c(=O)c12
Product: c1ccc2c(c1)Oc1cccc3cnnc-2c13

Procedure:
Prepared from the compound 11 (R═H) and 1.5 equivalent of hydrazine to give benzopyrano[4,3,2-de]phthalazine according to General Procedure C. To a solution of 0.3 g of benzopyrano[4,3,2-de]phthalazine in 7.5 mL of concentrate sulfuric acid is dropwise added 2.0 mL of fuming sulfuric acid at 0° C. The mixture is stirred for 3 hours at 0° C. and poured into 100 mL of ice-cold water. The precipitation is collected by filtration, washed with water to give of a white solid product, mp>300° C. (dec.). 1H-NMR (400 MHz, DMSO-d6); 12.7 (s, 1H), 8.35 (s, 1H), 7.92-7.90 (m, H), 7.76-7.71 (m, 2H), 7.38 (d, 1 H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[C@@H:26]1([NH2:33])[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[NH2:32]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:32][C@@H:27]3[CH2:28][CH2:29][CH2:30][CH2:31][C@H:26]3[NH2:33])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N[C@@H]3CCCC[C@H]3N)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and trans-cyclohexane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 451, 1H NMR (400 MHz, CD3OD) δ ppm 8.06-7.96 (d, J=7.8 Hz, 1 H), 7.83 (d, J=7.33 Hz, 1 H), 7.70 (s, 1 H), 7.60 (td, J=7.52, 1.14 Hz, 1 H), 7.50-7.38 (m, 2 H), 7.28 (dd, J=8.46, 1.64 Hz, 1 H), 6.13 (s, 1 H), 5.20-5.11 (m, 2 H), 3.72-3.60 (m, 1 H), 3.58-3.49 (m, 1 H), 3.42-3.35 (m, 2 H), 3.35-3.30 (m, 1 H), 2.87 (td, J=10.17, 3.92 Hz, 1 H), 2.42 (s, 3 H), 2.10 (d, J=5.31 Hz, 1 H), 2.01 (d, J=13.14 Hz, 1 H), 1.89 (d, J=8.08 Hz, 2 H), 1.67-1.56 (m, 1 H), 1.51-1.41 (m, 2 H), 1.32-1.17 (m, 1 H).
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Br[CH2:26][C:27]1[C:28]([I:34])=[CH:29][C:30]([F:33])=[N:31][CH:32]=1>C(#N)C.C(Cl)(Cl)Cl.C(O)(C)C>[F:33][C:30]1[N:31]=[CH:32][C:27]([CH2:26][C:5]#[N:6])=[C:28]([I:34])[CH:29]=1
Reactant: C[Si](C)(C)C#N
Reactant: Fc1cc(I)c(CBr)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Solvent: CC(C)O
Product: N#CCc1cnc(F)cc1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Combine trimethylsilyl cyanide (297 mg, 3.0 mmol) and tetrabutylammonium fluoride (785 mg, 3.0 mmol) in 20 mL of acetonitrile under nitrogen. Add 5-bromomethyl-2-fluoro-4-iodo-pyridine (0.63 g, 2.0 mmol) to the above solution. Stir the mixture for 2 h at RT. Dilute the mixture with chloroform/IPA (3/1). Wash the solution with water and subsequently with saturated aqueous sodium chloride. Dry it over sodium sulfate. Concentrate the solution in vacuo. Purify by column chromatography (5% methanol in DCM) to afford the title compound as a yellow, waxy solid (500 mg, 96%). MS (ES) m/z 263 [M+1]+.
Reaction SMILES: [CH:1]1([N:4]([CH2:12][C:13]2[CH:18]=[C:17]([CH:19]=[CH2:20])[CH:16]=[C:15]([Cl:21])[C:14]=2[Cl:22])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:3][CH2:2]1.C1C=CC(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC1(C)C(C)(C)OB[O:55]1.B(O[O-])=O.[Na+]>C1COCC1>[CH:1]1([N:4]([CH2:12][C:13]2[CH:18]=[C:17]([CH2:19][CH2:20][OH:55])[CH:16]=[C:15]([Cl:21])[C:14]=2[Cl:22])[C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10])[CH2:3][CH2:2]1
Reactant: C=Cc1cc(Cl)c(Cl)c(CN(C(=O)OC(C)(C)C)C2CC2)c1
Reactant: CC1(C)OBOC1(C)C
Agent: O=BO[O-]
Agent: [Na+]
Agent: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1cc(CCO)cc(Cl)c1Cl)C1CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1,1-Dimethylethyl cyclopropyl[(2,3-dichloro-5-ethenylphenyl)methyl]carbamate (1 eq.) from the previous step, [Ir(COD)Cl]2 (0.025 eq.) and DPPB (0.05 eq.) were combined in THF (0.11 M). To this solution was then added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.3 eq.) and the resulting red solution was stirred at RT for 12 h. Finally, sodium perborate (0.1 M aqueous solution, 1 eq.) was added and the now black biphasic solution was vigorously stirred at RT for another 12 h. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were then washed further with 1 N aq. NaOH, water and brine. This was then dried over Na2SO4, filtered and the filtrate concentrated in vacuo to afford a pale yellow oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→3:7 (v/v) EtOAc:Hex) afforded the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1([CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([NH:23]C(=O)OC(C)(C)C)=[CH:22][C:16]=3[S:15](=[O:32])(=[O:31])[N:14]=2)[C:3]1=[O:33].[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][C:42]=1[S:49](Cl)(=[O:51])=[O:50]>>[OH:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([NH:1][S:49]([C:42]2[CH:43]=[C:44]([O:47][CH3:48])[CH:45]=[CH:46][C:41]=2[O:40][CH3:39])(=[O:51])=[O:50])([CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[C:3](=[O:33])[C:4]=1[C:13]1[NH:18][C:17]2[CH:19]=[CH:20][C:21]([NH:23][S:15]([CH3:16])(=[O:32])=[O:31])=[CH:22][C:16]=2[S:15](=[O:31])(=[O:32])[N:14]=1
Reactant: CC(C)CCC1(N)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Reactant: COc1ccc(OC)c(S(=O)(=O)Cl)c1
Product: COc1ccc(OC)c(S(=O)(=O)NC2(CCC(C)C)C(=O)C(C3=NS(=O)(=O)c4cc(NS(C)(=O)=O)ccc4N3)=C(O)c3ccccc32)c1

Procedure:
Follow same procedure as Example 18D treating the product of Example 18C with 2,5-dimethoxybenzenesulfonyl chloride (9.6 mg, 0.05 mmol). 1H NMR (d6-DMSO) δ 13.45 (s, 1H), 10.30 (s, 1H), 8.69 (s, 1H), 8.03, 8.01 (d, 1H), 7.73, 7.70 (d, 1H), 7.66-7.56 (m, 2H), 7.40-7.33 (t, 1H), 7.28-7.16 (m, 2H), 7.06, 7.03 (d, 1H), 6.93-6.87 (m, 1H), 6.34, 6.33 (d, 1H), 3.95 (s, 3H), 3.41 (s, 3H), 3.10 (s, 3H), 2.37-2.16 (m, 2H), 2.01-1.85 (m, 1H), 1.33-1.14 (m, 2H), 0.68-0.57 (q, 6H); MS (ESI) m/z 719 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:34])=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@@H:12]([F:14])[CH2:11][N:10]1[C:15](=[O:30])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([OH:26])[CH:24]=2)[C:19]([C:27](=[O:29])[CH3:28])=[CH:18]1)=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:42][C:43]1[NH:47][N:46]=[N:45][N:44]=1>CS(C)=O>[Cl:1][C:2]1[C:3]([F:34])=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@@H:12]([F:14])[CH2:11][N:10]1[C:15](=[O:30])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH2:42][C:43]3[NH:47][N:46]=[N:45][N:44]=3)[CH:24]=2)[C:19]([C:27](=[O:29])[CH3:28])=[CH:18]1)=[O:8]
Reactant: CC(=O)c1cn(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(O)ccc12
Reactant: ClCc1nnn[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(=O)c1cn(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(OCc3nnn[nH]3)ccc12

Procedure:
The title compound was prepared in a similar manner as described above for Example 585 from (2S,4R)-1-[2-(3-acetyl-6-hydroxy-indol-1-yl)-acetyl]-4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide Example 583 (60.0 mg, 0.122 mmol), cesium carbonate (120 mg, 0.367 mmol) and 5-(chloromethyl)-1H-tetrazole (44.0 mg, 0.366 mmol) in DMSO (2.5 mL). Solid. MS (LC/MS): 572 [M+H]+; tR (HPLC conditions k): 3.23 min.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(O)[O-].[Na+].[C-:16]#[N:17].[Na+]>O.C(O)C>[OH:10][CH:9]([CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:16]#[N:17]
Reactant: O=CCCc1ccccc1
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CC(O)CCc1ccccc1
Reaction time: 2 h
Yield: 47.1 %

Procedure:
3-Phenylpropionaldehyde (0.40 mole) was added dropwise to a solution of sodium bisulfite (0.80 mole) in 240 mL water and 50 mL 95% ethanol at room temperature over a 30 min period. A solution of sodium cyanide (0.40 mole) in 60 mL water was added dropwise to the stirred white suspension over a 20 min period at room temperature. After continuing stirring for an additional 2 hrs, the reaction mixture was extracted with ether (4×250 mL). The extracts were combined, dried (MgSO4) and concentrated in vacuo to give 30.4 g (47%) of 2-hydroxy-4-phenylbutyronitrile as a viscous pale yellow oil.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])[CH:5]=[O:6].Cl.NO>C(O)C>[N+:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[CH:3]=[N:2][O:6][CH:5]=1)([O-:15])=[O:14]
Reactant: CN(C)C=C(C=O)c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: NO
Solvent: CCO
Product: O=[N+]([O-])c1ccccc1-c1cnoc1
Yield: 86.5 %

Procedure:
A suspension of 75 g of 3-(dimethylamino)-2-(2-nitrophenyl)acrolein [prepared by the procedure of U. Hengartner et al., J. Org. Chem., 44, 3748 (1979)] and 47.3 g of hydroxylamine hydrochloride in 300 ml of ethanol was refluxed for 10 hours, then concentrated to dryness in vacuo. Water (400 ml) was added to the residue and the suspension filtered. The isolated solid was recrystallized from 2-propanol to yield 56 g of the title compound; m.p. 51°-54° C.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:33]=[C:32]3[C:28]([C:29]([NH:42][C:43](=[O:47])[CH2:44][CH2:45][CH3:46])=[N:30][N:31]3COCC[Si](C)(C)C)=[CH:27][CH:26]=2)[CH:20]=1.C(OCC)(=O)C>O1CCCC1>[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:33]=[C:32]3[C:28]([C:29]([NH:42][C:43](=[O:47])[CH2:44][CH2:45][CH3:46])=[N:30][NH:31]3)=[CH:27][CH:26]=2)[CH:20]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3cccnc3)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(=O)Nc1n[nH]c2cc(-c3cccnc3)ccc12
Temperature: 66 °C

Procedure:
13.3 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 900 mg of N-[6-(3-pyridyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 20 cm3 of tetrahydrofuran. The reaction medium is heated at about 66° C. for 21 hours. The heating is then stopped and 100 cm3 of ethyl acetate are added. This mixture is washed with 50 cm3 of saturated aqueous sodium hydrogen carbonate solution and then with 2×50 cm3 of distilled water and 50 cm3 of saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered through a sinter funnel and evaporated under reduced pressure (2 kPa; 50° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2 cm), eluting with ethyl acetate and collecting 25 cm3 fractions. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). After drying (90 Pa; 50° C.), 380 mg of N-[6-(3-pyridyl)-1H-indazol-3-yl]butanamide are thus obtained in the form of a white product melting at 205° C.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([C@@:11]23[CH2:20][C@H:15]([CH2:16][C:17](=O)[CH2:18]2)[N:14]([CH3:21])[CH2:13][C@H:12]3[CH3:22])[CH:8]=[CH:9][CH:10]=1)[CH3:3].Cl.[NH2:24][OH:25]>CCO>[CH:2]([O:4][C:5]1[CH:6]=[C:7]([C:11]23[CH2:20][CH:15]([CH2:16][C:17](=[N:24][OH:25])[CH2:18]2)[N:14]([CH3:21])[CH2:13][CH:12]3[CH3:22])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:1]
Reactant: CC(C)Oc1cccc([C@]23CC(=O)C[C@@H](C2)N(C)C[C@H]3C)c1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: CC(C)Oc1cccc(C23CC(=NO)CC(C2)N(C)CC3C)c1
Temperature: 25 °C
Yield: 87.5 %

Procedure:
5-(3-Isopropoxy-phenyl)-2,4-dimethyl-2-aza-bicyclo[3.3.1]nonan-7-one (2.2) (3.11 g, 13.0 mmole) and hydroxylamine hydrochloride (4.50 g, 64.8 mmol) in EtOH (absolute, 195 mL) were heated to reflux for 3 h. The reaction mixture was allowed to cool to room temperature and the ethanol was removed under reduced pressure. The crude oil was dissolved in 2 N NaOH (100 mL) and extracted with 3:1 CH2Cl2/THF (4×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure yielding crude product. The crude product was purified by flash chromatography (neutral alumina, Brockman activity II-III) eluting with 9:1 ethyl acetate:hexane to afford the title compound (3.6 g, 88%) as an off white solid. 1H NMR (CDCl3) δ 8.47 (br, 1H), 7.23 (t, J=7.8 Hz, 1H), 7.00-6.72 (m, 3H), 4.54 (m, 1H), 3.63 (d, J=17 Hz, 1H), 3.29 (br, 1H), 2.94-2.85 (m, 2H), 2.51 (d, J=15.9 Hz, 1H), 2.44-2.40 (m, 4H), 2.05-1.87 (m, 5H), 1.33 (d, J=6.0 Hz, 6H), 0.76 (d, J=6.9 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12]C(=O)C)=[CH:7][CH:6]=1)[CH3:3]>Cl>[CH3:3][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][CH:6]=1)[CH3:1]
Reactant: CC(=O)NCc1ccc(CN(C)C)cc1
Agent: Cl
Product: CN(C)Cc1ccc(CN)cc1
Yield: 66.8 %

Procedure:
N-(4-Dimethylaminomethylphenylmethyl)acetamide (22 g) was dissolved in 4N hydrochloric acid (100 ml) and the mixture was refluxed under heating for 3 hr 40 min. The solvent was evaporated and ethyl acetate was added. The resulting crystals were collected by filtration. The obtained crystals were dissolved in water (40 ml) and potassium carbonate was added to saturation, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and, after drying, the solvent was evaporated under reduced pressure to give the objective 4-(dimethylaminomethyl)phenylmethylamine (11.7 g), melting point 38-39° C.
Reaction SMILES: C1(O)(O)CCCC1.N1C=CC=CC=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C([O:28][C:29](=[O:31])[CH3:30])(=O)C>ClCCl>[C:29]([O:28][S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:22])=[O:21])(=[O:31])[CH3:30]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)OC(C)=O
Agent: OC1(O)CCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of 7 (10 g, 40 mmol, 1 equiv) and pyridine (22.6 mL, 280 mmol, 7 equiv) in dichloromethane (200 mL) was added p-toluenesulfonyl chloride (11.4 g, 60 mmol, 1.5 equiv). The mixture stirred at room temperature overnight. Pyridine (22.6 mL, 280 mmol, 7 equiv) and acetic anhydride (21.9 mL, 232 mmol, 5.8 equiv) were added at room temperature and the mixture was stirred overnight. The reaction was cooled to 5° C. and quenched with 2 N aq NaOH to pH 7. The aqueous layer was separated and extracted with dichloromethane (2×50 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. The resulting semi-solid was dissolved in isopropyl acetate (100 mL) and concentrated to dryness. This was repeated 2 more times. The resulting semi-solid was triturated in methyl tert-butyl ether (250 mL), filtered and dried under vacuum to afford 8.1 g of 8 (45%) as a pale yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:37])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:17][CH:16]2[C:34]([OH:36])=O)[CH:12]=[CH:13][CH:14]=1.CC1(C)[O:43][C@@H:42]([CH2:44][CH2:45][NH2:46])[CH2:41][O:40]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:43][C@H:42]([CH2:41][OH:40])[CH2:44][CH2:45][NH:46][C:34]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=2[F:37])[C:19]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:33])([CH3:31])[CH3:32])[NH:17]1)=[O:36]
Reactant: CC1(C)OC[C@H](CCN)O1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1
Yield: 89 %

Procedure:
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 26c (0.25 g, 0.44 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.2 g, 1.3 mmol), HATU (0.3 g, 0.79 mmol) and iPr2NEt (0.5 g, 3.9 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.21 g, 89%).
Reaction SMILES: [CH2:1]([C:10]1[CH:46]=[CH:45][C:13]([C:14]([C:16]2[CH:24]=[C:23]([C:25]([OH:27])=[O:26])[C:22]([C:28](=O)[C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:31][CH:30]=3)=[CH:21][C:17]=2[C:18]([OH:20])=[O:19])=O)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[H][H]>[Pd].O1CCCC1>[CH2:1]([C:10]1[CH:46]=[CH:45][C:13]([CH2:14][C:16]2[CH:24]=[C:23]([C:25]([OH:27])=[O:26])[C:22]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:33][CH:34]=3)=[CH:21][C:17]=2[C:18]([OH:20])=[O:19])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCc1ccc(C(=O)c2cc(C(=O)O)c(C(=O)c3ccc(CCCCCCCCC)cc3)cc2C(=O)O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCc1ccc(Cc2cc(C(=O)O)c(Cc3ccc(CCCCCCCCC)cc3)cc2C(=O)O)cc1

Procedure:
A mixture of 109 grams of 2,5-bis(4-nonylbenzoyl)terephthalic acid, 1500 mL of tetrahydrofuran, and 7.43 grams of 10% palladium on carbon (as a catalyst) was heated at 65° C. for 17 hours in an atmosphere of hydrogen at 270 kPa. The reaction mixture was filtered through Celite™ diatomaceous earth filter agent to remove the catalyst. The filtrate was concentrated in vacuo to give 2,5-bis(4-nonylbenzyl)terephthalic acid.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH:2]=[CH2:3].[C:7]([NH:15][NH2:16])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][CH:9]=1>CO>[CH2:1]([NH:4][C:5](=[O:6])[NH:16][NH:15][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][CH:9]=1)[CH:2]=[CH2:3]
Reactant: NNC(=O)c1cccnc1
Reactant: C=CCN=C=O
Solvent: CO
Product: C=CCNC(=O)NNC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 2.75 h
Yield: 92.4 %

Procedure:
Allyl isocyanate (16.8 g) was added dropwise at ambient temperature to a stirred suspension of nicotinic hydrazide (25 g) in methanol (500 ml), then the mixture was stirred at ambient temperature for 2.75 hours, concentrated in vacuo to 250 ml, then diluted with ether (750 ml). The resulting solid was collected by filtration and dried in vacuo to give 4-allyl-1-nicotinoylsemicarbazide as a colourless solid (37.1 g), m.p. 165-167° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C>[N:21]([CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1)=[N+:22]=[N-:23]
Reactant: O=c1c(CBr)cn(-c2ccccc2)c2cc(Cl)ccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.7 %

Procedure:
In a 25 mL round-bottomed flask, crude 3-bromomethyl-7-chloro-1-phenyl-1H-quinolin-4-one (0.184 g, 0.528 mmol) and sodium azide (34.3 mg, 0.528 mmol) were combined with DMF (3.5 mL) to give a yellow solution. The reaction mixture was stirred overnight at room temperature. The reaction mixture was poured over ice and the resulting white suspension was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered, then concentrated to afford the crude product as slightly yellow oil. The crude was purified by flash chromatography using 15%-45% ethyl acetate/hexanes to afford 3-azidomethyl-7-chloro-1-phenyl-1H-quinolin-4-one (75 mg, 46% yield) as a white solid.