Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:75][CH:76]1[CH2:81][CH2:80][N:79]([CH3:82])[CH2:78][CH2:77]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:75][CH:76]5[CH2:81][CH2:80][N:79]([CH3:82])[CH2:78][CH2:77]5)=[O:28])=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCC(N)CC1
Reactant: Cc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h

Procedure:
To a mixture of 0.050 g (0.116 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-benzoic acid (I-184) and 5 mL of dimethylformamide was added 0.0235 g (0.174 mmole) of 1-hydroxybenzotriazole, 0.0659 g (0.174 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.060 g (0.463 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0198 g (0.174 mmole) of 4-amino-1-methylpiperidine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0536 g) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-N-(1-methyl-piperidin-4-yl)-benzamide (I-185) as a white solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[C@@H:21]4[C@@H:16]([C:17]5[CH:25]=[CH:24][C:23]([C:26]([OH:28])=O)=[CH:22][C:18]=5[CH2:19][CH2:20]4)[CH2:15][CH2:14][CH2:13]3)=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:29][NH:30][CH3:31]>>[CH3:29][N:30]([CH3:31])[C:26]([C:23]1[CH:24]=[CH:25][C:17]2[C@@H:16]3[C@H:21]([CH2:20][CH2:19][C:18]=2[CH:22]=1)[N:12]([C:10]([C:8]1[CH:7]=[CH:6][C:5]2[NH:1][CH:2]=[N:3][C:4]=2[CH:9]=1)=[O:11])[CH2:13][CH2:14][CH2:15]3)=[O:28]
Reactant: O=C(O)c1ccc2c(c1)CC[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Reactant: CNC
Product: CN(C)C(=O)c1ccc2c(c1)CC[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Yield: 20 %

Procedure:
The title compound is prepared from cis-4-(1H-benzoimidazole-5-carbonyl)-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline-8-carboxylic acid and dimethylamine (2 mol/L in tetrahydrofuran) following a procedure analogous to that described in Example 1. Yield: 20% of theory; LC (method 1): tR=2.08 min; Mass spectrum (ESI+): m/z=403 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.ClC1C(Cl)=CC(C(F)(F)[F:30])=CN=1.ClC1C(OC)=CC(B(O)O)=C(F)C=1>>[Cl:1][C:2]1[C:3]([C:12]2[CH:13]=[C:14]([O:19][CH3:20])[C:15]([Cl:18])=[CH:16][C:17]=2[F:30])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: COc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: COc1cc(B(O)O)c(F)cc1Cl
Product: COc1cc(-c2ncc(C(F)(F)F)cc2Cl)c(F)cc1Cl
Yield: 19 %

Procedure:
In a preparation similar to that described above for 3-chloro-2-(4-chloro-3-methoxyphenyl)-5-trifluoromethylpyridine, reaction of 8.9 g (41 mmol) of 2,3-dichloro-5-trifluoromethylpyridine and 7.9 g (41 mmol) of 4-chloro-2-fluoro-5-methoxybenzeneboronic acid and subsequent purification of the crude product by chromatography on silica gel (methylene chloride as eluent) resulted in 2.6 g of colorless crystals.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[N:19]=[CH:18][C:17]([CH:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH3:21])=[CH:16][C:15]=1[B:28]1[O:32]C(C)(C)C(C)(C)[O:29]1.B(OC(C)C)(OC(C)C)OC(C)C>C1COCC1>[F:13][C:14]1[C:15]([B:28]([OH:29])[OH:32])=[CH:16][C:17]([CH:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH3:21])=[CH:18][N:19]=1
Reactant: CC(c1cnc(F)c(B2OC(C)(C)C(C)(C)O2)c1)N1CCOCC1
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(c1cnc(F)c(B(O)O)c1)N1CCOCC1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 80.6 %

Procedure:
To a solution of diisopropylamine (Aldrich) (0.640 mL, 4.57 mmol) in THF (10 mL) at −40° C. in 100 mL 3-neck round-bottom flask was added butyllithium solution, 1.6 m in hexanes (Aldrich) (2.85 mL, 4.57 mmol) dropwise via the addition funnel. After the addition, it was continued to stir at −40° C. for 20 min then cooled to −78° C. To this reaction mixture was added 4-(1-(6-fluoropyridin-3-yl)ethyl)morpholine (Example 339 step 3) (0.800 g, 3.81 mmol) in THF (10 mL) dropwise via the addition funnel. It was continued to stir at −78° C. after the addition. After 1 h, triisopropyl borate (Aldrich) (1.309 mL, 5.71 mmol) was added into the reaction mixture dropwise via the addition funnel. After the addition, it was continued to stir at −78° C. for 20 min then removed the cooling bath and slowly warmed up to rt and stirred for 1 h. The reaction mixture was quenched with 1 N NaOH (15 mL). The aqueous layer was extracted with EtOAc (2×15 mL)—the organic layer was discard; the aqueous layer was acidified to a pH of about 5 to 6 using 5N HCl. The resulting mixture was extracted with EtOAc (2×15 mL) and CHCl3 (2×15 mL). The combined organic layers were dried over MgSO4 and concentrated to afford the product as a light brown amorphous solid (780 mg). MS (ESI pos. ion) m/z: 255.1. 1H NMR (400 MHz, CDCl3) δ ppm 1.38 (dd, J=11.44, 6.75 Hz, 3H) 2.36 (d, J=4.30 Hz, 2H) 2.45-2.60 (m, 2H) 3.35-3.47 (m, 1H) 3.63-3.77 (m, 4H) 8.15 (dd, J=9.00, 2.35 Hz, 1H) 8.19-8.27 (m, 2H) 8.33 (d, J=9.00 Hz, 1H).
Reaction SMILES: [Cl-].[CH3:2][C:3]1[CH2:8][CH2:7][CH2:6][C:5]([CH3:10])([CH3:9])[C:4]=1[CH2:11][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[Br:36][C:37]1[CH2:42][CH2:41][CH2:40][CH2:39][C:38]=1[CH:43]=O.CCCCCC>O1CCCC1>[Br:36][C:37]1[CH2:42][CH2:41][CH2:40][CH2:39][C:38]=1/[CH:43]=[CH:11]/[C:4]1[C:5]([CH3:9])([CH3:10])[CH2:6][CH2:7][CH2:8][C:3]=1[CH3:2]
Reactant: O=CC1=C(Br)CCCC1
Reactant: CC1=C(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)C(C)(C)CCC1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1=C(/C=C/C2=C(Br)CCCC2)C(C)(C)CCC1
Temperature: -60 °C
Reaction time: 0.17 h
Yield: 97.7 %

Procedure:
A suspension of ((2,6,6-trimethyl-1-cyclohexen-1-yl)methyl)triphenylphosphonium chloride (18 g) in tetrahydrofuran (300 ml) was cooled to -60° C., treated dropwise with n-butyllithium (1.4M in hexane; 32 ml), and then stirred a further 10 minutes. To this cold solution was added the 2-bromocyclohexene-1-carboxaldehyde (8.5 g,75% pure by HNMR analysis) dissolved in tetrahydrofuran, and the mixture was allowed to warm to room temperature after which it was stirred for a further 2 hours. Hexane was then added to the reaction and the resulting mixture was washed with water, 50% aqueous methanol and dried (magnesium sulphate). Removal of the solvents yielded the crude (E)-1-bromo-2-(2-(2,6,6-trimethyl-1-cyclohexen-1-yl)ethenyl)-cyclohexene (12.5 g) as a mixture of isomers which was used, as is, in the next step. Standard transmetalation and reaction with DMF yielded a cruce aldehyde (4.5 g) which was dissolved in tetrahydrofuran (100 ml) and reacted with an excess of the phosphonate as in Example 1to give methyl (2E,4E)-3-methyl-5-(2-((E)-2(2,6,6-trimethyl-cyclohexen-1-yl)ethenyl)-1-cyclohexen-1-yl)-2,4-pentadienoate (3 g) as an oil after purification by HPLC (2.5% ether in hexane). Hydrolysis with aqueous potassium hydroxide solution gave crystalline (2E,4E)-3-Methyl-5-(2-((E)-2(2,6,6-trimethyl-cyclohexen-1-yl)ethenyl)-1-cyclohexen-1-yl)-2,4-pentadienoic acid (1.6 g from hexane-tetrahydrofuran).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:19])=[C:7]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([Cl:18])[CH:17]=2)[C:13]#[N:14])[CH:8]=1.[Cl:20][C:21]1[CH:29]=[C:28]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24].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>CN(C=O)C>[Cl:20][C:21]1[CH:29]=[C:28]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:27]=[CH:26][C:22]=1[C:23]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:19])=[C:7]([O:9][C:10]2[CH:11]=[C:12]([C:13]#[N:14])[CH:15]=[C:16]([Cl:18])[CH:17]=2)[CH:8]=1)=[O:24]
Reactant: N#Cc1cc(Cl)cc(Oc2cc(CN)ccc2Cl)c1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2)c(Cl)c1
Yield: 69.2 %

Procedure:
2-Chloro-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]phenyl}methyl)-4-(methylsulfonyl)benzamide was prepared in a similar manner as described herein from 3-{[5-(aminomethyl)-2-chlorophenyl]oxy}-5-chlorobenzonitrile (0.025 g, 0.085 mmol), 2-chloro-4-(methylsulfonyl)benzoic acid, (0.03 g, 0.13 mmol), HATU (0.05 g, 0.13 mmol), DIPEA (0.025 mL, 0.13 mmol) and DMF (1 mL). The crude material was purified by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA). The desired fractions were neutralized and extracted with EtOAc. The organic extracts were combined, dried over Na2SO4, filtered and evaporated to afford the title compound (0.030 g, 69%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 9.20 (t, 1H), 8.02 (d, 1H), 7.92 (dd, 1H), 7.83 (d, 1H), 7.69 (d, 1H), 7.62 (d, 1H), 7.48 (d, 1H), 7.41 (t, 1H), 7.31 (dd, 1H), 7.23 (d, 1H), 4.46 (d, 2H), 3.30 (s, 3H). MS: m/z 508.9 (M+1).
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].I[C:13]1[C:18]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=[C:15]([CH3:34])[N:14]=1.[C:35]([C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1)#[N:36]>O>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[N:23]=[CH:22][CH:21]=[C:20]2[O:19][C:18]1[C:13]([C:41]2[CH:42]=[C:37]([CH:38]=[CH:39][CH:40]=2)[C:35]#[N:36])=[N:14][C:15]([CH3:34])=[CH:16][CH:17]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3cccc(C#N)c3)c2cc1OC
Temperature: 70 °C
Reaction time: 5 h
Yield: 91.4 %

Procedure:
N,N-Dimethylformamide (1 ml) and a 2 M aqueous potassium carbonate solution (1 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg) and 3-cyanophenylboronic acid (52 mg) under an argon atmosphere, and the mixture was stirred at 70° C. for 5 hr. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (43 mg, yield 92%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2Cl.BrC1C=CC(N)=CC=1.[NH2:24][CH2:25][CH2:26][CH2:27][N:28]1[CH2:32][CH2:31][CH2:30][C:29]1=[O:33]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2[NH:24][CH2:25][CH2:26][CH2:27][N:28]1[CH2:32][CH2:31][CH2:30][C:29]1=[O:33]
Reactant: O=[N+]([O-])c1cnc2ccc(Br)cc2c1Cl
Reactant: NCCCN1CCCC1=O
Agent: Nc1ccc(Br)cc1
Product: O=C1CCCN1CCCNc1c([N+](=O)[O-])cnc2ccc(Br)cc12
Yield: 87.8 %

Procedure:
6-Bromo-4-chloro-3-nitroquinoline (50.62 g, 177.8 mmol), prepared from 4-bromoaniline according to the methods described in Parts A-D of Example 1, was treated with 1-(3-aminopropyl)pyrrolidin-2-one (27.5 mL, 196 mmol) according to the method described in Part E of Example 1 to provide 61.41 g of 1-[3-(6-bromo-3-nitroquinolin-4-ylamino)propyl]pyrrolidin-2-one as a solid.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20]([C:24]1[CH:25]=[C:26]([CH:33]=[C:34]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:35]=1[OH:36])[CH2:27][CH2:28][C:29](OC)=[O:30])([CH3:23])([CH3:22])[CH3:21]>>[C:37]([C:34]1[CH:33]=[C:26]([CH:25]=[C:24]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:35]=1[OH:36])[CH2:27][CH2:28][C:29]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:30])([CH3:39])([CH3:40])[CH3:38]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 2.5 h

Procedure:
The general procedure of Example 1 is repeated, but using 337.0 g (1.246 mole) of octadecyl alcohol and 391.9 g (1.340 mole) of methyl 3,5-di-tert-butyl-4-hydroxyhydrocinnamate and a reflux temperature of between 189 and 201° C. After 2.5 hours, analysis of the contents of the reaction flask using Gas shows a mixture of 32.1 wt % of the title compound, 32.0 wt % of methyl 3,5-di-tert-butyl-4-hydroxyhydrocinnamate and 29.6 wt % octadecyl alcohol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]#[CH:19])=[CH:10][C:9]=1[CH3:20])[CH3:6])[CH3:2].Br[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1.CCN(CC)CC>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]#[C:19][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)=[CH:10][C:9]=1[CH3:20])[CH3:6])[CH3:2]
Reactant: C#CCCCOc1ccc(OC(C)(C)C(=O)OCC)c(C)c1
Reactant: FC(F)(F)c1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCCC#Cc2ccc(C(F)(F)F)cn2)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.6 %

Procedure:
A degassed (argon) solution of 152 mg (0.50 mmol) 2-methyl-2-(2-methyl-4-pent-4-ynyloxy-phenoxy)-propionic acid ethyl ester (example 13A]), 124 mg (0.55 mmol) 2-bromo-5-(trifluoromethyl)pyridine and 0.21 ml (1.5 mmol) Et3N in 5 ml acetonitrile was treated with 18 mg (0.03 mmol) of PdCl2(PPh3)2 and 3 mg (0.03 mmol) of CuI. After stirring for 3 h at room temperature the reaction mixture was partitioned between cold aqueous 10% KHSO4 and ether (three times). Washing of the organic layer with aqueous 10% NaCl solution, drying (Na2SO4) and evaporation of the solvents, followed by flash chromatography (SiO2, n-heptane/EtOAc 95:5 to 9:1) yielded 170 mg of the title compound as yellow viscous oil.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)=[O:2].[CH3:12][O:13][C:14](=[O:17])[CH2:15][NH2:16]>>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:16][CH2:15][C:14]([O:13][CH3:12])=[O:17])=[O:9])=[CH:10][CH:11]=1)=[O:2]
Reactant: COC(=O)CN
Reactant: O=Cc1ccc(C(=O)O)cc1
Product: COC(=O)CNC(=O)c1ccc(C=O)cc1
Yield: 81.5 %

Procedure:
In an analogous manner to 35, 4-formyl benzoic acid 24 (1.0 g, 6.66 mmol) was reacted with glycine methyl ester (653 mg, 7.33 mmol) to give 1.2 gm (81%) of methyl 2-(4-formylbenzamido)acetate 37 as an off-white solid (81%).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[CH2:13]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([O:1][N:2]2[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]2([CH3:12])[CH3:11])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: C1CCCCCCC1
Product: CC1(C)CC(O)CC(C)(C)N1OC1CCCCCCC1

Procedure:
The title compound is prepared from 1-oxyl-2,2,6,6-tetramethylpiperidin-4-ol and cyclooctane following a procedure to that of Example 5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[C:14]([O:18][C:19]([CH2:21][O:22][NH2:23])=[O:20])([CH3:17])([CH3:16])[CH3:15].C[O-].[Na+]>CO>[C:14]([O:18][C:19]([CH2:21][O:22][N:23]=[C:9]([C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=1)[C:10]([OH:12])=[O:11])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: O=C(O)C(=O)c1ccc(O)c(Cl)c1
Reactant: CC(C)(C)OC(=O)CON
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)CON=C(C(=O)O)c1ccc(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.1 %

Procedure:
A mixture of 2-(3-chloro-4-hydroxyphenyl)glyoxylic acid (2.0 g.), O-t-butoxycarbonylmethylhydroxylamine (1.62 g.) and methanol (20 ml.) was adjusted to pH 5 to 6 by adding an 1 N methanol solution of sodium methoxide and stirred for 3 hours at ambient temperature. The reaction mixture was concentrated to dryness under reduced pressure and the residue was dissolved in an 1 N aqueous solution of sodium hydroxide to adjust to pH 7.0. The aqueous solution was washed with ether, adjusted to pH 2.0 with 10% hydrochloric acid under ice-cooling and extracted with ether. The extract was washed with water and dried over magnesium sulfate. The solution was concentrated to dryness under reduced pressure to give crystals of 2-t-butoxycarbonylmethoxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid (syn isomer) (2.6 g.), mp 116° to 118° C. (dec.).
Reaction SMILES: [C:1]1(=[O:8])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.[CH2:9]=[CH:10][C:11](=[CH2:13])[CH3:12].[Cr](O)(O)(=O)=O>C(O)(=O)C.O>[CH3:13][C:11]1[CH:10]=[CH:9][C:3]2[C:4]([CH:5]=[CH:6][C:1](=[O:8])[C:2]=2[CH:12]=1)=[O:7]
Reactant: C=CC(=C)C
Reactant: O=C1C=CC(=O)C=C1
Agent: O=[Cr](=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc2c(c1)C(=O)C=CC2=O
Temperature: 25 °C
Yield: 31.8 %

Procedure:
A solution of 1,4-benzoquinone (13.9 g, 128 mmol) and isoprene (13.1 ml, 131 mmol) was stirred in glacial acetic acid (44 ml) for 68 hours at room temperature. The mixture was diluted with water (44 ml) and refluxed for 11/2 hours. The mixture was cooled to room temperature and acetic acid (84 ml) and chromic acid [chromium trioxide (29.4 g) in water (30 ml)] was added sequentially, before refluxing for a further 11/2 hours. After cooling, the mixture was diluted with water (200 ml) and extracted with ether (3×50 ml). The combined ether fractions were washed with dilute sodium hydroxide solution (2M; 2×50 ml), water (2×50 ml), saturated sodium chloride solution (50 ml) and dried over magnesium sulphate. Filtration and evaporation of solvent under reduced pressure, and repeated recrystallisation from petroleum ether yielded the title compound (7 g).
Reaction SMILES: [OH:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:13](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[CH3:13][O:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1cccc([N+](=O)[O-])c1O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1c(C=O)cccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 72 %

Procedure:
To a solution of 2-hydroxy-3-nitrobenzaldehyde in DMF was added portionwise cesium carbonate (3 eq), followed by iodomethane (1.2 eq.). The solution was warmed to 60° C. for 2 hours, then cooled to room temperature and filtered. The filtrate was concentrated under vacuum and purified by column chromatography on SPE cartridge (Silica) using as eluent cyclohexane-ethyl acetate (8:2) to give the product in 72% yield.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:17][C@H:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]([CH3:19])([CH3:18])[CH2:10]2)[C:5]([F:20])=[CH:4][N:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:32][C:33]1[C:34]([F:47])=[CH:35][C:36]([Br:46])=[C:37]([N:39]2[C:43](=[O:44])[N:42]([CH3:45])[N:41]=[N:40]2)[CH:38]=1.C(=O)(O)[O-].[Na+]>C(O)(C)C>[CH3:18][C:11]1([CH3:19])[CH2:10][C@H:9]([NH:8][C:6]2[C:5]([F:20])=[CH:4][N:3]=[C:2]([NH:32][C:33]3[C:34]([F:47])=[CH:35][C:36]([Br:46])=[C:37]([N:39]4[C:43](=[O:44])[N:42]([CH3:45])[N:41]=[N:40]4)[CH:38]=3)[N:7]=2)[CH2:17][C@H:16]2[N:12]1[CH2:13][CH2:14][CH2:15]2
Reactant: CC1(C)C[C@H](Nc2nc(Cl)ncc2F)C[C@@H]2CCCN21
Reactant: Cn1nnn(-c2cc(N)c(F)cc2Br)c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cn1nnn(-c2cc(Nc3ncc(F)c(N[C@@H]4C[C@@H]5CCCN5C(C)(C)C4)n3)c(F)cc2Br)c1=O
Temperature: 110 °C
Yield: 52.6 %

Procedure:
(7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine (1.4525 g. 4.86 mmol) and p-toluenesulfonic acid (1.7288 g, 9.09 mmol) were weighed out and added to a large reaction tube containing 1-(5-amino-2-bromo-4-fluorophenyl)-4-methyl-1H-tetrazol-5(4H)-one (2.10 g, 7.29 mmol). 42 mL isopropyl alcohol was added, and the tube was sealed and heated overnight at 110° C. The reaction was basified with saturated aqueous sodium bicarbonate and extracted three times with ethyl acetate. The combined organic layer was washed with brine and dried over sodium sulfate. Product solution was filtered, concentrated onto a plug of silica, and purified by column chromatography. Pure fractions were combined, concentrated and dried under high vacuum to give 1.4063 g of the title compound (53% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C@@H:19]3[CH2:23][CH2:22][CH2:21][C@H:20]3[C:24]([OH:26])=[O:25])=[O:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:29]I.O>CN(C=O)C>[CH3:29][N:16]([C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:11][CH:12]=1)[C:17]([C@@H:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[C:24]([OH:26])=[O:25])=[O:18]
Reactant: CI
Reactant: O=C(O)[C@@H]1CCC[C@H]1C(=O)Nc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)[C@@H]1CCC[C@H]1C(=O)O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of rac-trans-2-(4′-nitro-biphenyl-4-ylcarbamoyl)-cyclopentanecarboxylic acid (3.54 g, 10 mmol) in DMF cooled at 0° C. was added sodium hydride (0.48 g, 12 mmol) gradually. The mixture was stirred at room temperature for 15 min followed by the addition of methyl iodide (0.7 mL). The reaction mixture was stirred for 2 h. The reaction was then mixed with water and extracted with ethyl acetate. The organic layer was washed with water and brine. The organic layer dried over sodium sulfate, filtered and concentrated to give rac-trans-2-[methyl-(4′-nitro-biphenyl-4-yl)-carbamoyl]-cyclopentanecarboxylic acid as a yellow solid. With a method similar to that used above, trans-2-[(4′-amino-biphenyl-4-yl)-methyl-carbamoyl]-cyclopentanecarboxylic acid was prepared by the hydrogenation of trans-2-[methyl-(4′-nitro-biphenyl-4-yl)-carbamoyl]-cyclopentanecarboxylic acid. This material was directly used in the next step without further purification. LCMS calcd for C20H22N2O3 (m/e) 338, obsd 339 (M+H).