Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:38]3[CH:37]=[CH:36][CH:35]=[C:34]([C:33]([F:44])([F:43])[F:32])[CH:39]=3)[C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:30])(=[O:31])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCS(=O)(=O)CC1)n2-c1cccc(C(F)(F)F)c1)N1CCN(C2CCC2)CC1
Yield: 60 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone (example 202), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (60%).
Reaction SMILES: O1CCCC1.[C:6]([C:10]1[CH:20]=[CH:19][C:13]([O:14][CH2:15][C:16]([OH:18])=O)=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7].Cl.[NH2:22][C@@H:23]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[C:27]([CH3:36])[CH:26]=1)[CH3:24]>C(N(CC)CC)C>[C:6]([C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][C:16]([NH:22][C@@H:23]([C:25]2[CH:30]=[CH:29][C:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[C:27]([CH3:36])[CH:26]=2)[CH3:24])=[O:18])=[CH:19][CH:20]=1)([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1
Reactant: Cc1cc([C@@H](C)N)ccc1NS(C)(=O)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc([C@@H](C)NC(=O)COc2ccc(C(C)(C)C)cc2)ccc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.7 %

Procedure:
To a tetrahydrofuran (THF) (2.0 ml) solution of (4-tert-butylphenoxy)acetic acid (140 mg, 0.7 mmol) 1,1′-dicarbonyldiimidazole (110 mg, 0.7 mmol) was added and the mixture was stirred for 1 hour at ambient temperature. N-{4-[(1R)-1-aminoethyl]-2-methylphenyl}methanesulfonamide hydrochloride (180 mg, 0.7 mmol) and triethylamine (0.5 ml) were added to the mixture. After being stirred for 1 hour at ambient temperature, white precipitate appeared. It was filtered and the solvent was removed under reduced pressure to give a residue, which was applied to a silica gel chromatography column and eluted with methylene dichloride/ethyl acetate=1/1 to furnish 90 mg (31% yield) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].[CH:34]1([NH:37][CH2:38][C@@H:39]2[CH2:43][CH2:42][CH2:41][NH:40]2)[CH2:36][CH2:35]1>>[CH:34]1([NH:37][CH2:38][C@@H:39]2[CH2:43][CH2:42][CH2:41][N:40]2[C:30]([C:26]2[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])(=[O:11])=[O:12])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:31])[CH2:36][CH2:35]1
Reactant: C1CN[C@H](CNC2CC2)C1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)N1CCC[C@H]1CNC1CC1
Yield: 73.4 %

Procedure:
5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (167 mg, 0.33 mmol) was condensed with cyclopropyl-(S)-1-pyrrolidine-2-ylmethyl-amine (69 mg, 0.49 mmol) to give 152 mg (72%) of the titled compound.
Reaction SMILES: N1C=CN=CC=1[N:7]1[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]1.ClCC([N:18]1[CH2:22][C:21](F)(F)C[C@H:19]1[C:25]#[N:26])=O.C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C.Cl>C(#N)C.C(OCC)C>[N:18]1[CH:19]=[CH:25][N:26]=[CH:21][C:22]=1[CH:12]1[CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8][NH:7]1
Reactant: NC1CCN(c2cnccn2)CC1
Reactant: N#C[C@@H]1CC(F)(F)CN1C(=O)CCl
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: Cl
Solvent: CCOCC
Solvent: CC#N
Product: NC1CCNC(c2cnccn2)C1
Temperature: 55 °C
Reaction time: 8 h
Yield: 145.5 %

Procedure:
63 mg of 1-(2-pyrazinyl)-4-amino-piperidine (0.32 mmol) and 62 mg (2S)-1-(2-chloroacetyl)-4,4-difluoro-2-pyrrolidine carbonitrile (0.32 mmol) and 285 mg of polymer-bound 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (PBEMP) (0.73 mmol) are dissolved in 20 ml dry acetonitrile and stirred at 55° C. for 8 hours. The resin is removed by filtration, the filtrate is concentrated by vacuum and the residue is purified by column chromatography using chloroform—methanol (9:1) as eluent to result an oil, which is treated with hydrochloric acid in diethylether result in 83 mg (60%) of title compound, as white crystals. M.p.: 158-160° C. 1H-NMR (400 MHz, DMSO-d6): δ 1.54 (m, 2H), 2.15 (m, 2H), 2.80-2.95 (m, 4H), 4.20-4.25 (m, 4H), 4.55 (d, 2H,), 5.20 (t, 1H), 7.00 (d, 1H), 7.87 (dd, 1H), 8.50 (d, 1H); 9.38 (br, 2H).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7](S([O-])(=O)=O)=[CH:8][C:9]([C:11](=[O:12])[C:4]2=[CH:3][CH:2]=1)=[O:10].[Na+].[CH3:18][NH:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>O>[CH3:18][N:19]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[C:7]1[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[C:11](=[O:12])[C:9](=[O:10])[CH:8]=1
Reactant: CNC1CCCCC1
Reactant: O=C1C=C(S(=O)(=O)[O-])c2ccccc2C1=O
Agent: [Na+]
Solvent: O
Product: CN(C1=CC(=O)C(=O)c2ccccc21)C1CCCCC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 10.4 g of 1,2-naphthoquinone-4-sulfonic acid-sodium salt in 350 ml of water is stirred at room temperature for 30 minutes. To this solution is added 4.52 g of N-methylcyclohexylamine in one portion. The solution is stirred five hours at room temperature and the precipitate then filtered. The product is washed with 200 ml of water and dried at 100° C. in vacuo overnight to afford 4-(N-methylcyclohexylamino)-1,2-naphthoquinone melting at 168°-170° C. The preparation of the same compound from 4-ethoxy-1,2-naphthoquinone is reported in J. Med. Chem. 13, 97 (1970).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[C:11]1([CH:17]2[CH2:23][C:22](=O)O[C:19](=[O:20])[CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC(C)=O>C1COCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[N:9]3[C:19](=[O:20])[CH2:18][CH:17]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH2:23][C:22]3=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: O=C1CC(c2ccccc2)CC(=O)O1
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: O=C1CC(c2ccccc2)Cc2nc3cc(Cl)c(Cl)cc3n21
Reaction time: 0.5 h
Yield: 18.7 %

Procedure:
The solution of commercial 4,5-dichloro-1,2-phenylenediamine (0.38 g) and 3-phenylglutaric anhydride (0.4 g) in THF (1 ml) was heated shortly and kept at rt for 0.5 h. The solvent was removed in vacuo and the residue redissolved in acetic acid (3 ml). The dark solution was heated to reflux overnight. Then all volatiles were removed in vacuo and the residue was heated with ethanol (5 ml). After reccoling to rt the precipitate was collected by filtration, washed with ethanol, and dried to give a crude (0.39 g). The crude was decolorized in boiling acetone solution with activated carbon and filtered over Celite. Concentration of the filtrate and drying of the residue afforded 7,8-dichloro-3-phenyl-3,4-dihydropyrido[1,2-a]benzimidazol-1(2H)-one (0.13 g) as colourless crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[C:8]([CH3:22])([CH3:21])[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1.[O-:23][CH2:24][CH3:25].[Na+]>CN(C=O)C>[CH2:24]([O:23][C:2]1[N:7]=[C:6]2[C:8]([CH3:22])([CH3:21])[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1)[CH3:25]
Reactant: CC[O-]
Reactant: COc1ccc(CN2C(=O)c3ccc(Cl)nc3C2(C)C)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc2c(n1)C(C)(C)N(Cc1ccc(OC)cc1)C2=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.9 %

Procedure:
To solution of 2-chloro-6-(4-methoxy-benzyl)-7,7-dimethyl-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one (intermediate A-16 [F], 3.15 g, 10 mmol) in DMF (30 mL) was added sodium ethoxide (1.02 g, 15 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 hours before it was quenched by water and extracted with EtOAc. The organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give title product (2.9 g, 89%) as a solid. MS: 327.2 (M+H+).
Reaction SMILES: C1(S[CH:8]=[CH:9][C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[O:11])C=CC=CC=1.C(OC1C=CC(C2C=CC=CC=2)=CC=1)(=O)C#C.[CH2:42]([OH:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[CH2:42]([O:49][CH:8]=[CH:9][C:10]([O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:17][CH:18]=1)=[O:11])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=C(C=CSc1ccccc1)Oc1ccc(-c2ccccc2)cc1
Reactant: OCc1ccccc1
Agent: C#CC(=O)Oc1ccc(-c2ccccc2)cc1
Product: O=C(C=COCc1ccccc1)Oc1ccc(-c2ccccc2)cc1
Yield: 94 %

Procedure:
The compound 7 was prepared according to the method described for compound 4 employing compound 1 (300 mg, 1.34 mmol) and benzylalcohol (161 mg, 1.48 mmol) to give white solid compound 7 (419 mg, 94%). 1H NMR (400 MHz, CDCl3) δ 5.00 (s, 2H), 5.53 (d, J=12.5 Hz, 1H), 7.18 (d, J=8.2 Hz, 2H), 7.39 (m, 8H), 7.57 (t, J=4.8 Hz, 4H), 7.88 (d, J=12.5 Hz, 1H). HRMS ESI (m/z): Calculated for C22H18O3 ([M+H]+): 331.1256. found: 331.133.
Reaction SMILES: C(O)C.[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:14]=[CH:13][C:12](=[O:15])[N:11]([CH2:16][CH2:17][C@H:18]3[CH2:20][O:19]3)[C:10]=2[N:21]=1.[NH2:22][C@H:23]1[CH2:27][N:26]([C:28]2[CH:29]=[CH:30][C:31]3[O:32][CH2:33][C:34](=[O:38])[NH:35][C:36]=3[N:37]=2)[C:25](=[O:39])[CH2:24]1.C(OC(=O)N[C@@H]1CC(=O)NC1)(C)(C)C>O>[OH:19][C@@H:18]([CH2:17][CH2:16][N:11]1[C:12](=[O:15])[CH:13]=[N:14][C:9]2[CH:8]=[CH:7][C:6]([O:5][CH3:4])=[N:21][C:10]1=2)[CH2:20][NH:22][C@H:23]1[CH2:27][N:26]([C:28]2[CH:29]=[CH:30][C:31]3[O:32][CH2:33][C:34](=[O:38])[NH:35][C:36]=3[N:37]=2)[C:25](=[O:39])[CH2:24]1
Reactant: COc1ccc2ncc(=O)n(CC[C@H]3CO3)c2n1
Reactant: N[C@@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Agent: CC(C)(C)OC(=O)N[C@H]1CNC(=O)C1
Solvent: O
Solvent: CCO
Product: COc1ccc2ncc(=O)n(CC[C@H](O)CN[C@@H]3CC(=O)N(c4ccc5c(n4)NC(=O)CO5)C3)c2n1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
In a mixed solvent (12 ml) of ethanol and water (9:1) were suspended 6-methoxy-4-{2-[(2S)-oxiran-2-yl]ethyl}pyrido[2,3-b]pyrazin-3(4H)-one (290 mg, 1.17 mmol) and 6-[(4R)-4-amino-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (which was synthesized in the same manner as those of Reference Examples 20, 21 and 22, using the [(3R)-5-oxopyrrolidin-3-yl]carbamic acid tert-butyl ester synthesized with reference to WO2004/22536; 291 mg, 1.17 mmol). The obtained mixture was stirred in a sealed tube at 80° C. for 16 hours.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[C:22](=O)([O:25]C)[O:23][CH3:24]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH:14]([CH3:18])[C:15](=[O:17])[CH2:16][C:22]([O:23][CH3:24])=[O:25])=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)OC
Reactant: CC(=O)C(C)Oc1ccc(OCc2ccccc2)cc1
Agent: [Na]
Product: COC(=O)CC(=O)C(C)Oc1ccc(OCc2ccccc2)cc1
Temperature: 85 °C
Reaction time: 0.25 h

Procedure:
3-(4-Benzyloxyphenoxy)-2-butanone (5.0 g) was dissolved in 25 ml of dimethyl carbonate and added to a 50 ml, three-necked, round-bottom flask fitted with a thermometer, condenser, magnetic stirrer and nitrogen sweep. The solution was heated to 85° C. in an oil bath, then charged with 0.51 g of sodium over a period of 0.5 hour. The resulting clear yellow solution began off-passing after 15 minutes, and then turned a cloudy yellow. After 1 hour, the condenser was replaced with a Vigreux column and distillation head, and the bath temperature was raised to 130° C. Methanol was distilled off for 45 minutes. After approximately 4.5 hours, the reaction was stopped and the solution let cool to room temperature. The dimethyl carbonate was stripped off, and the residue rediluted with 50 ml of ethyl acetate. The solution was then washed with a solution of 50 ml of ice water and 5 ml of acetic acid and then with 50 ml of water. The organic phase was dried over magnesium sulfate, filtered, and stripped. The crude yield was 6.06 g of an orange oil. This was submitted for analysis and found to contain 82% of the desired product, methyl 4-(4-benzyloxyphenoxy)-3-oxopentanoate.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[N:7]=[C:6]([O:24][C@@H:25]([CH3:31])[C:26]([O:28]CC)=O)[CH:5]=1)(=[O:3])[NH2:2].CO.[NH3:34]>>[NH2:34][C:26](=[O:28])[C@@H:25]([O:24][C:6]1[N:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)=[CH:12][CH:11]=2)[N:9]=[C:4]([C:1]([NH2:2])=[O:3])[CH:5]=1)[CH3:31]
Reactant: CCOC(=O)[C@H](C)Oc1cc(C(N)=O)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Reactant: N
Solvent: CO
Product: C[C@H](Oc1cc(C(N)=O)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1)C(N)=O
Yield: 31 %

Procedure:
A solution of (S)-ethyl 2-((6-carbamoyl-2-(4-(4-fluorophenoxy)phenyl)pyrimidin-4-yl)oxy)propanoate (0.762 g, 1.79 mmol) in 7M ammonia in methanol (10 mL, 70 mmol) was heated in a sealed tube overnight at 50° C. After cooling, the reaction mixture was evaporated in vacuo and the residue chromatographed over silica gel with 25-100% acetone in hexanes. The product fractions were evaporated in vacuo and the residue triturated with 5 mL MeOH. The solid was filtered and rinsed again with 2 mL MeOH. The MeOH filtrate and washings were evaporated in vacuo and triturated with 2 mL MeOH, filtered, and rinsed again with 1 mL MeOH. The first and second batches of solid were combined and dried under vacuum at 40° C. to give (S)-6-((1-amino-1-oxopropan-2-yl)oxy)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamide as a white powder (0.220 g, 0.555 mmol, 31% yield). 1H NMR (400 MHz, DMSO-d6): 8.59 (2H, d, J=8.8 Hz), 8.50 (1H, s), 7.96 (1H, s), 7.69 (1H, s), 7.33-7.25 (2H, m), 7.24 (1H, s), 7.23-7.15 (3H, m), 7.06 (2H, d, J=8.8 Hz), 5.36 (1H, q, J=6.8 Hz), 1.52 (3H, d, J=7.0 Hz). LC/MS: m/z=397.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:17]3)=[CH:12][CH:11]=2)O)=[N:4][CH:5]=[CH:6][N:7]=1.[C:26]1(=[O:36])[NH:30][C:29](=[O:31])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[C:3]([CH:8]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][C:16]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[N:17]3)=[CH:12][CH:11]=2)[N:30]2[C:26](=[O:36])[C:27]3[C:28](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:29]2=[O:31])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Temperature: 0 °C

Procedure:
To a suspension of (3-chloropyrazin-2-yl)-(2-phenylquinolin-7-yl)-methanol (1.215 g, 3.49 mmol), phthalimide (566 mg, 3.85 mmol), and PS-PPh3 (loading 2.12 mmol/g; 3.29 g, 6.97 mmol) in dry THF (40 mL), cooled by ice/water, is added DIAD (830 μL, 852 mg, 4.22 mmol). The cooling bath is removed and the flask is vortexed at it for ld. More phthalimide (50 mg, 0.34 mmol), PS-PPh3 (300 mg, 0.636 mmol), and DIAD (80 μL, 82 mg, 0.41 mmol) are added, and vortexing is continued for 2d. The resin is filtered off on a glass frit (porosity M) and washed with CH2Cl2. The combined filtrates and washings are concentrated in vacuo and chromatographed on silica gel [Jones Flashmaster, 50 g/150 mL cartridge, eluting with CH2Cl2 (1-22)→2% EtOAc in CH2Cl2 (23-38)→5% (39-61)], mixed fractions are combined and chromatographed again [50 g/150 mL cartridge, eluting with CH2Cl2 (1-22)→2% EtOAc in CH2Cl2 (23-33)→3% (34-55)→5% (56-68)] to obtain the title compound as white foam. 1H NMR (CDCl3, 400 MHz) δ 7.14 (s, 1H), 7.43-7.55 (m, 3H), 7.72-7.79 (m, 3H), 7.82-7.90 (m, 4H), 8.09 (s, 1H), 8.09-8.14 (m, 2H), 8.22 (d, J=8.8 Hz, 1H), 8.40 (d, J=2.4 Hz, 1H), 8.51 (d, J=2.4 Hz, 1H). MS (ES+): m/z 476.9/478.9 (100/38) [MH+]. HPLC: tR=3.5 min (MicromassZQ, nonpolar—5 min).
Reaction SMILES: Cl.[CH:2]([N:5]1[C:14]2[C:9](=[C:10]([CH3:15])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([C:16]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:17])[C:6]1=[O:26])([CH3:4])[CH3:3].Br[CH:28]([CH3:36])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH:2]([N:5]1[C:14]2[C:9](=[C:10]([CH3:15])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([C:16]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:28]([CH3:36])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:22][CH2:21]2)=[O:17])[C:6]1=[O:26])([CH3:4])[CH3:3]
Reactant: Cc1cccc2c1cc(C(=O)NCC1CCNCC1)c(=O)n2C(C)C
Reactant: CC(Br)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cccc2c1cc(C(=O)NCC1CCN(C(C)C(=O)OC(C)(C)C)CC1)c(=O)n2C(C)C
Temperature: 70 °C
Reaction time: 23 h
Yield: 65 %

Procedure:
A mixture of 1-isopropyl-5-methyl-2-oxo-N-(piperidin-4-ylmethyl)-1,2-dihydroquinoline-3-carboxamide hydrochloride (467 mg, 0.98 mmol, step 4 in preparation 3), tert-butyl 2-bromopropanoate (0.24 mL, 1.47 mmol), and triethylamine (0.41 mL, 2.93 mmol) in tetrahydrofuran (30 mL) was stirred at 70° C. for 23 h. After cooling to room temperature, the mixture was poured onto saturated aqueous sodium hydrogen carbonate (100 mL), and the aqueous layer was extracted with dichloromethane (100 mL×2). The combined organic layer was dried over magnesium sulfate, and concentrated in vacuo. The residue was chromatographed on a column of silica gel eluting with ammonia/methanol/dichloromethane (0.1:1:30) to give 299 mg (65%) of the title compound as a yellow amorphous.
Reaction SMILES: C(OC)(=O)/C=C/C=C/C(OC)=O.[Cl:13][C:14]1[CH:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]>CC(C)C(O)COC(CO)C.[Pd]>[Cl:13][CH:14]1[CH2:23][CH:22]([C:24]([O:26][CH3:27])=[O:25])[CH2:21][CH2:20][CH:15]1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)c1ccc(C(=O)OC)c(Cl)c1
Agent: [Pd]
Agent: CC(CO)OCC(O)C(C)C
Agent: COC(=O)/C=C/C=C/C(=O)OC
Product: COC(=O)C1CCC(C(=O)OC)C(Cl)C1
Temperature: 165 °C

Procedure:
In a Parr pressure reactor, a stirred suspension of trans,trans dimethyl muconate (6.1 g, 36 mmol) in dimethyldipropyleneglycol (120 ml, 0.3 M) is heated under vinyl chloride pressure (18 psi (0.124 MPa) at 23° C.) to 165° C. for 48 hours. After cooling to room temperature, the reaction mixture is diluted using the same solvent to 200 ml in a volumetric flask, transferred into a round-bottom flask equipped with a magnetic stirring bar, and Pd/C catalyst is added (360 mg of Johnson-Matthey 5 percent Pd/C #6, 0.2 mol percent) at room temperature. The flask is equipped with a reflux condenser, flitted gas dispersion tube, and internal T probe. Under N2 flow (190 ml/min) and stirring (190 rpm) the mixture is heated to reflux while samples are taken at appropriate intervals (t=0.0, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0 h) to monitor the progress of the reactions occurring. After 8 hour reaction time, dimethyl chloro-terephthalate is present. Some material also undergoes C—Cl bond cleavage and dimethyl 2-chloro-cyclohexane-1,4-dicarboxylate is also formed.
Reaction SMILES: C(OC(N1CC[C@H]([C@@H](C2CCCCC2)O)C1)=O)(C)(C)C.[C:21]([O:25][C:26]([N:28]1[CH2:32][CH2:31][C@H:30]([CH:33]=[O:34])[CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:45][C:46]1([F:55])[CH2:51][CH2:50][CH:49](C(Cl)=O)[CH2:48][CH2:47]1.S(C)C>C1COCC1>[C:21]([O:25][C:26]([N:28]1[CH2:32][CH2:31][CH:30]([CH:33]([CH:49]2[CH2:50][CH2:51][C:46]([F:55])([F:45])[CH2:47][CH2:48]2)[OH:34])[CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C(Cl)C1CCC(F)(F)CC1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C=O)C1
Agent: CC(C)(C)OC(=O)N1CC[C@H]([C@H](O)C2CCCCC2)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)(C)OC(=O)N1CCC(C(O)C2CCC(F)(F)CC2)C1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
The title compound was prepared in a manner similar to that described in Preparation 9 for the synthesis of (S)-3-((R)-cyclohexylhydroxymethyl) pyrrolidine-1-carboxylic acid t-butyl ester. (S)-3-Formylpyrrolidine-1-carboxylic acid t-butyl ester and LiHMDS were dissolved in THF under nitrogen and cooled at −78° C. 4,4-Difluoro-cyclohexanecarbonyl chloride (prepared by treatment of 4,4-difluorocyclohexane carboxylic acid with thionyl chloride in THF at 50° C. for 2 hours), was then added and the resulting mixture was stirred at −78° C. then allowed to reach room temperature overnight. BH3.Me2S in THF was added and the resulting mixture stirred at room temperature for 1 hour, then refluxed for 1 hour. The solids (1.03 g) were separated and dissolved in 1:1 AcOH:H2O (20 mL) and purified by preparative HPLC (BDS, 40-60%). This was repeated twice to yield:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12]([OH:14])=O)[O:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH:1]([C:4]1[CH:5]=[C:6]([C:12]([NH:15][C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:14])[O:7][C:8]=1[CH:9]([CH3:10])[CH3:11])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: CC(C)c1cc(C(=O)O)oc1C(C)C
Product: CCOC(=O)c1cccc(NC(=O)c2cc(C(C)C)c(C(C)C)o2)c1
Yield: 89 %

Procedure:
In the same manner as that of Example 2, 4,5-diisopropylfuran-2-carboxylic acid (60 mg, 0.306 mmol) was condensed with ethyl 3-aminobenzoate, and the resultant was purified by silica gel chromatography [hexane-ethyl acetate (7:2)] to obtain ethyl 3-[(4,5-diisopropylfuran-2-carbonyl)amino]benzoate (93 mg, 89%) as colorless needles.
Reaction SMILES: C1([C@@H]([N:9]2[CH2:15][CH2:14][C@@H:13]3[CH2:16][C@H:10]2[C:11](=[O:17])[O:12]3)C)C=CC=CC=1.[CH3:18][OH:19]>[Pd]>[CH3:18][O:19][C:11](=[O:17])[C@H:10]1[CH2:16][C@@H:13]([OH:12])[CH2:14][CH2:15][NH:9]1
Reactant: C[C@@H](c1ccccc1)N1CC[C@@H]2C[C@H]1C(=O)O2
Reactant: CO
Agent: [Pd]
Product: COC(=O)[C@H]1C[C@@H](O)CCN1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of (1S,5R)-2-((S)-1-phenylethyl)-6-oxa-2-azabicyclo[3.2.1]octan-7-one (2.95 g) and 10% palladium on activated carbon (570 mg) in methanol (75 mL) was stirred at room temperature for 6 hr under hydrogen (3.5 kgf/cm2). The catalysts were removed by filtration and washed with methanol. The combined organic layers were evaporated in vacuo. A mixture of the residue and 10% palladium on activated carbon (500 mg) in methanol (75 mL) was stirred at room temperature for 8 hr under hydrogen (3.5 kgf/cm2). The catalysts were removed by filtration and washed with methanol. The combined organic layers were evaporated in vacuo. The mixture of the residue and 10% palladium on activated carbon (504 mg) in methanol (75 mL) was stirred at room temperature for 8 hr under hydrogen (4.0 kgf/cm2). The catalysts were removed by filtration and washed with methanol. The combined organic layers were evaporated in vacuo to give the title compound (2.11 g): 1H NMR (400 MHz, CDCl3) δ 1.32-1.49 (m, 2H), 1.83 (br s, 2H), 1.93-1.95 (m, 1H), 2.27-2.32 (m, 1H), 2.61-2.69 (m, 1H), 3.22 (dt, J=12.7, 3.9 Hz, 1H), 3.39 (dd, J=2.9, 10.7 Hz, 1H), 3.71-3.78 (m, 1H), and 3.75 (m, 3H).