Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2-:1][C:2]([CH3:4])=[O:3].[CH2-]C(C)=O.[C:9]([OH:18])(=[O:17])[CH:10]([CH:12]([C:14]([OH:16])=[O:15])O)O.CC(C)([O-])C.[K+].Cl.C(Cl)(=O)C>O1CCCC1.CO>[CH3:1][C:2]1([CH3:4])[O:16][C:14](=[O:15])/[C:12](=[CH:10]/[C:9]([OH:18])=[O:17])/[O:3]1
Reactant: [CH2-]C(C)=O
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)Cl
Solvent: CO
Product: CC1(C)OC(=O)/C(=C/C(=O)O)O1
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 77 %

Procedure:
A stirred solution of tartaric acid bis(acetonide) prepared as in Example 1 (1.0 kg) in tetrahydrofuran (5.0 L) was cooled to −40° C. A chilled 0.75 M solution of potassium tert-butoxide in tetrahydrofuran (7.0 L) was added and stirring was continued for 15 min at −40° C. In a separate reactor, a 1.2 M solution of HCl was generated by reaction of acetyl chloride (0.50 L) with methanol (0.31 L) in tetrahydrofuran (5.0 L) 0-5° C. The original reaction is quenched by addition of the chilled HCl solution. The mixture was allowed to warm to room temperature with stirring over the course of 1 h, after which the THF content was reduced to <2% by vacuum distillation. Ethyl acetate (20 L) was added and the mixture was concentrated to 10 L. Deionized water (8.0 L) was added and the pH was adjusted to <2.5 with 1 N HCl. The organic phase was separated and the aqueous phase was further extracted with ethyl acetate (5.0 L). The combined organics were concentrated to a volume of 3 L by vacuum distillation whereupon heptane (6.0 L) was added. The product mixture was vigorously agitated at 15° C. for 1 h after which the crystalline product was collected by filtration and washed with heptane (2×2.0 L). Vacuum drying at 50° C. afforded Z-2,2-dimethyl-5-carboxymethylene-1,3-dioxolan-4-one (577 g, 77%) as fine white needles. NMR and HPLC analysis indicated the product purity was 100%.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].CN1CCCC1=O.[NH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25].C([O-])([O-])=O.[K+].[K+]>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])=[C:3]([CH3:11])[CH:4]=1)([O-:10])=[O:9]
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: NCCCCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc([N+](=O)[O-])ccc1NCCCCCO
Temperature: 60 °C
Yield: 94.4 %

Procedure:
2 g of 2-fluoro-5-nitrotoluene were added to a solution of 20 ml of N-methylpyrrolidinone, 1.6 g of 5-amino-1-pentanol and 2.14 g of K2CO3. The reaction medium was heated at 60° C. for 12 hours and, after cooling to room temperature, was then poured into a water and ice mixture. The yellow precipitate formed was filtered off, reslurried in water and then dried over P2O5. 2.9 g of 5-(4-nitro-2-methylphenylamino)pentan-1-ol (19) were obtained.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[C:4](=[O:15])[NH:5][C:6](=[O:14])[N:7]([CH2:9][CH2:10][CH2:11][CH:12]=O)[CH:8]=1.[F:18][C:19]([F:33])([F:32])[C:20]1[CH:25]=[CH:24][C:23]([C@:26]23[CH2:31][C@H:30]2[CH2:29][NH:28][CH2:27]3)=[CH:22][CH:21]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Cl:52]C(Cl)C>C(OCC)(=O)C>[ClH:52].[F:1][C:2]([F:17])([F:16])[C:3]1[C:4](=[O:15])[NH:5][C:6](=[O:14])[N:7]([CH2:9][CH2:10][CH2:11][CH2:12][N:28]2[CH2:29][C@H:30]3[C@:26]([C:23]4[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:33])[F:32])=[CH:25][CH:24]=4)([CH2:31]3)[CH2:27]2)[CH:8]=1
Reactant: CC(Cl)Cl
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Reactant: O=CCCCn1cc(C(F)(F)F)c(=O)[nH]c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cl
Product: O=c1[nH]c(=O)n(CCCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of 4-(5-trifluoromethyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-butyraldehyde (Prep24, 22 mg, 0.09 mmol) in dichloroethane (1 mL), (1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep4, 204 mg, 0.09 mmol), AcOH (7.9 mg, 0.13 mmol) and NaBH(AcO)3 (22 mg, 0.18) were added and the mixture was stirred at room temperature overnight. Ethyl acetate was added and the solution was washed with aqueous saturated NaHCO3. The organic phase was dried (Na2SO4) and evaporated. The crude was purified by flash chromatography with DCM-MeOH—NH4OH (95-5-1) to give the title compound (31 mg, 76% yield) as a free base.
Reaction SMILES: [O:1]1[CH2:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3][CH2:2]1.[C:9]([NH:28][C:29]1[S:30][CH:31]=[C:32](/[C:34](=[N:66]/[O:67][CH3:68])/[C:35]([NH:37][CH:38]2[C:64](=[O:65])[N:40]3[C:41]([C:48]([O:50][CH:51]([C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)[C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)=[S:49])=[C:42]([C:45](=O)C)[CH2:43][S:44][C@H:39]23)=[O:36])[N:33]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1CCOCC1.[F:75][C:76]([F:89])([F:88])[S:77](OC[CH:82]1[CH2:87][CH2:86][O:85][CH2:84][O:83]1)(=[O:79])=[O:78]>FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(N(CC)CC)C.N1C=CC=CC=1>[F:75][C:76]([F:89])([F:88])[S:77]([O:8][CH2:7][CH:5]1[CH2:4][O:3][CH2:2][O:1][CH2:6]1)(=[O:79])=[O:78].[C:9]([NH:28][C:29]1[S:30][CH:31]=[C:32](/[C:34](=[N:66]/[O:67][CH3:68])/[C:35]([NH:37][CH:38]2[C:64](=[O:65])[N:40]3[C:41]([C:48]([O:50][CH:51]([C:58]4[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=4)[C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=4)=[S:49])=[C:42]([CH2:45][CH:87]4[CH2:82][O:83][CH2:84][O:85][CH2:86]4)[CH2:43][S:44][C@H:39]23)=[O:36])[N:33]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: OCC1COCOC1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(C(C)=O)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=S(=O)(OCC1CCOCO1)C(F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1COCCN1
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(CC3COCOC3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Product: O=S(=O)(OCC1COCOC1)C(F)(F)F
Yield: 92 %

Procedure:
1,3-Dioxan-5-ylmethyl trifluoromethanesulfonate was prepared in the same manner as in Example 27 (a) from 1,3-dioxan-5-ylmethanol (205 mg), pyridine (0.15 ml) and trifluoromethanesulfonic acid anhydride (5.39 mg). On the other hand, diphenylmethyl 7-[(Z)-2-(2-tritylaminothiazol-4-yl) -2-methoxyiminoacetamido]-3-acetylthio-3-cephem-4-carboxylate (500 mg) was reacted with morpholine and triethylamine in the same manner as in Example 27 (b), followed by reacting the resulting reaction product with the 1,3-dioxan-4-ylmethyl trifluoromethanesulfonate in the same manner as in Example 27 (b). The reaction solution so obtained was post-treated in the same manner as in Example 27 (b) and the produced compound was recovered and purified similarly to Example 27 (b) to afford the titled compound (490 mg; 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[CH:5][CH:4]=1.[NH:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH2:14][N:17]2[CH2:18][CH2:19][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:21][CH2:22]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COc1ccc2ccc(=O)n(CC=O)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2n1
Reaction time: 0.33 h
Yield: 94.9 %

Procedure:
To a solution of 1.6 g of (7-methoxy-2-oxo-1,8-naphthyridin-1(2H)-yl)acetaldehyde in 70 mL of dichloromethane, 1.5 g of tert-butyl (piperidin-4-yl)carbamate and 0.42 mL of acetic acid were added, the mixture was stirred for 20 minutes, then 2.3 g of sodium triacetoxyborohydride was added to the reaction mixture and the mixture was stirred at room temperature for 2 hours 10 minutes. Thereto were added water, a saturated aqueous sodium hydrogen carbonate solution and chloroform, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of chloroform:methanol=50:1 to obtain 2.8 g of tert-butyl (1-(2-(7-methoxy-2-oxo-1,8-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white foam.
Reaction SMILES: [CH2:1]([C@H:4]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:5][C@@H:6]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:2]=[CH2:3].I[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH2:38][OH:39])=[CH:32][CH:31]=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:11]([O:10][C:8]([NH:7][C@H:6]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:5][C@H:4]([CH2:1]/[CH:2]=[CH:3]/[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH2:38][OH:39])=[CH:32][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: OCCCc1ccc(I)cc1
Reactant: C=CC[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](C/C=C/c1ccc(CCCO)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of di-tert-butyl (4S)-4-allyl-N-(tert-butoxycarbonyl)-L-glutamate (940 mg, 2.53 mmol) in 5 mL acetonitrile under an argon atmosphere was added 3-(4-iodophenyl)propan-1-ol (740 mg, 2.82 mmol), triethylamine (394 μl, 2.82 mmol), and palladium(II) acetate (106 mg, 0.47 mmol). The mixture was stirred in a pressure tube at 80° C. for 2 h. After cooling to room temperature, the solvent was removed under reduced pressure and the crude material was purified on silica gel using a hexane/ethyl acetate gradient, and the appropriate fractions were combined and concentrated.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([NH2:14])=[O:13].C[O:16][C:17](=O)[C:18](=O)[C:19]1[CH:20]=[C:21]2[C:26]3=[C:27]([CH2:29][CH2:30][N:25]3[CH2:24][CH2:23][CH2:22]2)[CH:28]=1.CC(C)([O-])C.[K+].N1CCCCC1.C(O)(=O)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[C:12](=[O:13])[NH:14][C:17](=[O:16])[C:18]=1[C:19]1[CH:20]=[C:21]2[C:26]3=[C:27]([CH2:29][CH2:30][N:25]3[CH2:24][CH2:23][CH2:22]2)[CH:28]=1
Reactant: COC(=O)C(=O)c1cc2c3c(c1)CCN3CCC2
Reactant: NC(=O)Cc1c[nH]c2ccc(Br)cc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: O=C1NC(=O)C(c2c[nH]c3ccc(Br)cc23)=C1c1cc2c3c(c1)CCN3CCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
To a solution of 2-(5-bromo-1H-indol-3-yl)-acetamide (500 mg, 1.98 mmol) and oxo-(1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-acetic acid methyl ester (404 mg, 1.65 mmol) in anhydrous tetrahydrofuran at 0° C. was added a solution of potassium tert-butoxide (4.95 ml, 4.95 mmol; 1M solution in tetrahydrofuran) dropwise over 5 minutes. The reaction was stirred for a further 30 minutes then cooled to 0° C. and quenched with water (50 ml) and acidified to pH6 with aqueous 2M hydrochloric acid. The mixture was extracted with dichloromethane (3×50 ml) and the combined organic extracts were dried over anhydrous sodium sulfate and evaporated to dryness. The residue was dissolved in N,N-dimethylformamide (4 ml) and treated with piperidine (99 μl, 1.00 mmol) and acetic acid (57 μl, 1.00 mmol). The mixture was heated to 150° C. for 5 minutes under microwave conditions then partitioned between ethyl acetate (50 ml) and water (30 ml). The aqueous layer was removed and the organic layer was washed with water (2×30 ml). The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by flash column chromatography (SiO2, 1% methanol to 10% methanol in dichloromethane) to provide 3-(5-bromo-1H-indol-3-yl)-4-(1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-pyrrole-2,5-dione as a red solid (340 mg). 400 MHz 1H NMR (CDCl3) δ: 8.71 (s, 1H), 7.96 (d, J=2.4 Hz, 1H), 7.48 (s, 1H), 7.27 (m, 2H), 7.08 (s, 1H), 6.94 (s, 1H), 6.56 (s, 1H), 3.36 (t, J=8.0 Hz, 2H), 3.07 (m, 2H), 3.83 (t, J=8.0 Hz, 2H), 2.47 (t, J=6.8 Hz, 2H), 2.04 (m, 2H); LCMS: 448 and 450 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][C:7]([OH:9])=O.[N+]([O-])(O)=O.[O:18]([CH2:22][CH2:23][NH2:24])[N+:19]([O-:21])=[O:20].C(OC(C)C)(C)C>>[O:18]([CH2:22][CH2:23][NH:24][C:7](=[O:9])[CH2:6][O:5][C:4]1[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=1[O:2][CH3:1])[N+:19]([O-:21])=[O:20]
Reactant: NCCO[N+](=O)[O-]
Reactant: COc1ccccc1OCC(=O)O
Solvent: CC(C)OC(C)C
Solvent: O=[N+]([O-])O
Product: COc1ccccc1OCC(=O)NCCO[N+](=O)[O-]
Yield: 28.2 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.77 g of 2-methoxyphenoxyacetic acid and 0.60 g of nitroxyethylamine nitrate, 0.27 g of the title compound was obtained as colorless needles (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: CSC.[N+:4]([C:7]1[CH:24]=[CH:23][C:10]([CH:11]=[N:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)([O-:6])=[O:5].[C:25]1([CH:31]=[N+]=[N-])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl.C(OC)(C)(C)C.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[N+:4]([C:7]1[CH:24]=[CH:23][C:10]([CH:11]2[CH:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:12]2[S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)([O-:6])=[O:5]
Reactant: Cc1ccc(S(=O)(=O)N=Cc2ccc([N+](=O)[O-])cc2)cc1
Reactant: [N-]=[N+]=Cc1ccccc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: COC(C)(C)C
Solvent: CSC
Product: Cc1ccc(S(=O)(=O)N2C(c3ccccc3)C2c2ccc([N+](=O)[O-])cc2)cc1

Procedure:
To a stirred solution of dimethylsulphide (5 μl, 0.07 mmol), rhodium (II) acetate (2 mg, 0.005 mmol) and N-(4-nitrobenzylidene)toluene-p-sulphonamide (102 mg, 0.33 mmol; J. C. S. Perkin I (1981) 2435-2442) in dichloromethane (2 ml) was added phenyldiazomethane (prepared as in Example 36; 8.11 ml of a 0.074M solution in t-butylmethylether) over a period of 12 hours. Upon completion of the addition the solvent was removed in vacuo and the residue was chromatographed using silica gel elating with 15:85 ethyl acetate:petrol to give the title compound as a mixture of trans and cis isomers. Trans isomer (48 mg, 37%) δH (CDCl3) 8.10-8.19(2H,m), 7.53-7.64(4H,m), 6.95-7.41(7H,m), 4.27(1H,d,J=6 Hz), 4.16(1H,d,J=6 Hz), 2.36(3H,s)ppm. Cis isomer (9 mg; 7%) δH (CDCl3) 8.23-8.33(2H,m); 7.15-7.60(11H,m), 4.13(1H,d,J=2 Hz) 3.87(1H,d,J=2 Hz) 1.68(3H,s)ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][C:26]=2[C:33](O)=[O:34])[N:8]([CH3:24])[C:9](=[O:23])[N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:11]=1[CH3:12])=[O:5])[CH3:2].C(N(CC)CC)C.[N:43]1([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][C:26]=2[C:33]([N:46]2[CH2:47][CH2:48][N:43]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:44][CH2:45]2)=[O:34])[N:8]([CH3:24])[C:9](=[O:23])[N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:11]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1C(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-(2-carboxy-4-cyano-phenyl)-3,6-dimethyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid ethyl ester (intermediate 10)(30.0 mg, 0.06 mmol) is suspended in N,N-dimethylformamide (0.5 mL) and triethylamine (20.0 μL, 0.14 mmol) is added. The mixture is stirred at room temperature for 5 min and O-(7-azabonzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate (24.6 mg, 0.065 mmol) is added and the mixture is stirred for 15 min. A solution of tert-butyl 1-piperazinecaboxylate (17.2 mg, 0.09 mmol) in N,N-dimethylformamide (0.5 mL) and triethylamine (20.0 μL, 0.14 mmol) is added and the reaction mixture stirred at room temperature for 2 h. The crude product is purified by reversed phase HPLC. ESI mass spectrum [M-tBu+H]+=600; Retention time HPLC: 1.21 min (HPLC method Z018_S08).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](Cl)[CH:6]=[CH:7][CH:8]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=1.P>C1(C)C=CC=CC=1.C(Cl)C=CC1C=CC=CC=1.[Pd]>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH2:18][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:13][CH:12]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: COc1cccc(Cl)c1
Agent: [Pd]
Agent: ClCC=Cc1ccccc1
Agent: P
Solvent: Cc1ccccc1
Product: COc1cccc(CC(=O)c2ccc(F)cc2)c1
Yield: 75.9 %

Procedure:
This reaction is carried out in the same manner as the reaction in example 3. The difference is that, the reactants are m-methoxyphenyl chloride (143.7 mg, 1.0 mmol), 1-(4′-fluorophenyl)ethanone (347.2 mg, 2.5 mmol), palladium cinnamyl chloride (7.8 mg, 0.015 mmol), 2-Methoxy-6-(N-methyl-N-phenyl-amino)phenyldicyclohexyl)phosphine (18.4 mg, 0.045 mmol), K3PO43H2O (664.2 mg, 2.5 mmol) in 3 mL dry toluene at 110° C. for 22.8 h. 1-(4′-Fluorophenyl)-2-(3′-methoxyphenyl)-1-ethanone (185.5 mg) was obtained with a yield of 75% as liquid. 1H NMR (300 MHz, CDCl3) δ 8.05-7.98 (m, 2H, ArH), 7.27-7.18 (m, 1H, ArH), 7.12-7.04 (m, 2H, ArH), 6.86-6.75 (m, 3H, ArH), 4.20 (s, 2H, CH2), 3.75 (s, 3H, OCH3); 13C NMR (75 MHz, CDCl3) δ 195.8, 167.2, 163.9, 159.7, 135.7, 132.8, 132.7, 131.2, 131.1, 129.6, 121.6, 115.7, 115.4, 115.0, 112.2, 55.0, 45.4; 19F NMR (282 MHz, CDCl3) 6-104.9; IR (neat) v (cm−1) 3072, 3002, 2940, 2836, 1682, 1597, 1506, 1491, 1455, 1437, 1331, 1264, 1232, 1157, 1099, 1050, 1002; MS (70 eV, EI) m/z (%): 245 (M++1, 3.27), 244 (M+, 17.36), 123 (100).
Reaction SMILES: [CH:1]1[C:17]2[C:16]3[C:8](=[C:9]4[C:13](=[CH:14][CH:15]=3)[CH2:12][CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.O.ClC1C(=O)C(C#N)=C(C#N)C(=[O:27])C=1Cl>C(O)(=O)C.CCOCC>[CH:1]1[C:17]2[C:16]3[C:8](=[C:9]4[C:13](=[CH:14][CH:15]=3)[C:12](=[O:27])[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)CCc1c-2ccc2c1CCC2
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CC(=O)O
Solvent: O
Solvent: CCOCC
Product: O=C1CCc2c1ccc1c2CCc2ccccc2-1
Yield: 76.4 %

Procedure:
The hydrocarbon (5) 48 mg; 0.22 mmol) was dissolved in hot acetic acid (15 ml) and water (5 ml) was added slowly with stirring to maintain homogeneity of the solution. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (198 mg, 0.88 mmol) was added, changing the color of the solution to dark green. Stirring was continued at reflux for 30 min. during which time the color of the solution changed to dark red. The reaction mixture was cooled and diluted with ether, and the ether layer was washed with water and aqueous NaOH. The solution was dried over MgSO4 and evaporated to provide a white solid which was chromatographed on a column of Florisil™. Elution with ether yielded 6 (39 mg, 76%):m.p. 127°-128° C.; NMR δ272 (t,l,H15 or16), 2.85-2.91 (m,4,H6,7), 3.07 (t,l,H15 or16), 7.24-7.31 (m,3,H2,3,4), 7.67-7.77 (m,3,H1,11,12) Anal. Calc'd. for C17H14O: C,87.25; H,6.02. Found: C,87.13; H,6.03.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[H-].[Na+].Cl.Cl[CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[O:11][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: ClCc1cccnc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2cccnc2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.8 %

Procedure:
3-Fluoro-4-nitrophenol (7.5 g) is added to a stirred suspension of sodium hydride (2.2 g, 60% dispersion in mineral oil) in DMF (50 mL). The mixture is stirred at ambient temperature for 30 minutes. To this mixture is added a solution prepared by the addition of sodium hydride (2.2 g, 60% dispersion in mineral oil) to a stirred suspension of 3-chloromethylpyridine hydrochloride (8.2 g) in DMF (50 mL). The resulting mixture is stirred at 90° C. for 16 hours then cooled to ambient temperature. The reaction mixture is concentrated in vacuo and the residue partitioned between dichloromethane (100 mL) and water (100 mL). The aqueous phase is extracted four times with dichloromethane (100 mL). The combined organic phases are washed with brine (100 mL), dried over magnesium sulphate, filtered and concentrated in vacuo to give an orange solid. Recrystallisation from ethyl acetate gives 3-(3-fluoro-4-nitrophenoxymethyl)pyridine (4.6 g) as pale orange/brown cystals.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[CH:4][CH:3]=1.[CH3:16][CH:17]([CH3:20])[CH:18]=O.N1CCCCC1.C(O)(=O)C>C(O)(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8](=[CH:16][CH:17]([CH3:20])[CH3:18])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[CH:14][CH:15]=1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Reactant: CC(C)C=O
Solvent: C1CCNCC1
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CCOC(=O)C(=CC(C)C)C(=O)c1ccc(F)cc1

Procedure:
A solution of 210 g (1 mol) of ethyl 4-fluorobenzoylacetate and 144 g (2 mol) of 2-methylpropanal are stirred overnight at 50° C. with 7 ml of piperidine and 5 ml of acetic acid in 100 ml of isopropanol. After reaction is complete, the batch is concentrated at about 15 Torr and the crude product (270 g, about 85%) is reacted without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]([C:36](O)=[O:37])([CH3:35])[CH3:34])=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[F:70][C:71]1([F:77])[CH2:76][CH2:75][NH:74][CH2:73][CH2:72]1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]([CH3:34])([CH3:35])[C:36]([N:74]2[CH2:75][CH2:76][C:71]([F:77])([F:70])[CH2:72][CH2:73]2)=[O:37])=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1
Reactant: FC1(F)CCNCC1
Reactant: CC(C)(Oc1ccc(Br)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(Oc1ccc(Br)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12)C(=O)N1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.5 %

Procedure:
To a mixture of racemic(2′R, 3R, 4′S)-2′-[5-bromo-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (40 mg, 0.065 mmol), EDCI (18.7 mg, 0.098 mmol), HOBt (15 mg, 0.098 mmol) and DIPEA (75 mg, 0.6 mmol) in THF (2 mL) was added 4,4-difluoropiperidine hydrochloride (30 mg, 0.195 mmol). The mixture was stirred at room temperature overnight, purified by prep-HPLC to give the title compound as a white solid (19mg).