Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[S:20][C:19]=2[CH2:33][CH3:34])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:35][NH:36][CH2:37][CH2:38][C:39]([O:41]CC)=[O:40]>>[CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][CH:24]=3)[S:20][C:19]=2[CH2:33][CH3:34])[O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([N:36]([CH3:35])[CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:14])=[CH:16][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC
Reactant: CCc1sc(-c2ccc(C(F)(F)F)cc2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Product: CCc1sc(-c2ccc(C(F)(F)F)cc2)cc1C(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 50.1 %

Procedure:
An operation similar to that in Example 69-(9) was performed using 4-(cyclohexyl{2-ethyl-5-[4-(trifluoromethyl)phenyl]thiophen-3-yl}methoxy)benzoic acid (250 mg) synthesized in Example 69 (8) and ethyl 3-(methylamino)propanoate (80.5 mg) to give the title compound (147 mg, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:25])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([O:8][C:16](=[O:25])[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(Cl)c1
Reactant: O=C(Cl)CCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCc1ccccc1)Oc1cccc(Cl)c1
Reaction time: 0.5 h

Procedure:
To a solution of 3-chlorophenol (1, 50.1 g, 0.3 mol), triethylamine (TEA, 85 mL), and CH2Cl2 (500 mL) at 23° C. was added hydrocinnamoyl chloride (2, 31 mL, 0.3 mol) over 5 minutes. After 30 minutes, the reaction mixture was concentrated in vacuo. The crude slurry was then dissolved in 10:1 hexanes:EtOAc (300 mL) and washed with 1 N NaOH (100 mL) and brine (100 mL). The organic layer was dried (MgSO4) and filtered through a plug of silica gel (10:1 hexanes:EtOAc rinse). The eluent was concentrated to afford 78 g of a slightly yellow oil, which was used without any further purification.
Reaction SMILES: [F:1][C:2]([F:13])([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][OH:4].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CCCCCC>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:4][CH2:3][C:2]([F:13])([F:1])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCC(F)(F)CCc1ccccc1
Reactant: BrCCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCCCCC
Product: FC(F)(CCc1ccccc1)COCCCCCCBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Intermediate 2 (0.60 g, 3.22 mmol) in 1,6-dibromohexane (1.74 mL, 11.27 mmol) was added tetrabutylammonium bromide (21 mg, 0.064 mmol) and 50% sodium hydroxide (1.2 mL). The mixture was stirred at room temperature overnight. The crude reaction was diluted with n-hexane (20 mL), washed with water (2×10 mL), dried (Na2SO4), and the solvent removed under reduced pressure. The title compound was obtained (2.1 g, 52% purity) and was used in the next step without further purification.
Reaction SMILES: [C:1]([O:11][C:12](=[C:14]([F:16])[F:15])[F:13])([C:4]([C:7]([F:10])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].CO.[C:19]([O:24]OC(=O)C1C=CC=CC=1)(CC)(C)C>>[C:1]([O:11][CH:12]([C:14]([CH2:19][OH:24])([F:15])[F:16])[F:13])([C:4]([C:7]([F:10])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: CCC(C)(C)OOC(=O)c1ccccc1
Reactant: FC(F)=C(F)OC(F)(F)C(F)(F)C(F)(F)F
Solvent: CO
Product: OCC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)F

Procedure:
C3F7OCFHCF2CH2OH was prepared by the reaction of C3F7OCF═CF2 (53 g, 0.2 mol) with methanol (63.7 g, 2.0 mol) using t-amylperoxybenzoate (1.0 g) as free radical initiator at 106° C. The product reaction mixture was washed with water and distilled and the distillation fraction of b.r.=115-117° C. used in the next step.
Reaction SMILES: C[CH:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[C:5]([N+:11]([O-:13])=[O:12])=[C:4]([NH:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[N:3]1S.[CH3:21][O-:22].[Na+].C(N(CC)CC)C>CO>[CH3:21][O:22][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[C:5]([N+:11]([O-:13])=[O:12])=[C:4]([NH:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[N:3]=1
Reactant: CCNC1=NC(C)N(S)C(NC(CC)CC)=C1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCNc1nc(OC)nc(NC(CC)CC)c1[N+](=O)[O-]
Yield: 74.5 %

Procedure:
30 g (0.1 mol) of 2-methyl-mercapto-4-ethylamino-5-nitro-6-(3-pentyl-amino)-pyrimidine are dissolved in 400 ml of methanol. A solution of 8.1 g (0.15 mol) of sodium methylate in 100 ml of methanol is added together with 20 ml of triethylamine to the previously prepared solution. The mixture is refluxed for 16 hours, evaporated, and the residue is treated with 200 ml of water. After extracting 3 times with ether, the extracts are dried over MgSO4, dried, filtered, and the ethereal solution is evaporated, to leave as residue 21.1 g of 2-methyoxy-4-ethylamino-5-nitro-6-(3-pentylamino)-pyrimidine with a boiling point of 162° C/0.001 Torr (74.5% of theory).
Reaction SMILES: [CH2:1]([N:8]([CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32])[C:9](=O)[CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([N:8]([CH2:9][CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)[CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1OCCN(Cc1ccccc1)C(=O)CCc1c[nH]c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccccc1OCCN(CCCc1c[nH]c2ccccc12)Cc1ccccc1
Temperature: 25 °C
Yield: 86 %

Procedure:
To a solution of N-benzyl-3-(1H-indol-3-yl)-N-[2-(2-methoxy-phenoxy)-ethyl]-propion-amide in tetrahydrofuran (50 mL) at room temperature was added lithium aluminum hydride (1.8 g). The reaction was heated to reflux for 12 hours then allowed to cool to room temperature. The reaction was quenched with saturated ammonium chloride and the solid precipitates filtered through celite. The solvent was concentrated under vacuum and the product purified by chromatography (5% methanol-methylene chloride) to afford 2.0 g (86%) of product as a yellow oil. MS EI m/e 414 (M+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[C:5]2=O.O.[NH2:23][NH2:24]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:6]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)=[CH:7][NH:24][N:23]=2)[C:9]([OH:8])=[CH:10][C:11]=1[OH:12]
Reactant: NN
Reactant: COc1cccc(-c2coc3cc(O)c(Cl)cc3c2=O)c1
Solvent: O
Product: COc1cccc(-c2c[nH]nc2-c2cc(Cl)c(O)cc2O)c1
Yield: 46 %

Procedure:
This compounds was synthesised in the same manner as described above. 6-Chloro-7-hydroxy-3-(3-methoxy-phenyl)-chromen-4-on (1.0 g, 3.3 mmol), Hydrazine hydrate (8 ml). The quenched reaction was extracted into ethyl acetate, washed (water), dried (MgSO4), and the solvent removed under vacuum to give 4-Chloro-6-[4-(3-methoxy-phenyl)-1H-pyrazol-3-yl]-benzene-1,3-diol as a white solid (0.48 g, 46%); Rf 0.5 ethyl acetate/hexane (80/20)].
Reaction SMILES: CO.C[C:4]1[C:9]([CH:10]=O)=[CH:8][N:7]=[C:6]([NH:12][CH2:13][CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[N:5]=1.[F:23][C:24]1[C:25]([CH3:32])=[C:26]([NH2:31])[C:27]([NH2:30])=[CH:28][CH:29]=1>C1(C)C=CC=CC=1.O=[Mn]=O>[F:23][C:24]1[CH:29]=[CH:28][C:27]2[NH:30][C:10]([C:9]3[CH:8]=[N:7][C:6]([NH:12][CH2:13][CH2:14][CH2:15][CH:16]4[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]4)=[N:5][CH:4]=3)=[N:31][C:26]=2[C:25]=1[CH3:32]
Reactant: Cc1c(F)ccc(N)c1N
Reactant: Cc1nc(NCCCC2CCN(C)CC2)ncc1C=O
Agent: O=[Mn]=O
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1c(F)ccc2[nH]c(-c3cnc(NCCCC4CCN(C)CC4)nc3)nc12
Reaction time: 0.5 h

Procedure:
A mixture of 4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidin-5-yl}-methanol (0.14 g, 0.49 mmol) in toluene (3 mL) was added MnO2 (0.22 g, 2.48 mmol). After 30 min at 70° C., the mixture was filtered through diatomaceous earth. The filtrate was concentrated and immediately dissolved in DMF. A portion of this solution (corresponding to 0.05 mg, 0.17 mmol of 4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carbaldehyde) was then treated with 4-fluoro-3-methyl-benzene-1,2-diamine (1.1 equiv.) and Na2H2S2O5 (1.25 equiv.) at 90° C. for 12 h. The reaction mixture was purified by FCC to afford the title compound. MS: mass calcd. for C22H29FN6, 396.24; m/z found, 397.2 [M+H]+. 1H NMR (CD3OD): 8.62 (s, 1H), 7.55 (dd, J=8.0, 3.9 Hz, 1H), 7.17 (dd, J=10.3, 8.8 Hz, 1H), 3.60 (t, J=6.9 Hz, 2H), 3.10-2.99 (m, 2H), 2.71 (s, 3H), 2.66 (d, J=1.4 Hz, 3H), 2.44 (s, 3H), 2.26-2.17 (m, 2H), 1.98-1.88 (m, 2H), 1.87-1.77 (m, 2H), 1.55-1.36 (m, 5H).
Reaction SMILES: [O:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([NH2:10])[C:4]=2[CH:3]=[CH:2]1.C([O-])(=O)C.[Na+].[I:16]I.[OH-].[Na+]>C(O)(=O)C.O1CCCC1>[I:16][C:2]1[O:1][C:9]2[CH:8]=[CH:7][N:6]=[C:5]([NH2:10])[C:4]=2[CH:3]=1
Reactant: II
Reactant: Nc1nccc2occc12
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Nc1nccc2oc(I)cc12
Temperature: 25 °C
Reaction time: 96 h
Yield: 68.1 %

Procedure:
Furo[3,2-c]pyridin-4-ylamine (7.8 g) was dissolved in 175 mL of glacial acetic acid and sodium acetate (14.3 g) added in portions (exothermic!). Subsequently a solution of iodine (44.2 g) in 150 mL of tetrahydrofuran was added dropwise and the resulting mixture allowed to stir for 4 d at ambient temperature. The mixture was poured on ice and the pH value adjusted to pH 10 by adding 10 N sodium hydroxide solution, followed by extraction with ethyl acetate. The organic extract was washed several times with sodium thiosulfate solution and brine, dried (Na2SO4) and concentrated. The crude product was purified by silica chromatography (ethyl acetate/isohexane=5/5, 7.5/2.5, 10/0) to give 10.3 g (68%) of the title compound as a brownish solid. M.p. 170-173° C.; EI-MS: 260 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[S:10][CH2:11][C:12]#[CH:13].[OH:14]O>C(O)(=O)C>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[S:10]([CH2:11][C:12]#[CH:13])=[O:14]
Reactant: C#CCSc1c(O)cc(C)oc1=O
Reactant: OO
Solvent: CC(=O)O
Product: C#CCS(=O)c1c(O)cc(C)oc1=O
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a suspension of 23.1 g. (0.124 mole) of 4-hydroxy-6-methyl-3-propargylthio-2-pyrone in 200 ml. of glacial acetic acid was added 14.1 g. (0.124 mole) of 30% hydrogen peroxide in 50 ml. of glacial acetic acid dropwise over a period of 20 minutes. The reaction mixture was stirred at room temperature for approximately 60 hours and then poured into 400 ml. of ice water. When no precipitate appeared, the solution was extracted with four 100 ml. portions of chloroform, and the extract was dried over anhydrous sodium sulfate. The chloroform was removed by evaporation in vacuo, leaving a solid residue and some acetic acid. The latter was removed by desiccation over sodium hydroxide at 0.2 mm. Hg. for four hours. The crude product was then recrystallized from ethanol, giving 17.7 g. (67 percent) of pale yellow crystals, m.p. 131°-134°C. A second recrystallization from ethanol gave the pure 4-hydroxy-6-methyl-3-propargylsulfinyl-2-pyrone as pale yellow needles, m.p. 133.5°-134.5°C.
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH2:14][C:15]([OH:17])=O)[N:10]3[CH:23]=[CH:24][CH:25]=[C:9]3[C:8]2=[O:26])=[C:4]([F:29])[CH:3]=1.O[N:31]1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.N.Cl>ClCCl.C(#N)C>[CH2:21]([O:20][C:18]([C:11]1([CH2:14][C:15](=[O:17])[NH2:31])[N:10]2[CH:23]=[CH:24][CH:25]=[C:9]2[C:8](=[O:26])[N:7]([CH2:6][C:5]2[CH:27]=[CH:28][C:2]([Br:1])=[CH:3][C:4]=2[F:29])[C:12]1=[O:13])=[O:19])[CH3:22]
Reactant: O=C1CCC(=O)N1O
Reactant: CCOC(=O)C1(CC(=O)O)C(=O)N(Cc2ccc(Br)cc2F)C(=O)c2cccn21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)C1(CC(N)=O)C(=O)N(Cc2ccc(Br)cc2F)C(=O)c2cccn21
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
A mixture of 2-(4-bromo-2-fluorobenzyl)-4-ethoxycarbonyl-1,3-dioxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-acetic acid (21.4 g), N-hydroxysuccinimide (5.8 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (10.5 g) in dichloromethane (150 ml) was stirred at 25° C. for 1 hour, and 7.8% (w/w) ammonia in acetonitrile (40 ml) was added. The resulting mixture was stirred at 25° C. for 1 hour, poured into 5% hydrochloric acid, and extracted with dichloromethane. The extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (18.5 g, 86.4%) as colorless crystals, mp 190°-192° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1([F:19])[CH2:13][CH2:12][CH:11]([C:14](OCC)=[O:15])[CH2:10][CH2:9]1>C(OCC)C>[F:7][C:8]1([F:19])[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1
Reactant: CCOC(=O)C1CCC(F)(F)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCC1CCC(F)(F)CC1

Procedure:
To a suspension of lithium aluminum hydride (2.6 g, 69 mmol) in diethyl ether (160 mL) was added slowly a solution of commercially available ethyl 4,4-difluorocyclohexanecarboxylate (Matrix, 11.0 g, 57 mmol) in diethyl ether (20 mL). The reaction mixture was refluxed for 4 hours, then cooled in an ice bath, quenched cautiously with sequential addition of water (2.6 mL), 15% NaOH (2.6 mL) and water (7.8 mL) and extracted with ethyl acetate (3×100 mL). The mixture was filtered and concentrated to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[O:15])[N:11]=[C:10]2SC)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:18]([NH:21][C:22]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[NH:23])([CH3:20])[CH3:19]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[O:15])[NH:11][C:10]2=[N:23][C:22]([NH:21][CH:18]([CH3:20])[CH3:19])=[N:24][C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CSC1=NC(=O)C(=O)N1c1ccc(Cl)c(Cl)c1
Reactant: CC(C)NC(=N)NC(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Product: CC(C)NC(=NC(=O)OC(C)(C)C)N=C1NC(=O)C(=O)N1c1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Yield: 22.6 %

Procedure:
To the solution of the crude dione 15 (0.7 g, 2.5 mmol) in 25 ml of dry CHCl3 was added N-isopropyl-N′-(tert-butoxycarbonyl)-guanidine (17) (0.5 g, 2.5 mmol). The reaction mixture was heated at 50° C. for 16 hours. The reaction was quenched with water, extracted with chloroform and dried over Na2SO4. The solvent was removed in vacuo and the crude product was purified with a silica gel column and was eluted with 3% EtOAc/CHCl3 to yield 4c as a white solid (0.25 g, 22%), mp 227° C. 1H NMR (300 MHz, CDCl3): δ 7.55 (d, J=2.4 Hz, 1H), 7.53(d, J=8.6 Hz, 1H), 7.27 (dd, J=8.6 and 2.4 Hz, 1H), 4.15 (m, 1H), 1.54 (s, 9H), 1.24 (d, J=6.6 Hz, 6H); 13C NMR: δ 170.50, 168.40, 159.34, 156.09, 153.00, 132.51, 132.09, 131.34, 130.38, 128.62, 125.62, 85.59, 45.05, 29.70, 22.34. IR: 2979, 2930, 1766, 1729, 1532, 1474, 1142, 775, 734 cm−1. MS (m/z): 444 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[CH:4]=[N:5][C:6]([CH3:11])([CH3:10])[CH2:7][O:8][CH3:9].[BH4-].[Na+].C([O-])(O)=O.[Na+].O>CO>[F:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6]([CH3:11])([CH3:10])[CH2:7][O:8][CH3:9]
Reactant: COCC(C)(C)N=Cc1ccc(F)cc1F
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCC(C)(C)NCc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 95 %

Procedure:
A solution of the obtained N-(2,4-difluorobenzylidene)-N-[dimethyl(methoxymethyl)methyl]amine in methanol (7 ml) was cooled to 0° C. in ice-water bath. To the solution was added NaBH4 (117.1 mg, 3.09 mmol). The mixture was gradually warmed to room temperature and stirred for 14 hours. The mixture was added to sat. NaHCO3 aqueous solution and water was added to dissolve the precipitated white solid. The mixture was then extracted three times with ethyl acetate and dried over MgSO4. The mixture was concentrated and purified by silica gel chromatography (hexane/ethyl acetate/triethylamine=50/25/1) to give N-(2,4-difluorophenylmethyl) -N-[dimethyl(methoxymethyl)methyl]amine (378.8 mg; 95% in 3 steps).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:43])[C@H:4]([NH:32]C(OCC1C=CC=CC=1)=O)[CH2:5][N:6]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH3:31])[CH2:7][C:8](=O)[CH:9]([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>O1CCCC1.C(N(CC)CC)C.[Pd]>[CH3:1][O:2][C:3]([C@H:4]1[CH2:5][N:6]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])[CH2:7][CH:8]([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:32]1)=[O:43]
Reactant: COC(=O)[C@@H](CN(CC(=O)C(c1ccccc1)c1ccccc1)Cc1ccccc1OC)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CN(Cc2ccccc2OC)CC(C(c2ccccc2)c2ccccc2)N1
Yield: 57.8 %

Procedure:
(2R)-2-Benzyloxycarbonylamino-3-[N-(2-methoxybenzyl)-N-(2-oxo-3,3-diphenylpropyl)amino]propionic acid methyl ester (1.55 g) was dissolved in a mixture of tetrahydrofuran (50 ml) and triethylamine (0.744 ml), and the whole was hydrogenated over 10% palladium-charcoal (50% wet, 0.15 g) at room temperature under atmospheric pressure for 4 hours. After removal of the catalyst by filtration, the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate (2:1) as an eluent. The fractions containing the objective compound were collected and evaporated under reduced pressure to give (2R)-6-benzhydryl-4-(2-methoxybenzyl)piperazine-2-carboxylic acid methyl ester (663.8 mg) as a yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH:7]1[C:12](N=C=S)=[CH:11][C:10]2[C:16]([O:18][C:19]3([C:29]4[CH:30]=[CH:31][C:32]([OH:34])=[CH:33][C:28]=4[O:27][C:21]4[CH:22]=[C:23]([OH:26])[CH:24]=[CH:25][C:20]3=4)[C:9]=2[CH:8]=1)=[O:17]>CN(C)C=O>[CH:7]1[CH:12]=[CH:11][C:10]([C:16]([OH:18])=[O:17])=[C:9]([C:19]2[C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=3[O:27][C:28]3[C:29]=2[CH:30]=[CH:31][C:32]([CH:33]=3)=[O:34])[CH:8]=1
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Two ml of Fab solution were brought to pH 9.0 by the addition of solid sodium carbonate (Na2CO3). A solution of 1.5 mg of fluorescein isothiocyanate (FITC) in 0.1 ml dry dimethylformamide (DMF) was slowly added (over 1/2 min.) with stirring at room temperature. After an additional 2 hrs., the solution was briefly clarified on a Brinkmann centrifuge (21/2 min.) and applied for separation into a column of Sephadex G-25 (0.9×15 cm) equilibrated with 0.05 M KPO4 buffer at pH 8.0. The yellow protein band (first band eluted) was collected. The final solution was 10.4 mg/ml in protein and degree of labeling 4.1 fluoresceins per Fab.
Reaction SMILES: [C:1]([C:3]1[CH:28]=[CH:27][C:6]([CH2:7][C@@:8]23[CH2:15][C@H:14]([NH2:16])[CH2:13][N:12]2[C:11](=[O:17])[N:10]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)[C:9]3=[O:26])=[CH:5][CH:4]=1)#[N:2].[C:29](O)(=[O:34])[CH2:30][C:31]([NH2:33])=[O:32].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C1COCC1.C(Cl)CCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C@@:8]23[CH2:15][C@H:14]([NH:16][C:29](=[O:34])[CH2:30][C:31](=[O:32])[NH2:33])[CH2:13][N:12]2[C:11](=[O:17])[N:10]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)[C:9]3=[O:26])=[CH:27][CH:28]=1)#[N:2]
Reactant: NC(=O)CC(=O)O
Reactant: N#Cc1ccc(C[C@@]23C[C@H](N)CN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N#Cc1ccc(C[C@@]23C[C@H](NC(=O)CC(N)=O)CN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A mixture of (5S,7S)-5-(4-cyanobenzyl)-3-(3,5-dichlorophenyl)-7-amino-1,3-diazabicyclo[3.3.0]octane-2,4-dione (200 mg), malonamic acid (59.5 mg), EDC (112 mg), HOBT (97.5 mg) and DIEA (168 μL) in THF (5 mL) was stirred overnight at room temperature. The reaction mixture was evaporated. The residue was dissolved in EtOAc and the resulting solution was washed with water, saturated aqueous NaHCO3 solution, brine, dried (Na2SO4) and concentrated to give 212 mg of the titled compound. MS (m/z) 500 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][C:14]([S:22]([CH3:25])(=[O:24])=[O:23])=[N:15]2.[OH:26]OS([O-])=O.[K+]>CO.C1COCC1.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([C:10]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][C:14]([S:22]([CH3:25])(=[O:23])=[O:24])=[N:15]2)=[O:26]
Reactant: O=S([O-])OO
Reactant: COc1ccc2nc(S(C)(=O)=O)ccc2c1Sc1ccc(F)cc1F
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc2nc(S(C)(=O)=O)ccc2c1S(=O)c1ccc(F)cc1F
Yield: 45.9 %

Procedure:
5-(2,4-Difluoro-phenylsulfanyl)-2-methanesulfonyl-6-methoxy-quinoline 101 (230 mg) was dissolved in 9 mL (1:1:1 MeOH/THF/H2O) and was treated with 1 gram of OXONE™. After 3 hours the mixture was partitioned between CH2Cl2 and water. The product was purified by chromatography (10% MeOH/CH2Cl2) to afford 110 mg of 5-(2,4-difluoro-benzenesulfinyl)-2-methanesulfonyl-6-methoxy-quinoline 301; ([M+H]+)=398.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl>O>[NH2:1][C@@H:2]([CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[C:11]([OH:13])=[O:12]
Reactant: N[C@@H](CCc1ccccc1)C(=O)O
Agent: Cl
Solvent: O
Product: N[C@@H](CCC1CCCCC1)C(=O)O

Procedure:
896 mg of L-homophenylalanine (2(S)-amino-4-phenylbutyric acid) are hydrogenated in 25 ml of water and 5.5 ml of 1N HCl in the presence of 18 mg of Nishimura catalyst (rhodium oxide/platinum oxide). The reaction mixture is filtered while warm. The title compound crystallises out of the filtrate in the form of white crystals after the addition of 5.5 ml of 1N NaOH. M.p. 265°-266°; Rf (R)=0.09.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:11]=[C:12]([C:17]([N+:20]([O-:22])=[O:21])=[CH:18][N:19]=1)[C:13]([O:15]C)=O)[CH2:3][CH2:2]2.[CH3:23][NH2:24]>CO>[N:1]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[N:4]([C:10]1[CH:11]=[C:12]([C:17]([N+:20]([O-:22])=[O:21])=[CH:18][N:19]=1)[C:13]([NH:24][CH3:23])=[O:15])[CH2:3][CH2:2]2
Reactant: CN
Reactant: COC(=O)c1cc(N2CCN3CCC2CC3)ncc1[N+](=O)[O-]
Solvent: CO
Product: CNC(=O)c1cc(N2CCN3CCC2CC3)ncc1[N+](=O)[O-]
Temperature: 90 °C

Procedure:
Methyl 2-(1,4-diazabicyclo[3.2.2]nonan-4-yl)5-nitroisonicotinate (Intermediate 27A) (0.1 g, 0.46 mmol) and 2M methylamine in methanol (5 mL) were sealed in a tube and heated at 90° C. overnight. The reaction mixture was concentrated and purified by a 10 g silica column eluting with 0-10% methanol in DCM to afford 2-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-N-methyl-5-nitroisonicotinamide (96 mg, 0.31 mmol).