Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:10]2[C:23](=[O:24])[N:22]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[C:28]([Cl:33])[CH:27]=3)[CH:21]=[C:20]([CH3:34])[C:11]=2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]=12)C1C=CC=CC=1.C(O)C>[Pd].C(O)(=O)C>[Cl:33][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][C:29]=1[F:32])[CH2:25][N:22]1[CH:21]=[C:20]([CH3:34])[C:11]2[N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]3=[C:9]([OH:8])[C:10]=2[C:23]1=[O:24]
Reactant: Cc1cn(Cc2ccc(F)c(Cl)c2)c(=O)c2c(OCc3ccccc3)c3n(c12)CCN(C)C3=O
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cn(Cc2ccc(F)c(Cl)c2)c(=O)c2c(O)c3n(c12)CCN(C)C3=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 10-(benzyloxy)-2-(3-chloro-4-fluorobenzyl)-4,8-dimethyl-7,8-dihydropyrido-[3′,4′:4,5]pyrrolo[1,2-a]pyrazine-1,9(2H,6H)-dione (0.20 g, 0.40 mmol) and 5% Pd/C (40 mg) in a mixture ethanol (100 mL) and acetic acid (11 mL) was stirred under an atmosphere of hydrogen gas (1 atm) at room temperature for 1 hr. The reaction mixture was filtered through a pad of Celite. The filtrate was concentrated under vacuum, and the residue subjected to reverse phase HPLC purification. Collection and lyophilization of appropriate fractions provided the title product.
Reaction SMILES: [OH:1][NH:2]/[C:3](/[C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[N:10][CH:11]=1)=[N:4]\[H].[O:20]=[C:21]1[C:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:24][CH2:23][N:22]1[CH2:38][C:39](O)=O.Cl.C(N=C=NCCCN(C)C)C>ClC(Cl)C>[O:20]=[C:21]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:24][CH2:23][N:22]1[CH2:38][C:39]1[O:1][N:2]=[C:3]([C:6]2[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[N:10][CH:11]=2)[N:4]=1
Reactant: [H]/N=C(\NO)c1ccc(NC(=O)OC(C)(C)C)nc1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1ccc(-c2noc(CN3CCC(c4ccccc4)(c4ccccc4)C3=O)n2)cn1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A solution of (Z)-tert-butyl 5-(N-hydroxycarbamimidoyl)pyridin-2-ylcarbamate (0.131 g, 0.5 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (0.153 g, 0.5 mmol; Example 1C) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.199 g, 1.0 mmol) were stirred together in dichloroethane (7.0 mL) at room temperature for 2 hours. The reaction was then heated to 85° C. and stirred overnight. The reaction was cooled, loaded onto a SF25-40 column (Analogix®) and the product eluted using a gradient of 10% ethyl acetate/hexanes to 70% ethyl acetate over 30 minutes (Flow=30 mL/minute) to supply the title compound.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][C@H:16]1[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9].CCO.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][C@H:16]1[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([C:2]2[N:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:27]=1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: Brc1ncccn1
Reactant: CC(C)(C)OC(=O)N1CCOC[C@H]1Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCOC[C@H]1Cc1cccc(-c2ncccn2)c1
Temperature: 80 °C

Procedure:
2-Bromopyrimidine (43 mg, 0.27 mmol) was added in one portion to a RT solution of (R)-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-morpholine-4-carboxylic acid tert-butyl ester B-7 (100 mg, 0.25 mmol) in dioxane (0.76 mL) under argon. EtOH (0.38 mL) was then added followed by 2M aq. Na2CO3 (0.38 mL, 0.74 mmol) and argon was bubbled through the resulting suspension for 1 min. Pd(dppf)Cl2.DCM (12 mg, 6 mol %) was added in one portion and the resulting mixture was heated to 80° C. for 2 h. The reaction mixture was cooled to RT, quenched into water and filtered through a celite plug washing with TBME. The layers were separated and the aqueous phase was extracted with TBME (3×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered through a second celite plug and evaporated in vacuo to give the crude product that was purified by prep. HPLC (method E) to give the title compound as a yellow oil. LC-MS B: tR=0.79 min; [M+H]+=356.05.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[CH:8]=[O:9])=[N:4][N:3]=[N:2]1.[CH2:14]=[C:15]([CH3:17])[CH3:16].CS(O)(=O)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:15]([N:3]1[N:2]=[N:1][C:5]([C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[CH:8]=[O:9])=[N:4]1)([CH3:17])([CH3:16])[CH3:14]
Reactant: O=Cc1ccccc1-c1nnn[nH]1
Reactant: C=C(C)C
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)n1nnc(-c2ccccc2C=O)n1

Procedure:
In an autoclave, 6.4 g (36.7 mmol) of 2-(tetrazol-5-yl)-benzaldehyde (Step 61.1) in 50 ml of toluene are heated at 110° C. for 1.5 hours with ≈3 g of isobutene and 0.432 ml of methanesulfonic acid. When cold the reaction mixture is diluted with 300 ml of ethyl acetate, washed four times with water and once with brine, dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2; hexane/ethyl acetate=4:1) and crystallization from hexane with a small amount of diethyl ether at −20° C. yield 2-(2-tert-butyl-tetrazol-5-yl)-benzaldehyde; TLC: Rf=0.36 (hexane/ethyl acetate=10:1).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:27])[NH:10][C@@H:11]([CH2:21][C:22]2[NH:26][CH:25]=[N:24][CH:23]=2)[C:12](=[O:20])[NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:7]1)=[O:5])C.[Li+].[OH-]>CO.O>[NH:24]1[CH:23]=[C:22]([CH2:21][C@H:11]([NH:10][C:9]([C@H:8]2[O:7][C@@H:6]2[C:4]([OH:5])=[O:3])=[O:27])[C:12](=[O:20])[NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:26]=[CH:25]1
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)Nc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(Nc1ccccc1)[C@H](Cc1c[nH]cn1)NC(=O)[C@H]1O[C@@H]1C(=O)O
Yield: 38.7 %

Procedure:
Synthesized following general saponification procedure using the following quantities: the corresponding peptidomimetic epoxide ethyl ester 18a (155 mg, 0.3 mmol); LiOH (14 mg, 0.58 mmol); MeOH/H2O (1.5 mL: 0.5 mL: 0.5 mL); yielded 28 as a white solid (40 mg, 27.1%). 1H NMR (MeOD-d4, 400 MHz): δ 8.66 (s, 1H); 7.57-7.55 (d, 2H, J=7.86 Hz); 7.29-7.27 (t, 3H); 7.10-7.07 (t, 1H); 4.97-4.94 (q, 1H); 3.64-3.63 (d, 1H, J=1.66 Hz); 3.529-3.525 (d, 1H, J=1.66 Hz); 3.36-3.15 (m, 2H). 13C NMR (MeOD-d4, 100 MHz): 169.79, 167.26, 166.95, 137.90, 134.99, 128.37, 124.10, 120.11, 54.13, 52.94, 51.67. ESI-HRMS (m/z): [M+H+] calcd. for C16H16N4O5: 345.1194, observed: 345.1185. HPLC Method 1: Rt=18.2 min, purity=95.2%.
Reaction SMILES: C(Cl)(Cl)Cl.[F:5][C:6]([F:11])([F:10])[C:7]([OH:9])=[O:8].C(OC(=O)[NH:18][C:19](=[NH:53])[C:20]1[S:21][C:22]([S:51][CH3:52])=[C:23]([S:25]([C:28]2[CH:29]=[C:30]([C:34]3[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=3[NH:41][C:42](=[O:50])[CH2:43][CH2:44][CH2:45][S:46](=[O:49])(=[O:48])[NH2:47])[CH:31]=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH:24]=1)(C)(C)C>>[F:5][C:6]([F:11])([F:10])[C:7]([OH:9])=[O:8].[C:19]([C:20]1[S:21][C:22]([S:51][CH3:52])=[C:23]([S:25]([C:28]2[CH:29]=[C:30]([C:34]3[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=3[NH:41][C:42](=[O:50])[CH2:43][CH2:44][CH2:45][S:46](=[O:49])(=[O:48])[NH2:47])[CH:31]=[CH:32][CH:33]=2)(=[O:26])=[O:27])[CH:24]=1)(=[NH:18])[NH2:53]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)CCCS(N)(=O)=O)c1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)CCCS(N)(=O)=O)c1
Reaction time: 1 h
Yield: 36 %

Procedure:
A solution of dichloromethane/trifluoroacetic acid (1/1) [1 mL] was added (imino-{4-[6′-methyl-2′-(4-sulfamoyl-butyrylamino)-biphenyl-3-sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester (0.010 g, 0.015 mmol) [example 210, step a] at room temperature and stirred for 1 hour. The reaction mixture was evaporated and purified via reverse-phase HPLC [acetonitrile/water (0.01% TFA)] to give the title compound (0.005 g, 36%) as a solid. 1H-NMR (MeOD): δ 8.30 (s, 1H), 8.04 (md, 1H, J=7.6 Hz), 7.88 (t, 1H, J=1.6 Hz), 7.70 (t, 1H, J=7.6 Hz), 7.54 (md, 1H, J=7.6 Hz), 7.36 (t, 1H, J=7.6 Hz), 7.29 (d, 1H, J=6.8 Hz), 7.19 (d, 1H, J=8.0 Hz), 2.77–2.72 (m, 5H), 2.16 (t, 2H, J=7.2 Hz), 2.09 (s, 3H), 1.76 (m, 2H). ESI-MS (m/z): Calcd. for C23H26N4O5S4: 566.08; found: 567.1.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1Cl.[C:10]1([NH:16][C:17]#[N:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Na]>O1CCOCC1.O>[C:17]([N:16]([C:2]1[N:4]=[C:5]([N:16]([C:17]#[N:18])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=[C:8]([N:16]([C:17]#[N:18])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:1]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)#[N:18]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: N#CNc1ccccc1
Agent: [Na]
Solvent: C1COCCO1
Solvent: O
Product: N#CN(c1ccccc1)c1nc(N(C#N)c2ccccc2)nc(N(C#N)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 9.20g (0.05 mole) of cyanuric chloride in 100 ml of dioxane was added to 100 ml of ice water. To this mixture at room temperature was added dropwise a solution of 0.15 mole of sodium phenylcyanamide in 70 ml of water over a 30 minute period. After stirring for 3 hours at room temperature, the reaction mixture was refluxed for 16 hours. After cooling to room temperature the reaction mixture was filtered. The residue was washed with water and dried to give 17.2g (80%) of of TNCT, m.p. 209°-215°. Recrystallization from toluene gave 10.8g with an m.p. of 215°-218°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:12])[CH3:11].C1C(=O)N([Br:20])C(=O)C1.[O-]S([O-])=O.[Na+].[Na+]>C(#N)C>[Br:20][C:5]1[CH:4]=[C:3]([CH:10]([CH3:12])[CH3:11])[C:2]([F:1])=[CH:7][C:6]=1[O:8][CH3:9]
Reactant: COc1ccc(C(C)C)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1cc(F)c(C(C)C)cc1Br
Temperature: 35 °C
Reaction time: 3.5 h

Procedure:
2-fluoro-1-isopropyl-4-methoxybenzene (compound of formula 3, Scheme 3) (34.3 g, 0.204 mol) was dissolved in acetonitrile (400 mL). The solution was warmed to 35° C., and NBS (40 g, 0.225 mol) was added in a single solid addition. The reaction was maintained at 35° C. and was completed in 3-4 hours. The reaction was quenched with 2M Na2SO3 (40 mL, 0.08 mol). The resulting mixture was concentrated to ¼ of the total volume and diluted with water (400 mL) and petroleum ether (300 mL). The organic layer was cut and washed with water (300 mL), dried over Na2SO4 and filtered. The solvent was removed under reduced pressure to yield 1-bromo-4-fluoro-5-isopropyl-2-methoxybenzene (compound of formula 4, Scheme 3) as a slightly yellow oil (49.26 g, 98%). 1H NMR (CDCl3) δ 1.22 (d, J=6.9 Hz, 6H), 3.14 (sept., J=6.9 Hz, 1H), 3.85 (s, 3H), 6.60 (d, J=11.8 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H).
Reaction SMILES: C([NH:8][CH:9]1[CH2:12][CH:11]([CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]1[F:22])C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH2:15]([O:14][CH2:13][CH:11]1[CH2:12][CH:9]([NH2:8])[CH:10]1[F:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: FC1C(COCc2ccccc2)CC1NCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: NC1CC(COCc2ccccc2)C1F
Reaction time: 22 h

Procedure:
Benzyl-(3-benzyloxymethyl-2-fluoro-cyclobutyl)-amine (0.34 g, 1.21 mmol) was dissolved in 10 mL MeOH and this was treated with 20% Pd(OH)2 on carbon (0.07 g, 0.11 mmol). This was subjected to the hydrogenolysis conditions (50 psi). After 22 hr, the reaction mixture was filtered through celite and the filtrated was concentrated and was purified by silica gel flash chromatography (Hexane: EtOAc=1:1) to give 0.16 g (63%, Rf=0.30 (CH2Cl2:MeOH=15:1)). 1H NMR (CDCl3, 400 MHz): δ 2.08-2.16 (m, 2H), 2.96-3.12 (m, 1H), 3.52-3.64 (m, 2H), 3.88-3.94 (m, 1H), 4.55 (s, 2H), 5.03-5.19 (td, 1H, J=52.8, 6.0), 7.25-7.38 (m, 5H). 13C NMR (CDCl3, 100 MHz): δ 23.12-23.21 (d, J=9.0), 42.13-42.34 (d, J=21), 48.30, 70.07, 74.39, 87.46-89.63 (d, J=217), 128.98, 129.05, 129.61, 139.63. MS (FAB): expected for C12H16FNO (M+H)+ 210.26. Found 210.12885.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:23]I>>[Cl:1][C:2]1[N:11]=[C:10]([N:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])[CH3:23])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(Nc2nc(Cl)nc3ccccc23)c(OC)c1
Reactant: CI
Product: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)c(OC)c1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(2,4-dimethoxy-phenyl)-amine and methyl iodide by a procedure similar to Example 36 (91% yield). 1H NMR (CDCl3): 7.70-7.73 (m, 1H), 7.54 (ddd, J=8.7, 6.3 and 2.1 Hz, 1H), 7.10 (d, J=8.7 Hz, 1H), 6.93-7.23 (m, 2H), 6.50-6.57 (m, 2H), 3.87 (s, 3H), 3.67 (s, 3H), 3.52 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[O:33][CH2:34][CH:35]([CH3:37])[CH3:36])[CH:28]=[O:29].[I-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:34]([O:33][C:32]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][C:25]=1[CH2:24][N:12]([CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[S:10][CH:11]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1)[CH:35]([CH3:37])[CH3:36]
Reactant: c1ccc(CCNc2nc(-c3ccccc3)cs2)cc1
Reactant: CC(C)COc1ccc(C=O)cc1CCl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)COc1ccc(C=O)cc1CN(CCc1ccccc1)c1nc(-c2ccccc2)cs1
Temperature: 0 °C
Yield: 98.3 %

Procedure:
To a solution of 4-phenyl-N-(2-phenylethyl)-1,3-thiazole-2-amine (0.95 g, 3.40 mmol) in N,N-dimethylformamide (7 mL) was added sodium hydride (60% in oil, 0.14 g, 3.40 mmol) under stirring at 0° C., and the mixture was stirred at the same temperature for 5 min. Then, 3-(chloromethyl)-4-isobutoxybenzaldehyde (0.70 g, 3.09 mmol) and sodium iodide (0.51 g, 3.40 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-3/1) to give the title compound (1.43 g, yield 99%) as a pale-yellow oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[Li].[N:7]12[CH2:14][CH2:13][C:10]([C:15]([O:17]CC)=O)([CH2:11][CH2:12]1)[CH2:9][CH2:8]2>C1COCC1>[N:7]12[CH2:8][CH2:9][C:10]([C:15]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[OH:17])([CH2:11][CH2:12]1)[CH2:13][CH2:14]2
Reactant: [Li]c1cccs1
Reactant: CCOC(=O)C12CCN(CC1)CC2
Solvent: C1CCOC1
Product: OC(c1cccs1)(c1cccs1)C12CCN(CC1)CC2
Temperature: 25 °C
Yield: 59.5 %

Procedure:
A solution of 2-thienyllithium (1.0M in THF, 9.10 mL, 9.10 mmol) was chilled down to −30° C. under Ar. Ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (0.4196 g, 2.289 mmol) in THF (8 mL) was slowly added to the reaction mixture over 20 min. The reaction was allowed to warm up to room temperature over 16 h. The reaction was quenched with water and then evaporated to dryness. H2O and DCM were added, causing a light brown solid to crash out. This solid was filtered off to give the title compound (0.4161 g, 59.5%). EI-MS m/z 306(M+H+) Rt (1.35 min).
Reaction SMILES: [CH2:1]([C:4]1[C:17]2[O:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:18])[C:8]=2[CH:7]=[C:6]([Br:19])[C:5]=1[OH:20])[CH:2]=C.ClC1C=CC=C(C(OO)=O)C=1.C(Cl)(Cl)Cl.[C:36](=[O:39])([O-])[O-:37].[K+].[K+]>O>[Br:19][C:6]1[C:5]2[O:20][CH:2]([C:36]([OH:37])=[O:39])[CH2:1][C:4]=2[C:17]2[O:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:9](=[O:18])[C:8]=2[CH:7]=1
Reactant: C=CCc1c(O)c(Br)cc2c(=O)c3ccccc3oc12
Reactant: O=C([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(O)C1Cc2c(c(Br)cc3c(=O)c4ccccc4oc23)O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 45.8 %

Procedure:
A mixture of 4-allyl-2-bromo-3-hydroxy-9-oxo-9H-xanthene (3.0 g), m-chloroperbenzoic acid (10 g) and chloroform (250 ml) was stirred at room temperature for 5 hours and thereafter left to stand overnight. To the mixture, potassium carbonate (20 g) and water (400 ml) were added and the resulting mixture was extracted with chloroform. The chloroform layer was dried and the solvent distilled off. The residue was dissolved in acetone (300 ml) and, to the stirred solution, a mixture of chromium trioxide (5 g), water (25 ml) and concentrated sulfuric acid (8 g) was added dropwise at room temperature. After standing overnight, the mixture was filtered and the filtrate was evaporated to dryness under vacuum. After addition of water, the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 1.5 g of 4-bromo-1,2-dihydro-6-oxo-6H-furo[2,3-c]xanthene-2-carboxylic acid. m.p. 283°-286° C. This compound showed a mass spectrum having a molecular ion peak at m/e 360.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17](Cl)=[O:18].[NH2:20][C:21]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][CH:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH2:31][CH2:30]2)=[CH:25][C:22]=1[C:23]#[N:24]>>[C:23]([C:22]1[CH:25]=[C:26]([N:29]2[CH2:34][CH2:33][CH:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH2:31][CH2:30]2)[CH:27]=[CH:28][C:21]=1[NH:20][C:17]([C:3]1[CH:4]=[N:5][N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[C:2]=1[CH3:1])=[O:18])#[N:24]
Reactant: N#Cc1cc(N2CCC(N3CCOCC3)CC2)ccc1N
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(C(F)(F)F)cc1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)cc2C#N)cnn1-c1ccc(C(F)(F)F)cc1
Yield: 39.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 5-methyl-1-(4-trifluoromethylphenyl)pyrazole-4-carboxylic chloride (0.9 g) and 2-amino-5-(4-morpholinopiperidin-1-yl)benzonitrile (0.9 g), the title compound (0.67 g) was obtained, melting point: 210–212° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[N+]([O-])([O-])=[O:11].[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>CO>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:1]=[O:11])=[CH:3][CH:4]=1
Reactant: COc1ccc(C)cc1
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CO
Product: COc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
A 1.22 g quantity of p-methyl anisole and 23.0 g of ammonium cerium(IV) nitrate are placed into a reactor, and 100 ml of methanol is further placed into the reactor. The mixture is stirred at room temperature for about 30 minutes. After the completion of the reaction, the methanol is distilled off from the reaction mixture. The residue is diluted with water and then subjected to extraction with benzene three times. The extract is washed with an aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and distilled to remove the solvent. The residue is distilled in a vacuum, giving 1.308 g of anisaldehyde (b.p. 90°-92° C./2 mm Hg). Yield: 96.2%.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([O:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])=[C:9]([C@H:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:8]([CH3:30])=[CH:7][C:5]=2[N:6]=1.[NH:31]1[CH2:34][CH2:33][CH2:32]1.[NH4+].[Cl-]>C1COCC1>[N:31]1([C:2]2[S:3][C:4]3[C:10]([O:11][S:12]([C:15]([F:17])([F:16])[F:18])(=[O:14])=[O:13])=[C:9]([C@H:19]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:8]([CH3:30])=[CH:7][C:5]=3[N:6]=2)[CH2:34][CH2:33][CH2:32]1
Reactant: C1CNC1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1OS(=O)(=O)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N3CCC3)sc2c1OS(=O)(=O)C(F)(F)F
Temperature: 70 °C

Procedure:
To a solution of 32 (50 mg, 0.094 mmol) in THF (1 mL) was added azetidine (20 μL). The reaction mixture was heated at 70° C. for 30 min. A saturated solution of NH4Cl (3 mL) was added, and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layer were dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hexanes) to give 38 mg of 33. LCMS-ESI+: calc'd for C20H25F3N2O6S2: 511.1 (M+H+). Found: 511.0 (M+H+).
Reaction SMILES: [Cl-].[CH:2]1([CH2:9][NH2+:10][CH2:11][CH2:12]Cl)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[N:22]=[C:23]=[S:24]>>[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[N:22]=[C:23]1[N:10]([CH2:9][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:11][CH2:12][S:24]1
Reactant: S=C=Nc1cccc(Cl)c1Cl
Reactant: ClCC[NH2+]CC1CCCCCC1
Agent: [Cl-]
Product: Clc1cccc(N=C2SCCN2CC2CCCCCC2)c1Cl

Procedure:
2-Hydroxyethylamine was reacted with cycloheptylmethyl bromide according to Method B2a to give N-cycloheptylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cycloheptylmethyl -N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,3-dichlorophenyl isothiocyanate to give 2-(2,3-dichlorophenylimino)-3-(cycloheptylmethyl)-1,3-thiazolidine.
Reaction SMILES: [Br:1][CH:2]([CH2:11]Br)[C:3]([CH3:10])([CH3:9])[C:4]([O:6][CH2:7]C)=[O:5].[OH-].[K+]>CO.O>[Br:1][C:2](=[CH2:11])[C:3]([CH3:10])([CH3:9])[C:4]([O:6][CH3:7])=[O:5]
Reactant: CCOC(=O)C(C)(C)C(Br)CBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=C(Br)C(C)(C)C(=O)OC
Yield: 39.4 %

Procedure:
Ethyl 3,4-dibromo-2,2-dimethylbutanoate (6.3 g), prepared as described in Example 3 above, was treated with 3.6 g of potassium hydroxide in 50 mL of 4:1 methanol:water and stirred 16 hours at ambient temperature. The solution was diluted with 100 mL of water and extracted with ether. The organic layer was washed with a saturated brine solution, dried and concentrated in vacuo to give 1.7 g of methyl 3-bromo-2,2-dimethylbut-3-enoate as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][N:7]=1.[CH2:21]([CH:27]1[CH2:31][C:30](=[O:32])[O:29][C:28]1=[O:33])[CH:22]=[CH:23][CH2:24][CH2:25][CH3:26]>C1(C)C=CC=CC=1>[F:20][C:19]1[CH:18]=[CH:17][C:4]([CH2:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[NH:8][N:7]=2)=[CH:3][C:2]=1[NH:1][C:30]([CH2:31][CH:27]([CH2:21][CH:22]=[CH:23][CH2:24][CH2:25][CH3:26])[C:28]([OH:33])=[O:29])=[O:32]
Reactant: Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: CCCC=CCC1CC(=O)OC1=O
Solvent: Cc1ccccc1
Product: CCCC=CCC(CC(=O)Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)C(=O)O

Procedure:
A stirred mixture of 4-(3-amino-4-fluorobenzyl)-2H-phthalazin-1-one (0.1 g, 0.37 mmol; prepared in a manner similar to that described in Example 23), 3-hex-2-enyldihydrofuran-2,5-dione (0.068 g, 0.37 mmol) and toluene (10 ml) was heated under reflux for 20 hours, then the resulting solid was collected by filtration from the hot mixture, washed with ethyl acetate (3 ml) and dried in vacuo to give 2-{[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenylcarbamoyl]methyl}oct-4-enoic acid (0.061 g) as an off-white solid, m.pt. 179–181° C.; 250 MHz 1H-nmr (d6-DMSO) δ (ppm): 0.7–0.9 (t, 3H) (CH3), 1.1–1.35 (m, 2H) (—CH2CH3), 1.75–2.0 (m, 2H) (—CH2CH2CH3), 2.0–2.3 (m, 2H) (—CH2CH═CH—), 2.3–2.8 (2×m obscured by DMSO signal, 2H+1H) (—CH2CH(CO2H)CH2—), 4.2 (s, 2H) (ArCH2—), 5.15–5.5 (m, 2H) (—CH═CH—) 6.9–7.2 (m, 2H) (2×ArH), 7.65–8.0 (m, 4H) (4×ArH), 8.2 (d, 1H) (ArH), 12.1 (br s, 1H) (CO2H), 12.6 (s, 1H) (CONH); m/z (M+H)+. 452, 93.7% purity.