Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[NH:20][N:19]=2)=[CH:13][C:12]=1[NH:29][C:30]([CH2:32][CH:33]([CH2:37][CH:38]=[CH:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:34](O)=[O:35])=[O:31]>CN(C)C=O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[NH:20][N:19]=2)=[CH:13][C:12]=1[N:29]1[C:30](=[O:31])[CH2:32][CH:33]([CH2:37][CH:38]=[CH:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:34]1=[O:35]
Reactant: CCCCCC=CCC(CC(=O)Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCCC=CCC1CC(=O)N(c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 45.8 %

Procedure:
O-Benzotriazol-1-yl-N,N,N′N′-tetramethyluronium tetrafluoroborate (0.107 g, 0.33 mmol) and diisopropylethylamine (0.098 ml, 0.56 mmol) were added sequentially at ambient temperature to a stirred solution of 2-{[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenylcarbamoyl]methyl}-dec-4-enoic acid (0.123 g, 0.26 mmol) in dimethylformamide (2 ml), the mixture was stirred at ambient temperature for 48 hours, then it was added dropwise to ice-cold water (10 ml). The product was extracted into ethyl acetate (2×5 ml), the extracts were combined, dried (MgSO4) and the solvent was removed in vacuo. The residue was triturated with hexane (3 ml) and the resulting solid was collected by filtration and dried in vacuo to give 1-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]-3-oct-2-enylpyrrolidine-2,5-dione (0.055 g) as an off-white solid, m.pt 138–141° C.; 250 MHz 1H-nmr (d6-DMSO) δ (ppm): 0.7–0.9 (m, 3H) (CH3), 1.1–1.4 (m, 6H) (—CH2CH2CH2CH3) 1.9–2.1 (m, 2H) (—CH2-nBu), 2.3–2.6 (m, 1H+2H) (—CHCH2CH═CH—), 2.8–3.2 (m, 2H) (ring CH2), 4.4 (s, 2H) (ArCH2—), 5.25–5.45 and 5.45–5.7 (2×m, 2×1H) (—CH═CH—) 7.2–7.3 (m, 1H)(ArH), 7.3–7.5 (m, 1H) (ArH), 7.5–7.6 (m, 1H) (ArH), 7.8–8.05 (m, 3H)(3×ArH), 8.3 (d, 1H) (ArH), 12.65 (s, 1H) (CONH); m/z (M+H)+. 462, 90% purity.
Reaction SMILES: [Mg].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1Br)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:17]12[O:23][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22]2>O1CCCC1>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C@@H:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]1[OH:23])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Brc1ccccc1OCc1ccccc1
Reactant: C1CCC2OC2C1
Agent: [Mg]
Solvent: C1CCOC1
Product: O[C@@H]1CCCC[C@H]1c1ccccc1OCc1ccccc1
Temperature: -30 °C
Yield: 69629.6 %

Procedure:
A mixture of 3.24 g (0.1 35 mol) of magnesium and 20 ml of tetrahydrofuran was charged into a three-necked flask of 300 ml and stirred. Then, a solution of 35.6 g of o-benzyloxyphenylbromide in 80 ml of tetrahydrofuran was added dropwise at a temperature of 60° C. or less. After the dropping was stopped, the mixture was cooled to -30° C., 0.65 g of cuprous chloride was added, and the mixture was stirred for 10 minutes. To the mixture, a solution of 13.3 g (0.135 mol ) of cyclohexene oxide in 15 ml tetrahydrofuran was added dropwise at -30° C. After the dropping was stopped. The temperature was raised to 0° C., and the mixture was stirred for three hours at 0° C. After the temperature was raised to room temperature, the mixture was charged into a separatory funnel and extracted with 600 ml of methylene chloride, and the organic layer was washed with 600 ml of saturated ammonium sulfate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled away under reduced pressure. The concentrate was distilled under reduced pressure to obtain 26.5 g (0,094 mol) of (±)-trans-2-(2-benzyloxyphenyl)-1-cyclohexanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:14])[C:5]2[CH:9]=[C:8](C(O)=O)[S:7][C:6]=2[CH:13]=1.C1CCN2C(=NCCC2)CC1>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]([F:14])[C:5]2[CH:9]=[CH:8][S:7][C:6]=2[CH:13]=1
Reactant: O=C(O)c1cc2c(F)cc(Br)cc2s1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)N(C)C
Product: Fc1cc(Br)cc2sccc12
Yield: 97 %

Procedure:
Using analogous reaction condition and reagents as described in Example 25 for the preparation of I-25c above, 6-bromo-4-fluoro-benzo[b]thiophene-2-carboxylic acid (I-26c: 1.8 g, 6.47 mmol) in DMA (4 mL) and DBU (4.0 g, 26.54 mmol) were heated in microwave to afford the crude product. Purification by column chromatography on silica gel (100% hexane) afforded 1.45 g of the product (97% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][C:8]([NH2:12])=[CH:9][CH:10]=2)[CH2:5][NH:4][CH2:3]1.Cl[C:15]1[N:20]=[C:19]2[N:21]([CH3:35])[C:22](=[O:34])[N:23]([C:26]3[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:33])[C:24](=[NH:25])[C:18]2=[CH:17][N:16]=1.ClC1N=C2NC(=O)N(C3C(Cl)=CC=CC=3Cl)C(=N)C2=CN=1>>[Cl:32][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:33])[C:26]=1[N:23]1[C:24](=[NH:25])[C:18]2[C:19](=[N:20][C:15]([NH:12][C:8]3[CH:7]=[C:6]4[C:11]([C:2]([CH3:13])([CH3:1])[CH2:3][NH:4][CH2:5]4)=[CH:10][CH:9]=3)=[N:16][CH:17]=2)[N:21]([CH3:35])[C:22]1=[O:34]
Reactant: Cn1c(=O)n(-c2c(Cl)cccc2Cl)c(=N)c2cnc(Cl)nc21
Reactant: CC1(C)CNCc2cc(N)ccc21
Agent: N=c1c2cnc(Cl)nc2[nH]c(=O)n1-c1c(Cl)cccc1Cl
Product: Cn1c(=O)n(-c2c(Cl)cccc2Cl)c(=N)c2cnc(Nc3ccc4c(c3)CNCC4(C)C)nc21

Procedure:
160 mg of the entitled compound was obtained as a white solid according to the same method as in Example 2, for which, however, 4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-amine was used in place of 2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-amine in Example 2, and 7-chloro-3-(2,6-dichlorophenyl)-4-imino-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one obtained in Production Example 7 was used in place of 7-chloro-3-(2,6-dichlorophenyl)-4-imino-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[N:11]=2)=[CH:6][CH:5]=1)([O-])=O.[Na].O.O.Cl.FC(F)(F)C1C=CC(C(N)=N)=CC=1>CCO.C(Cl)(Cl)Cl.CCOC(C)=O>[F:25][C:22]([F:23])([F:24])[C:19]1[CH:18]=[CH:17][C:16]([C:12]2[N:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=3)[CH:15]=[CH:14][N:13]=2)=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccnc(-c3ccc(C(F)(F)F)cc3)n2)cc1
Agent: Cl
Agent: N=C(N)c1ccc(C(F)(F)F)cc1
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(-c2ccnc(-c3ccc(C(F)(F)F)cc3)n2)cc1
Reaction time: 0.5 h
Yield: 91 %

Procedure:
4-(4-Nitrophenyl)-2-(4-trifluoromethyl-phenyl)-pyrimidine. To 82.7 mg (3.60 mmol) of sodium metal dissolved in 3 mL of absolute EtOH was added 938 mg (3.60 mmol) of 4-trifluoromethylbenzamidine hydrochloride dihydrate followed by 4 mL of EtOH. After 30 min, 498 mg (2.26 mmol) of 3-dimethylamino-1-(4-nitrophenyl)-propenone was added and the mixture was heated at reflux approximately 66 h and was allowed to cool. The mixture was concentrated to a tan solid which was triturated under saturated sodium bicarbonate. The solid was collected and air dried to give 937 mg. It was then dissolved in chloroform/EtOAc and was passed over silica gel eluting with 7:3 chloroform/EtOAc to afford 710 mg (91%) of the title compound. 1H NMR δ 9.01 (d, J=5.3 Hz, 1H), 8.73 (d, J=8.2 Hz, 2H), 8.43 (s, 4H), 7.82 (d, J=8.1 Hz, 2H), 7.76 (d, J=5.2 Hz, 1H); EIMS 345 (M+, 100), 299 (57); mp 175-176.5° C. Anal. Calcd. for C17H10F3N3O2: C, 59.13; H, 2.92; N, 12.17. Found: C, 58.82; H, 2.63; N, 11.98.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[N:10]=[C:11]([CH2:14][OH:15])[S:12][CH:13]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:3][C:4]1([C:9]2[N:10]=[C:11]([CH2:14][O:15][S:23]([CH3:26])(=[O:25])=[O:24])[S:12][CH:13]=2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(c2csc(CO)n2)OCCO1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(c2csc(COS(C)(=O)=O)n2)OCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-yl]-methanol (18.460 g, 91.73 mmol) in dry CH2Cl2 (300 mL) was treated at 0° C. with Et3N (16.59 mL, 118.62 mmol) followed by DMAP (1.132 g, 9.17 mmol) and Ms-Cl (9.17 mL, 115.83 mmol). After stirring at 0° C. for 1 h, the reaction was quenched with water (80 mL). The layers were separated and the aq. layer extracted with CH2Cl2 (3×) The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude methanesulfonic acid 4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl ester as a brown oil. Part of this crude material (2.756 g, 9.87 mmol) in DMF (20 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (10.60 g of a 10% solution in acetone, 9.29 mmol) in DMF (20 mL) pre-treated for 30 min with DIPEA (3.18 mL, 18.59 mmol) and the reaction mixture was stirred overnight at 50° C. Water (25 mL), followed by EA (50 mL) were added. The aq. layer was extracted with EA (50 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (1:2 hept-EA) gave the title compound as a yellow solid: TLC:rf (1:2 hept-EA)=0.52. LC-MS-conditions 02: tR=0.88 min, [M+H]+=297.84.
Reaction SMILES: [CH3:1][C:2]([C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:25])[C:20]2[S:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)(C(OCC)=O)[C:3]([O:5]CC)=[O:4].[OH-].[Na+]>>[C:20]1([C:19]([C:16]2[CH:17]=[CH:18][C:13]([CH:2]([CH3:1])[C:3]([OH:5])=[O:4])=[CH:14][CH:15]=2)=[O:25])[S:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1ccc(C(=O)c2cccs2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C(=O)O)c1ccc(C(=O)c2cccs2)cc1

Procedure:
A mixture of 30.3 parts of diethyl 2-methyl-2-[p-(2-thenoyl)phenyl]malonate and 200 parts of sodium hydroxide solution 5% is stirred and refluxed for 6 hours. The reaction mixture is allowed to cool while stirring. The whole is filtered and the aqueous phase is separated. The latter is washed with benzene, acidified with concentrated hydrochloric acid solution and stirred for 15 minutes. The product is extracted with chloroform. The extract is washed with water, dried, filtered and evaporated. The oily residue is triturated twice in petroleumether. The solid product is filtered off and crystallized twice from acetonitrile: first at -20° C and then at 0° C, yielding p-(2-thenoyl)hydratropic acid; mp. 124.3° C; also named p-(2-thenoyl)-α-methyl-phenylacetic acid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:11]([CH2:16][C:17]([F:20])([F:19])[F:18])[CH2:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[C:9]#[N:10])#[N:2].[CH2:21]([NH2:23])[CH3:22]>>[C:1]([C:3]1[CH:4]=[C:5]([N:11]([CH2:16][C:17]([F:20])([F:19])[F:18])[CH2:12][C:13]([NH:23][CH2:21][CH3:22])=[O:15])[CH:6]=[CH:7][C:8]=1[C:9]#[N:10])#[N:2]
Reactant: N#Cc1ccc(N(CC(=O)O)CC(F)(F)F)cc1C#N
Reactant: CCN
Product: CCNC(=O)CN(CC(F)(F)F)c1ccc(C#N)c(C#N)c1

Procedure:
Synthesized in a manner similar to example 3 using N-(3,4-dicyanophenyl)-N-(2,2,2-trifluoroethyl)glycine and ethylamine: MS (ES) m/z 311 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([CH:17]=[O:18])=[N:9]2)=[N:6][CH:7]=1.BrC1C=CC(N2C(C(F)(F)F)=CC(C(O)=O)=N2)=NC=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:61][NH:62][O:63][CH3:64].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([F:14])([F:16])[F:15])=[CH:11][C:10]([C:17]([N:62]([O:63][CH3:64])[CH3:61])=[O:18])=[N:9]2)=[N:6][CH:7]=1
Reactant: O=Cc1cc(C(F)(F)F)n(-c2ccc(Br)cn2)n1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)c1cc(C(F)(F)F)n(-c2ccc(Br)cn2)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1cc(C(F)(F)F)n(-c2ccc(Br)cn2)n1
Temperature: 65 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
Step-1: 1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carbaldehyde: To a stirred solution of 1-(5-bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (6.20 g, 18.45 mmol), in DMF (50 mL) was successively added EDC.HCl (4.24 g, 22.14 mmol), HOBT (3.11 g, 20.29 mmol), N,O-dimethylhydroxylamine hydrochloride (2.70 g, 27.7 mmol) and triethylamine (5.14 mL, 36.9 mmol). After stirring the reaction mixture at 65° C. for 12 h, the reaction was cooled to RT. Water (60 mL) was added to the above reaction followed by ethyl acetate (100 mL). The layers were separated and aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried (Na2SO4) and filtered. The filtrate was rotary evaporated and the crude product was purified by flash column chromatography (silica gel, ethyl acetate-hexanes system as eluent) to afford 4.20 g (60%) of the 1-(5-bromopyridin-2-yl)-N-methoxy-N-methyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide as white solid. 1HNMR (400 MHz, DMSO-d6) δ 8.74 (d, J=2.5 Hz, 1H), 8.37 (dd, J=2.5 & 8.5 Hz, 1H), 7.88 (d, J=8.5 Hz, 1H), 7.50 (s, 1H), 3.77 (s, 3H), 3.34 (s, 3H); ESI-MS (m/z) 379, 381 [(MH)+, Br79,81].
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][Cl:12])[CH:6]=[CH:5][N:4]=1.[OH-].[NH4+].[CH:15](O)=[O:16]>>[CH:15]([NH:1][CH2:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][Cl:12])[CH:6]=[CH:5][N:4]=1)=[O:16]
Reactant: NCc1cc(CCCCl)ccn1
Reactant: O=CO
Agent: [NH4+]
Agent: [OH-]
Product: O=CNCc1cc(CCCCl)ccn1

Procedure:
A solution of 2-aminomethyl-4-(3-chloropropyl)pyridine (0.47 g) in 1 ml of formic acid is heated at 90° for 18 hours, cooled to 0° and made basic by the addition of saturated ammonium hydroxide solution. Extraction with methylene chloride (4×10 ml), drying over sodium sulfate and evaporation yields 2-(N-formylaminomethyl)-4-(3-chloropropyl)pyridine (IR 1674 cm-1) which is heated at 90° in phosphorus oxychloride (0.75 g) for 15 hours. Excess phosphorus oxychloride is evaporated with toluene and the residue is suspended in methylene chloride (15 ml), cooled to 0° and made basic with saturated ammonium hydroxide. Extraction with methylene chloride (4×15 ml), drying over sodium sulfate and preparative thin layer chromatography (silica gel, EtOAc) of the residue yields 7-(3-chloropropyl)-imidazo[1,5-a]pyridine (Rf=0.24, EtOAc) as a gum; NMR (CDCl3) 3.58 (t, 2H), 6.42 (q, 1H), 7.21 (s, 1H), 7.32 (s, 1H), 7.88 (d, 1H), 8.07 (s, 1H).
Reaction SMILES: [CH2:1]1COCC1.[O:6]=[C:7]1[C@@H:13]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:12][CH2:11][C:10]2[CH:22]=[CH:23][CH:24]=[CH:25][C:9]=2[NH:8]1.CI>[H-].[Na+].CCOC(C)=O.CCCCCCC.CCOC(C)=O>[CH3:1][N:8]1[C:9]2[CH:25]=[CH:24][CH:23]=[CH:22][C:10]=2[CH2:11][CH2:12][C@H:13]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])[C:7]1=[O:6]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2ccccc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CI
Product: CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CCc2ccccc21

Procedure:
0.898 mg of sodium hydride in suspension at 60% in oil (22.44 mmol) is introduced, at AT, into a 500 ml round-bottomed flask, with stirring and under an argon atmosphere, containing 260 ml of THF and 6.2 g of 2a (22.44 mmol). The medium is stirred for 1 h and then 3.823 g (26.94 mmol) of methyl iodide are added. The medium is left stirring overnight, 500 ml of EtOAc are added and the organic phase is washed twice with 500 ml of water. The organic phase is dried over MgSO4, filtered and then evaporated to dryness. 6.85 g of crude product are obtained. After chromatography on a silica cartridge (250 g, eluent heptane/EtOAc—as an EtOAc gradient: 10 to 50%). 4.47 g of product 7a (white solid) are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[CH:5]([OH:9])[C:6]([OH:8])=O.Cl.[NH2:15][C@H:16]([C:18]([C:20]1([NH2:43])[C:26](=[O:27])[N:25]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:24]2[CH:33]=[CH:34][CH:35]=[CH:36][C:23]=2[N:22]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:21]1=[O:42])=[O:19])[CH3:17]>>[F:13][C:11]1[CH:10]=[C:4]([CH:5]([OH:9])[C:6]([NH:15][C@H:16]([C:18]([C:20]2([NH2:43])[C:26](=[O:27])[N:25]([CH2:28][C:29]([CH3:32])([CH3:30])[CH3:31])[C:24]3[CH:33]=[CH:34][CH:35]=[CH:36][C:23]=3[N:22]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:21]2=[O:42])=[O:19])[CH3:17])=[O:8])[CH:3]=[C:2]([F:1])[CH:12]=1
Reactant: C[C@H](N)C(=O)C1(N)C(=O)N(CC(C)(C)C)c2ccccc2N(CC(C)(C)C)C1=O
Reactant: O=C(O)C(O)c1cc(F)cc(F)c1
Agent: Cl
Product: C[C@H](NC(=O)C(O)c1cc(F)cc(F)c1)C(=O)C1(N)C(=O)N(CC(C)(C)C)c2ccccc2N(CC(C)(C)C)C1=O

Procedure:
Following General Procedure I above using 3,5-difluoromandelic acid (Lancaster) and 3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-V), the title compound was prepared as a white solid (melting point=116-126° C.). Purification was by flash chromatography eluting with CH2Cl2/EtOAc (1:1 gradient to 2:3). Rf=0.54 and 0.40 (CH2Cl2/EtOAc, 1:1).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[OH:22][N:23]=[C:24]1[CH2:28][CH2:27][NH:26][CH2:25]1.FC(F)(F)C([O-])=O.C(N(CC)CC)C.CS(C)=O>C(#N)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:26]2[CH2:27][CH2:28][C:24](=[N:23][OH:22])[CH2:25]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: ON=C1CCNC1
Agent: O=C([O-])C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Nc1c(F)c(N2CCC(=NO)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1

Procedure:
298 mg of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3 -carboxylic acid 535 mg of 3-hydroxyiminopyrrolidine-trifluoroacetate and 404 mg of triethylamine were reacted at 80° C. for 15 hours using as a solvent a mixture of 5 ml of dimethyl sulfoxide and 15 ml of acetonitrile. After cooling, the precipitate thereby formed was collected by filtration and recrystallized from a mixture of 10 ml of dimethyl sulfoxide and 15 ml of isopropanol to give 210 mg of the desired product as yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:23])[N:9]([CH2:13][C:14]3[C:15](=[O:22])[NH:16][C:17]([CH3:21])=[CH:18][C:19]=3[CH3:20])[CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:24].[F:25][C:26]([F:40])([F:39])[CH2:27]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:23])[N:9]([CH2:13][C:14]3[C:15](=[O:22])[NH:16][C:17]([CH3:21])=[CH:18][C:19]=3[CH3:20])[CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[CH:4][C:3]=1[O:24][CH2:27][C:26]([F:40])([F:39])[F:25]
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: Cc1cc(C)c(CN2CCOc3ccc(O)c(Cl)c3C2=O)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CN2CCOc3ccc(OCC(F)(F)F)c(Cl)c3C2=O)c(=O)[nH]1
Temperature: 150 °C
Yield: 14.6 %

Procedure:
A mixture of 6-chloro-4-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7-hydroxy-3,4-dihydro-1,4-benzoxazepin-5(2H)-one (124d, 100 mg, 0.287 mmol), toluene-4-sulfonic acid 2,2,2-trifluoro-ethyl ester (73.0 mg, 0.287 mmol), potassium carbonate (79.0 mg, 0.574 mmol), and anhydrous DMF (6 mL) was heated at 150° C. for 45 minutes in the microwave. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase was separated, washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, MeOH/EtOAc) to give the title compound (Example 124, 18 mg, 16% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.62 (br. s., 1H), 7.33 (d, J=8.93 Hz, 1H), 7.05 (d, J=8.93 Hz, 1H), 5.94 (s, 1H), 4.84 (q, J=8.60 Hz, 2H), 4.62 (s, 2H), 4.02 (br. s., 2H), 3.41 (br. s., 2H), 2.21 (s, 3H), 2.14 (s, 3H); MS 431.1 [M+1].
Reaction SMILES: [C:1]([CH:6]([NH:15][C@H:16]([C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[C:25](=[O:31])[CH2:26][O:27]C(=O)C)=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O:3][CH2:4][CH3:5])=[O:2].[ClH:32]>>[ClH:32].[C:1]([CH:6]([NH:15][C@H:16]([C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[C:25](=[O:31])[CH2:26][OH:27])=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)C(CCc1ccccc1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)COC(C)=O
Agent: Cl
Product: CCOC(=O)C(CCc1ccccc1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)CO

Procedure:
A solution of N-formyl, N-(1-carbethoxy-3-phenylpropyl)(L)-alanyl(S)-2-(2-acetoxy-1-oxoethyl)-pyrrolidine (460 mg; 1 mmol) in 5 ml of 5% ethanolic hydrochloric acid (5.5 ml of 38% aqueous HCl in 60 ml of ethanol) can be kept at 25° for 2 days. It can then be concentrated under reduced pressure and the residue triturated with ether to give N-(1-carbethoxy-3-phenylpropyl)(L)-alanyl (S)-2-(2-hydroxy-1-oxoethyl)-pyrrolidine hydrochloride.
Reaction SMILES: [N:1](/[C:4](=[CH:10]/[CH:11]=[CH:12]/[C:13]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=1[O:21][CH3:22])/[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+]=[N-].[C:23]1([P:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH3:22][O:21][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[C:13]=1/[CH:12]=[CH:11]/[CH:10]=[C:4](/[N:1]=[P:29]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)\[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)/C(=C\C=C\c1c(OC)cccc1OC)N=[N+]=[N-]
Solvent: ClCCl
Product: CCOC(=O)/C(=C\C=C\c1c(OC)cccc1OC)N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
Add, dropwise, a solution of 5 g of ethyl (2E,4E)-2-azido-5-(2,6-dimethoxyphenyl)penta-2,4-dienoate (16.5 mmol) in 60 mL of DCM to a solution of 4.37 g (16.7 mmol) of triphenylphosphine in 40 mL of DCM. Stir the reaction mixture for 2 h at RT, then concentrate under reduced pressure. Solidify the residue obtained in 100 mL of isopropyl ether, then filter on a frit and rinse with 50 mL of isopropyl ether, giving 7.9 g of ethyl (2E,4E)-5-(2,6-dimethoxyphenyl)-2-[(triphenylphosphoranylidene)amino]penta-2,4-dienoate in the form of a white solid.
Reaction SMILES: COC(OC)N(C)C.[N+:9]([C:12](=[C:16]1[NH:21][CH2:20][CH2:19][CH2:18][S:17]1)[C:13](=[O:15])C)([O-:11])=[O:10]>C(Cl)(Cl)Cl.CO.C(Cl)Cl>[N+:9]([C:12](=[C:16]1[NH:21][CH2:20][CH2:19][CH2:18][S:17]1)[CH:13]=[O:15])([O-:11])=[O:10]
Reactant: CC(=O)C(=C1NCCCS1)[N+](=O)[O-]
Agent: COC(OC)N(C)C
Solvent: ClCCl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=CC(=C1NCCCS1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.95 g of N,N-dimethyl formamide dimethyl acetal in 25 ml of chloroform was added dropwise at room temperature to a mixture of 8.0 g of 2 b in 50 ml of chloroform and the mixture was stirred for one hour at room temperature, then was heated to reflux and stirred for 12.5 hours. The solvent then was evaporated under reduced pressure to give a mushy solid, which was passed through fluorosil, using methylene chloride, then methanol, as eluents. The resulting material then was passed through fluorosil using a 99:1 mixture of methylene chloride and methanol as eluent to give 21 as a yellow solid, m.p.: 171°-172°.