Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:11][CH:10]=[CH:9][N:5]2[C:6](=[O:8])[CH:7]=1.C(OCC)(=O)CC(C)=O.[Br:21]N1C(=O)CCC1=O.C(Cl)(Cl)Cl>C1C=CC=CC=1>[Br:21][C:7]1[C:6](=[O:8])[N:5]2[CH:9]=[CH:10][S:11][C:4]2=[N:3][C:2]=1[CH3:1]
Reactant: Cc1cc(=O)n2ccsc2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: CCOC(=O)CC(C)=O
Solvent: c1ccccc1
Product: Cc1nc2sccn2c(=O)c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7-methyl-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p. 127°-129° C., (4 g), prepared according to Example 1 using ethyl acetoacetate, dissolved in benzene (100 ml) was reacted with N-bromo-succinimide (4.7 g) under stirring at room temperature for 1 hour. The precipitate was dissolved by adding chloroform and the solution was washed with water: evaporation in vacuo to dryness and crystallization of the residue from methanol gave 6-bromo-7-methyl-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p. 233°-234° C. (5.1 g), which was reacted with 3-pyridine-carboxaldehyde (3.4 g) in methanol (190 ml) in the presence of sodium methoxide (2.2 g) under stirring at the reflux temperature for 2 hours. After cooling the precipitate was filtered and washed with water until neutral: crystallization from CH2Cl2 -methanol gave 5.18 g of 6-bromo-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p. 208°-209° C., NMR (CDCl3) δppm: 6.99 (d) (1H, C-2 proton), 7.33 (dd) (1H, C-5 pyridyl proton), 7.59 (d) (1H, β-ethenyl proton), 7.95 (d) (1H, α-ethenyl proton), 7.96 (d) (1H, C-3 proton), 7.98 (m) (1H, C-4 pyridyl proton), 8.58 (bd) (1H, C-6 pyridyl proton), 8.82 (bs) (1H, C-2 pyridyl proton); JHαHβ =16 Hz.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[S:10][C:11]([Cl:47])=[C:12]([C:14](=[N:37][O:38][CH2:39][C:40]([O:42]C(C)(C)C)=[O:41])[C:15]([NH:17][CH:18]2[C:35](=[O:36])[N:20]3[C:21]([C:32]([OH:34])=[O:33])=[C:22]([CH2:25][S:26][C:27]4[S:28][CH:29]=[N:30][N:31]=4)[CH2:23][S:24][C@H:19]23)=[O:16])[N:13]=1.C(OC(C)C)(C)C>C(Cl)Cl.C1(OC)C=CC=CC=1>[NH2:8][C:9]1[S:10][C:11]([Cl:47])=[C:12]([C:14](=[N:37][O:38][CH2:39][C:40]([OH:42])=[O:41])[C:15]([NH:17][CH:18]2[C:35](=[O:36])[N:20]3[C:21]([C:32]([OH:34])=[O:33])=[C:22]([CH2:25][S:26][C:27]4[S:28][CH:29]=[N:30][N:31]=4)[CH2:23][S:24][C@H:19]23)=[O:16])[N:13]=1
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1nc(N)sc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Solvent: COc1ccccc1
Product: Nc1nc(C(=NOCC(=O)O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nncs4)CS[C@H]23)c(Cl)s1
Temperature: 25 °C
Yield: 80.1 %

Procedure:
Trifluoroacetic acid (10 ml) was added to a solution of 7-[2-(2-amino-5-chlorothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.5 g) in methylene chloride (5.0 ml) and anisole (2.5 ml) under ice-cooling, and then the mixture was stirred for an hour at ambient temperature. The resulting solution was dropwise added to diisopropyl ether (100 ml) and then precipitates were collected by filtration. The precipitates were added to a mixture of water and ethyl acetate, and adjusted to pH 7.5 with 10% aqueous solution of sodium hydroxide. The aqueous layer was separated and adjusted to pH 2.2 with 10% aqueous hydrochloric acid to give the precipitates, which were filtered off and dried over phosphorus pentoxide in vacuo to give 7-[2-(2-amino-5-chlorothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(1.83 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][CH2:24][CH3:25])=[C:6]([CH:21]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][N:12]=1)[CH2:9][CH3:10].[C:26]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[C:6]([CH:21]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][N:12]=1)[CH2:9][CH3:10]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCCOc1ccc(Br)cc1CN(CC)c1ccc(C(=O)OC)cn1
Solvent: C1CCOC1
Solvent: CC(C)CO
Product: CCN(Cc1cc(Br)ccc1OCC(C)C)c1ccc(C(=O)OC)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60.6 %

Procedure:
A solution of the methyl-2-[N-(5-bromo-2-(hydroxy-benzyl)-N-ethylamino]pyridine-5-carboxylate (reference example 1, paragraph 7) (0.5 g, 1.37 mmol) in THF (15 ml) was treated with triphenylphosphine (0.39 g, 1.49 mmol) and diazoethyldicarboxylate. The reaction was stirred at ambient temperature for five minutes and then isobutyl alcohol (0.152, 2.06 mmol,) added. The reaction was then stirred at ambient temperature for 18 hours. partitioned between ethyl acetate and water and the aqueous layer washed with ethyl acetate (×2). The organic layers were combined, washed with water and brine, dried (MgSO4) and evaporated. The residue was subjected to chromatography (eluant: ethyl acetate/hexane) to give the title compound (0.35 g, 60%) as an off-white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:26])[CH:12]=[C:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(NC1C=CC(C(=O)CC2CCN(CC3C=CC=CC=3)CC=2)=CC=1)(=O)C>C(O)C.C1(C)C=CC=CC=1.[Pt]=O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:26])[CH2:12][CH:13]2[CH2:14][CH2:15][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:17][CH2:18]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(=O)C=C2CCN(Cc3ccccc3)CC2)cc1
Agent: O=[Pt]
Agent: CC(=O)Nc1ccc(C(=O)CC2=CCN(Cc3ccccc3)CC2)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)Nc1ccc(C(=O)CC2CCN(Cc3ccccc3)CC2)cc1
Reaction time: 5.5 h

Procedure:
In a mixed solution of 80 ml of ethanol and 30 ml of toluene was dissolved 7.10 g of the mixture of N-acetyl-4[(1-benzyl-4-piperidinyliden)acetyl]aniline and N-acetyl-4[(1-benzyl-1,2,5,6-tetrahydropyridin-4-yl)acetyl]aniline obtained in Reference example 14, and then 0.10 g of platinum oxide was added thereto. The mixture was stirred under a hydrogen stream for 5.5 hours. After the reaction, the catalyst was removed by filtration and condensed under reduced pressure. The residue obtained was applied to silica gel column chromatography to obtain 5.54 g of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH:9]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[S:24][C:23]3[C:18](=[N:19][CH:20]=[CH:21][C:22]=3Cl)[CH:17]=2)=[O:15])[CH2:10]1)[S:3](=[O:8])(=[O:7])[N:4]([CH3:6])[CH3:5].[CH3:26][C:27]1[NH:28][C:29]2[C:34]([CH:35]=1)=[CH:33][C:32]([NH2:36])=[CH:31][CH:30]=2>>[CH3:1][N:2]([CH:9]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[S:24][C:23]3[C:18](=[N:19][CH:20]=[CH:21][C:22]=3[NH:36][C:32]3[CH:33]=[C:34]4[C:29](=[CH:30][CH:31]=3)[NH:28][C:27]([CH3:26])=[CH:35]4)[CH:17]=2)=[O:15])[CH2:10]1)[S:3](=[O:8])(=[O:7])[N:4]([CH3:6])[CH3:5]
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: CN(C)S(=O)(=O)N(C)C1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N5CCC(N(C)S(=O)(=O)N(C)C)C5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from (+/−)-dimethylsulfamic acid methyl-{1-[7-chloro-thieno[3,2-b]pyridine-2-carbonyl]-pyrrolidin-3-yl}-amide and 2-methyl-1H-indol-5-ylamine by a procedure analogous to Example 1C. MS: 513 (MH+); HPLC Rf: 4.76 min.; HPLC purity 92%.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH2:5]([N:9]=[C:10]=[O:11])[CH2:6][CH2:7][CH3:8].C(=O)=O>ClCCl>[OH:2][CH2:1][CH2:3][NH:4][C:10]([NH:9][CH2:5][CH2:6][CH2:7][CH3:8])=[O:11]
Reactant: NCCO
Reactant: CCCCN=C=O
Agent: O=C=O
Solvent: ClCCl
Product: CCCCNC(=O)NCCO
Temperature: 30 °C
Yield: 113 %

Procedure:
61.7 Grams (1 mole @ 99% purity) of ethanolamine and 170 grams of dichloromethane were charged to a flask equipped with stirrer, thermometer, feed tank, distillation head and condenser. 101 Grams (1 mole @ 98% purity) of butyl isocyanate was fed dropwise with stirring and cooling (dry ice bath) during 1.5 hrs. such that the temperature of the reaction mixture was maintained at about 30° C. At this time some solid had been formed and it was redissolved by heating to 46° C. The mixture was stirred at 46° C. for an additional two hours and then freed of volatile materials by stripping at 90° C. and 2 mm Hg leaving 181 g of solid product. This material could be recrystallized from 2-butanone giving tiny white crystals melting at 67° C.
Reaction SMILES: [F:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.[Li+].[OH-].Cl>C1COCC1.O>[F:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2cnc(F)cc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2cnc(F)cc2c1
Reaction time: 2 h
Yield: 90.7 %

Procedure:
A slurry of 88 (413 mg, 2.013 mmol) and LiOH (56 mg, 2.34 mmol) in THF (9.8 mL) and water (1.5 mL) was stirred at RT for 1.5 h. An additional 50 mg of LiOH was added (total: 106 mg, 4.43 mmol), and the reaction was stirred for an additional 2 h. The THF was removed on a rotary evaporator. The reaction mixture was suspended in water (10 mL) and treated with 10M HCl in water (0.604 mL, 6.04 mmol). A white cloudy precipitate was collected by vacuum filtration. The precipitate was washed with water (2×2 mL) and dried under house vacuum over night to afford 349 mg (100%) of 3-fluoroisoquinoline-6-carboxylic acid (90) as a white solid, which was used in the next step without further purification.
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.[C:32]1([C:38]2([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[C@@H:46]3[C@@H:42]([CH2:43][NH:44][CH2:45]3)[C@@:41]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[O:54][CH3:55])([OH:47])[C@@H:40]([OH:56])[CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[CH3:63][O:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=1[C@H:71]([CH3:75])[C:72](O)=[O:73].[Cl-].[Na+]>C(Cl)Cl.O>[C:57]1([C:38]2([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C@@H:46]3[C@@H:42]([CH2:43][N:44]([C:72](=[O:73])[C@H:71]([C:66]4[CH:67]=[CH:68][CH:69]=[CH:70][C:65]=4[O:64][CH3:63])[CH3:75])[CH2:45]3)[C@@:41]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[O:54][CH3:55])([OH:47])[C@@H:40]([OH:56])[CH2:39]2)[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: COc1ccccc1[C@@]1(O)[C@@H]2CNC[C@@H]2C(c2ccccc2)(c2ccccc2)C[C@@H]1O
Reactant: COc1ccccc1[C@H](C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1[C@H](C)C(=O)N1C[C@@H]2[C@H](C1)C(c1ccccc1)(c1ccccc1)C[C@H](O)[C@@]2(O)c1ccccc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.8 %

Procedure:
30 mg of 1-hydroxybenzotriazole hydrate, 0.66 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 0.6 cm3 of diisopropylethylamine are added to a solution of 1.1 g of (3aS,4S,5S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-perhydroisoindole-4,5 -diol and 0.58 g of (S)-2-(2-methoxyphenyl)-propanoic acid in 30 cm3 of methylene chloride, cooled to 0° C. The mixture is stirred at room temperature for 3 hours and 30 minutes and 100 cm3 of water and 50 cm3 of an aqueous saturated solution of sodium chloride are added. The organic phase is decanted, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The yellow residue obtained is chromatographed over a Merck silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 30 cm) by eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (60/40 by volume) and collecting fractions of 25 cm3. Fractions 6 to 14 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.9 g of (3aS,4S,5S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[2-(2-methoxyphenyl)-(S)-propionyl]-perhydroisoindole-4,5-diol which melts at 256° C. is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[C:19]([C:21]1([OH:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)#[CH:20]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(N(CC)CC)C.[I-]>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:20]#[C:19][C:21]2([OH:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(I)cc1
Reactant: C#CC1(O)CCCCC1
Agent: Cl[Pd]Cl
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(CC1CCCC1)c1ccc(C#CC2(O)CCCCC2)cc1
Temperature: 70 °C
Yield: 109.2 %

Procedure:
A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (716 mg, 2.0 mmol) and triethylamine (2 mL, 0.01 mmol) in N,N-dimethylformamide (2 mL) was treated with 1-ethynyl cyclohexanol (621 mg, 5.0 mmol). The resulting reaction mixture was degassed with argon and then treated with cooper iodide (10 mg, 0.05 mmol) and bis(triphenylphosphine)palladium (II) chloride (15 mg, 0.02 mmol). The reaction was then heated at 70° C. for 24 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. The residue was diluted with ethyl acetate (40 mL) and then washed with a half-saturated aqueous sodium chloride solution (1×20 mL). The aqueous layer was back extracted with ethyl acetate (1×40 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 ethyl acetate/hexanes) afforded 3-cyclopentyl-2-[4-(1-hydroxy-cyclohexylethynyl)-phenyl]-propionic acid methyl ester (774 mg, 98%) as a cream solid: mp 76-78° C.; EI-HRMS m/e calcd for C23H30O3 (M+) 354.2194, found 354.2194.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:13][O:14]CC1C=CC=CC=1)=O)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[NH2:11][C@H:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:13][OH:14]
Reactant: CC(C)(C)OC(=O)[C@H](COCc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H](N)CO
Temperature: 65 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
A mixture of 29.24 g (0.076 mol) of (L) N-(benzyloxycarbonyl)-O-benzylserine, t-butyl ester from Reference Example 1, 24.1 g (0.38 mol) of ammonium formate and 38.3 g of 10% palladium on carbon in 600 ml of methanol was heated at 65° C. for 20 hours and stirred at room temperature overnight. The mixture was filtered through diatomaceous earth and the filter pad was washed with methanol. The filtrate was concentrated to give 12.18 g (99.6%) of product as described in Synthetic Commun., 26:2723 (1996).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH:25]1([C@H:28]([NH2:30])[CH3:29])[CH2:27][CH2:26]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:30][C@@H:28]([CH:25]4[CH2:27][CH2:26]4)[CH3:29])=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: C[C@@H](N)C1CC1
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N[C@H](C)C3CC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)-1-cyclopropylethanamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.17-0.27 (m, 1H) 0.27-0.36 (m, 1H) 0.36-0.44 (m, 1H) 0.44-0.53 (m, 1H) 0.94-1.07 (m, 1H) 1.25 (d, J=6.82 Hz, 3H) 2.43 (s, 3H) 3.42-3.57 (m, 1H) 7.66 (dd, J=8.08, 1.52 Hz, 1H) 7.69-7.75 (m, 1H) 7.78 (d, J=7.58 Hz, 1H) 8.17 (br. s., 1H) 8.43 (d, J=6.32 Hz, 2H) 8.59 (d, J=8.08 Hz, 1H) 8.85-8.95 (m, 1H) 13.19 (br. s., 1H). MS m/z [M+H]+ 388.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[C:42]([CH3:44])[N:41]=[C:40]([CH:45]3[CH2:47][CH2:46]3)[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[C:42]([CH3:44])[N:41]=[C:40]([CH:45]3[CH2:46][CH2:47]3)[CH:39]=2)[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C2CC2)n1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)nc(C4CC4)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J8) (240 mg, 0.75 mmol) and 3-[3-(2-cyclopropyl-6-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K36) (264 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (282 mg, 63%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][N:9]1[C:15]2[CH:16]=[CH:17][C:18]([C:20]#[C:21][CH2:22][CH2:23][CH2:24][NH2:25])=[CH:19][C:14]=2[C:13](=[O:26])[N:12]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:11][C:10]1=[O:32].[C:33](S(O)(=O)=O)([NH2:35])=[NH:34]>C(=O)(O)[O-].[K+]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][N:9]1[C:15]2[CH:16]=[CH:17][C:18]([C:20]#[C:21][CH2:22][CH2:23][CH2:24][NH:25][C:33]([NH2:35])=[NH:34])=[CH:19][C:14]=2[C:13](=[O:26])[N:12]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:11][C:10]1=[O:32]
Reactant: N=C(N)S(=O)(=O)O
Reactant: CN1C(=O)CN(CCC(=O)O)C(=O)c2cc(C#CCCCN)ccc21
Agent: O=C([O-])O
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)CN(CCC(=O)O)C(=O)c2cc(C#CCCCNC(=N)N)ccc21
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To a magnetically stirred solution of 6 mgs of 1-methyl-4-(2-carboxyethyl)-7-(5-amino-1-pentynyl)-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione trifluoracetate (0.017 mmol) in 1.0 mL 10% potassium bicarbonate was added 31.0 mgs of formamidine sulfonic acid (0.25 mmol). After 30 minutes, the reaction mixture was quenched with 0.5 mL acetic acid and concentrated in vacuo. The resulting residue was diluted with 2 mL water and purified by high pressure liquid chromatography, using a 1/2" C-18 reverse-phase column, eluting with a solvent gradient of 10:90 methanol(0.1% trifluoracetic acid)/water (0.1% trifluoracetic acid), time 0 to 10 min, to 50:50 methanol(0.1% trifluoracetic acid)/water (0.1% trifluoracetic acid), time 10 min to 40 min, flow=10 ml/min (Rt= 36.8 min, un detection 254 nm) to yield 4.5 mgs (67%) 1-methyl-4-(2-carboxyethyl)-7-(5-guanidino-1-pentynyl)-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione trifluoracetate. HRMS (FAB) molecular ion m/z=386.1823 (cald. C19H24N5O4, 386.1829). 1H NMR (D2O) 7.60 (1H, d, 4JHH, Ar--H o-CON), 7.51 (1H, dd, 4JHH =2 Hz, 3JHH =8 Hz, Ar--H p-CON), 7.20 (1H, d, 3JHH =8 Hz, Ar--H m-CON), 4.05 (1H, d, 2JHH =14 Hz, NCHHCO), 3.92 (1H, m, NCHHCH2), 3.72 (1H, d, 2JHH =14 Hz, NCHHCO), 3.40 (1H, m, NCHHCH2), 3.23-3.15 (5H, NCH3, H2NC(=NH2)NHCH2), 2.58 (2H, m, CH2CO2), 2.38 (2H, t, 3JHH=7 Hz, CHCCH2), 1.76 (2H, p, 3JHH =7 Hz, CH2CH2CH2).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12](=[O:14])[CH3:13])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>>[N:1]1[C:10]2[CH2:9][CH:8]([NH:11][C:12](=[O:14])[CH3:13])[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Nc1ccc2cccnc2c1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)NC1CCc2cccnc2C1
Yield: 24.6 %

Procedure:
Reaction of N-(quinol-7-yl)acetamide (33 mg, 0.177 mmol) using the general procedure for small scale hydrogenations (workup with NaOH in place of saturated NaHCO3) provided N-(5,6,7,8-tetrahydroquinolin-7-yl)acetamide (8.3 mg, 25%): 1H NMR □ 1.72–1.83 (m, 1H), 1.99 (s, 3H), 2.04–2.20 (m, 2H), 2.72–2.95 (m, 3H), 3.25 (dd, 1H, J=5, 17 Hz), 4.29–4.40 (m, 1H), 5.72 (br s, 1H), 7.05 (dd, 1H, J=4, 8 Hz), 7.38 (d, 1H, J=8 Hz), 8.35 (d, 1H, J=4 Hz); 13C NMR □ 23.9, 26.5, 28.7, 39.0, 45.6, 121.9, 131.4, 137.0, 147.7, 154.8, 170.1; MS m/z: 213 (M+Na+). N-(1,2,3,4-tetrahydroquinolin-7-yl)acetamide also was isolated (6.5 mg, 20%): 1H NMR □ 1.24–1.28 (s, 1H), 1.87–1.95 (m, 2H), 2.70 (dd, 2H, J=6, 6 Hz), 3.28 (dd, 2H, J=5, 5 Hz), 6.46 (d, 1H, J=8 Hz), 6.84 (d, 1H, J=8 Hz), 6.93 (s, 1H), 7.03 (br s, 1H); 13C NMR □ 22.1, 24.7, 26.6, 37.9, 105.6, 108.3, 117.6, 129.6, 136.5, 145.1, 168.1; MS m/z: 213 (M+Na+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:50]=[CH:49][C:6]([CH2:7][N:8]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([OH:36])=O)=[CH:32][C:31]=5F)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:51]([N:58]1[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]1)([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52]>>[C:54]([O:53][C:51]([N:58]1[CH2:63][CH2:62][N:61]([C:34](=[O:36])[C:33]2[CH:32]=[CH:31][C:30]([N:27]3[C:17]4[N:18]=[C:19]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[N:20]=[C:15]([C:12]5[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]6[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:50][CH:49]=6)[CH2:40][C:41]6[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=6)=[N:14][CH:13]=5)[C:16]=4[CH2:29][CH2:28]3)=[CH:38][CH:37]=2)[CH2:60][CH2:59]1)=[O:52])([CH3:57])([CH3:55])[CH3:56]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3F)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)cc3)cn2)cc1

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-fluoro-benzoic acid (65.6 mg, 0.0968 mmol) obtained in Step A in Example 1-D-21 and 1-Boc-piperazine (36.1 mg, 0.194 mmol) instead of 1-pyridine-3-yl-piperazine, amidation was carried out in the same manner as Step B in Example 1-D-21, a crude product of 4-{4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-benzoyl}-piperazine-1-carboxylic acid tert-butyl ester was obtained as a yellow solid (89.9 mg), and then the PMB groups and BOC group were removed according to the above Deprotection method 3, to obtain the desired compound (D-141) as a yellow powder (29.6 mg, 60%).
Reaction SMILES: C(Cl)(=O)C.CO.[C:7]([O:11][CH3:12])(=[O:10])[CH2:8][SH:9].[CH:13]1[CH:27]=[C:26]2[C:16]([CH:17](O)[C:18]3[C:23]([CH:24]=[CH:25]2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:14]=1>C(OCC)(=O)C>[CH:22]1[C:23]2[CH:24]=[CH:25][C:26]3[CH:27]=[CH:13][CH:14]=[CH:15][C:16]=3[CH:17]([S:9][CH2:8][C:7]([O:11][CH3:12])=[O:10])[C:18]=2[CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)CS
Reactant: OC1c2ccccc2C=Cc2ccccc21
Solvent: CO
Solvent: CC(=O)Cl
Solvent: CCOC(C)=O
Product: COC(=O)CSC1c2ccccc2C=Cc2ccccc21
Reaction time: 0.25 h
Yield: 87.2 %

Procedure:
Acetyl chloride (171 μL, 2.4 mmol) is carefully added to 8 mL of dry methanol and the solution is stirred for 15 minutes. Methyl thioglycolate (257 μL, 2.9mmol) and dibenzosuberenol (Aldrich) (0.50 g, 2.4 mmol) are added, and the reaction is stirred for 5 minutes. The reaction is diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate, water, then brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil is chromatographed on silica gel eluting with ethyl acetate:toluene:hexane (3:27:70) to give 0.62 g (87%) of methyl (5H-dibenzo[a,d]cyclohepten-5-yl-thio)acetate: melting point 74°-76° C.