Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH3:16][O:17][CH:18]([CH2:22][CH3:23])[C:19](Cl)=[O:20].C(N(CC)CC)C>CC(C)=O>[CH3:16][O:17][CH:18]([CH2:22][CH3:23])[C:19]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:20]
Reactant: CCC(OC)C(=O)Cl
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCC(OC)C(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1
Temperature: 0 °C
Yield: 62.3 %

Procedure:
20.3 g (0.1 mole) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone were stirred with 18.1 g (0.12 mole) of 2-methoxybutyryl chloride and 10.1 g (0.1 mole) of triethylamine in 200 ml of absolute acetone for 3 hours at room temperature. 100 g of ice were added, the crystals were filtered off under suction and recrystallized from dimethylformamide/water, and the resulting product was dried at 50° C. under greatly reduced pressure. 18.9 g (63%) of 6-[p-(2-methoxybutyrylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone were obtained. Mp.: 151°-152° C.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>C(O)C>[F:8][C:7]1[C:2]([NH:10][NH2:11])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: NN
Reactant: Fc1cccnc1Cl
Solvent: O
Solvent: CCO
Product: NNc1ncccc1F
Temperature: 60 °C
Reaction time: 72 h

Procedure:
To a solution of 9.59 g of 2-chloro-3-fluoropyridine in 6 ml of ethanol there was added 6 ml of hydrazine monohydrate, and the mixture was stirred at 60° C. for 3 days. The solution was adsorbed onto 50 g of NH silica gel and purified by NH silica gel column chromatography (ethyl acetate-heptane) to give the title compound (403 mg) as a yellow solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:36]=[CH:35][C:10]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH:17]=[CH:18][C:19]=3[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.[C:37](OC(=O)C)(=[O:39])[CH3:38]>N1C=CC=CC=1>[C:37]([NH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)[CH:17]=[CH:18][C:19]=3[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:12])=[CH:35][CH:36]=2)[CH2:3]1)(=[O:39])[CH3:38]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)c1ccc(N2CC[C@@H](N)C2)cc1
Solvent: c1ccncc1
Product: CC(=O)N[C@@H]1CCN(c2ccc(C(=O)Nc3cc(-c4ccc(F)cc4)ccc3NC(=O)OC(C)(C)C)cc2)C1
Temperature: 25 °C
Reaction time: 19 h
Yield: 87.5 %

Procedure:
To a solution of 404 (0.295 g, 0.601 mmol) in pyridine (3.0 mL) under nitrogen was added acetic anhydride (1.59 mL, 16.84 mmol), and the mixture was stirred for 19 h at room temperature. The solvent was evaporated and the residue obtained was evaporated twice with toluene and triturated with a mixture of Et2O and hexanes. The solid was filtered, air-dried and then dried under vacuum to afford the title compound 407 as a light pink solid (280 mg, 85%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[Cl:9][CH:10]([CH3:18])[C:11](=O)[CH2:12][C:13](OC)=[O:14].[OH-].[Na+]>>[Cl:9][CH:10]([C:11]1[N:8]=[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]2[C:13](=[O:14])[CH:12]=1)[CH3:18]
Reactant: COC(=O)CC(=O)C(C)Cl
Reactant: Cc1cccc(N)n1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc2nc(C(C)Cl)cc(=O)n12
Temperature: 110 °C
Reaction time: 5 h
Yield: 33 %

Procedure:
To a manually stirred polyphosphoric acid (30 g, 200 mmol) in a 200 mL beaker was added 6-methyl-2-pyridinamine (Aldrich, 4.7 g, 43 mmol), followed by methyl 4-chloro-3-oxopentanoate (8.584 g, 52.15 mmol). The mixture was heated with stirring at 110° C. for 5 h. After being cooled, the dark slurry was transferred on to 100 g of ice. The pH of the mixture was adjusted to 6-7 with 10% sodium hydroxide. The mixture was extracted with methylene chloride. The combined organic layers were washed with water, brine, dried over magnesium sulfate and evaporated to dryness. The residue was purified on silica gel, eluting with 0-10% methanol in methylene chloride, to yield the desired product (3.16 g, 32.7%). LCMS calculated for C11H12ClN2O (M+H)+: m/z=223.1. Found: 223.2.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:20][S:17]([C:14]2[CH:13]=[CH:12][C:11]([Cl:10])=[CH:16][CH:15]=2)(=[O:19])=[O:18])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: O=S(=O)(N=Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A stirred solution consisting of 7.03 g (5.0 mmol) of 4-chlorobenzaldehyde, 9.58 g (5.0 mmol) of 4-chlorobenzenesulfonamide, 8 g of 4A molecular sieves and 0.1 g of Amberlite IR-120 in 90 mL of toluene was heated to reflux. The reaction vessel was fitted with a Dean Stark trap which was filled with 4A molecular sieves. The mixture was heated for 4 hours, at which point TLC analysis showed conversion to sulfonimine. The mixture was allowed to cool to room temperature and was filtered. Concentration of the filtrate and subsequent recrystallization of the crude product from CHCl3 -hexane gave 7.84 g (50%) of sulfonimine as a white crystalline material: IR 3090, 1598, 1582, 1553, 1321, 1084 cm1 ; 1H NMR (CDCl3, TMS, 60 MHz) & 9.02 (s, 1), 7.73 (A2B2, 4, Δ√=24 Hz, JAB =8 Hz), 7.67 (A2B2, 4, Δ√=23 Hz, JAB =9 Hz); m.p. 128.0 ° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH3:16])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18].[OH:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[CH3:27])[NH2:23]>C(O)C>[CH2:15]([O:14][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:23][C:22]3[CH:24]=[CH:25][C:26]([CH3:27])=[C:20]([OH:19])[CH:21]=3)=[C:3]([C:17]#[N:18])[CH:4]=[N:5]2)=[CH:10][C:9]=1[O:12][CH3:13])[CH3:16]
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Cc1ccc(N)cc1O
Solvent: CCO
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(C)c(O)c3)c2cc1OC
Yield: 54.8 %

Procedure:
A mixture of 500 mg (1.90 mmol) 4-chloro-7-ethoxy-6-methoxy-3-quinolinecarbonitrile, 30 ml ethanol, and 281 mg (2.28 mmol) 3-hydroxy-4-methylaniline was heated to reflux under N2 overnight. Removed heat and made basic with saturated sodium bicarbonate. Stripped solvents and slurried residue in hexane. Collected solids, washed with water, and dried in vacuo, giving 364 mg off-white solid: mass spectrum (electrospray m/e): M+H=349.9.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[NH:10][CH:11]1[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15]I.[H-].[Na+]>C1COCC1>[CH2:1]([O:8][C:9](=[O:14])[N:10]([CH:11]1[CH2:12][CH2:13]1)[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: O=C(NC1CC1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)OCc1ccccc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of cyclopropyl-carbamic acid benzyl ester (11.8 g) and methyl iodide (excess) in THF (80 mL) and DM (20 mL) at 0° C. was added NaH (2.20 g, 91.6 mmol) and the resulting mixture was warmed to room temperature and stirred overnight. The reaction was then quenched at 0° C. by sat NaHCO3. The separated aqueous phase was extracted several times with EtOAc. The combined extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (5% to 20% EtOAc/hexanes) to give cyclopropyl-methyl-carbamic acid benzyl ester (11.32 g, 91%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:22]([CH2:23][CH2:24][CH3:25])=[C:21]([C:26]([O-])=[O:27])[N:20]=[N:19]3)=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].C1C=C[C:33]2N(O)N=[N:36][C:34]=2[CH:35]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[CH:34]1([NH:36][C:26]([C:21]2[N:20]=[N:19][N:18]([C:15]3[CH:16]=[CH:17][C:12]([C:10]([NH:9][CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:11])=[CH:13][CH:14]=3)[C:22]=2[CH2:23][CH2:24][CH3:25])=[O:27])[CH2:35][CH2:33]1
Reactant: On1nnc2ccccc21
Reactant: CCCc1c(C(=O)[O-])nnn1-c1ccc(C(=O)NCCN2CCOCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(C(=O)NCCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 138.9 %

Procedure:
Sodium 1-(4-{[(2-morpholin-4-ylethyl)amino]carbonyl}phenyl)-5-propyl-1H-1,2,3-triazole-4-carboxylate (642 mg, 1.34 mmol) obtained in Example 61b), HOBt (91.6 mg, 0.671 mmol, 0.5 eq.) and cyclopropylamine (0.125 ml, 1.74 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 9.0 ml), WSC (315 mg, 1.61 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated, dissolved in ethyl acetate (35 ml) and washed with 2% aqueous sodium carbonate solution and saturated brine. The aqueous layers were each extracted with ethyl acetate (25 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated, and ethyl acetate and diethyl ether were added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (397 mg, 0.932 mmol, 69.6%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C@:9]([NH2:16])([CH3:15])[C:10]([F:14])([F:13])[CH2:11][OH:12])=[O:5])[CH3:2].[N:17]#[C:18]Br>>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C@:9]1([CH3:15])[C:10]([F:14])([F:13])[CH2:11][O:12][C:18]([NH2:17])=[N:16]1)=[O:5])[CH3:2]
Reactant: N#CBr
Reactant: CCOC(=O)[C@H]1C[C@@H]1[C@@](C)(N)C(F)(F)CO
Product: CCOC(=O)[C@H]1C[C@@H]1[C@@]1(C)N=C(N)OCC1(F)F
Yield: 61 %

Procedure:
Starting from (1S,2S)-2-((R)-1-amino-2,2-difluoro-3-hydroxy-1-methyl-propyl)-cyclopropane-carboxylic acid ethyl ester (intermediate J5.3) the cyclization with cyanogen bromide yielded the (1S,2S)-2-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-cyclopropanecarboxylic acid ethyl ester (61% yield) as a white solid. MS (ISP): m/z=263.2 [M+H]+.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][CH2:8][Br:9])[C:3](Br)=[O:4].[C:10]([O:13][CH2:14][CH:15]([NH:21][C:22]([C:24]1[C:29]([I:30])=[C:28]([NH2:31])[C:27]([I:32])=[C:26]([C:33]([NH:35][CH:36]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[CH2:37][O:38][C:39](=[O:41])[CH3:40])=[O:34])[C:25]=1[I:47])=[O:23])[CH2:16][O:17][C:18](=[O:20])[CH3:19])(=[O:12])[CH3:11]>CC(N(C)C)=O>[C:44]([O:43][CH2:42][CH:36]([NH:35][C:33]([C:26]1[C:27]([I:32])=[C:28]([NH:31][C:3](=[O:4])[CH:2]([Br:1])[CH2:6][CH2:7][CH2:8][Br:9])[C:29]([I:30])=[C:24]([C:22]([NH:21][CH:15]([CH2:16][O:17][C:18](=[O:20])[CH3:19])[CH2:14][O:13][C:10](=[O:12])[CH3:11])=[O:23])[C:25]=1[I:47])=[O:34])[CH2:37][O:38][C:39](=[O:41])[CH3:40])(=[O:46])[CH3:45]
Reactant: CC(=O)OCC(COC(C)=O)NC(=O)c1c(I)c(N)c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c1I
Reactant: O=C(Br)C(Br)CCCBr
Solvent: CC(=O)N(C)C
Product: CC(=O)OCC(COC(C)=O)NC(=O)c1c(I)c(NC(=O)C(Br)CCCBr)c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c1I
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2,5-Dibromopentanoyl bromide prepared as described in example 8a (15.9 g, 49.3 mmol) was added dropwise to a stirred solution of N,N'-bis[2-(acetyloxy)-1-[(acetyloxy)methyl]ethyl]-5-amino-2,4,6-triiodo-1,3-benzenedicarboxamide (33 g, 37.8 mmol) in dimethylacetamide (250 ml) at 0°. After the addition, the reaction mixture was stirred at 0° for 1 hour, and then at room temperature for 22 hours. The solution was then added slowly dropwise to a well stirred mixture of ice-water (2 L), when a white solid separated out. This was collected by filtration, washed with ice-water (3×50 ml), and dried in vacuo to obtain the crude product (40.1 g, 91.5% pure). Recrystallization from ethyl acetate furnished analytically pure N,N'-bis[2-(acetyloxy)-1-[(acetyloxy)methyl]ethyl]-5-[(2,5-dibromo-1-oxopentyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamide as an off-white crystalline compound (35.3 g, 84% yield), m.p. 240°-243°.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH2:25])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[N:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH:25][C:26](=[O:33])[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[N:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@H](Nc1cncc(-n2cnc3cc(N)ccc32)n1)c1ccccc1
Product: C[C@H](Nc1cncc(-n2cnc3cc(NC(=O)c4ccccc4)ccc32)n1)c1ccccc1
Yield: 52.9 %

Procedure:
In a procedure analogous to example 32, reaction of 1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-5-amine (33 mg, 0.10 mmol) and benzoyl chloride (14 mg, 0.10 mmol) furnished the product (23 mg, 53%) after chromatography.
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([N:14]2[CH2:19][CH2:18][CH2:17][C@@H:16]([CH3:20])[C@H:15]2[CH2:21][NH2:22])=[O:13])[N:3]=[CH:4][CH:5]=1.Cl[C:24]1[N:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1>>[N:1]1[N:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([N:14]2[CH2:19][CH2:18][CH2:17][C@@H:16]([CH3:20])[C@H:15]2[CH2:21][NH:22][C:24]2[N:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)=[O:13])[N:3]=[CH:4][CH:5]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: C[C@@H]1CCCN(C(=O)c2ccccc2-n2nccn2)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2ccccc2-n2nccn2)[C@@H]1CNc1ncc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using (2-(2H-1,2,3-triazol-2-yl)phenyl)((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 446 [M+1]. 1H NMR (300 MHz, DMSO-d6) δ 8.75-6.80 (m, 9H), 4.95-2.80 (m, 5H), 1.80-0.50 (m, 8H); ESI MS (M+H) 446.
Reaction SMILES: Br.[CH3:2][C:3]([CH3:46])([CH3:45])[CH2:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24])[C:12]([C:25]([NH:27][C:28]1[N:33]=[CH:32][C:31]([NH:34]C(=O)OCC3C=CC=CC=3)=[CH:30][CH:29]=1)=[O:26])=[CH:11]2)=[O:6]>>[NH2:34][C:31]1[CH:30]=[CH:29][C:28]([NH:27][C:25]([C:12]2[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:14]3[C:10]([CH:11]=2)=[CH:9][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([CH3:46])([CH3:45])[CH3:2])=[CH:16][CH:15]=3)=[O:26])=[N:33][CH:32]=1
Reactant: CC(C)(C)CC(=O)Nc1ccc2c(c1)cc(C(=O)Nc1ccc(NC(=O)OCc3ccccc3)cn1)n2Cc1ccccc1F
Agent: Br
Product: CC(C)(C)CC(=O)Nc1ccc2c(c1)cc(C(=O)Nc1ccc(N)cn1)n2Cc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
46.8 mg (0.19 mmol) of hydrogen bromide (33% strength solution in acetic acid) are added to 29 mg (0.05 mmol) of benzyl 6-({[5-[(3,3-dimethylbutanoyl)amino]-1-(2-fluorobenzyl)-1H-indol-2-yl]carbonyl}amino)-3-pyridinylcarbamate (Example XLI), and the mixture is stirred at RT overnight. The solvent is removed under reduced pressure and the residue is purified by preparative HPLC. This gives 6 mg (27%) of the product.
Reaction SMILES: [ClH:1].C([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:25]([NH:27][C:28]1[CH:37]=[C:36]2[C:31]([C:32]([CH3:39])=[CH:33][C:34](=[O:38])[O:35]2)=[CH:30][CH:29]=1)=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:24])[NH2:23])=[O:15])(OCC1C=CC=CC=1)=O.[H][H].CCOCC>CO.[C].[Pd]>[ClH:1].[NH2:12][CH2:13][C:14]([NH:16][C@H:17]([C:25]([NH:27][C:28]1[CH:37]=[C:36]2[C:31]([C:32]([CH3:39])=[CH:33][C:34](=[O:38])[O:35]2)=[CH:30][CH:29]=1)=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:23])[NH2:24])=[O:15]
Reactant: [H][H]
Reactant: Cc1cc(=O)oc2cc(NC(=O)[C@H](CCCNC(=N)N)NC(=O)CNC(=O)OCc3ccccc3)ccc12
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Cc1cc(=O)oc2cc(NC(=O)[C@H](CCCNC(=N)N)NC(=O)CN)ccc12
Yield: 94.1 %

Procedure:
7-(Nα -carbobenzoxyglycyl-L-arginyl)amino-4-methylcoumarin hydrochloric acid salt (559 mg, 1 mM) was dissolved in methyl alcohol (50 ml) and palladium-carbon catalyst (50 mg) was added thereto. This mixture was stirred while being treated with hydrogen gas for 3 hours. The catalyst was removed by filtration and the thus obtained filtrate was concentrated to yield solid material. To the residue ether (50 ml) was added to yield a powder. The powder was separated by filtration and dried to give 7-(glycyl-L-arginyl)amino-4-methylcoumarin hydrochloric acid salt [II] (400 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:7]=1.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>>[F:11][C:10]([F:13])([F:12])[C:9]([NH:8][C:6]1[CH:7]=[C:2]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH:3]=[CH:4][C:5]=1[O:15][CH3:16])=[O:14]
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccc(Br)cc1NC(=O)C(F)(F)F
Product: COc1ccc(C#C[Si](C)(C)C)cc1NC(=O)C(F)(F)F
Yield: 37.9 %

Procedure:
N-[5-Bromo-2-(methyloxy)phenyl]-2,2,2-trifluoroacetamide (5.79 g, 19.4 mmol) and (trimethylsilyl)acetylene (4.1 mL, 29.1 mmol) were coupled according to the procedure of Example 56, Step B to give the desired product (2.32 g, 38%). ES-LC/MS m/z=314 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[O:22]=[C:23]1[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([NH:32][CH:33]=[O:34])[CH:29]=2)[NH:24]1>>[CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=[C:31]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([NH:32][CH:33]=[O:34])[CH:29]=2)[NH:24][C:23]1=[O:22]
Reactant: O=CNc1ccc2c(c1)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3ccc(NC=O)cc32)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Yield: 85.1 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-formamide as starting materials to give N-{3-[3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-formamide (62 mg, 85.1%) as an orange solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:23]([F:26])([F:25])[F:24])=[N:15][C:16]([C:17](=[O:22])N(OC)C)=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][Mg]Br.[Cl-].[NH4+]>O1CCCC1.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:23]([F:25])([F:26])[F:24])=[N:15][C:16]([C:17](=[O:22])[CH3:27])=[C:10]2[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)OC(C)(C)C)CC2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)OC(C)(C)C)CC2
Yield: 91.1 %

Procedure:
1-(Methoxy-methyl-carbamoyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester 27e (0.3 g, 0.79 mmol) was dissolved in 20 mL of tetrahydrofuran under stirring, and methylmagnesium bromide (1.13 mL, 1.58 mmol) was then added dropwise to the solution at 0° C. The reaction mixture was reacted at 0° C. for 1.5 hours and monitored by thin layer chromatography until the disappearance of the starting materials. 50 mL of saturated ammonium chloride and 10 mL of saturated brine were added to the reaction mixture. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic phase was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 1-acetyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester 27f (0.24 g, yield 90%) as a yellow oil.
Reaction SMILES: Cl[P:2]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:6])[O:3][CH2:4][CH3:5].[NH2:17][CH:18]1[C:24](=[O:25])[N:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:22]2[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=2[S:20][CH2:19]1.C(N(CC)CC)C>O1CCCC1>[CH2:4]([O:3][P:2]([NH:17][CH:18]1[C:24](=[O:25])[N:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:22]2[CH2:32][CH:33]=[CH:34][CH:35]=[C:21]2[S:20][CH2:19]1)([CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6])[CH3:5]
Reactant: CCOC(=O)CN1C(=O)C(N)CSc2ccccc21
Reactant: CCOP(=O)(Cl)CCCCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1C(=O)C(NP(=O)(CCCCc2ccccc2)OCC)CSC2=CC=CCC21
Reaction time: 0.33 h

Procedure:
A mixture of crude chloro (4-phenylbutyl)phosphinic acid, ethyl ester (2.44 mmole), dry tetrahydrofuran (10 ml.), and (±)-3-amino-3,4-dihydro-4-oxo-1,5-benzothiazepine-5(2H)-acetic acid, ethyl ester (0.65 g., 2.05 mmole) at 0° (ice bath) in an argon atmosphere is treated dropwise with triethylamine (0.86 ml., 3.0 eq.) in tetrahydrofuran (5 ml.) over 1 minute. After standing at 0° for 20 minutes the ice bath is removed and the reaction mixture is stirred for 16 hours. The reaction mixture is diluted with ethyl acetate and washed successively with saturated sodium bicarbonate, 5% potassium bisulfate and brine, dried (MgSO4), and evaporated. The residue (1.2 g.) is chromatographed on silica (60 g.) eluting with acetone/hexane (1:1) to give 0.8 g. of (±)-dihydro-3-[[ethoxy(4-phenylbutyl)phosphinyl]amino]-4-oxo-1,5-benzothiazepine-5(2H)-acetic acid, ethyl ester as an oil after evaporation. TLC (acetone/hexane; 2:1) two spots at Rf =0.59,0.65(isomers at phosphorus).
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH:9]([CH:11]2[CH2:13][CH2:12]2)O)=[CH:3][CH:2]=1.P(Br)(Br)[Br:16].[Br-].[Li+]>[Br-].[Zn+2].[Br-]>[C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH:9]=[CH:11][CH2:12][CH2:13][Br:16])=[CH:3][CH:2]=1
Reactant: Cc1ccc(CCC(O)C2CC2)cc1
Reactant: BrP(Br)Br
Agent: [Br-]
Agent: [Li+]
Agent: [Zn+2]
Product: Cc1ccc(CCC=CCCBr)cc1

Procedure:
6-(p-Tolyl)-3-hexenyl bromide [V; Ar is 4-CH3C6H4, R is H] was prepared from 2-(p-tolyl)ethyl cyclopropyl carbinol (Preparation B8), phosphorus tribromide, lithium bromide and zinc bromide according to the procedure given above in Preparation C1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8](=[O:13])[CH2:7][CH2:6]2.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:16][N:17](/[CH:19]=[C:9]1/[C:8](=[O:13])[CH2:7][CH2:6][C:5]2[C:10]/1=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH3:18]
Reactant: COc1ccc2c(c1)CCC(=O)C2
Reactant: COC(OC)N(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COc1ccc2c(c1)CCC(=O)/C2=C/N(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
6-methoxy-3,4-dihydronaphthalen-2(1H)-one (460 mg, 2.61 mmol) was dissolved in N,N-dimethylformamide dimethyl acetal (8 mL, 26.1 mmol) at room temperature. Within 5 minutes the solution had turned dark green in color. Next, p-toluenesulfonic acid (10 mg, 0.053 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and dried under vacuum to afford the title compound as a dark red oil. LC/MS M+1=232.2. The material was used for subsequent reactions without further purification.