Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15]([NH:17][CH2:18][CH2:19][C:20](O)=[O:21])=[O:16])[CH:13]=3)[C:8]([CH2:23][CH3:24])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:26]([O:33][NH2:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([O:33][NH:34][C:20]([CH2:19][CH2:18][NH:17][C:15]([C:12]1[CH:13]=[C:14]2[C:9]([C:8]([CH2:23][CH3:24])=[N:7][N:6]2[CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[CH:10][CH:11]=1)=[O:16])=[O:21])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCc1nn(C2CCCC2)c2cc(C(=O)NCCC(=O)O)ccc12
Reactant: NOCc1ccccc1
Agent: Cl
Product: CCc1nn(C2CCCC2)c2cc(C(=O)NCCC(=O)NOCc3ccccc3)ccc12
Yield: 71.9 %

Procedure:
This compound was prepared according to the method of Example 37, using 250 mg (0.759 mmol, 1.0 equiv) 3-[(1-cyclopentyl-3-ethyl-1H-indazole-6-carbonyl)-amino]-propionic acid and 121 mg (0.759 mmol, 1.0 equiv) O-benzylhydroxylamine hydrochloride as starting materials, to give 237 mg (72%) of a white solid: mp 134-136° C.; Anal. calcd for C25H30N4O3: C, 69.10; H, 6.96; N, 12.89. Found: C, 69.36; H, 6.75; N, 12.85.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]([C:11]2[CH:12]=[C:13]([C:28](O)=[O:29])[CH:14]=[C:15]3[C:20]=2[O:19][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:17][C:16]3=[O:27])[CH3:10])=[CH:4][CH:3]=1.[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][NH:35][CH3:36]>>[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][N:35]([CH3:36])[C:28]([C:13]1[CH:14]=[C:15]2[C:20](=[C:11]([CH:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH3:10])[CH:12]=1)[O:19][C:18]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[CH:17][C:16]2=[O:27])=[O:29]
Reactant: CC(Nc1ccc(F)cc1)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: CNCCN(C)C
Product: CC(Nc1ccc(F)cc1)c1cc(C(=O)N(C)CCN(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 15.9 %

Procedure:
8-(1-(4-fluorophenylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (80 mg, 0.19 mmol) was reacted with N1,N1,N2-trimethylethane-1,2-diamine (0.030 mL, 0.23 mmol) using a procedure similar to the one described in Example 2.00 to afford N-(2-(dimethylamino)ethyl)-8-(1-(4-fluorophenylamino)ethyl)-N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (15.0 mg, 15.6%) as a white solid. Mass Spectrum: M+H+ 497. NMR Spectrum: (DMSOd6) 1.49 (d, 3H), 1.74 (bs, 3H), 2.01 (bs, 1H), 2.18 (s, 3H), 2.66 (bs, 1.5H), 2.89 (bs, 2H), 3.05 (bs, 1.5H), 3.47 (bs, 1H), 3.50-3.64 (m, 4H), 3.71-3.79 (m, 4H), 4.93-5.01 (m, 1H), 5.59 (s, 1H), 6.29 (bs, 1H), 6.46 (dd, 2H), 6.84 (dd, 2H), 6.54 (d, 1H), 6.73 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:12])([CH3:11])[CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.[F:13][C:14]([F:30])([F:29])[C:15]1[O:19][N:18]=[C:17]([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=2)[C:23](O)=[O:24])[N:16]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:12])([CH3:11])[CH2:9][NH:10][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][CH:28]=[C:20]([C:17]3[N:16]=[C:15]([C:14]([F:30])([F:29])[F:13])[O:19][N:18]=3)[CH:21]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(CN)c1cccc(Br)c1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: CC(C)(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1cccc(Br)c1
Yield: 83 %

Procedure:
This compound was synthesized from 2-(3-bromophenyl)-2-methylpropan-1-amine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (90 mg, yield 83%). MS (ESI) m/z: Calculated for C20H17BrF3N3O2: 467.05. found: 468.0 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH3:40][O:41][C:42]1[C:43]([CH3:70])=[C:44]([C:61]([O:68][CH3:69])=[C:62]([O:66][CH3:67])[C:63]=1[O:64][CH3:65])[CH2:45][C:46]1[CH:47]=[CH:48][C:49](O)=[C:50]([CH:59]=1)[C:51]([N:53]1[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1)=[O:52].[OH-].[Na+]>C1C=CC=CC=1>[CH3:40][O:41][C:42]1[C:43]([CH3:70])=[C:44]([C:61]([O:68][CH3:69])=[C:62]([O:66][CH3:67])[C:63]=1[O:64][CH3:65])[CH2:45][C:46]1[CH:47]=[CH:48][C:49]([O:8][CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[C:50]([CH:59]=1)[C:51]([N:53]1[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1)=[O:52]
Reactant: COc1c(C)c(Cc2ccc(O)c(C(=O)N3CCCCC3)c2)c(OC)c(OC)c1OC
Reactant: OCc1ccncc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: COc1c(C)c(Cc2ccc(OCc3ccncc3)c(C(=O)N3CCCCC3)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.6 %

Procedure:
4-Pyridinemethanol (0.254 g, 2.33 mmol), triphenylphosphine (0.611 g, 2.33 mmol) and diethylazodicarboxylate (0.406 g, 2.33 mmol) were added to a benzene solution (30 ml) of N-[5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-hydroxybenzoyl]piperidine (0.500 g, 1.17 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into an aqueous 2N sodium hydroxide solution (15 ml) and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=1:5) to obtain the titled compound (0.375 g, 0.721 mmol, 62%).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19][C:20]([F:23])([F:22])[F:21])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35](O)=[O:36])=[CH:27][CH:26]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35]([NH:1][CH:2]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19][C:20]([F:23])([F:22])[F:21])[CH:14]=2)[CH:3]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)[OH:4])=[O:36])=[CH:27][CH:26]=1
Reactant: NC(Cc1cccc(SC(F)(F)F)c1)C(O)c1ccc(F)cc1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1cccc(SC(F)(F)F)c1)C(O)c1ccc(F)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-{3-[(trifluoromethyl)thio]phenyl}propan-1-ol (450 mg, 1.51 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (287 mg, 1.51 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (435 mg, 2.27 mmol) and 1-hydroxybenzotriazole hydrate (231 mg, 1.51 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-ethyl acetate). Recrystallization from ethyl acetate-hexane gave the objective substance (447 mg, 57%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][OH:13])=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:27])[C:24]([CH3:26])=[CH2:25]>C(Cl)Cl.C(OCC)C>[C:23]([O:13][CH2:12][C:11]1[CH:10]=[CH:9][C:8]([O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:15][CH:14]=1)(=[O:27])[C:24]([CH3:26])=[CH2:25]
Reactant: C=C(C)C(=O)Cl
Reactant: OCc1ccc(OC2CCCCO2)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: C=C(C)C(=O)OCc1ccc(OC2CCCCO2)cc1
Reaction time: 3.5 h
Yield: 8.8 %

Procedure:
To a stirred solution of 62.4 g (0.3 mol) of 4-tetrahydropyranyloxy benzyl alcohol and 58.5 mL of triethylamine in 225 mL of methylene chloride and 225 mL of diethyl ether cooled in an ice bath was added dropwise 31.9 mL (0.33 mol) of methacrylyl chloride at a rate such that the temperature did not exceed 30° C. After 3.5 hr, the mixture was filtered, and the filtrate was evaporated. The residual oil was treated with ether and triethylamine and washed with water. The organic layer was dried (sodium sulfate) and evaporated to a yellow oil, which, on standing, gradually crystallized. The crystals were rinsed with a small amount of methanol to give 7.3 g of colorless crystals, m.p. 36-36.7° C. The product can be recrystallized from hexane at low temperature. 1H NMR (360 MHz, THF-d8): 1.5-1.82 (m's, 6H, CH2), 1.90 (m, 3H, CH3C=), 3.5 (m, 1H, OCH 2), 3.8 (m, 1H, OCH2), 5.07 (s, 2H, ArCH2OOC), 5.40 (t, J=3, 1H, OCHO), 5.52 (m, 1H, =CH), 6.05 (m, 1H, =CH), 7.0 (m, 2H, ArH), 7.27 (m, 2H, ArH).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9]([C:11]1([CH2:24][CH2:25][CH2:26][CH2:27]Br)[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:10].[N:29]1([C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9]([C:11]1([CH2:24][CH2:25][CH2:26][CH2:27][N:32]2[CH2:33][CH2:34][N:29]([C:35]3[CH:44]=[CH:43][C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[N:36]=3)[CH2:30][CH2:31]2)[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:10]
Reactant: O=C(NCc1ccccn1)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Product: O=C(NCc1ccccn1)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(pyridin-2-ylmethyl)-amide and 2-piperazin-1-yl-quinoline.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]([Cl:25])[N:17]=1>C(O)C>[Cl:25][C:18]1[N:17]=[C:16]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cl)nc1Nc1ccccc1

Procedure:
A mixture of aniline (7.24 g, 78 mmol), triethylamine (13 mL, 93 mmol), and 2,6-dichloro-3-nitropyridine (15 g, 78 mmol) was stirred overnight in 500 mL ethanol at room temperature under nitrogen. The solid that formed was filtered off, washed with water and ethanol, and dried. The solid was purified by column chromatography eluting with 20% ethyl acetate/hexane (8.62 g, 44%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=O)=[CH:5][CH:4]=1.[NH2:14][OH:15]>CO.CC(O)=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[N:14][OH:15])=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc2c(c1)C(=O)CCC2
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc2c(c1)C(=NO)CCC2
Reaction time: 1 h

Procedure:
To a solution of 7-methoxytetralone (15 g) in MeOH (175 mL), NH2OH (50% in H2O, 15.7 mL) and AcOH (4 mL) was added. After stirring for 1 hour, the solution was concentrated until a solid began to appear. The reaction was poured into dilute aqueous NaHCO3 (500 mL), and the resulting solid was filtered to provide the title compound (17.8 g): 1H NMR (DMSO-d6) δ 11.08 (s, 1H), 7.35 (s, 1H), 7.08 (d, 1H), 6.84 (d, 1H), 3.71 (s, 3H), 2.62-2.49 (m, 4H), 1.77-1.64 (m, 2H).
Reaction SMILES: [C:1]([OH:5])(C)([CH3:3])[CH3:2].[CH2:6]([C:8]1[CH:9]=[CH:10]C(C=C)=[N:12][CH:13]=1)[CH3:7].BrN1C(=O)CCC1=O.[OH-].[Na+]>O>[CH2:9]([C:8]1[CH:6]=[CH:7][C:2]([CH:1]2[CH2:3][O:5]2)=[N:12][CH:13]=1)[CH3:10]
Reactant: CC(C)(C)O
Reactant: C=Cc1ccc(CC)cn1
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1ccc(C2CO2)nc1
Reaction time: 1 h
Yield: 92 %

Procedure:
To a mixture of 750 mL tert-butanol and 2250 mL water, 200 g (1.488 mol) of 5-ethyl-2-vinyl-pyridine was dissolved and under stirring 324 g (1.786 mol) N-bromosuccinimide was added in 30 min. at 25-30° C. Stirring was continued for 1 hr. and 178.6 g (4.46 mol) of NaOH dissolved in 2250 mL water was added into it. Reaction mixture was stirred for 45 min. Product was extracted twice with 1100 mL methyl tert-butyl ether. Organic layers were combined, washed with brine, dried over magnesium sulfate and concentrated in vacuo to yield 206.13 g (92%) of 6.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][CH:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH2:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:28](=O)[CH2:29][CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH2:17]2)[CH2:28][CH2:29][CH3:30])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc2c(c1)CC(NCC1CCN(C(=O)OC(C)(C)C)CC1)CC2
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCN(CC1CCN(C(=O)OC(C)(C)C)CC1)C1CCc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 102.9 %

Procedure:
To a solution of 4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (2.1 g, 5.6 mmol) and propionaldehyde (0.45 mL, 6.23 mmol) in dichloroethane (20 mL) under a nitrogen atmosphere was added sodium triacetoxyborohydride (3.09 g, 14.15 mmol, 2.5 eq.) in a single portion. The reaction was stirred at room temperature for 24 h then concentrated in vacuo. The residue was partitioned between EtOAc (75 mL) and 5% aq. KOH (50 mL). The aqueous phase was extracted twice more with EtOAc (2×30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated onto silica (10 kg). This was placed on top of a flash column and eluted with 20% acetone in hexanes. The fractions containing product were pooled and concentrated to afford 4-{[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (2.4 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[C:18]1[C:22]([CH3:23])=[CH:21][S:20][CH:19]=1)[C:12]([OH:14])=O.O[N:25]=[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35])[NH2:27].CCN(C(C)C)C(C)C>>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:12]2[O:14][N:27]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])[N:25]=2)[CH:15]=[CH:16][C:17]=1[C:18]1[C:22]([CH3:23])=[CH:21][S:20][CH:19]=1
Reactant: COc1cc(C(=O)O)ccc1-c1cscc1C
Reactant: COc1ccccc1C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1noc(-c2ccc(-c3cscc3C)c(OC)c2)n1

Procedure:
Oxalyl chloride (120 μL; 1.45 mmol; 3 eq.), Intermediate 29 (120 mg; 0.48 mmol; 1 eq.), Intermediate 1 (80 mg; 0.48 mmol, 1 eq.) and DIEA (250 μL; 1.45 mmol; 3 eq.) were reacted according to general procedure 2. Purification by precipitation from DCM/n-pentane afforded the title compound as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:36][C:37]1[CH:42]=[C:41]([F:43])[C:40]([F:44])=[CH:39][C:38]=1[F:45])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:32]([F:35])([F:34])[F:33])=[N:19][C:20]([C:21]([N:23]3[CH2:28][CH2:27][CH:26]([C:29](=[O:31])[NH2:30])[CH2:25][CH2:24]3)=[O:22])=[C:14]2[CH2:13]1)=[O:11])(C)(C)C.[ClH:47]>C(OCC)(=O)C>[ClH:47].[NH2:7][C@H:8]([CH2:36][C:37]1[CH:42]=[C:41]([F:43])[C:40]([F:44])=[CH:39][C:38]=1[F:45])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:32]([F:35])([F:34])[F:33])=[N:19][C:20]([C:21]([N:23]3[CH2:28][CH2:27][CH:26]([C:29]([NH2:30])=[O:31])[CH2:25][CH2:24]3)=[O:22])=[C:14]2[CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCC(C(N)=O)CC3)c2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Product: NC(=O)C1CCN(C(=O)c2nc(C(F)(F)F)n3c2CN(C(=O)C[C@H](N)Cc2cc(F)c(F)cc2F)CC3)CC1
Yield: 74 %

Procedure:
(R)-[3-[1-(4-Carbamoyl-piperidine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 7a (0.18 g, 0.27 mmol) and 2 mL of ethyl acetate were added into the reaction flask. A solution of 2.3 N hydrochloric acid in 6 mL of ethyl acetate was then added to the flask. The reaction mixture was reacted at room temperature for 3.5 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure to obtain the title compound (R)-1-{7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carbonyl}-piperidine-4-carboxylic acid amide hydrochloride 7 (0.12 g, yield 74%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][C:11](=O)[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14].Cl.[Br:21][C:22]1[CH:23]=[C:24]([NH:28][NH2:29])[CH:25]=[CH:26][CH:27]=1>C(O)(=O)C>[Br:21][C:22]1[CH:23]=[C:24]([N:28]2[CH:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[CH2:10][C:11]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])=[N:29]2)[CH:25]=[CH:26][CH:27]=1
Reactant: NNc1cccc(Br)c1
Reactant: O=C(C=Cc1ccc(F)cc1F)C(F)(F)C(F)(F)F
Agent: Cl
Solvent: CC(=O)O
Product: Fc1ccc(C2CC(C(F)(F)C(F)(F)F)=NN2c2cccc(Br)c2)c(F)c1
Temperature: 95 °C
Reaction time: 5 h
Yield: 35.1 %

Procedure:
1-(2,4-Difluoro-phenyl)-4,4,5,5,5-pentafluoro-pent-1-en-3-one (4.8 g, 16.9 mmol) prepared in Step 3 and 3-bromophenylhydrazine hydrochloride (4.2 g, 18.6 mmol) were added to acetic acid (50.0 mL). The reaction mixture was stirred at 95° C. for 5 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The mixture was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane) to give 2.7 g of the titled compound as a yellow liquid.
Reaction SMILES: Cl[CH:2]([C:7]1[O:8][C:9]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:10]=2[C:11]=1[CH3:12])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])=[CH:22][CH:21]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].Cl>CN(C)C=O>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:9]2[O:8][C:7]([CH:2]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])=[CH:24][CH:25]=3)[CH2:3][CH:4]([CH3:6])[CH3:5])=[C:11]([CH3:12])[C:10]=2[CH:13]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Reactant: COc1ccc2oc(C(Cl)CC(C)C)c(C)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)c1ccc(NC(CC(C)C)c2oc3ccc(OC)cc3c2C)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 40 %

Procedure:
A mixture of 2-(1-chloro-3-methylbutyl)-5-methoxy-3-methyl-1-benzofuran (380 mg) synthesized above, ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (350 mg) synthesized in Example 1(2), sodium iodide (443 mg), sodium carbonate (314 mg) and N,N-dimethylformamide (10 mL) was stirred at 80° C. for 5 hr. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane) to give the title object compound (266 mg, 40%) as a yellow oil.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][C:11](=O)[CH2:12]2)=[CH:7][CH:6]=1>CCOCC.CCCCC.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][NH:2][C:11]1[CH2:10][CH2:9][C:8]2[C:13](=[CH:14][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[CH:12]=1
Reactant: COc1ccc2c(c1)CC(=O)CC2
Reactant: CN
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOCC
Solvent: CCCCC
Product: CNC1=Cc2cc(OC)ccc2CC1
Reaction time: 0.5 h

Procedure:
This compound was prepared according to the procedure described by Evans, et al., J. Org. Chem. 35, 4122 (1970) as follows. Into a dry, nitrogen purged, 500 ml, 3-neck flask fitted with mechanical stirrer, dropping funnel and nitrogen inlet tube was added a solution of 14.3 g (460 mmole) methylamine in anhydrous ether (100 ml) and a solution of 20.0 g (113.5 mmole) 7-methoxy-2-tetralone in same solvent (100 ml) and the solution was placed under a slow stream of nitrogen and cooled to -18° (ice-methanol). A solution of 11.56 g (61 mmole) titanium tetrachloride in pentane (50 ml) was added dropwise with stirring over 30 min period. After the addition, the reaction mixture was stirred at room temperature for 1 hr and then fast filtered. The solid residue was washed with ether (50 ml) and the filtrate and washings were combined. Removal of the solvent in vacuo gave 20.6 g (96%) of XIId as an oxygen-sensitive oil which crystallized on standing; IR (neat), 3430 (NH), 1630 cm-1 (C=C--N); NMR δ, 2.15 (m, 2, benzylic), 2.55 (m, 2, allylic), 2.70 (s, 3, NCH3), 3.15 (broad, NH), 3.70 (s, 3, OCH3), 5.13 (s, 1, C-1H), 6.25-6.90 (m, 3, ArH).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[NH:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:20]#[N:21])[C:14]=2[CH:13]=[CH:12]1.[H-].[Na+].CN(C=O)C>O>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([C:20]#[N:21])[C:14]=3[CH:13]=[CH:12]2)=[CH:4][CH:5]=1
Reactant: N#Cc1cccc2[nH]ccc12
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ccc3c(C#N)cccc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.4 %

Procedure:
1-(Chloromethyl)-4-methoxybenzene (30.3 g, 193 mmol) was added to a slurry of 1H-indole-4-carbonitrile (25.0 g, 176 mmol) and NaH (7.74 g, 193 mmol) in DMF (586 mL, 176 mmol) at 0° C., and the resulting mixture was stirred at ambient temperature for 24 hours. The reaction mixture was poured into water and extracted with ethyl acetate (3×). The combined organic layers were washed with water and brine, dried (Na2SO4) and concentrated to afford a crude residue, which was purified by column chromatography eluting with an ethyl acetate/hexanes gradient to give 1-(4-methoxybenzyl)-1H-indole-4-carbonitrile (46.0 g, 175 mmol, 99%). 1H NMR (400 MHz, CDCl3) 7.89 (d, J=8.2 Hz, 1H), 7.81 (d, J=3.1 Hz, 1H), 7.54 (d, J=7.4 Hz, 1H), 7.26 (t, J=7.8 Hz, 1H), 7.21 (d, J=8.6 Hz, 2H), 6.87 (d, J=8.6 Hz, 2H), 6.64 (d, J=2.7 Hz, 1H), 5.44 (s, 2H), 3.70 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH3:10])[C:3](=O)[CH2:4][CH2:5][C:6](O)=[O:7].[NH2:11][NH2:12]>C(O)C>[CH:2]([C:3]1[CH2:4][CH2:5][C:6](=[O:7])[NH:11][N:12]=1)([CH3:10])[CH3:1]
Reactant: CC(C)C(=O)CCC(=O)O
Reactant: NN
Solvent: CCO
Product: CC(C)C1=NNC(=O)CC1

Procedure:
5-Methyl-4-oxohexanoic acid (3.60 g, 25.0 mmol) and anhydrous hydrazine (0.80 g, 26.0 mmol) were heated for 3 hours in ethanol (36.0 ml) under stirring. After the reaction solution was concentrated under reduced pressure, hexane was added to the residues to precipitate crystals, and the crystals were collected by filtration to give 4,5-dihydro-6-isopropyl-3(2H)-pyridazinone as crystals. The yield was 3.10 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:15]([O-:17])=[O:16])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[N:10]=[CH:9]1.N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>>[F:1][C:2]1[CH:3]=[C:4]([N+:15]([O-:17])=[O:16])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH2:13][O:14][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[N:10]=[CH:9]1
Reactant: O=[N+]([O-])c1ccc(-n2cnc(CO)c2)c(F)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Product: CC(C)(C)[Si](C)(C)OCc1cn(-c2ccc([N+](=O)[O-])cc2F)cn1
Reaction time: 0.5 h

Procedure:
3-Fluoro-4-(4-hydroxymethylimidazol-1-yl)nitrobenzene (26.7 g) and imidazole (15.3 g) were suspended in dry N,N-dimethylformnamide (190 ml) and stirred under argon on an ice-bath. t-Butyldimethylsilylchloride (25.5 g) was added in one portion, and stirring continued at ice temperature for 30 minutes, then at ambient temperature overnight. Solvent was evaporated in vacuo at 30° C., the residue diluted with water (200 ml) and extracted into ethyl acetate (700 ml). After washing with water (2×300 ml), brine, and drying over magnesium sulfate, solvent was evaporated (finally on high vacuum) to give an oil which solidified (39.2 g). This was used in the next stage with no further purification.