Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[N:14]([C:15](=[O:25])[C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH:12]1[CH2:26][CH2:27][C:9]2(OCC(O)=O)[CH2:10][CH2:11]1)=[O:5])[CH3:2].F[P-](F)(F)(F)(F)F.N1([O:49][C:50](N(C)C)=[N+:51]([CH3:53])[CH3:52])C2N=CC=CC=2N=N1.C1C[O:60][CH2:59]C1.CNC>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:13]2[N:14]([C:15](=[O:25])[C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:8][CH:9]1[CH2:10][CH2:11][C:12]2([O:60][CH2:59][C:50](=[O:49])[N:51]([CH3:53])[CH3:52])[CH2:26][CH2:27]1)=[O:5])[CH3:2]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC1CCC2(OCC(=O)O)CC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC1CCC2(OCC(=O)N(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a solution of 5-benzyloxy-1-carboxymethoxy-6-oxo-3,7-diazatricyclo[7.2.2.02,7]trideca-2,4-diene-4-carboxylic acid ethyl ester (25 mg, 0.057 mmol) in DMF (1 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (43 mg, 0.11 mmol) and 4-(dimethylamino)pyridine (DMAP) (14 mg, 0.11 mmol) and the mixture stirred at room temperature for 15 min under N2. To this was added a 2M THF solution of dimethylamine (0.057 mL, 0.11 mmol) and the mixture stirred at room temperature for 90 min. The mixture was concentrated and the residue taken up in ethyl acetate (10 mL), washed with 1N HCl followed by brine, then dried (Na2SO4) and concentrated to provide the title compound (36 mg, 0.057 mmol, 100% yield) as a crude amber film: HPLC: retention time=2.15 min; LCMS: m/z 470 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 1.23 (3H, t, J=6.6 Hz), 1.65-1.76 (2H, m), 1.88-2.01 (2H, m), 2.11-2.26 (4H, m), 2.46 (1H, brs), 2.90 (3H, s), 2.95 (3H, s), 4.10 (2H, t, J=7.0 Hz), 4.23-4.33 (4H, m), 5.24 (2H, s), 7.27-7.38 (3H, m), 7.46 (2H, d, J=7.0 Hz).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([C:15]4[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][C:16]=4[CH3:23])[CH:11]=[C:10]([C:24]([NH:26][CH2:27][C:28]4[C:29](=[O:36])[NH:30][C:31]([CH3:35])=[CH:32][C:33]=4[CH3:34])=[O:25])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)=[CH:17][C:16]=4[CH3:23])[CH:11]=[C:10]([C:24]([NH:26][CH2:27][C:28]4[C:29](=[O:36])[NH:30][C:31]([CH3:35])=[CH:32][C:33]=4[CH3:34])=[O:25])[C:9]=3[CH:8]=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)cc3C)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)cc3C)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34 %

Procedure:
To a stirred solution of 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(4-formyl-2-methylphenyl)-1H-indazole-4-carboxamide (0.15 g, 0.31 mmol) in methanol (5 mL), morpholine (0.081 g, 0.93 mmol) and acetic acid (0.01 g, 0.311 mmol) were added at room temperature and reaction stirred at room temperature for 18 h. Then NaBH3CN (0.023 g, 0.37 mmol) was added and reaction stirred again at room temperature for 18 h. On completion, methanol was removed under reduced pressure and water added to the residue. The aqueous phase was extracted with 10% MeOH/DCM and the combined organic layers dried over sodium sulfate and concentrated to obtain crude material which was purified by column chromatography to afford 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(2-methyl-4-(morpholinomethyl)phenyl)-1H-indazole-4-carboxamide (34% yield). LCMS: 554.30 (M+1)+; HPLC: 95.54% (@ 254 nm) (Rt; 5.595); 1H NMR (DMSO-d6, 400 MHz) δ 11.49 (s, 1H), 8.52 (t, 1H), 8.38 (s, 1H), 7.78 (s, 1H), 7.54 (s, 1H), 7.02-7.28 (m, 3H), 5.86 (s, 1H), 5.22-5.26 (m, 1H), 4.34 (d, 2H, J=4.4 Hz), 3.58 (t, 4H), 3.47 (s, 2H), 2.37 (s, 4H), 2.25 (s, 3H), 2.18 (s, 3H), 2.09-2.06 (m, 2H), 2.09 (s, 3H), 1.98-2.03 (m, 2H), 1.86 (m, 2H), 1.66-1.69 (m, 2H).
Reaction SMILES: C(O)C.C(Cl)(Cl)Cl.[C:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:19][N:18]=2)=[CH:13][CH:12]=1)(=[O:10])[CH3:9].[BH4-].[Na+]>O>[OH:10][CH:8]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:19][N:18]=2)=[CH:15][CH:16]=1)[CH3:9]
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(C(C)=O)cc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCOc1cnc(-c2ccc(C(C)O)cc2)nc1
Reaction time: 4 h
Yield: 99.9 %

Procedure:
To a mixed solvent of 200 ml of ethanol and 100 ml of chloroform were added 35.5 g (0.1 mole) of 2-(4-acetylphenyl)-5-decyloxypyrimidine, and while maintaining the temperature at 30° to 35° C., 2.65 g (0.07 mole) of sodium borohydride were gradually added thereto. After stirring at the same temperature for 4 hours, the reaction mixture was poured into 500 ml of water and extracted with 400 ml of ethyl acetate. The organic phase was washed sufficiently, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 35.6 g (yield: 99.9 %) of 2-{4-(1-hydroxyethyl)phenyl}-5-decyloxypyrimidine.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=CC=1CC(OCC)=O)(=[O:4])=[O:3].C([N:21]=[C:22]=[O:23])CCC>>[CH2:5]([S:2]([NH:1][C:22]([NH2:21])=[O:23])(=[O:3])=[O:4])[CH2:10][CH2:9][CH3:8]
Reactant: CCOC(=O)Cc1ccccc1S(N)(=O)=O
Reactant: CCCCN=C=O
Product: CCCCS(=O)(=O)NC(N)=O

Procedure:
Following the procedure of Example 1, ethyl o-aminosulfonylbenzeneacetate was reacted with n-butyl isocyanate to form the N-(n-butyl)sulfonylurea derivative; m.p. 140°-142°.
Reaction SMILES: [CH:1]1([C:4](=[O:20])[CH2:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[C:9]=2[S:16]([CH3:19])(=[O:18])=[O:17])=[O:7])[CH2:3][CH2:2]1.[CH:21](OCC)(OCC)[O:22][CH2:23][CH3:24]>C(OC(=O)C)(=O)C>[CH:1]1([C:4](=[O:20])[C:5](=[CH:21][O:22][CH2:23][CH3:24])[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[C:9]=2[S:16]([CH3:19])(=[O:18])=[O:17])=[O:7])[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1c(C(=O)CC(=O)C2CC2)ccc(F)c1F
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)c1ccc(F)c(F)c1S(C)(=O)=O)C(=O)C1CC1
Yield: 112.1 %

Procedure:
A mixture of 3-cyclopropyl-1-(3,4-difluoro-2-methylsulphonylphenyl)propane-1,3-dione (0.85 g) and triethyl orthoformate (1.04 g) in acetic anhydride was stirred and heated at reflux for 4 hours. It was evaporated to dryness and the residue was treated with toluene and re-evaporated to give 3-cyclopropyl-1-(3,4-difluoro-2-methylsulphonylphenyl)-2-ethoxy methylenepropane-1,3-dione (1.13 g) as a brown oil which was not purified further.
Reaction SMILES: [CH:1]1([NH2:11])[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.[CH2:12](N(CC)CC)C.Br[CH2:20][C:21]([O:23]C)=[O:22]>CCCCCC>[CH3:12][N:11]([CH:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1)[CH2:20][C:21]([OH:23])=[O:22]
Reactant: COC(=O)CBr
Reactant: CCN(CC)CC
Reactant: NC1CCCC2CCCCC12
Solvent: CCCCCC
Product: CN(CC(=O)O)C1CCCC2CCCCC21
Reaction time: 24 h

Procedure:
To a stirred solution of 203 parts of decahydro-1-naphthalenamine and 161 parts of N,N-diethylethanamine in 40 parts of hexane were added dropwise 122 parts of methyl bromoacetate. Upon complete addition, stirring was continued for 24 hours at room temperature. The precipitate was filtered off and the filtrate was concentrated to dry, yielding methyl N-(decahydro-1-naphthalenyl)glycine (intermediate 5).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:13])[CH2:11][Cl:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]([O:18][CH2:19]OC)(=[O:17])[CH2:15][CH3:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCCCCC>[CH2:1]([O:8][CH2:9][CH:10]([O:13][CH2:19][O:18][C:14](=[O:17])[CH2:15][CH3:16])[CH2:11][Cl:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(CCl)COCc1ccccc1
Reactant: CCC(=O)OCOC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCCCCC
Product: CCC(=O)OCOC(CCl)COCc1ccccc1

Procedure:
204.0 g of 3-benzyloxy-1-chloro-2-propanol, 660 ml of hexane, 626.3 g of methoxymethyl propionate and 5.79 g of p-toluenesulfonic acid mono-hydrate were placed into a 2-liter 3-neck round bottom flask equipped with a thermometer, mechanical stirrer, nitrogen inlet and an efficient distillation column. The reaction mixture was heated to reflux. The distillate was taken off at about 10:1 to 15:1 reflux ratio keeping the head temperature below 60° C. Samples were taken to monitor the progress of the reaction. The reaction was quenched when the desired level of methyl acetal was reached which is usually less than about 4% methyl acetal. The quench was carried out by rapidly adding a solution of 11.55 g of sodium carbonate in 310 ml of water directly to the hot reaction mixture. The aqueous layer was washed with additional water and/or base to remove any residual propionic acid. The volatiles were removed to leave the crude product as a mobile liquid. Yield: 285.2 g, (97.8%); 92.6% pure.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([CH:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][C:18]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([N:31]=[C:32]=[O:33])[CH:26]=4)=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:34][C:35]1([CH3:42])[O:39][C@@H:38]([CH2:40][OH:41])[CH2:37][O:36]1.N1C=CC=CC=1>C1COCC1.CCOC(C)=O.CC1(C)O[C@@H](CO)CO1>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([CH:14]2[CH2:15][C:16]3[CH:17]=[C:18]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:33])[O:41][CH2:40][C@H:38]5[CH2:37][O:36][C:35]([CH3:42])([CH3:34])[O:39]5)[CH:26]=4)[CH:19]=[CH:20][C:21]=3[CH2:22][CH2:23]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC[C@H](CO)O1
Reactant: CC(C)(C)c1cccc(NC(=O)C2CCc3ccc(Oc4ccnc(N=C=O)c4)cc3C2)c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)OC[C@H](COC(=O)Nc2cc(Oc3ccc4c(c3)CC(C(=O)Nc3cccc(C(C)(C)C)c3)CC4)ccn2)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
A solution of N-(3-tert-butylphenyl)-7-[(2-isocyanatopyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalene-2-carboxamide (250 mg, 0.56 mmol), [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol (150 mg, 1.13 mmol) and pyridine (0.091 mL, 1.13 mmol) in THF (10 mL) was allowed to stir at rt. After 2 h, additional pyridine (0.14 mL) and [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol (0.220 mg) were added. The reaction mixture was heated at 70° C. overnight and then another portion of pyridine (0.10 mL) and [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol (0.150 mg g) were added. Heating continued for an additional 2 h and then the reaction mixture was subjected to MWI at 135° C. for 5 min. The reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give [(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl {4-[(7-{[(3-tert-butylphenyl)amino]carbonyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-oxy]pyridin-2-yl}carbamate (290 mg, 89%) as a white solid. LCMS: (FA) ES+574.4.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].Cl.[NH2:6][C@H:7]([CH:26]([CH3:28])[CH3:27])[C:8]([N:10]1[CH2:15][CH2:14][C@@:13]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)([OH:16])[C:12]([CH3:25])([CH3:24])[CH2:11]1)=[O:9].C1COCC1>C(N(CC)CC)C>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C@@:13]2([OH:16])[CH2:14][CH2:15][N:10]([C:8](=[O:9])[C@H:7]([NH:6][C:3]([NH:2][CH3:1])=[O:4])[CH:26]([CH3:28])[CH3:27])[CH2:11][C:12]2([CH3:24])[CH3:25])=[CH:22][CH:21]=1
Reactant: CC(C)[C@@H](N)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Reactant: CN=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)N[C@@H](C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction tube was charged with methyl isocyanate (3 μL), (R)-2-amino-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methylbutan-1-one hydrochloride (20 mg) and THF (2 mL). Triethylamine (7.4 μL) was added and the reaction mixture was shaken overnight at rt. After this time, the resulting solution concentrated and purified by preparative silica gel chromatography (100% EtOAc to 20% MeOH/CH2Cl2) to provide Example 510. MS found: (M+H)+=396.3.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=1)(=[O:25])=[O:24].[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][NH2:41])[CH:35]=1>>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:41][CH2:40][C:36]3[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=3)=[O:19])=[CH:20][CH:21]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=1)(=[O:24])=[O:25]
Reactant: COc1cccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)c1
Reactant: NCc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Product: COc1cccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)NCc4cccnc4)cc3)oc2C)c1
Yield: 25.9 %

Procedure:
Method E. Reaction of oxalyl chloride (50 λL, 0.57 mmol) and benzoic acid 38 (146 mg, 0.38 mmol) with subsequent coupling to 3-pyridinylmethylamine (43 λL, 0.42 mmol) gave benzamide 39 (47 mg, 26%) as a white powder: mp (EtOAc) 143-145° C.; 1H NMR δ 9.23 (t, J=5.8Hz, 1 H, CONH), 8.56 (d, J=1.6Hz, 1 H, H-2′), 8.46 (dd, J=4.7, 1.4Hz, 1 H, H-6′), 8.00 (br d, J=8.5Hz, 2 H, H-2, H-6), 7.91 (br d, J=8.5Hz, 2 H, H-3, H-5), 7.74 (br d, J=7.9Hz, 1 H, H-4′), 7.53 (br dd, J=8.9, 7.6Hz, 1 H, H-5″), 7.34-7.39 (m, 2H, H-5′, H-2″), 7.25-7.29 (m, 2 H, H-4″, H-6″), 4.70 (s, 2 H, CH2SO2), 4.51 (d, J=5.8Hz, 2 H, CH2N), 3.79 (s, 3 H, OCH3), 2.17 (s, 3 H, CH3); 13C NMR δ 165.5, 159.4, 158.0, 150.1, 148.9, 148.1, 139.7, 135.4, 135.2, 134.9, 130.4, 128.8, 128.1 (2), 125.9, 125.4 (2), 123.5, 120.3, 120.1, 112.8, 55.6, 52.7, 40.5, 9.7; MS m/z 478.6 (WE, 100%). Anal. calcd for C25H23N3O5S.½CH3OH: C, 62.06, 5.11; N, 8.51. Found: C, 62.23; H, 4.90; N, 8.66%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:11][C:12](C)([O-])C.[K+].I[C:18]1[CH:19]=[CH:20][C:21]2[N:22]([CH:24]=[C:25]([NH:27][C:28](=[O:30])[CH3:29])[N:26]=2)[N:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[O:10][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([CH:24]=[C:25]([NH:27][C:28]([CH:29]3[CH2:12][CH2:11]3)=[O:30])[N:26]=2)[N:23]=1
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc(O)cc1N
Reactant: CC(=O)Nc1cn2nc(I)ccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Yield: 125.6 %

Procedure:
Using 3-amino-4-methoxyphenol (408 mg, 2.93 mmol), N,N-dimethylformamide (16 mL), potassium tert-butoxide (343 mg, 3.05 mmol), N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)acetamide (800 mg, 2.44 mmol) and potassium carbonate (169 mg, 1.22 mmol), and in the same manner as in Example 216, the title compound (1.04 g, 42%) was obtained as a brown powder.
Reaction SMILES: [CH3:1][C:2]1[CH2:6][CH:5]=[C:4]([CH3:7])[CH:3]=1.[CH2:8]([C:10]1[CH2:14][CH:13]=[CH:12][CH:11]=1)[CH3:9].O.[Ru:16](Cl)(Cl)Cl>C(O)C.[Zn]>[CH3:7][C:4]1([Ru:16][C:10]2([CH2:8][CH3:9])[CH:14]=[CH:13][CH:12]=[CH:11]2)[CH:5]=[CH:6][C:2]([CH3:1])=[CH:3]1
Reactant: Cl[Ru](Cl)Cl
Reactant: CCC1=CC=CC1
Reactant: CC1=CCC(C)=C1
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: CCC1([Ru]C2(C)C=CC(C)=C2)C=CC=C1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
In an argon atmosphere, 3.0 mL of 1,3-dimethylcyclopentadiene and 3.0 mL of ethylcyclopentadiene were added to a solution prepared by dissolving 0.51 g of ruthenium chloride hydrate in 40 mL of ethanol. Thereafter, 4.1 g of a zinc powder was added thereto. The mixture was stirred at 70° C. for 3 hours. The solvent was distilled off under vacuum, and hexane was added to the residue. The insoluble matter was removed by filtration, and the solvent was thereafter distilled off under vacuum. The resultant residue was distilled and then separated with an alumina column. Thus, 0.24 g of a yellow liquid was obtained (yield, 43%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O=C1[N:44](P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.C(=O)([O-])[O-].[NH4+].[NH4+]>O1CCCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](=[O:23])[NH2:44])=[C:15]2[CH2:14]1)=[O:12])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(N)=O)c2C1)Cc1cc(F)c(F)cc1F
Yield: 109.2 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.15 g, 0.27 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.206 g, 1.08 mmol) and triethylamine (0.25 mL, 1.62 mmol) were dissolved in 10 mL of tetrahydrofuran under stirring. After stirring for 10 minutes, ammonium carbonate (78 mg, 0.81 mmol) was added. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-(1-carbamoyl-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 24a (0.162 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:21]([CH3:23])[CH3:22])([CH2:19][CH3:20])[C:10]([C:12]2[CH:17]=[CH:16][C:15](F)=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[CH2:24]([CH2:26][NH2:27])[OH:25]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:21]([CH3:23])[CH3:22])([CH2:19][CH3:20])[C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:27][CH2:26][CH2:24][OH:25])=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: CCC(Cc1ccc(N)cc1)(C(=O)c1ccc(F)cc1)N(C)C
Product: CCC(Cc1ccc(N)cc1)(C(=O)c1ccc(NCCO)cc1)N(C)C
Yield: 36.8 %

Procedure:
23.5 g (0.078 mol) 2-[(4-aminophenyl)methyl]-1-(4-fluorophenyl)-2-dimethylamino-1-butanone are reacted with ethanol amine (33.4 g, 0.55 mol) under conditions as described for example 1.2. The crude product obtained is purified by first by filtration over silica gel using hexane/ethyl acetate 1:1→ethyl acetate as the eluent, followed by flash chromatography on silica gel (eluant: ethyl acetate). 10.2 g (37%) 2-[(4-aminophenyl)methyl]-1-[4-(2-hydroxyethyamino)phenyl]-2-dimethylamino-1-butanone are obtained as a viscous yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5](P(OC)(OC)=O)[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:4].[Br:23][C:24]1[CH:25]=[C:26]([CH:29]=O)[S:27][CH:28]=1.C1CCN2C(=NCCC2)CC1>ClCCl>[CH2:10]([O:9][C:7]([NH:6]/[C:5](=[CH:29]\[C:26]1[S:27][CH:28]=[C:24]([Br:23])[CH:25]=1)/[C:3]([O:2][CH3:1])=[O:4])=[O:8])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)/C(=C/c1cc(Br)cs1)NC(=O)OCc1ccccc1
Yield: 67.9 %

Procedure:
The title compound was prepared according to the method of Example 94a, employing N-(benzyloxycarbonyl)-α-phosphonoglycine trimethyl ester (10.0 g, 30.2 mmol), 4-bromothiophene-2-carbaldehyde (7.52 g, 39.4 mmol), and DBU (5.34 g, 35.1 mmol) in dry dichloromethane (200 mL). Recrystallization from 4:1 (v/v) hexane/ethyl acetate afforded the title compound (8.13 g, 20.5 mmol, 68%) as a white solid. 1H NMR (300 MHz, d6-DMSO) δ3.71 (s, 3H), 5.12 (bs, 2H), 7.10-7.51 (bm, 5H), 7.59 (s, 1H), 7.71 (s, 1H), 7.87 (s, 1H), 8.98 (bs, 1H). MS APCI, m/z=354, 352. LC/MS: 2.53 min.
Reaction SMILES: CN(C=O)C.C(OC([N:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:23](O)=O)[CH:19]=2)[CH2:14]1)=O)(C)(C)C.C(Cl)(=O)C(Cl)=O.[NH2:32][C:33]1[C:34](=[S:48])[NH:35][C:36]([C:39]2([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:41][CH2:40]2)=[CH:37][CH:38]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(Cl)Cl.C1(C)C=CC=CC=1>[C:42]1([C:39]2([C:36]3[N:35]=[C:34]4[S:48][C:23]([C:18]5[CH:19]=[C:20]6[C:15](=[CH:16][CH:17]=5)[CH2:14][NH:13][CH2:22][CH2:21]6)=[N:32][C:33]4=[CH:38][CH:37]=3)[CH2:40][CH2:41]2)[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: Nc1ccc(C2(c3ccccc3)CC2)[nH]c1=S
Reactant: CC(C)(C)OC(=O)N1CCc2cc(C(=O)O)ccc2C1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: c1ccc(C2(c3ccc4nc(-c5ccc6c(c5)CCNC6)sc4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
DMF (27.8 μL, 0.358 mmol) was added to a solution of 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid (198.6 mg, 0.716 mmol) and oxalyl chloride (66 μL, 0.757 mmol) in DCM (7.0 mL), and the resulting mixture was stirred at 25° C. for 4 h. The reaction mixture was then concentrated in vacuo and 3-amino-6-(1-phenylcyclopropyl)pyridine-2(1H)-thione (175 mg, 0.720 mmol) was added. The resulting mixture was taken up in toluene (7.0 mL) and stirred at 25° C. for 5 min then at 100° C. for 1.5 h. (±)-10-camphorsulfonic acid (184 mg, 0.792 mmol) was then added, and the resulting mixture was heated at 100° C. for 1.5 h. The reaction mixture was subsequently cooled to 25° C. and purified by column chromatography (silica gel, 0-10% MeOH/DCM) to provide crude product, which was taken up in DCM (100 mL) and sequentially washed with sat. aq. NaHCO3 and brine. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo to provide 5-(1-phenylcyclopropyl)-2-(1,2,3,4-tetrahydroisoquinolin-6-yl)thiazolo[5,4-b]pyridine as a light yellow solid. MS (ESI) m/z: Calculated: 383.1; Observed: 384.1 (M++1).
Reaction SMILES: [O:1]=[C:2]([CH3:15])[CH2:3][CH2:4][N-:5][CH2:6][CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O.N1CCCCC1.C(O)(=[O:33])C>CC(O)C>[C:2]([C:3](=[CH:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([Cl:16])[CH:18]=1)[C:4]([NH:5][CH2:6][CH:7]=[CH:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:33])(=[O:1])[CH3:15]
Reactant: CC(=O)O
Reactant: O=Cc1cccc(Cl)c1
Reactant: CC(=O)CC[N-]CC=Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: CC(=O)C(=Cc1cccc(Cl)c1)C(=O)NCC=Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
30.0 mg (1.38 mmol) of 3-oxo-N-(3-phenyl-2-propen-1-yl) butylamide and 194 mg (1.38 mmol) of 3-chlorobenzaldehyde were dissolved in 20 ml of 2-propanol. 4.14 mg (0.0690 mmol) of piperidine and 5.67 mg (0.0690 mmol) of acetic acid were added thereto and-stirred at room temperature for 2 days. After the solvent was evaporated under reduced pressure, ethyl acetate was added to the reaction mixture. After washing with 1 N hydrochloric acid and then with saturated aqueous sodium hydrogencarbonate solution, the organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1) to obtain the title compound.