Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]([CH:13]([CH3:15])[CH3:14])[C:7](=[O:16])[CH2:6][C:5]2([CH3:18])[CH3:17].C(=[NH:32])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CCOCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:32][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]([CH:13]([CH3:15])[CH3:14])[C:7](=[O:16])[CH2:6][C:5]2([CH3:18])[CH3:17]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Cc1cc2c(cc1Br)C(C)(C)CC(=O)N2C(C)C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1cc2c(cc1N)C(C)(C)CC(=O)N2C(C)C
Temperature: 80 °C
Reaction time: 1 h
Yield: 30.1 %

Procedure:
A solution of 6-bromo-1-isopropyl-4,4,7-trimethyl-2-oxo-1,2,3,4-tetrahydroquinoline (Compound 17, 2.86 g, 9.2 mmol), benzophenone imine (1.54 g, 8.5 mmol) in 25.0 mL of toluene was degassed with argon for 20 minutes. To this solution was added sodium t-butoxide (1.16 g, 1.2 mmol), tris(dibenzylideneacetone)dipalladium(0) (97 mg, 0.11 mmol) and BINAP (0.18 g, 0.29 mmol) consecutively. The reaction mixture was then heated at 80° C. for 24 hours. Thereafter it was cooled to room temperature, diluted with ether, filtered and concentrated. The residue was diluted with tetrahydrofuran (10.0 mL) and and 10% aqueous HCl and stirred for 1 hour. 0.5 M HCl and 30% hexane in ethyl acetate were then added. The layers were separated and the aqueous layer was made alkaline using saturated NaHCO3 and water. The aqueous layer was extracted with methylene chloride (2×). The combined organic extracts were washed with brine and dried (Na2SO4). The filtered solution was concentrated under reduced pressure and the crude product was purified by silica gel chromatography (30% ethyl acetate in hexanes) to give the title compound (0.63 g, 56%) as a solid.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][C:30]([CH3:45])([CH3:44])[C:31]([NH:33][C:34]4[CH:43]=[CH:42][C:37]([C:38]([O:40]C)=[O:39])=[CH:36][CH:35]=4)=[O:32])=[O:28])=[CH:23][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>O1CCCC1.CO>[CH:1]1([C:7]2[C:8]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][C:30]([CH3:45])([CH3:44])[C:31]([NH:33][C:34]4[CH:43]=[CH:42][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=4)=[O:32])=[O:28])=[CH:23][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(NC(=O)C(C)(C)NC(=O)c2ccc3c(C4CCCCC4)c4n(c3c2)CCOc2cc(OC)ccc2-4)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)OCCn1c-2c(C2CCCCC2)c2ccc(C(=O)NC(C)(C)C(=O)Nc3ccc(C(=O)O)cc3)cc21
Temperature: 25 °C
Reaction time: 64 h
Yield: 94.3 %

Procedure:
To a solution of methyl 4-{2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]-2-methylpropionylamino}benzoate (81 mg, 0.13 mmol) in tetrahydrofuran (8.0 ml) and methanol (2.0 ml) was added 2N aqueous sodium hydroxide solution (1.0 ml, 2.0 mmol), and the mixture was stirred at room temperature for 64 hr. The solvent was evaporated under reduced pressure, 1N aqueous HCl solution (3.0 ml, 3.0 mmol) and methanol (1.0 ml) were added, and the mixture was stirred. The precipitate was collected by filtration to give 4-{2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]-2-methylpropionylamino}benzoic acid (73 mg, yield 92%).
Reaction SMILES: Br[C:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Mg].C(OCCC(C)C)CC(C)C.[Br:34][C:35]1[CH:36]=[C:37]([CH:48]=[C:49]([Br:51])[CH:50]=1)[C:38]([C:40]1[CH:45]=[C:44]([Br:46])[CH:43]=[C:42]([Br:47])[CH:41]=1)=O>CCCCCC>[C:16]1([C:2]2[C:38]([C:40]3[CH:45]=[C:44]([Br:46])[CH:43]=[C:42]([Br:47])[CH:41]=3)([C:37]3[CH:36]=[C:35]([Br:34])[CH:50]=[C:49]([Br:51])[CH:48]=3)[C:11]3[C:10]([C:3]=2[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: BrC(=C(c1ccccc1)c1ccccc1)c1ccccc1
Reactant: O=C(c1cc(Br)cc(Br)c1)c1cc(Br)cc(Br)c1
Agent: CC(C)CCOCCC(C)C
Agent: [Mg]
Solvent: CCCCCC
Product: Brc1cc(Br)cc(C2(c3cc(Br)cc(Br)c3)C(c3ccccc3)=C(c3ccccc3)c3ccccc32)c1
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
A mixture of bromotriphenylethylene (14.143 g, 42.19 mmol), magnesium (903 mg, 37.2 mmol) and i-pentylether (100 cm3) was heated to reflux for 1.75 h. Heating was temporarily removed and 1 (14.00 g, 28.12 mmol) was added. The mixture was heated to reflux under nitrogen for 20 h and then allowed to cool. Hexane (100 cm3) was added and the mixture was allowed to stand for 30 min. The resultant precipitate was collected and washed with hexane. The solid was mixed with dichloromethane (200 cm3) and aqueous ammonium chloride (1 M, 200 cm3) and stirred until fully dissolved. The aqueous layer was separated and extracted with dichloromethane (3×30 cm3) and the combined organic layers washed with aqueous ammonium chloride (1 M, 100 cm3) and water (100 cm3), dried over anhydrous magnesium sulphate, filtered and the solvent removed. The residue was triturated with boiling ethanol, cooled and filtered to give 2 (16.34 g, 79%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([NH2:16])=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].[F:19][C:20]([F:32])([F:31])[C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.C(N(CC)CC)C.Cl>O1CCCC1>[F:18][C:2]([F:1])([F:17])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([NH:16][S:27]([C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:31])[F:32])=[CH:26][CH:25]=3)(=[O:29])=[O:28])=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(N1CCc2ccc(NS(=O)(=O)c3ccc(C(F)(F)F)cc3)cc2CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1 g (2.68 mmol) of 3-(trifluoroacetyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-7-amine and 947 mg (3.87 mmol) of 4-(trifluoromethyl)benzenesulfonyl chloride were dissolved in 20 ml of tetrahydrofuran at room temperature, and 1.62 ml (11.62 mmol) of triethylamine were added dropwise to the solution, which was stirred at room temperature overnight. After evaporation of the solvent, 20 ml of water were added and acidified with 1 mol of hydrochloric acid, and the aqueous phase was extracted with 50 ml of diethyl ether. The residue obtained after drying with sodium sulfate and after removal of the solvent was separated by column chromatography (cyclohexane/ethyl acetate 6:1).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[F:18])[N:14]=[C:13]([N:19]1[CH:23]=[C:22]([C:24]([O:26]CC)=[O:25])[CH:21]=[N:20]1)[NH:12][C:11]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][NH:31][CH2:32][CH3:33]>>[CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[F:18])[N:14]=[C:13]([N:19]1[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[CH:21]=[N:20]1)[N:12]=[C:11]2[N:31]([CH2:32][CH3:33])[CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCNC
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(Cc4ccccc4)cc3c(=O)[nH]2)c1
Product: CCN(C)c1nc(-n2cc(C(=O)O)cn2)nc2cc(F)c(Cc3ccccc3)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-benzyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and N-methylethanamine in step E. MS (ESI): predicted mass calcd. for C22H20FN5O2, 405.2
Reaction SMILES: C1CO[C:8]23OCC[O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15](/[C:16](=[N:28]/[OH:29])/[CH2:17][CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])O1.C=C1C2[C@](C)(CCC(=[O:49])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1>>[OH:29]/[N:28]=[C:16]1/[C@@H:15]2[C@@H:25]([C@:23]3([CH3:24])[CH:18]([CH2:17]/1)[CH2:19][C:20](=[O:49])[CH2:21][CH2:22]3)[CH2:26][CH2:27][C@@:4]1([CH3:5])[C@H:6]2[CH2:7][CH2:8][C:3]1=[O:12]
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Reactant: C[C@]12CCCCC1C/C(=N\O)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C[C@]12CCC(=O)CC1C/C(=N\O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 50 %

Procedure:
The title compound II-at was prepared in 50% yield from 3,3:17,17-bis(ethylendioxy)-7-(E)-hydroxyiminoandrostane by the procedure described above for the preparation of 6-methyleneandrostane-3,17-dione (II-ac, Prepn. 13). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography (SiO2, n-hexane/EtOAc 6/4). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS: δ 10.37 (1H, s), 2.99 (1H, m), 2.58-0.67 (19H, m), 1.12 (3H, s), 0.82 (3H, s).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][C:3]1([CH3:27])[CH3:26].[C-:28]#[N:29].[K+]>CN(C)C=O>[C:28]([C:2]1([OH:1])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][C:3]1([CH3:27])[CH3:26])#[N:29]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)C(C)(C)C3)c(F)c2)C(=O)O1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(C#N)C(C)(C)C3)c(F)c2)C(=O)O1
Yield: 78 %

Procedure:
By reacting (S)—N-{3-[4-(4-oxo-3,3-dimethyl-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.40 mmol) and potassium cyanide (2.6 mmol) in dimethylformamide (10 ml) followed by silica gel chromatographic separation of diastereomer the compound was obtained in 78% yield. M.P. 65-68° C. and MS (M+1)=405 (MH+, 100%) for M.F.=C20H25FN4O4.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15](O)=[O:16])[CH2:10][C@H:9]1[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)=[O:7].[NH:37]1[CH2:42][CH2:41][S:40][CH2:39][CH2:38]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[F:33][C:31]([F:34])([F:32])[C:29]1[CH:28]=[C:5]([CH:4]=[C:3]([C:2]([F:36])([F:35])[F:1])[CH:30]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([N:37]2[CH2:42][CH2:41][S:40][CH2:39][CH2:38]2)=[O:16])[CH2:10][C@H:9]1[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)=[O:7]
Reactant: C1CSCCN1
Reactant: O=C(O)CN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: O=C(CN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1)N1CCSCC1
Reaction time: 3 h
Yield: 90.5 %

Procedure:
To a stirred mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(carboxymethyl)-2-(1H-indol-3-ylmethyl)piperazine (0.4 g) and thiomorpholine (0.08 g) in dry N,N-dimethylformamide (4 ml) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.16 g) and 1-hydroxybenzotriazole (0.12 g) at room temperature. After 3 hours, the reaction mixture was poured into aqueous sodium bicarbonate solution (40 ml) and the resulting precipitate was collected by filtration. The crude product obtained was purified by column chromatography on silica gel using toluene-ethyl acetate (1:2) as an eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(thiomorpholinocarbonylmethyl)piperazine (0.42 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[C@@H:13]([CH2:17]O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:39].CO>CN(C)C(=O)C.ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[C@@H:13]([CH2:17][Br:39])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=C(OCc1ccccc1)N1C[C@H](CO)[C@@H](O)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Solvent: CO
Product: O=C(OCc1ccccc1)N1C[C@H](CBr)[C@@H](O)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
(3R,4R)-(1-Benzyloxycarbonyl-4-hydroxypyrrolidin-3-yl)methanol (503 mg) and triphenylphosphine (577 mg) were dissolved in N,N-dimethylacetamide (10 mL) While this solution was chilled in an ice water bath, carbon tetrabromide (730 mg) in dichloromethane (2 mL) was added dropwise. After the reaction mixture was stirred at room temperature for 5 hours, methanol (1 mL) was added and the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), washed with saturated brine (2×10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (eluant: ethyl acetate: hexane=2:1) to give (3S,4R)-1-benzyloxycarbonyl-3-bromomethyl-4-hydroxypyrrolidine as a milky white syrup (503 mg).
Reaction SMILES: [CH:1]([NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:21]3[CH:20]=[C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[N:18]=[CH:17][C:16]=3[NH:15]/[C:14]/2=[N:31]\[C:32]([C:34]2[CH:35]=[CH:36][C:37]3C=CS[C:38]=3[CH:42]=2)=[O:33])[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[F:43][C:44]([F:56])([F:55])[O:45]C1C=C(C=CC=1)C(O)=O>>[CH:1]([NH:4][C:5]([C@@H:7]1[CH2:8][CH2:9][C@H:10]([N:13]2[C:21]3[CH:20]=[C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[N:18]=[CH:17][C:16]=3[NH:15]/[C:14]/2=[N:31]\[C:32](=[O:33])[C:34]2[CH:35]=[CH:36][CH:37]=[C:38]([O:45][C:44]([F:56])([F:55])[F:43])[CH:42]=2)[CH2:11][CH2:12]1)=[O:6])([CH3:2])[CH3:3]
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc4ccsc4c3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Reactant: O=C(O)c1cccc(OC(F)(F)F)c1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3cccc(OC(F)(F)F)c3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Yield: 50.3 %

Procedure:
The title compound was prepared using a method analogous to the preparation of (E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide, using 3-(trifluoromethoxy)benzoic acid. The material was purified via preparative HPLC (0.1% NH4OH in ACN/H2O) to provide (E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-3-(trifluoromethoxy)benzamide (50.3% yield). MS m/z=617.4 [M+H], calc 616.67 for C31H39F3N6O4. 1H NMR (CDCl3) δ ppm: 12.32 (br. s., 1H), 8.30-8.43 (m, 2H), 8.10 (d, J=0.8 Hz, 1H), 7.28-7.31 (m, 1H), 7.01 (s, 1H), 5.34 (d, J=1.0 Hz, 1H), 4.77-4.91 (m, 1H), 4.45-4.55 (m, 2H), 4.14-4.29 (m, 1H), 2.46-2.95 (m, 8H), 2.20-2.27 (m, 2H), 1.73-1.89 (m, 4H), 1.58-1.73 (m, 5H), 1.41-1.57 (m, 3H), 1.22 (d, J=6.6 Hz, 6H).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH3:3].[I-].CC[O-].[Na+].[C:10]1([N:16]2[C:22]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=3[NH:20][C:19](=[O:28])[CH2:18][C:17]2=[O:29])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([N:16]2[C:22]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=3[N:20]([CH2:1][CH2:2][CH3:3])[C:19](=[O:28])[CH2:18][C:17]2=[O:29])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCBr
Reactant: O=C1CC(=O)N(c2ccccc2)c2cc(Cl)ccc2N1
Agent: CC[O-]
Agent: [I-]
Agent: [Na+]
Product: CCCN1C(=O)CC(=O)N(c2ccccc2)c2cc(Cl)ccc21

Procedure:
In the same manner by acting propyl bromide or iodide in the presence of sodium ethylate, starting from 1-phenyl 8-chloro 1,2,4,5-tetrahydro 2,4-dioxo 3H-1,5-benzodiazepine, there is obtained 1-phenyl 5-propyl 8-chloro 1,2,4,5-tetrahydro 2,4-dioxo 3H-1,5-benzodiazepine (R1 = H, R2 = Cl, R3 =C3H7, R4 = C6H5) melting at 192°-194° C upon recrystallisation in ethanol. Analysis: c18H17ClN2O2 ; Calculated: C % 65.75; H % 5.21; N % 8.52; Found : 65.66; 5.17; 8.60.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:40])=[C:9]([CH2:11][O:12][C:13]2[CH:39]=[CH:38][C:16]([CH2:17][N:18]3[CH:22]=[C:21]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20](OS(C(F)(F)F)(=O)=O)=[N:19]3)=[CH:15][CH:14]=2)[N:10]=1.[F:41][C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.C1(C)C=CC=CC=1>[F:41][C:42]1[CH:47]=[CH:46][C:45]([C:20]2[C:21]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][N:18]([CH2:17][C:16]3[CH:38]=[CH:39][C:13]([O:12][CH2:11][C:9]4[N:10]=[C:6]([C:2]5[O:1][CH:5]=[CH:4][CH:3]=5)[O:7][C:8]=4[CH3:40])=[CH:14][CH:15]=3)[N:19]=2)=[CH:44][CH:43]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)nc1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)nc1-c1ccc(F)cc1
Yield: 17.4 %

Procedure:
Tetrakis(triphenylphosphine)palladium (878 mg) was added to a mixture of ethyl 3-[1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy)benzyl]-3-trifluoromethanesulfonyloxy-1H-pyrazol-4-yl]propionate (2.22 g), 4-fluorophenylboronic acid (798 mg), 2N aqueous sodium carbonate solution (10 ml), ethanol (10 ml), and toluene (30 ml). This mixture was refluxed under an argon atmosphere for 13 hours. Ethyl acetate was added to this reaction mixture, which was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-(4-fluorophenyl)-1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-1H-pyrazol-4-yl]propionate (350 mg, yield: 17%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[CH:18][N:19]([CH3:21])[CH3:20])[C:10]2=[O:22])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br.O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[CH:18][N:19]([CH3:20])[CH3:21])[C:10]2=[O:22])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(N2C(=O)C(=CN(C)C)c3ccccc32)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CN(C)C=C1C(=O)N(c2cccc(O)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Under nitrogen, a solution of title product of Example C1 (0.468 g, 1.59 mmoles) in 5 ml CH2Cl2 was cooled to -78°. Boron tribromide (0.45 ml, 4.77 mmoles) was added. After stirring 20 minutes at ×78°the reaction mixture was allowed to warm to room temperature, stirred 2 hours, diluted with 25 ml. of water and then 20 ml CH2Cl2, stirred 15 minutes, and the pH adjusted to 6-7 with saturated NaHCO3. The aqueous layer was separated and extracted 2×25 ml CH2Cl2. The three organic layers were combined, dried over MgSO4, and concentrated to solids in vacuo, 0.402 g. Recrystallization from CH2Cl2 /hexane gave purified title product, 0.320 g, m.p. 200°-203°.
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]2([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:26][CH:25]=[CH:24][CH2:23]2)[N:16]=3)=[C:9]([F:33])[CH:8]=1.C1COCC1.[OH-].[Na+]>CC(=O)OCC>[F:33][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[C:13]1[S:14][C:15]2[C:20]([N:21]=1)=[CH:19][CH:18]=[C:17]([C:22]1([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:23][CH:24]=[CH:25][CH2:26]1)[N:16]=2)[CH:2]=[O:1]
Reactant: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(C3(c4ccccc4)CC=CC3)nc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC=CC4)nc3s2)c(F)c1
Reaction time: 0.5 h

Procedure:
A slurry of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-phenylcyclopent-3-enyl)-thiazolo[5,4-b]pyridine (0.550 g, 1.20 mmol) in 8 mL 1:1 THF/5N HCl was heated to 70° C. in a sealed vial. After 30 min, the reaction mixture was cooled, treated with ice, 10N NaOH until basic, and EA. The organic layer was washed with water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 3-fluoro-4-(5-(1-phenylcyclopent-3-enyl)-thiazolo[5,4-b]pyridine-2-yl)benzaldehyde which was used without further purification. MS (ESI) m/z: Calculated: 400.1; Observed: 401.1 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([NH:11][C:12]([O:14]CC)=O)[CH3:10])=[CH:4][CH:3]=1.O.[NH2:19][NH2:20]>C(O)CCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:10])[NH:11][C:12](=[O:14])[NH:19][N:20]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)NC(C)C(=O)c1ccc(Br)cc1
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: CC1NC(=O)NN=C1c1ccc(Br)cc1
Yield: 43.8 %

Procedure:
A mixture of 4'-bromo-2-ethoxycarbonylaminopropiophenone (4.29 g), hydrazine hydrate (8 g) and n-butanol (50 ml) was refluxed under heating for 68 hours. The solution was evaporated to dryness, and the resultant residue was dissolved in a mixture of chloroform and methanol. The solution was washed with water and the washings were extracted with chloroform. The combined organic layer was dried over magnesium sulfate and evaporated to dryness. The resultant residue was washed with diisopropyl ether and recrystallized from ethanol to give colorless crystals of 6-(4-bromophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (1.68 g), m.p. 213.5°~215° C.
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]([NH:6][C:7]1[C:12]([Cl:13])=[CH:11][C:10]([CH3:14])=[C:9]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[C:22]([OH:29])[C:21]=2[CH2:30][CH2:31][CH3:32])[CH:8]=1)=[O:5].[OH-].[Na+]>CO>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([O:19][CH2:18][CH2:17][CH2:16][O:15][C:9]2[CH:8]=[C:7]([NH:6][C:4](=[O:5])[C:3]([OH:33])=[O:2])[C:12]([Cl:13])=[CH:11][C:10]=2[CH3:14])=[C:21]([CH2:30][CH2:31][CH3:32])[C:22]=1[OH:29])(=[O:28])[CH3:27]
Reactant: CCCc1c(OCCCOc2cc(NC(=O)C(=O)OC)c(Cl)cc2C)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCCCOc2cc(NC(=O)C(=O)O)c(Cl)cc2C)ccc(C(C)=O)c1O

Procedure:
A suspension of 6.1 g (12.8 mmol) of N-{3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-4-methyl-6-chlorophenyl}-oxamic acid methyl ester in 200 ml of methanol and 14.1 ml of N sodium hydroxide solution is heated under reflux for 90 minutes. The reaction mixture is concentrated under reduced pressure, dissolved in hot water and, after cooling, acidified with dilute hydrochloric acid. The product that has formed is filtered off, washed with water and recrystallised from acetone. N-{3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-4-methyl-6-chlorophenyl}-oxamic acid having a melting point of 183°-184° (decomposition) is obtained. The acid is dissolved in 350 ml of acetone, and one equivalent of triethanolamine is added thereto. The solution is concentrated under reduced pressure to approximately one third and ether is added. The product that has formed is filtered off and washed with ether. The triethanolammonium salt of N-{3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-4-methyl-6-chlorophenyl}-oxamic acid having a melting point of 70° (decomposition) is obtained.