Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:9])[C:5]([O:7]C)=O)=[C:2]=[S:3].[NH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[NH2:17].CC(C)([O-])C.[K+].O>O1CCCC1.C(O)(=O)C>[CH3:9][C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:1][C:2](=[S:3])[N:17]([NH:16][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[C:5]1=[O:7]
Reactant: NNc1ccccn1
Reactant: COC(=O)C(C)(N=C=S)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC1(c2ccccc2)NC(=S)N(Nc2ccccn2)C1=O
Temperature: 5 °C
Yield: 59.6 %

Procedure:
2 g (9 mmol) of methyl 2-isothiocyanato-2-phenylpropionate are dissolved in 30 ml of tetrahydrofuran. A solution containing 0.99 g of 2-hydrazinopyridine and 10 ml of tetrahydrofuran is added: the temperature of the mixture rises from 20 to 30° C. and a solid precipitates. The mixture is allowed to react for 0.5 hour at 30° C. and then is cooled to 5° C. A solution containing 1 g of potassium tert-butoxide and 10 ml of tetrahydrofuran is then added: the mixture becomes violet in color. The mixture is left to return to room temperature and is left to react for 2 hours. The mixture is poured into 150 ml of water. The mixture is neutralized with acetic acid. The product is extracted with 150 ml of ethyl acetate. The solution is washed with water, dried over magnesium sulfate and then treated with active charcoal. The solution is concentrated and the product is crystallized from 20 ml of diethyl ether. The above-mentioned product is filtered and is dried under vacuum. 1.6 g (yield: 60%) of 5-methyl-5-phenyl-3-(2-pyridylamino)-2-thiohydantoin is obtained as a pale-yellow solid melting at 80° C.
Reaction SMILES: O=O.[CH:3]1[C:15]2[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[OH:16]N1C(=O)C2=CC=CC=C2C1=O>C(#N)C1C=CC=CC=1>[C:3]1(=[O:16])[C:15]2[C:7]([C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:6][CH:5]=[CH:4]1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=O
Solvent: N#Cc1ccccc1
Product: O=C1C=CC=C2C1=Cc1ccccc12
Temperature: 100 °C
Reaction time: 6 h
Yield: 28 %

Procedure:
In an oxygen atmosphere, a mixture of 10 millimoles of fluorene, 1 millimole of N-hydroxyphthalimide, 0.05 millimole of acetylacetonatomanganese Mn(AA)3 and 25 milliliters of benzonitrile was stirred at a temperature of 100° C. for six hours. Products in the reaction mixture were analyzed with gas chromatography, and fluorene was transformed into fluorenone (yield 28%) with a transformation rate of 32 percent.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:18]3[CH:19]=[C:20]4[O:25][CH2:24][O:23][C:21]4=[CH:22][C:17]=3[CH2:16][CH:15]([CH3:26])[N:14]([C:27](=[O:30])[NH:28][CH3:29])[N:13]=2)=[CH:8][CH:7]=1>ClCCl>[CH3:29][NH:28][C:27]([N:14]1[CH:15]([CH3:26])[CH2:16][C:17]2[CH:22]=[C:21]3[O:23][CH2:24][O:25][C:20]3=[CH:19][C:18]=2[C:12]([C:9]2[CH:10]=[CH:11][C:6]([NH:5][C:3]([NH:2][CH3:1])=[O:4])=[CH:7][CH:8]=2)=[N:13]1)=[O:30]
Reactant: CNC(=O)N1N=C(c2ccc(N)cc2)c2cc3c(cc2CC1C)OCO3
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)Nc1ccc(C2=NN(C(=O)NC)C(C)Cc3cc4c(cc32)OCO4)cc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 79 %

Procedure:
After adding 0.5 ml (8.5 mmol) of methyl isocyanate to 0.6 g (1.7 mmol) of 1-(4-aminophenyl)-3-methylcarbamoyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine (see Example 98) dissolved in 45 ml of anhydrous dichloromethane, the reaction mixture was stirred at 25° C. for 6 days. Then the crystalline precipitate was filtered, washed with 3×2 ml of dichloromethane and dried at 60° to 80° C. to obtain 0.55 g (79.7%) of the pure aimed product, m.p.: 181°-183° C.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](Cl)=[O:9])(=[O:4])=[O:3].[CH2:14]1[NH:19][CH2:18][CH2:17][N:16]2[CH2:20][CH2:21][CH2:22][C@@H:15]12.C(=O)([O-])[O-].[Na+].[Na+].[F:29][C:30]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:31]=1[NH2:32]>ClCCl>[F:29][C:30]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:31]=1[NH:32][S:2]([C:5]1[CH:13]=[CH:12][CH:11]=[C:7]([C:8]([N:19]2[CH2:18][CH2:17][N:16]3[CH2:20][CH2:21][CH2:22][C@H:15]3[CH2:14]2)=[O:9])[CH:6]=1)(=[O:4])=[O:3]
Reactant: O=C(Cl)c1cccc(S(=O)(=O)Cl)c1
Reactant: C1C[C@H]2CNCCN2C1
Reactant: Nc1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1cccc(S(=O)(=O)Nc2c(F)cccc2F)c1)N1CCN2CCC[C@H]2C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 3-(chlorosulfonyl)benzoyl chloride (0.474 g, 1.98 mmol) in anhydrous dichloromethane (10 mL) was added (S)-octahydropyrrolo[1,2-a]pyrazine (0.250 g, 1.98 mmol) in dichloromethane (4 mL) slowly over 10 minutes at room temperature. Then sodium carbonate (0.420 g, 3.96 mmol) was added. The mixture was stirred at room temperature for 5 hours. Then 2,6-difluoroaniline (2.56 g, 19.81 mmol) was added. The mixture was stirred at room temperature overnight and then concentrated. The residue was purified by chromatography on silica gel (dichloromethane, then methanol/dichloromethane=1:10) to give the title compound.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([O:8][CH3:9])[O:4][CH2:5][CH:6]=[O:7].[BH4-].[Na+]>O.CO>[OH:1][CH2:2][C@@H:3]([O:8][CH3:9])[O:4][CH2:5][CH2:6][OH:7]
Reactant: CO[C@H](C=O)OCC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CO[C@H](CO)OCCO
Reaction time: 0.33 h
Yield: 93.5 %

Procedure:
1,5-dioxo-2(S)-methoxy-3-oxa-pentane (D4) (1.5 g, 11 mmole), prepared as described in "Methods on Carbohydrate Chemistry" Acad. Press., Vol. 1, 445, (1962), was dissolved in a mixture of water (10 ml) and methanol (10 ml) and treated with sodiumborohydride (0.1 g) dissolved in water (2 ml). After 20 minutes the solution was brought to pH 7 with an acidic resin Dowex 50WX2, filtered off and the solvent was removed under reduced pressure to give 1.4 g (Yield 93%) of the title compound. TLC on Kieselgel Plate F254 (Merck), eluting system methylene chloride:methanol (10:1 by volume) brown spot at Rf =0.24 after heating the TLC plate previously sprayed with sulforic acid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[NH2:15][C:16]1[CH:17]=[C:18]([C:22]([C:24]2[C:28]3[CH:29]=[N:30][CH:31]=[C:32]([F:33])[C:27]=3[N:26]([CH:34]([CH3:37])[CH2:35][OH:36])[CH:25]=2)=[O:23])[CH:19]=[N:20][CH:21]=1>>[F:33][C:32]1[C:27]2[N:26]([CH:34]([CH3:37])[CH2:35][OH:36])[CH:25]=[C:24]([C:22]([C:18]3[CH:17]=[C:16]([NH:15][C:10](=[O:12])[CH2:9][C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:14])[F:13])=[CH:8][CH:7]=4)[CH:21]=[N:20][CH:19]=3)=[O:23])[C:28]=2[CH:29]=[N:30][CH:31]=1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: CC(CO)n1cc(C(=O)c2cncc(N)c2)c2cncc(F)c21
Product: CC(CO)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(C(F)(F)F)cc3)c2)c2cncc(F)c21

Procedure:
Prepared according to Method M (Example 206) using 4-trifluoromethylphenylacetic acid and (5-aminopyridin-3-yl)[7-fluoro-1-(2-hydroxy-1-methylethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]methanone (Enantiomer 2, Preparation 26).
Reaction SMILES: [O:1]=[C:2]([CH3:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]=[C:2]([CH3:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:9]
Reactant: BrCc1ccccc1
Reactant: CC(=O)CCCCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)CCCCCC(=O)OCc1ccccc1

Procedure:
Benzyl 7-oxooctanoate was prepared by benzylation of 7-oxooctanoic acid with benzyl bromide and potassium carbonate in dimethyl formamide.
Reaction SMILES: [Cl:1]C1C=CC=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][N:17]=[CH:18]2.CO>ClCCl>[ClH:1].[Br:12][C:13]1[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][N+:17]([O-:9])=[CH:18]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2cnccc2c1Br
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2c[n+]([O-])ccc2c1Br
Product: Cl
Reaction time: 1 h
Yield: 83.3 %

Procedure:
m-Chloroperbenzoic acid (1.4 g, 75%) was added in portions to a stirred solution of 5-bromo-6-methoxyisoquinoline (12 g, 5.04 mmol) in dichloromethane (12 ml). The mixture was stirred for 1 h then further dichloromethane (10 ml) added and the mixture stirred for an additional 2 h. Methanol (12 ml) was added and the mixture concentrated in vacuo to ˜9 ml, then 1M hydrochloric acid in diethyl ether (10 ml) was added. The mixture was diluted with ether and filtered, the precipitated solid was washed with diethyl ether and dried in vacuo to give crude 5-bromo-6-methoxyisoquinoline-N-oxide hydrochloride (1.22 g).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8](=[N:10][OH:11])[NH2:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14](Cl)(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.B(F)(F)F.CCOCC>O1CCOCC1>[C:15]1([C:14]2[O:11][N:10]=[C:8]([C:7]3[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[N:9]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(=NO)c1ccc([N+](=O)[O-])cc1
Agent: FB(F)F
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(-c2noc(-c3ccccc3)n2)cc1

Procedure:
A solution of 10.8 g. (0.06 mole) of p-nitrobenzamidoxime and 8.5 g. (0.06 mole) of benzoyl chloride in 250 ml. of dioxane is heated on a steam bath for one hour, followed by the addition of 2 ml. of BF3 -Et2O. After refluxing the solution overnight, the reaction mixture is cooled and the material which precipitates is collected by filtration to yield 8.1 g. (50%) of 5-phenyl-3-(4-nitrophenyl)-1,2,4-oxadizole.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]2[N:24]=[C:23]([NH:25][C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[N:31](C(OC(C)(C)C)=O)[N:30]=[CH:29]4)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH:12]=[CH:13][CH:14]=1)=[O:7].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:31]1[C:32]2[C:28](=[CH:27][C:26]([NH:25][C:23]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[C:15]([C:11]4[CH:10]=[C:9]([NH:8][C:6]([C@H:2]5[CH2:3][CH2:4][CH2:5][NH:1]5)=[O:7])[CH:14]=[CH:13][CH:12]=4)[N:24]=3)=[CH:34][CH:33]=2)[CH:29]=[N:30]1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(NC(=O)[C@H]5CCCN5)c4)nc4ccccc34)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1)[C@H]1CCCN1

Procedure:
To tert-butyl 5-(2-(3-((R)-pyrrolidine-2-carboxamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (65 mg, 0.12 mmol) was added a solution of 1:1 TFA:CH2Cl2 (2 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the residue was triturated with ethyl ether to get a yellow solid. Product was purified using prep HPLC (method 25-50—70 mins) to afford (2R)—N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)pyrrolidine-2-carboxamide. (64 mg, 100%).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC([F:35])=CC=2)=CSC=1C(OC)=O.C([O:47][CH2:48]C)(OCC)OCC.COC1C=CC(N)=CC=1>C(O)(=O)C>[F:35][C:20]1[CH:19]=[CH:18][C:17]([C:16]2[C:10]3[N:9]=[CH:8][N:7]([C:1]4[CH:6]=[CH:5][C:4]([O:47][CH3:48])=[CH:3][CH:2]=4)[C:12](=[O:13])[C:11]=3[S:14][CH:15]=2)=[CH:22][CH:21]=1
Reactant: CCOC(OCC)OCC
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccc(F)cc2)c1N
Solvent: CC(=O)O
Solvent: COc1ccc(N)cc1
Product: COc1ccc(-n2cnc3c(-c4ccc(F)cc4)csc3c2=O)cc1
Yield: 51 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(4-fluorophenyl)thiophene-2-carboxylate (80 mg, 0.32 mmol), triethyl orthoformate (2 ml), p-anisidine (72.9 mg, 0.59 mmol), and acetic acid (0.08 ml) were used to give 57 mg (0.16 mmol, 51% yield) of the title compound.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[O:19]([CH2:26]C(Cl)=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[C:30]1([CH2:40][NH2:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1>>[CH3:15][O:14][N:13]=[C:11]1[CH2:12][N:8]([C:6](=[O:7])[CH2:26][O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C@H:9]([C:16]([NH:41][CH2:40][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32][CH:31]=2)=[O:18])[CH2:10]1
Reactant: NCc1cccc2ccccc12
Reactant: O=C(Cl)COc1ccccc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)NCc2cccc3ccccc23)N(C(=O)COc2ccccc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, phenoxyacetyl chloride, and 1-naphthylmethylamine the title compound was obtained in 99% purity by LC/MS. MS(ESI+): m/z=432.2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([C:17]3[S:18][CH:19]=[C:20]([C:22]([O:24]CC)=[O:23])[N:21]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:5]2=[CH:4][CH:3]=1.[OH-].[Na+].Cl.[CH2:30]([OH:32])[CH3:31]>>[CH2:30]([O:32][C:2]1[N:7]=[C:6]2[N:8]([C:17]3[S:18][CH:19]=[C:20]([C:22]([OH:24])=[O:23])[N:21]=3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:5]2=[CH:4][CH:3]=1)[CH3:31]
Reactant: CCOC(=O)c1csc(-n2nc(-c3ccccc3)c3ccc(Cl)nc32)n1
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOc1ccc2c(-c3ccccc3)nn(-c3nc(C(=O)O)cs3)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ethanol (2 mL, manufactured by Wako Pure Chemical Industries, Ltd.) solution of ethyl 2-(6-chloro-3-phenyl-1H-pyrazolo[3,4-b]pyridin-1-yl)thiazole-4-carboxylate (33 mg), which had been synthesized from the compound of Reference Example 33 according to the method of Example 3, 5 M sodium hydroxide (500 μL, manufactured by Kanto Chemical Co., Inc.) was added, and the mixture was stirred for one hour at room temperature. 5 M hydrochloric acid (500 μL, manufactured by Kanto Chemical Co., Inc.) was added to neutralize the mixture, and then the mixture was extracted with chloroform (3×3 mL), washed with brine (3 mL), and dried (MgSO4). The solvent was then evaporated, to give 17.6 mg of the title compound. LC-MS: HPLC retention time 1.38 minutes, m/z (M+H) 367, condition C-1.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][O:7][C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([C:18](N(OC)C)=[O:19])[CH:14]=[N:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.F[C:27]1C=CC(COC2C=C3C(C=C(C(Cl)=O)C=N3)=CC=2)=CC=1.Cl.CNOC.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([C:18](=[O:19])[CH3:27])[CH:14]=[N:15]3)=[CH:10][CH:9]=2)=[CH:24][CH:25]=1
Reactant: CON(C)C(=O)c1cnc2cc(OCc3ccc(F)cc3)ccc2c1
Reactant: O=C(Cl)c1cnc2cc(OCc3ccc(F)cc3)ccc2c1
Agent: CNOC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)c1cnc2cc(OCc3ccc(F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
7-((4-Fluorobenzyl)oxy)-N-methoxy-N-methylquinoline-3-carboxamide. To a solution of 7-((4-fluorobenzyl)oxy)quinoline-3-carbonyl chloride in DCM (14 mL) was added N,O-dimethylhydroxylamine hydrochloride (207 mg, 2.12 mmol) and DIPEA (0.739 mL, 4.23 mmol). The reaction was stirred for 15 minutes at ambient temperature before being concentrated onto silica. Purification (FCC, SiO2, 0-80%, EtOAc/hexanes) afforded the title compound as a white solid (324 mg, 67%). 1H NMR (400 MHz, CDCl3) δ 9.18 (d, J=2.0 Hz, 1H), 8.54 (d, J=1.6 Hz, 1H), 7.81 (d, J=9.0 Hz, 1H), 7.52 (d, J=2.0 Hz, 1H), 7.51-7.44 (m, 2H), 7.32 (dd, J=2.3, 9.0 Hz, 1H), 7.11 (t, J=8.8 Hz, 2H), 5.21 (s, 2H), 3.59 (s, 3H), 3.45 (d, J=0.8 Hz, 3H). [M+H]=341.3.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[N:5]([O:10][CH:11]([O:19][N:20]2[C:25]([CH3:27])([CH3:26])[CH2:24][CH:23]([OH:28])[CH2:22][C:21]2([CH3:30])[CH3:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:4]([CH3:32])([CH3:31])[CH2:3]1.[C:33](Cl)(=[O:36])[CH:34]=[CH2:35]>>[C:33]([O:28][CH:23]1[CH2:22][C:21]([CH3:30])([CH3:29])[N:20]([O:19][CH:11]([O:10][N:5]2[C:6]([CH3:8])([CH3:9])[CH2:7][CH:2]([O:1][C:2](=[O:1])[CH:3]=[CH2:4])[CH2:3][C:4]2([CH3:31])[CH3:32])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:25]([CH3:27])([CH3:26])[CH2:24]1)(=[O:36])[CH:34]=[CH2:35]
Reactant: CCCCCCCC(ON1C(C)(C)CC(O)CC1(C)C)ON1C(C)(C)CC(O)CC1(C)C
Reactant: C=CC(=O)Cl
Product: C=CC(=O)OC1CC(C)(C)N(OC(CCCCCCC)ON2C(C)(C)CC(OC(=O)C=C)CC2(C)C)C(C)(C)C1

Procedure:
The title compound is prepared by the reaction of the compound prepared in Example 4 with acryloyl chloride.
Reaction SMILES: CSC.B(F)(F)F.C[N:9]([C:14](=[O:36])[C:15]1[CH:20]=[C:19]([Cl:21])[C:18]([O:22][C:23]2[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[C:26]([O:32]C)=[C:25]([F:34])[CH:24]=2)=[C:17]([Cl:35])[CH:16]=1)[CH2:10][C:11]([OH:13])=[O:12].ClCCl>O>[Cl:21][C:19]1[CH:20]=[C:15]([CH:16]=[C:17]([Cl:35])[C:18]=1[O:22][C:23]1[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[C:26]([OH:32])=[C:25]([F:34])[CH:24]=1)[C:14]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[O:36]
Reactant: COc1c(F)cc(Oc2c(Cl)cc(C(=O)N(C)CC(=O)O)cc2Cl)cc1C(C)C
Agent: FB(F)F
Solvent: ClCCl
Solvent: O
Solvent: CSC
Product: CC(C)c1cc(Oc2c(Cl)cc(C(=O)NCC(=O)O)cc2Cl)cc(F)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 10.9 %

Procedure:
Boron trifluoride dimethyl sulfide (2.0 mL) was added at room temperature to a stirred solution of methyl-N-[3,5-dichloro-4-(3-fluoro-5-isopropyl-4-methoxyphenoxy)benzoyl]glycine (50 mg, 0.11 mmol) and dichloromethane (8 mL). The reaction mixture was stirred at room temperature for 24 hours, poured out in water and extracted with ethyl acetate. The combined organic phases were washed with water, concentrated and the resulting residue purified on column (HPLC, ACE-C8, acetonitrile/0.05% formic acid in water, gradient elution from 5/95 to 60/40) to give 5 mg (20%) of N-[3,5-dichloro-4-(3-fluoro-4-hydroxy-5-isopropylphenoxy)benzoyl]glycine. LC-MS (ES−1): m/z 414.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl.CO.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][CH3:20])[CH2:16][CH2:17]2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: CCCN1CCN(c2ccc([N+](=O)[O-])c(OC)c2)CC1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCN1CCN(c2ccc(N)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 93.2 %

Procedure:
A mixture of 1-[3-(methyloxy)-4-nitrophenyl]-4-propylpiperazine (0.204 g, 0.73 mmol) and nickel(II) chloride hexahydrate (0.087 g, 0.37 mmol) was stirred in 2:1 MeOH/THF (7 mL) under N2 at rt. To this mixture was added NaBH4 (0.097 g, 2.6 mmol) in 2 equal portions over 5 min. The reaction was stirred at rt for about 45 min, then concentrated under vacuum. The residue was dissolved in DCM and poured through Celite, washing with DCM and EtOAc. The filtrate was concentrated and chromatographed on silica gel to give the title compound of step B (170 mg, 0.68 mmol, 93%) as a grey oil. 1H NMR (400 MHz, DMSO-d6): δ 6.50 (d, 1H, J=8.25), 6.47 (d, 1H, J=2.38 Hz), 6.26 (dd, 1H, J=2.47 and 8.34 Hz), 4.19 (br s, 2H), 3.72 (s, 3H), 2.90-2.94 (m, 4H), 2.43-2.47 (m, 4H), 2.25 (t, 2H, J=7.42 Hz), 1.44 (q, 2H, J=7.39 Hz), 0.86 (t, 3H, J=7.33 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15]([CH2:19][C:20]#N)=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:22].[Na+].[OH2:24]>C(O)C>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15]([CH2:19][C:20]([OH:24])=[O:22])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: Cc1nc2c(OCc3ccccc3)cccn2c1CC#N
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nc2c(OCc3ccccc3)cccn2c1CC(=O)O

Procedure:
A solution of 26 g of 8-benzyloxy-3-cyanomethyl-2-methyl-imidazo[1,2-a]pyridine, 50 ml of 15% sodium hydroxide solution 100 ml of water, and 100 ml of ethanol was heated at reflux for 6 hrs. The reaction mixture was distilled until 100 ml of distillate had been collected. The aqueous portion was washed twice with dichloromethane and then treated with a 6 N hydrochloric acid to pH 6. Filtration afforded 8-benzyloxy-2-methyl-imidazo[1,2-a]pyridine-3-acetic acid. 2.0 g of this acid was added to 1 g of lithium aluminium hydride in 100 ml of tetrahydrofuran and was stirred for 5 hrs. at room temperature. The reaction mixture was treated with 1 ml of water, 1 ml of 15% sodium hydroxide solution, then with 3 ml of water. Filtration of salts and evaporation of the filtrate gave the title product after recrystallizationfrom acetonitrile (m.p. 134°-138° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[CH3:19][C:20]1[O:24][N:23]=[C:22]([C@:25]([OH:29])([C:27]#[CH:28])[CH3:26])[CH:21]=1>>[OH:29][C@:25]([C:22]1[CH:21]=[C:20]([CH3:19])[O:24][N:23]=1)([CH3:26])[C:27]#[C:28][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)cn2CCO3)no1

Procedure:
10-Bromo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide (50 mg) was reacted with (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol similar to as described in Procedure G to afford 5.7 mg of 10-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide following reverse phase hplc purification. MS (Q1) 379 (M)+. 1H NMR (400 MHz, DMSO) δ 8.53 (d, J=2.2 Hz, 1H), 7.79 (s, 1H), 7.53 (s, 1H), 7.33 (dd, J=8.5, 2.2 Hz, 1H), 7.12 (s, 1H), 7.03 (d, J=8.5 Hz, 1H), 6.50 (d, J=18.3 Hz, 1H), 6.35 (s, 1H), 4.49 (s, 4H), 2.39 (d, J=11.3 Hz, 3H), 1.80 (s, 3H).
Reaction SMILES: Cl.C(OC([NH:9][CH2:10][C:11]1[CH:12]=[N:13][C:14]([CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:15][CH:16]=1)=O)(C)(C)C.CCCCCC>O1CCOCC1.CCOC(C)=O>[NH2:9][CH2:10][C:11]1[CH:12]=[N:13][C:14]([CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CC2CCCCC2)nc1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: NCc1ccc(CC2CCCCC2)nc1
Reaction time: 8 h
Yield: 88.8 %

Procedure:
Add 4N hydrogen chloride in dioxane (10 mL) to a solution of 3-tert-butoxycarbonylaminomethyl-6-cyclohexylmethyl-pyridine (345 mg, 1.13 mmol) in EtOAc (10 mL) and stir overnight. Concentrate in vacuo, suspend the solid obtained in diethyl ether and add hexane. Filter and wash the solid with hexane. Suspend the solid into dichloromethane, add saturated aqueous NaHCO3 and stir until both phases are clear (15 min). Extract the aqueous phase twice with dichoromethane. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo to obtain the title compound as an oil (205 mg, 97%) that was used without any further purification. MS (ES+) n7/z: 205 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([CH3:16])([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].C(N([CH2:23][CH3:24])CC)C.[CH2:25]1[CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:1][O:2][C:3](=[O:17])[C:4]([CH3:16])([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH:5][C:29]([CH2:25][C:26]1([C:24]2[CH:23]=[CH:7][CH:6]=[CH:4][CH:3]=2)[CH2:15][CH2:10][CH2:11][CH2:27]1)=[O:28]
Reactant: CCN(CC)CC
Reactant: COC(=O)C(C)(N)Cc1c[nH]c2ccccc12
Reactant: C1CCOC1
Product: COC(=O)C(C)(Cc1c[nH]c2ccccc12)NC(=O)CC1(c2ccccc2)CCCC1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a stirred solution of 1-phenyl 1-cyclopentyl methylchloroformate (0.65 g, 2.75 mmol) in dry THF (10 mL) was added a solution of α-methyl-DL-tryptophan methyl ester (0.60 g, 2.5 mmol) followed by triethylamine (0.5 g, 5.0 mmol) in dry THF. The reaction mixture was stirred for 30 minutes and then filtered, concentrated and chromatographed to give an oil (0.9 g, 90%). 1H NMR (200 MHz, CDCl3) δ 8.0 (1H, br s), 7.50 (1H, d, J 7 Hz), 7.40-7.0 (8H, m), 6.6 (1H, br s), 5.35 (1H, br s), 4.15 (2H, s), 3.65 (3H, s), 3.6-3.0 (2H, m), 2.10-1.85 (4H, m), 1.85-1.60 (4H, m), 1.55 (3H, s).