Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.N[C:4]1[O:5][C:6]2[CH:12]=[C:11]([CH2:13][CH2:14][C:15]3[N:16]=[C:17]4[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][N:18]4[C:25]=3[CH3:26])[CH:10]=[CH:9][C:7]=2[N:8]=1.[OH2:27]>Cl>[OH:27][C:4]1[O:5][C:6]2[CH:12]=[C:11]([CH2:13][CH2:14][C:15]3[N:16]=[C:17]4[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][N:18]4[C:25]=3[CH3:26])[CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: O
Reactant: COc1ccn2c(C)c(CCc3ccc4nc(N)oc4c3)nc2c1
Agent: Cl
Product: COc1ccn2c(C)c(CCc3ccc4nc(O)oc4c3)nc2c1

Procedure:
A mixture of 2-amino-6-[2-(7-methoxy-3-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole dihydrochloride (2.0 g) in 1N hydrochloric acid (25.3 ml) was was refluxed for 21 hours. The reaction mixture was added to water (50 ml) under ice-cooling and the resulting precipitate was collected by filtration. A mixture of obtained residue and water was adjusted to pH 8 with 20% potassium carbonate aqueous solution under stirring. A precipitate was collected by filtration and dried to give 2-hydroxy-6-[2-(7-methoxy-3-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (0.98 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C@H:8]([CH3:32])[C:9]([NH:11][NH:12][C:13]([C@@H:15]1[CH2:21][CH2:20][C@@H:19]2[CH2:22][N:16]1[C:17](=[O:31])[N:18]2[O:23]CC1C=CC=CC=1)=[O:14])=[O:10])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:33])[NH:7][C@H:8]([CH3:32])[C:9]([NH:11][NH:12][C:13]([C@@H:15]1[CH2:21][CH2:20][C@@H:19]2[CH2:22][N:16]1[C:17](=[O:31])[N:18]2[OH:23])=[O:14])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Reaction time: 2 h
Yield: 100.2 %

Procedure:
To a solution of compound 275 (400 mg, 0.86 mmol) in 30 mL of MeOH was added 0.8 g of Pd/C (10%, wet). The mixture was hydrogenated at room temperature for 2 h. The catalyst was removed by filtration through a celite pad. The filtrate was concentrated to afford compound 276 as a colorless gum (320 mg, 99%).
Reaction SMILES: [F:1][C:2]1[C:20](F)=[C:19]([F:22])[C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.Cl.Cl.[CH3:25][NH:26][CH:27]1[CH2:30][NH:29][CH2:28]1>>[F:1][C:2]1[C:20]([N:29]2[CH2:30][CH:27]([NH:26][CH3:25])[CH2:28]2)=[C:19]([F:22])[C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)c(F)c3nc21
Reactant: CNC1CNC1
Agent: Cl
Product: CNC1CN(c2c(F)cc3cc4c(=O)c(C(=O)O)cn(C)c4nc3c2F)C1
Yield: 84.5 %

Procedure:
7,9-Difluoro-1-methyl-8-(3-methylamino-1-azetidinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid was prepared under the conditions of Example 30, but starting with 1.5 g of 7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 1.2 g of 3-(methylamino)azetidine dihydrochloride. 1.54 g of 7,9-difluoro-1-methyl-8-(3-methylamino-1-azetidinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid, which decomposes at 302° C.
Reaction SMILES: F[C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:4]([CH3:21])[C:5]([C:19]#[N:20])=[C:6]2[C:10]=1[O:9][C:8]([N:11]([CH3:18])[CH2:12][C:13]1[NH:17][N:16]=[CH:15][N:14]=1)=[N:7]2.C(N(CC)CC)C.[CH3:35][N:36]([CH3:42])[C@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>CS(C)=O.ClCCl>[CH3:35][N:36]([CH3:42])[C@H:37]1[CH2:41][CH2:40][N:39]([C:2]2[C:3]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:4]([CH3:21])[C:5]([C:19]#[N:20])=[C:6]3[C:10]=2[O:9][C:8]([N:11]([CH3:18])[CH2:12][C:13]2[NH:17][N:16]=[CH:15][N:14]=2)=[N:7]3)[CH2:38]1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(N(C)Cc3ncn[nH]3)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(N(C)Cc3ncn[nH]3)nc2c1C#N
Temperature: 150 °C
Reaction time: 4 h
Yield: 43.1 %

Procedure:
7-Fluoro-5-methyl-2-[methyl(1H-1,2,4-triazol-5-ylmethyl)amino]-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-165) (0.24 g, 0.66 mmol) was dissolved in dimethyl sulfoxide (5 ml), then triethylamine (0.19 ml, 1.37 mmol) and (3S)-3-(dimethylamino)pyrrolidine (0.17 ml, 1.34 mmol) were added, followed by stirring in a sealed tube at an external temperature of about 150° C. for 4 hours. This was diluted with dichloromethane, and washed with water and brine. After drying over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane:methanol=10:1), then diisopropyl ether was added and the insoluble matter was collected by filtration to obtain a beige solid (0.13 g, 42%).
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([C:5]([C:12]#[N:13])=[CH:6][CH:7]=[C:8]2[CH3:11])=[N:3]1>CO.N.[Ni]>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([C:5]([CH2:12][NH2:13])=[CH:6][CH:7]=[C:8]2[CH3:11])=[N:3]1
Reactant: Cc1ccc(C#N)c2nn(C)cc12
Agent: [Ni]
Agent: N
Solvent: CO
Product: Cc1ccc(CN)c2nn(C)cc12
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 2,4-dimethyl-2H-indazole-7-carbonitrile (1 equiv.) in methanol and aq. ammonia solution (9:1), catalytic amount of Raney Nickel was added. Reaction mass was stirred at room temperature under hydrogen pressure (balloon pressure) for 2-5 h. On completion of reaction, it was filtered through celite bed and filtrate was concentrated under reduce pressure to afford the title compound (quant. yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]([C:12]2[C:17]([NH2:18])=[CH:16][CH:15]=[C:14]([CH3:19])[N:13]=2)=[O:11])=[N:6][C:7]=1[CH3:8].[F:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25](F)[CH:26]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]([C:12]2[C:17]([NH:18][C:25]3[CH:24]=[N:23][CH:22]=[C:21]([F:20])[CH:26]=3)=[CH:16][CH:15]=[C:14]([CH3:19])[N:13]=2)=[O:11])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(N)c(C(=O)Nc2ccc(F)c(C)n2)n1
Reactant: Fc1cncc(F)c1
Product: Cc1ccc(Nc2cncc(F)c2)c(C(=O)Nc2ccc(F)c(C)n2)n1

Procedure:
The title compound, light yellow solid, MS (ISP): m/e=356.1 (M+H+), was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (5-fluoro-6-methyl-pyridin-2-yl)-amide and 3,5-Difluoropyridine in accordance with the general method of example 7.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[NH:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[C:8]([F:15])=[CH:7][C:6]=1I.[C:18]([Si:22]([CH3:29])([CH3:28])[O:23][CH:24]([CH3:27])[C:25]#[CH:26])([CH3:21])([CH3:20])[CH3:19].O=O.Cl>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:1][O:2][C:3](=[O:17])[NH:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[C:8]([F:15])=[CH:7][C:6]=1[C:26]#[C:25][CH:24]([O:23][Si:22]([C:18]([CH3:19])([CH3:21])[CH3:20])([CH3:29])[CH3:28])[CH3:27]
Reactant: COC(=O)Nc1cc(C(F)(F)F)c(F)cc1I
Reactant: C#CC(C)O[Si](C)(C)C(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)Nc1cc(C(F)(F)F)c(F)cc1C#CC(C)O[Si](C)(C)C(C)(C)C
Yield: 138.9 %

Procedure:
The title compound (ISP-MS: m/e=361.2 ([M+])) was produced from (4-fluoro-2-iodo-5-trifluoromethyl-phenyl)-carbamic acid methyl ester as follows: (4-Fluoro-2-iodo-5-trifluoromethyl-phenyl)-carbamic acid methyl ester (1520 mg) was dissolved in triethylamine (20 mL). Bis-(triphenylphosphine)-palladium (II) dichloride (193 mg; 5 mol %), copper (I) iodide (52 mg; 5 mol %) and tert-butyl-dimethyl-(1-methyl-prop-2-ynyloxy)-silane (1.22 g; 1.2 equivalent) were added and the reaction mixture was heated 3 h at 50° C. under exclusion of oxygen. The reaction mixture was poured into chilled aqueous hydrochloric acid (25%) and extracted three times with ethyl acetate. The organic phases were pooled, dried over sodium sulfate and the solvent was removed. The residue was chromatographed on silica gel (eluant: hexane/ethyl acetate 95/5). 2.44 g of the {2-[3-(tert-butyl-dimethyl-silanyloxy)-but-1-ynyl]-4-fluoro-5-trifluoromethyl-phenyl}-carbamic acid methyl ester (quantitative yield) was obtained.
Reaction SMILES: [OH-].[Na+].[NH:3]([C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([C:15]([O:17]C)=[O:16])=[CH:12][C:11]=2[CH:19]=1)[C:4]([CH3:6])=[O:5]>CO>[NH:3]([C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([C:15]([OH:17])=[O:16])=[CH:12][C:11]=2[CH:19]=1)[C:4]([CH3:6])=[O:5]
Reactant: COC(=O)c1cc2cc(NC(C)=O)ccc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)Nc1ccc2oc(C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 81.1 %

Procedure:
3N NaOH (2 mL) was added to a solution of 9 (302 mg, 1.3 mmol) in methanol (20 mL) and the reaction mixture was stirred for 48 h at room temperature. Solvent was evaporated and water (20 mL) was added. The solution was neutralized to pH 2 using 20% HCl and the precipitate was filtered and washed with water. 10 was obtained as a grey powder (231 mg, 81% yield), mp: >300° C. 1 H NMR (DMSO-d6, ppm): 13.30 (s, 1 H, COOH), 10.01 (s, 1 H, NH), 8.16-8.15 (d, 1 H, J=1.9 Hz, Ar--H), 7.65-7.60 (m, 2 H, Ar--H), 7.53-7.50 (dd, 2 H, J=1.6, 8.4 Hz, Ar--H), 2.07 (s, 3 H, CH3CO), Anal. (C11H9NO4 0.3H2O), C, H, N.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:14]Br>C(Cl)(Cl)(Cl)Cl>[Br:14][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8](=[O:13])[C:9]([CH3:10])([CH3:12])[CH3:11]
Reactant: BrBr
Reactant: CC(C)(C)C(=O)Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)C(Br)c1ccccc1
Yield: 99.5 %

Procedure:
17.6 g (0.1 mol) of 1-phenyl-3,3-dimethyl-butan-2-one were dissolved in 100 ml of carbon tetrachloride, 5 ml (0.1 mole) of bromine were added dropwise thereto while stirring and under reflux, and the mixture was heated to the boil for one hour. After cooling, the distilling off the solvent, 25.4 g of 1-bromo-1-phenyl-3,3-dimethyl-butan-2-one of melting point 38°-42° C. were obtained in quantitative yield.
Reaction SMILES: [K].O[CH:3]=[CH:4][C:5](=O)[C:6]([CH3:9])([CH3:8])[CH3:7].C(O)C.O.[NH2:15][NH2:16]>O>[C:6]([C:5]1[CH:4]=[CH:3][NH:16][N:15]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: NN
Reactant: CC(C)(C)C(=O)C=CO
Agent: [K]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc[nH]n1
Temperature: 25 °C
Yield: 42.6 %

Procedure:
Under nitrogen atmosphere, mixture of 50.00 g of pinacolone and 42.00 g of methyl formate was cooled to 0° C., and then 56.00 g of potassium t-butoxide was added to the mixture over the period for 3 hours. During that, the temperature of the mixture was kept below 20° C. After that, the reaction mixture was stirred at 30° C. for 5 hours. Diethyl ether was added to the reaction mixture which was cooled to room temperature, as a result, solid was produced. The solid was collected by filtration, and dried under reduced pressure to give 32.12 g of 1-hydroxy-4,4-dimethyl-1-pentene-3-one potassium salt. 21.61 g of 1-hydroxy-4,4-dimethyl-1-pentene-3-one potassium salt was suspended to 150 ml of ethanol. 6.52 g of hydrazine hydrate was added to the suspension, and then refluxed for 7 hours. 50 ml of water was added to the reaction mixture which was cooled to room temperature, and the mixture was concentrated to 40 ml under reduced pressure. The concentrated solution was extracted by ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 6.83 g of 3-t-butyl-1H-pyrazole.
Reaction SMILES: [BH4-].[Li+].C[O:4][C:5]([C@H:7]1[CH2:11][C@@H:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][N:8]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=O>O1CCCC1>[C:23]([O:22][C:20]([N:8]1[CH2:9][C@H:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:11][C@@H:7]1[CH2:5][OH:4])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: COC(=O)[C@H]1C[C@@H](OCc2ccccc2)CN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@@H]1CO
Temperature: 25 °C
Yield: 79.6 %

Procedure:
Add lithium borohydride (0.0097 g, 0.44 mmol) to an ice cold solution of (2R,4R)-4-benzyloxypyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (0.1 g, 0.29 mmol) in tetrahydrofuran (1 mL). Warm slowly to room temperature over 18 hours. Cool in ice bath. Slowly add acetone (1 mL), concentrate and purify (silica gel chromatography, eluting with ethyl acetate/hexanes mixtures) to give the title compound as a colorless oil (0.071 g, 80%).
Reaction SMILES: C([O:4][C@H:5]1[C@@H:9]([NH:10][C:11](=[O:31])[C@H:12]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH:13][C:14](=[O:26])[NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7][O:6]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[OH:4][CH:5]1[CH:9]([NH:10][C:11](=[O:31])[C@H:12]([CH2:27][CH:28]([CH3:29])[CH3:30])[NH:13][C:14](=[O:26])[NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7][O:6]1
Reactant: CC(=O)O[C@@H]1OCC[C@@H]1NC(=O)[C@H](CC(C)C)NC(=O)Nc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)C[C@H](NC(=O)Nc1cccc2ccccc12)C(=O)NC1CCOC1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
(2S,3S)-2-Acetoxy-3-[[N-(1-naphthylcarbamoyl)-(L)-leucyl]amino]tetrahydrofuran (2.9 g) was suspended in methanol (50 ml) followed by addition of a solution of potassium carbonate (0.94 g) in water (5 ml) under ice-cooling and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4) and the solvent was distilled off to give 2-hydroxy-3-[[N-(1-naphthylcarbamoyl)-(L)-leucyl]amino]tetrahydrofuran (chemical formula below) (1.95 g, 72%). As recrystallized from dichloromethane-methanolisopropyl ether, colorless crystals, m.p. 177°-178° C., optical rotation [α]D +29.5° (c=0.25, dimethyl sulfoxide).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.C(O)(C(F)(F)F)=O>>[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]2[C:5]3[NH:6][C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]=3[CH2:3][CH2:2][NH:1]2)=[CH:16][CH:15]=1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: Cc1ccc(C=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C2NCCc3c2[nH]c2ccccc32)cc1
Yield: 99 %

Procedure:
This product was prepared using the same procedure as for Intermediate 1 with tryptamine (1.0 g, 6.2 mmol), 4-methylbenzaldehyde (0.74 g, 1 equiv.) and TFA (1 mL, 2 equiv.) to give the title compound (1.6 g, 100%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:18][CH2:17][CH2:16][CH:15]=[C:14]2[C:13](=[O:19])[NH:12][C:11](=[O:20])[CH2:10]3)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH:23]1([CH2:26]CS([O-])(=O)=O)[CH2:25][CH2:24]1.O>CN(C)C=O>[CH:23]1([CH2:26][N:12]2[C:11](=[O:20])[CH2:10][C:9]3([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)[C:14](=[CH:15][CH2:16][CH2:17][CH2:18]3)[C:13]2=[O:19])[CH2:25][CH2:24]1
Reactant: COc1cccc(C23CCCC=C2C(=O)NC(=O)C3)c1
Reactant: O=S(=O)([O-])CCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(C23CCCC=C2C(=O)N(CC2CC2)C(=O)C3)c1
Reaction time: 8 h

Procedure:
4a-(m-Methoxyphenyl)-1,3-diketo-1,2,3,4,4a,5,6, 7-octahydroisoquinoline (99 g, 0.365 moles) in 1000 ml of anhydrous dimethylformamide was added dropwise to a 55% suspension of sodium hydride in mineral oil (19.8 g) in 500 ml of dimethylformamide at 70°. The reaction mixture was heated for 1 hour at 80° and then cooled to 25°. Cyclopropylmethylmesylate (59.6 g) was added and the reaction mixture heated at 70°-80° for one hour and stirred overnight. It was poured into water and extracted with ether. The residue after evaporation of the ether was chromatographed on 800 g of Florisil. The final product, after evaporative distillation at 190° (1μ), amounted to 50 g.
Reaction SMILES: [C@@H:1]12[C:10](=[O:11])[O:9][C:7](=[O:8])[C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.C(OC(=O)C)(=[O:14])C.[O-]O.C1(C(C)C)C=CC=CC=1.[C:30]([O:39][O:40][C:41]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([CH3:43])[CH3:42])([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([CH3:32])[CH3:31]>>[C:30]([O:39][O:40][C:41]([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)([CH3:43])[CH3:42])([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([CH3:31])[CH3:32].[C@@H:1]1([C:10]([OH:9])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([OH:14])=[O:8]
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Reactant: CC(=O)OC(C)=O
Agent: CC(C)(OOC(C)(C)c1ccccc1)c1ccccc1
Agent: [O-]O
Solvent: CC(C)c1ccccc1
Product: O=C(O)[C@H]1CCCC[C@H]1C(=O)O

Procedure:
The reaction described in Example 2 was repeated with 14.7 gm (95 millimoles) cis-1,2-cyclohexanedicarboxylic anhydride substituted for the acetic anhydride. After a total reaction time of 125 minutes (at 18°±1° C.), 9.9% of the cumene hydroperoxide remained unreacted. The reaction was quenched (sodium acetate) after a total time of 245 minutes and, after recovery in a manner similar to Example 2, afforded 35.9 gm crude product which contained about 70% dicumyl peroxide. (An approximate value for dicumyl peroxide was obtained in this case because the elution of cis-1,2-cyclohexanedicarboxylic acid on the gas-liquid chromatography column partially overlapped with the dicumyl peroxide).
Reaction SMILES: C([O:5][C@H:6]1[CH2:15][CH2:14][CH2:13][C@@H:12]2[C@:7]1([CH3:20])[CH2:8][CH2:9][CH2:10][C@@H:11]2[O:16][C:17](=[O:19])[CH3:18])(C)(C)C.CO>C(Cl)(Cl)(Cl)Cl>[OH:5][C@H:6]1[CH2:15][CH2:14][CH2:13][C@@H:12]2[C@:7]1([CH3:20])[CH2:8][CH2:9][CH2:10][C@@H:11]2[O:16][C:17](=[O:19])[CH3:18]
Reactant: CC(=O)O[C@H]1CCC[C@]2(C)[C@@H](OC(C)(C)C)CCC[C@@H]12
Solvent: CO
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)O[C@H]1CCC[C@]2(C)[C@@H](O)CCC[C@@H]12
Reaction time: 0.25 h
Yield: 88.1 %

Procedure:
A solution of 4.08 g (14.45 mMol) of acetic acid (1S,4aS,5S,8aR)-5-tert-Butoxy-4a-methyl-decahydronaphtalen-1-yl ester in 7.25 ml of carbon tetrachloride is treated dropwise under stirring and argon atmosphere with 2.56 ml (18.8 mMol) of trimethylsilyljodide by keeping room temperature. After completed addition the reaction mixture is stirred for another 30 minutes, then 1.79 ml of methanol are added and the reaction kept for 15 minutes. The reaction mixture is evaporated in vacuo to dryness to yield 5.52 g. The residue is chromatographed over 500 g of silicagel with hexane/ethylacetate 4/1 to give 2.88 g (88%) of pure acetic acid (1S,4aS,5S,8aR)-5-hydroxy-4a-methyl-decahydronaphtalen-1-yl ester.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[C:13]1([CH:11]2[CH2:12][NH:8][CH2:9][CH2:10]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(C2CCNC2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To 612 mg (1.23 mmol) of (3S,4S)-3-[1-isopropyl-3-methyl-bicyclo[3.2.1]-2-oxo-1β,3,8-triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester in DCM (12 mL) was added TFA (3.3 mL). The reaction mixture was stirred for 0.75 hour at room temperature, neutralized with 1N NaOH (40 mL) and extracted with DCM. The organic layer was dried over sodium sulfate and concentrated to give 448 mg (88%) of (3R,4S)-3-[(1-isopropyl-3-methyl-bicyclo[3.2.1]-2-oxo-1β,3,8-triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine as a white foam.
Reaction SMILES: [N:1]([CH:4]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[O:7][CH2:6][CH2:5]1)=[N+]=[N-]>CO.[Pd]>[O:7]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:13]2[CH:4]([NH2:1])[CH2:5][CH2:6]1
Reactant: [N-]=[N+]=NC1CCOc2ncccc21
Agent: [Pd]
Solvent: CO
Product: NC1CCOc2ncccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
A catalytic amount of Pd/C (9 mg) was added to a solution of 4-azido-3,4-dihydro-2H-pyrano[2,3-b]pyridine (88 mg) in MeOH (5 mL). The flask closed with a septum, evacuated under house vacuum and hydrogen added via balloon. The resulting suspension was stirred at RT for 60 min, when the H2 balloon was removed, the mixture evacuated and filtered through a plug of celite, that was thoroughly rinsed with MeOH. Removal of the solvents gave the titled compound (73 mg), NMR CDCl3 1H δ 8.1 (dd, 1H), 7.7 (dd, 1H), 6.9 (dd, 1H), 4.5-4.3 (m, 2H), 4.1 (dd, 1H), 2.2 (m, 1H), 1.9 (m, 1H), 1.6 (br s, 2H); MH+=151.
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.[Cl:12][C:13]1[S:17][C:16]([C:18]([OH:20])=O)=[CH:15][CH:14]=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.[O:40]=[C:41]1[CH2:46][O:45][CH2:44][CH2:43][N:42]1[C:47]1[CH:52]=[CH:51][C:50]([NH:53][C:54]([CH:56]2[CH2:60][CH2:59][CH2:58][NH:57]2)=[O:55])=[CH:49][CH:48]=1>CN(C)C=O>[O:40]=[C:41]1[CH2:46][O:45][CH2:44][CH2:43][N:42]1[C:47]1[CH:48]=[CH:49][C:50]([NH:53][C:54]([C@H:56]2[CH2:60][CH2:59][CH2:58][N:57]2[C:18]([C:16]2[S:17][C:13]([Cl:12])=[CH:14][CH:15]=2)=[O:20])=[O:55])=[CH:51][CH:52]=1
Reactant: O=C(Nc1ccc(N2CCOCC2=O)cc1)C1CCCN1
Reactant: O=C(O)c1ccc(Cl)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(N2CCOCC2=O)cc1)[C@H]1CCCN1C(=O)c1ccc(Cl)s1

Procedure:
0.71 g (4.66 mmol) of 1-hydroxybenzotriazole hydrate, 0.76 g (4.66 mmol) of 5-chlorothiophenecarboxylic acid, 1.79 g (9.33 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (DAPECI) and 1.13 ml of N-methylmorpholine are added successively to a solution of 1.35 g (4.66 mmol) of N-[4-(3-oxomorpholin-4-yl)phenyl]pyrrolidine-2-carboxamide in 30 ml of dimethylformamide, and the resultant solution is stirred at room temperature for 12 hours. The reaction solution is subsequently evaporated to dryness under reduced pressure, the residue is taken up in 10 ml of 5% sodium hydrogencarbonate solution, and the sodium hydrogencarbonate solution is extracted twice with 10 ml of ethyl acetate each time. After the combined organic phases have been dried over sodium sulfate and the solvent has been stripped off, the solid residue is triturated with 20 ml of diethyl ether, giving 1.2 g (59.4%) of “AB1”, ESI 434; m.p. 195°.
Reaction SMILES: FC(F)(F)C(O)=[O:4].S(=O)(=O)(O)O.[C:13]([C:15]1[CH:16]=[C:17]([C:22]2[N:26]3[CH:27]=[CH:28][N:29]=[C:30]([NH:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[CH:35][CH:34]=4)[C:25]3=[N:24][CH:23]=2)[CH:18]=[CH:19][C:20]=1[OH:21])#[N:14].C(=O)([O-])[O-].[Na+].[Na+]>>[OH:21][C:20]1[CH:19]=[CH:18][C:17]([C:22]2[N:26]3[CH:27]=[CH:28][N:29]=[C:30]([NH:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([S:39](=[O:40])(=[O:41])[NH2:42])=[CH:35][CH:34]=4)[C:25]3=[N:24][CH:23]=2)=[CH:16][C:15]=1[C:13]([NH2:14])=[O:4]
Reactant: N#Cc1cc(-c2cnc3c(NCc4ccc(S(N)(=O)=O)cc4)nccn23)ccc1O
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)c1cc(-c2cnc3c(NCc4ccc(S(N)(=O)=O)cc4)nccn23)ccc1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Trifluoroacetic acid (1.5 ml) and conc. Sulphuric acid (1.5 ml) were added to 4-{[3-(3-cyano-4-hydroxy-phenyl)-imidazo[1,2-a]pyrazin-8-ylamino]-methyl}-benzenesulfonamide (0.093 g, 0.2 mmol) and the resulting solution was stirred at ambient temperature for 24 hours. The reaction mixture was neutralized with conc. Aqueous sodium carbonate solution and extracted with ethyl acetate (2×50 mL). The organic layers were combined and dried with magnesium sulphate, filtered and concentrated in vaccuo. The crude material was taken up in DMSO and purified by prep HPLC. The product, 2-hydroxy-5-[8-(4-sulfamoyl-benzylamino)-imidazo[1,2-a]pyrazin-3-yl]-benzamide, is obtained as a white solid (4.2 mg, 5%) (LC-MS m/z 439 [M+H]+).