Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)=O)(=O)[CH2:2][CH3:3].C([O-])(=O)C.[NH4+:20].C(O)(=O)C>O>[CH2:2]([C:1]1[O:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[N:20]=1)[CH3:3]
Reactant: CCC(=O)OCC(=O)c1ccc(O)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: CCc1nc(-c2ccc(O)cc2)co1
Temperature: 25 °C
Reaction time: 6 h
Yield: 66.9 %

Procedure:
A mixture of 6.2 parts of 2-(4-hydroxyphenyl)-2-oxoethyl propanoate, 2.7 parts of ammonium acetate and 52.5 parts of acetic acid was stirred for 6 hours at reflux temperature. An additional 2.7 parts of ammonium acetate were added and stirring was continued for 5 hours at reflux temperature and overnight at room temperature. The reaction mixture was poured into water and the precipitate was filtered off, yielding a first fraction of product. The aqueous layer was extracted with methylbenzene. The extract was dried, filtered and then combined with the first product fraction. The whole was dried, filtered and evaporated, yielding 3.8 parts (66.9%) of 4-(2-ethyl-4-oxazolyl)-phenol (interm. 12).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)[CH2:10][CH2:9]1)=[O:7].[H-].[Na+].CN(C=O)C.[CH2:37](Cl)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>O>[OH2:2].[CH2:37]([N:20]1[C:21]2[C:16](=[CH:15][C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:6](=[O:7])[C:5]4[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH2:13][CH2:12]3)=[CH:23][CH:22]=2)[CH2:17][CH2:18][C:19]1=[O:24])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[CH2:37]([N:20]1[C:21]2[C:16](=[CH:15][C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:6](=[O:7])[C:5]4[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH2:13][CH2:12]3)=[CH:23][CH:22]=2)[CH2:17][CH2:18][C:19]1=[O:24])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: ClCc1ccccc1
Reactant: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4)CC2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4Cc3ccccc3)CC2)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-[4-(3,4-Dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril (500 mg) and 70 mg of 60% oily sodium hydride were mixed with 5 ml of DMF and stirred at room temperature for 1 hour. Then, to the mixture was added dropwise 3 ml of DMF solution containing 0.17 ml of benzylchloride. After stirring for 4 hours at room temperature, the reaction mixture was poured into a large amount of water and organic substances were extracted with chloroform. The chloroform layer was washed with water and dehydrated. Chloroform was distilled off and the residue was recrystallized from ethanol to give 150 mg of 1-benzyl-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril hemihydrate, m.p. 131.5°-132.5° C., yellow powders. Elemental Analysis for
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].C[O-].[Na+:31]>CO>[Na+:31].[C:22]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([O-:15])(=[O:13])=[O:14])=[CH:9]2)=[CH:4][CH:3]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2ccc(S(=O)(=O)O)cc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: CC(=O)Nc1ccc2ccc(S(=O)(=O)[O-])cc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 3.75 g (16.8 mmol) of 7-amino-naphthalene-2-sulfonic acid (compound 1) was added 20 mL each of pyridine and acetic anhydride. The reaction was allowed to stir at ambient temperature for 24 hours. The black reaction was cooled in an ice bath and then 45 mL of methanol was added slowly. After 1 hour, a solution of sodium methoxide (425 mg of sodium in 10 mL methanol) was added. A precipitate formed. The suspension was allowed to stir for 2 hours and then the solid was collected by vacuum filtration and was washed with ethyl acetate. This provided 4.4 g of compound 130.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:11]=O)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.CC(O)C.[NH2:17][C:18]1[CH:27]=[CH:26][C:21]2[NH:22][C:23](=[O:25])[NH:24][C:20]=2[CH:19]=1>C(O)(=O)C>[Br:1][C:2]1[C:3](/[CH:11]=[N:17]/[C:18]2[CH:27]=[CH:26][C:21]3[NH:22][C:23](=[O:25])[NH:24][C:20]=3[CH:19]=2)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: O=Cc1cc2c(cc1Br)OCO2
Reactant: Nc1ccc2[nH]c(=O)[nH]c2c1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: O=c1[nH]c2ccc(/N=C/c3cc4c(cc3Br)OCO4)cc2[nH]1
Yield: 95 %

Procedure:
6-bromobenzo[d][1,3]dioxol-5-carbaldehyde (0.63 g, 1.31 mmol), IPA (6 ml), and 5-amino-1H-benzo[d]imidazole-2(3H)-one (0.2 g, 1.31 mmol) were put in a 25 ml flask, and acetic acid (10 ml) was slowly added dropwise thereto while the mixture was stirred under nitrogen charging conditions, followed by stirring for 12 hours under reflux conditions. After that, the temperature of the mixture was lowered to room temperature, and the thus obtained solid was washed with methylene chloride and methanol, followed by filtering, thereby obtaining clean (E)-5-((6bromobenzo[d][1,3]dioxol-5-yl)methyleneamino)-1H-benzo[d]imidazole-2(3H)-one at 95% yield.
Reaction SMILES: [Cl:1]C1SC2[NH:6][C:7]([C:9]([NH:11][CH:12]3[CH2:21][C:20]4[C:15](=CC=CC=4)[N:14](CCOC)[C:13]3=O)=[O:10])=[CH:8]C=2C=1.[ClH:28]>C(Cl)Cl.O1CCOCC1>[ClH:1].[ClH:28].[NH2:6][CH:7]1[CH2:8][C:13]2[C:12](=[CH:21][CH:20]=[CH:15][N:14]=2)[NH:11][C:9]1=[O:10]
Reactant: COCCN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC1Cc2ncccc2NC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl (2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3-yl)carbamate (Method 26, 263 mg, 1 mmol) was dissolved in DCM (10 mL) and treated with 4M HCl in dioxan (10 mL). After stirring at ambient temperature for 30 mins. the reaction mixture was evaporated under reduced pressure and the residue triturated with ether (20 mL), to give a white solid which was collected by filtration, washed with ether and dried. (234 mg, 100%).
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][CH2:5][SH:6].[CH2:7](Cl)/[CH:8]=[C:9](/[CH2:11][CH2:12][CH2:13][C@@H:14]([CH2:16][CH2:17][CH2:18][C@@H:19]([CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH3:20])[CH3:15])\[CH3:10].O>O1CCCC1.C1OCCOCCOCCOCCOCCOC1>[CH3:10][C:9]([CH2:11][CH2:12][CH2:13][CH:14]([CH3:15])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:20])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:8][CH2:7][S:6][CH2:5][CH2:4][NH2:3]
Reactant: NCCS
Reactant: C/C(=C\CCl)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=CCSCCN)CCCC(C)CCCC(C)CCCC(C)C
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
Under an atmosphere of argon, sodium hydride (9.60 g, 240 mmol, 60% dispersion in mineral oil) was added to a solution of 2-aminoethanethiol (15.3 g, 200 mmol) in 200 ml of tetrahydrofuran and the mixture was stirred at 20° C. for 30 minutes. To the reaction mixture, 18-crown-6 (50 mg, 0.190 mmol) was added and then a solution of phytyl chloride (1-chloro-3,7,11,15-tetramethyl-2-hexadecaene) [55.0 g, 175 mmol, prepared as described in Item a) given above] in 200 ml of tetrahydrofuran was added in dropwise for an hour at below 10° C. After stirring at 20°-30° C. for 24 hours, water was added to the reaction mixture until forming did not occur. The solvent was evaporated in vacuo to dryness and the remaining residue was extracted with ethyl ether. The ether layer was washed twice with water and an aqueous solution saturated with sodium chloride, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to dryness. The remaining residue was chromatographed on silica gel, eluting with CH2Cl2 /MeOH (10:1) to afford 50.9 g (81.8%) of the desired compound, as a pale brown oil.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH:31]=O)=[CH:25][CH:24]=1.N1CCCCC1>C(O)C>[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH:31]=[C:18]2[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]3[N:4]4[CH:3]=[CH:2][N:1]=[C:5]4[CH:6]=[CH:7][CH:8]=3)[C:19]2=[O:20])=[CH:25][CH:24]=1
Reactant: O=CCCc1ccc(F)cc1
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1SC(=CCCc2ccc(F)cc2)C(=O)N1CCCCSc1cccc2nccn12

Procedure:
To a solution of 964 mg (3.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 609 mg (4.0 mmol) of 3-(4-fluorophenyl)-1-propanal in 20 ml of ethanol, 26 mg (0.3 mmol) of piperidine was added, followed by refluxing for 4.5 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with purified water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, chloroform/methanol=50/1) to yield 0.88 g (64.2%, yellow oily substance) of the desired product.
Reaction SMILES: O.[NH2:2][NH2:3].C[O:5][C:6]([C:8]1[N:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH:15]2[C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH:20]=2)[N:11]=[C:10]([NH:30][C:31]2[CH:35]=[C:34]([CH3:36])[NH:33][N:32]=2)[CH:9]=1)=O>CO>[NH2:2][NH:3][C:6]([C:8]1[N:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH:15]2[C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH:20]=2)[N:11]=[C:10]([NH:30][C:31]2[CH:35]=[C:34]([CH3:36])[NH:33][N:32]=2)[CH:9]=1)=[O:5]
Reactant: NN
Reactant: COC(=O)c1cc(Nc2cc(C)[nH]n2)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Solvent: CO
Solvent: O
Product: Cc1cc(Nc2cc(C(=O)NN)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Yield: 68.2 %

Procedure:
Hydrazine mono-hydrate (1.6 ml, 20.6 mmol) was added to a mixture of 6-methoxycarbonyl-2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine (Example 56) (1.54 g, 3.45 mmol) in methanol (20.0 ml) at ambient temperature. The resulting reaction mixture was heated at reflux for 1 hour then allowed to cool. The resulting solid was collected by filtration and washed with methanol to give the title compound (1.05 g, 68.3%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17]C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[C:15](=[O:31])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[NH2:2].[OH-].[Na+]>O.[Pd]>[NH2:17][CH:16]1[C:15](=[O:31])[N:10]2[C:11]([C:12]([OH:14])=[O:13])=[C:6]([CH2:5][O:4][C:1](=[O:3])[NH2:2])[CH2:7][S:8][C@H:9]12
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)OCc3ccc([N+](=O)[O-])cc3)[C@H]2SC1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1

Procedure:
3-Carbamoyloxymethyl-7-p-nitrobenzyloxycarbonylamino-3-cephem-4-carboxylic acid (7.5 g.; 16.5 m. mole) was dissolved in water (100 ml) by adding 1 N sodium hydroxide solution to give a solution with a pH of 7.0. This solution was added to pre-hydrogenated 5% palladium on calcium carbonate catalyst (7.5 g.) in water (100 ml) and hydrogenation was continued for 41/2 hours. The reaction mixture was filtered and the filtrate was washed with ether and freeze dried. Thin layer chromatography of the solid residue in chloroform, acetone, acetic acid (50:50:7) revealed one spot with no starting material present. This residue was dissolved in water (25 ml) and the pH of the solution adjusted to 4.0 with 1 N hydrochloric acid resulting in the precipitation of a white solid. The mixture was cooled in the refrigerator and the white solid was collected and dried in vacuo. (1.954 g.). The filtrate was reduced to 5 ml by evaporation and a second crop of solid (0.320 g.) was obtained on cooling. Both crops were dried in vacuo and characterized as 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid. δ (TFA) 5.5 (4H, sharp s on top of AB quartet, H7, H6 and 3-CH2 -); δ (DMSO) 6.58 (2H, s, OCONH2, exchanges with D2O), 5.00 (2H, m, H7 and α-protons), 4.75 (3H, d overlapping AB quartet, H6 and 3-CH2) and 3.50 (2H, broad s, S-CH2) γ max (KBr) 1790 (β-lactam C=O), 1710, 1605 cn-1 ; λ max (H20) 265 nm (εm 7,203).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([Br:8])=[CH:5][C:6]=1I.[CH:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>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>[Br:1][C:2]1[S:3][C:4]([Br:8])=[CH:5][C:6]=1[C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C#CCCCCCCCC
Reactant: Brc1cc(I)c(Br)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCCCCCCCC#Cc1cc(Br)sc1Br
Temperature: 0 °C
Reaction time: 20 h

Procedure:
To a solution of the above prepared 2,5-dibromo-3-iodothiophene (3.43 grams, 9.3 mmol) and 1-decyne (1.45 grams, 10.5 mmol) in triethylamine (50 milliliters) were added dichlorobis(triphenylphosphine)palladium (II) (0.28 gram, 0.4 mmol) and copper(I) iodide (38 milligrams, 0.2 mmol) at 0° C. under argon. The reaction mixture was stirred at 0° C. for 6 hours and at room temperature for 20 hours under argon. After evaporation of the solvent, the product was purified by column chromatography on silica gel using hexane as eluent. 2,5-Dibromo-3-decynylthiophene was thus obtained as a colorless liquid was. Yield: 3.32 grams (94 percent).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][N:3]=1.Cl[CH2:9][CH:10]=O>O>[Br:1][C:2]1[S:6][C:5]2=[N:7][CH:9]=[CH:10][N:4]2[N:3]=1
Reactant: Nc1nnc(Br)s1
Reactant: O=CCCl
Solvent: O
Product: Brc1nn2ccnc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 5-bromo-1,3,4-thiadiazol-2-amine (60 g, 0.33 mol) in H2O (1.5 L), a solution of chloroacetaldehyde (50% wt in water, 64.5 mL, 0.50 mol) was added, and the mixture was stirred at reflux temperature for 5 h. A second portion of chloroacetaldehyde (20.6 mL, 0.5 eq) was added, and stirring was continued overnight. The starting material had been consumed completely, and the reaction mixture was cooled to RT. The solid was removed by filtration and washed with water. The mother liquor was neutralized with a sat. aq. solution of NaHCO3 and extracted with DCM (2×1 L). The organic layers were washed with brine (2×600 mL), dried and evaporated in vacuo. The brown residue obtained was triturated with a mixture of MeOH and MTBE (1:1, 70 mL) to afford the desired product as a pale yellow solid. The mother liquors were purified by chromatography (SiO2, DCM) to yield some more product. Combined yield: 9.4 g (14%). MS (ESI+): m/z=204 [M+H]+; 1H-NMR(CDCl3): 7.36 (d, 1H); 7.56 (d, 1H).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[F:7][C:8]1[CH:9]=[C:10]([NH:20][C:21]2[N:38]=[C:24]3[CH:25]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH2:26][C:27](=C)[CH2:28][CH2:29][N:23]3[N:22]=2)[CH:11]=[CH:12][C:13]=1[N:14]1[C:18]([CH3:19])=[N:17][CH:16]=[N:15]1>O.C1COCC1.[Cl-].[Na+].O.[Os](=O)(=O)(=O)=O>[F:7][C:8]1[CH:9]=[C:10]([NH:20][C:21]2[N:38]=[C:24]3[CH:25]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH2:26][C:27](=[O:2])[CH2:28][CH2:29][N:23]3[N:22]=2)[CH:11]=[CH:12][C:13]=1[N:14]1[C:18]([CH3:19])=[N:17][CH:16]=[N:15]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=C1CCn2nc(Nc3ccc(-n4ncnc4C)c(F)c3)nc2C(c2ccc(F)cc2)C1
Agent: O=[Os](=O)(=O)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ncnn1-c1ccc(Nc2nc3n(n2)CCC(=O)CC3c2ccc(F)cc2)cc1F
Reaction time: 1 h
Yield: 77.8 %

Procedure:
A solution of sodium periodate (2.78 g, 13.0 mmol) in water (10 mL) was added over a 10 min period via pipet to a vigorously stirred solution of the N-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-9-(4-fluorophenyl)-7-methylene-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine (1.88 g, 4.34 mmol) and osmium tetroxide (110 mg, 0.43 mmol) in THF (10.0 mL). The reaction was stirred for 1 h and then diluted with water (150 mL)/brine (100 mL) and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford 2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenylamino)-9-(4-fluorophenyl)-8,9-dihydro-5H-[1,2,4]triazolo[1,5-a]azepin-7(6H)-one (1.47 g, 78% yield). The crude product was used in the next step without further purification. LC-MS (M+H)+ 436.3. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.98 (1 H, s), 7.70 (1 H, dd, J=12.5, 2.1 Hz), 7.27-7.34 (1 H, m), 6.96-7.21 (5 H, m), 4.62 (1 H, dd, J=8.9, 3.7 Hz), 4.41-4.56 (2 H, m), 3.36 (1 H, dd, J=14.2, 9.0 Hz), 3.11 (1 H, dd, J=14.2, 3.8 Hz), 2.83-3.01 (2 H, m), 2.40 (3 H, s).
Reaction SMILES: F[C:2]1[C:22]([F:23])=[CH:21][C:5]2[C:6]3[C:7](=[O:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][N:10]([CH3:14])[C:11]=3[CH:12]=[N:13][C:4]=2[CH:3]=1.[CH3:24][C:25]1([CH3:31])[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]1.O>CS(C)=O>[CH3:24][C:25]1([CH3:31])[CH2:30][CH2:29][CH2:28][N:27]([C:2]2[C:22]([F:23])=[CH:21][C:5]3[C:6]4[C:7](=[O:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][N:10]([CH3:14])[C:11]=4[CH:12]=[N:13][C:4]=3[CH:3]=2)[CH2:26]1
Reactant: CCOC(=O)c1cn(C)c2cnc3cc(F)c(F)cc3c2c1=O
Reactant: CC1(C)CCCNC1
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1cn(C)c2cnc3cc(N4CCCC(C)(C)C4)c(F)cc3c2c1=O
Temperature: 80 °C

Procedure:
A suspension of 2 g of ethyl 8,9-difluoro-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate and 3.23 cm3 of 3,3-dimethylpiperidine in 40 cm3 of dimethyl sulphoxide was heated at a temperature in the region of 80° C. for 72 hours. After cooling to about 200° C., 200 cm3 of water was added to the reaction mixture. The precipitate obtained was dewatered and washed with 25 cm3 of water. The solid was taken up in 100 cm3 of dichloromethane, the residual water was decanted off; the organic solution was dried over magnesium sulphate and concentrated under reduced pressure (5 kPa) at about 40° C. 2.67 g of a mixture containing ethyl 9-(3,3-dimethylpiperidin-1-yl)-8-fluoro-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate and ethyl 8-(3,3-dimethylpiperidin-1-yl)-9-fluoro-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate was obtained. This mixture was purified by flash chromatography on silica gel (particle size 20-45 μm, diameter 10 cm, height 60 cm) at a pressure of 80 kPa, eluted with a mixture containing 99% dichloromethane and 1% methanol, and 70 cm3 fractions were collected. After concentration of fractions 16 to 39 under reduced pressure (5 kPa) at about 50° C., 0.85 g of ethyl 9-(3,3-dimethylpiperidin-1-yl)-8-fluoro-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate was obtained in the form of a yellow solid, which melted at around 218-220° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[O:5][CH2:6][CH2:7][Br:8].[O:13]=[S:14](Cl)Cl.OS(O)(=O)=O>N1C=CC=CC=1>[Br:8][CH2:7][CH2:6][O:5][C:4]1[CH:9]=[CH:10][C:11]2=[N:12][S:14](=[O:13])[N:1]=[C:2]2[CH:3]=1
Reactant: Nc1ccc(OCCBr)cc1N
Reactant: O=S(Cl)Cl
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Product: O=S1N=c2ccc(OCCBr)cc2=N1
Temperature: 0 °C
Yield: 17 %

Procedure:
To a cooled (ice-water) solution of 2-(3,4-diaminophenoxy)ethyl bromide (2.03 g, 8.8 mmol) in pyridine (40 mL) was added dropwise 0.65 mL (8.9 mml) of SOCl2 with stirring. The resulting mixture was stirred at r.t for 2 h, then 4N H2SO4 was added dropwise with cooling. The acidic (pH 5) mixture was extracted with CHCl3 (4×50 mL). The CHCl3 solution was washed with brine, dried (Na2SO4), then evaporated to give 420 mg (17%) of 5-(2-bromoethoxy)-2,1,3-benzothiadiazol-2-one as an orange-yellow powder. 1H NMR (CDCl3): 3.737 (t, 2H, J=6), 4.407 (t, 2H, J=6), 7.195 (d, 1H, J=2), 7.341 (dd, 1H, J=9; 2), 7.874 (d, 1H, J=9).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([B:9]([OH:11])[OH:10])[CH:6]=[CH:7][CH:8]=1.O[C:15]([C:18](O)([CH3:20])[CH3:19])([CH3:17])[CH3:16]>>[CH3:16][C:15]1([CH3:17])[C:18]([CH3:20])([CH3:19])[O:10][B:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:12])[F:13])[CH:4]=2)[O:11]1
Reactant: CC(C)(O)C(C)(C)O
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: CC1(C)OB(c2cccc(C(F)(F)F)c2)OC1(C)C
Yield: 47 %

Procedure:
The title compound (47%, oil) was prepared from 3-trifluoromethylphenylboronic acid and pinacol.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:32])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH:25]([F:30])[C:26]([F:29])([F:28])[F:27])[CH:23]=3)[N:18]([CH3:31])[N:17]=2)[CH2:9]1.[OH:33][C:34]1([C:41]2[S:42][CH:43]=[CH:44][N:45]=2)[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1>>[OH:33][C:34]1([C:41]2[S:42][CH:43]=[CH:44][N:45]=2)[CH2:35][CH2:36][CH:37]([N:8]2[CH2:11][CH:10]([NH:12][C:13](=[O:32])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([CH:25]([F:30])[C:26]([F:29])([F:28])[F:27])[CH:23]=4)[N:18]([CH3:31])[N:17]=3)[CH2:9]2)[CH2:38][CH2:39]1
Reactant: O=C1CCC(O)(c2nccs2)CC1
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(F)C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(NCC(=O)NC2CN(C3CCC(O)(c4nccs4)CC3)C2)c2cc(C(F)C(F)(F)F)ccc21

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-[1-methyl-5-(1,2,2,2-tetrafluoro-ethyl)-1H-indazol-3-ylamino]-acetamide TFA salt (as prepared in Example 65, Step B) and 4-hydroxy-4-thiazol-2-yl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][C:11]([F:21])=[CH:10][CH:9]=2)=[O:5])[CH3:2].Br[CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([F:34])[CH:32]=2)[CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([F:34])[CH:32]=3)[CH:27]=[CH:26][CH:25]=2)[C:8]2[C:13]([C:14]=1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][C:11]([F:21])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: Fc1ccc2cccc(CBr)c2c1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)[nH]c2ccc(F)cc12
Product: CCOC(=O)Cc1c(C(=O)OCC)n(Cc2cccc3ccc(F)cc23)c2ccc(F)cc12

Procedure:
Using general procedure B, 3-ethoxycarbonylmethyl-5-fluoro-1H-indole-2-carboxylic acid ethyl ester (Lit. 10) was coupled with 1-bromomethyl-7-fluoro-naphthalene (from Example 49.3.) to give 3-ethoxycarbonylmethyl-5-fluoro-1-(7-fluoro-naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid ethyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give 3-carboxymethyl-5-fluoro-1-(7-fluoro-naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid as a white solid. MS: 394.1 ([M−H]−).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[S:7][C:8]([C:11]([NH:13][CH2:14][CH2:15][CH:16]3[CH:23]4[CH2:24][CH:19]5[CH2:20][CH:21]([CH2:25][CH:17]3[CH2:18]5)[CH2:22]4)=[O:12])=[CH:9][N:10]=2)[CH2:2]1.[CH:26]([NH2:29])([CH3:28])[CH3:27]>C(O)C>[CH:26]([NH:29][CH2:2][CH:3]([OH:1])[CH2:4][O:5][C:6]1[S:7][C:8]([C:11]([NH:13][CH2:14][CH2:15][CH:16]2[CH:17]3[CH2:25][CH:21]4[CH2:20][CH:19]([CH2:24][CH:23]2[CH2:22]4)[CH2:18]3)=[O:12])=[CH:9][N:10]=1)([CH3:28])[CH3:27]
Reactant: O=C(NCCC1C2CC3CC(C2)CC1C3)c1cnc(OCC2CO2)s1
Reactant: CC(C)N
Solvent: CCO
Product: CC(C)NCC(O)COc1ncc(C(=O)NCCC2C3CC4CC(C3)CC2C4)s1
Temperature: -20 °C
Reaction time: 12 h

Procedure:
This example illustrates methods for preparing the compounds of the present invention. In this example a mixture containing 12 g. (0.0314 mole) of 1,2-epoxy-3-(5-[2-(adamant-2-yl)ethylaminocarbonyl]thiazol-2-yloxy)-propane, 12 g. (0.203 mole) of isopropylamine and 20 ml. of ethanol is allowed to stand at room temperature for 12 hours. The mixture is then evaporated under vacuum to remove the solvent and the resulting residue dissolved in 50 ml. of ethyl acetate and cooled to -20° C, and maintained at this temperature for 2 hours. The mixture is then filtered and the resulting filter cake washed with cold (about 0° C) ethyl and then recrystallized from ethyl acetate affording 1-isopropylamino-3-(5-[2-(adamant-2-yl)ethylaminocarbonyl]thiazol-2-yloxy)-propan-2-ol.