Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][CH2:19][N:20]=[N+:21]=[N-:22])=[CH:15][CH:14]=[C:13]([F:23])[CH:12]=2)[C:5]([O:7][CH3:8])=[O:6].[CH3:25][O-].[Na+].CI>CO>[CH3:1][O:2][C:3](=[O:24])[C:4]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][CH2:19][N:20]=[N+:21]=[N-:22])=[CH:15][CH:14]=[C:13]([F:23])[CH:12]=2)([CH3:25])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C(C(=O)OC)c1[nH]c2cc(F)ccc2c1CCN=[N+]=[N-]
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: COC(=O)C(C)(C(=O)OC)c1[nH]c2cc(F)ccc2c1CCN=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-[3-(2-azidoethyl)-6-fluoro-1H-indol-2-yl]-propanedioic acid dimethyl ester (37 mmol) in dry MeOH (0.25 L) at 0° C. under argon was added a solution of 25% NaOMe in MeOH (8.56 mL, 37.4 mmol). The mixture was stirred for 30 min at 0° C. MeI (3.56 mL, 56.6 mmol) was added. The mixture was refluxed for 42 h, cooled, and concentrated. The residue was partitioned between H2O and Et2O. The Et2O extracts were washed with H2O, dried, and concentrated to an oil. This oil was purified by silica chromatography to give the title compound: TLC Rf=0.50 (CH2Cl2); MS (ESI+) m/z 371.1; 1H NMR (CDCl3, 300 MHz) δ 9.63 (1H), 7.44 (1H), 7.05 (1H), 6.97 (1H), 3.82 (6H), 3.44 (2H), 2.94 (2H), 1.93 (3H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1([NH:14][C:15]2[C:16](=[O:35])[N:17]([C:21]3[CH:22]=[C:23]([CH:30]=[C:31]([F:34])[C:32]=3[CH3:33])[C:24]([NH:26][CH:27]3[CH2:29][CH2:28]3)=[O:25])[CH:18]=[CH:19][N:20]=2)[CH2:13][CH2:12]1.[CH3:36][NH2:37]>O.O1CCOCC1>[CH:27]1([NH:26][C:24](=[O:25])[C:23]2[CH:22]=[C:21]([N:17]3[CH:18]=[CH:19][N:20]=[C:15]([NH:14][C:11]4([C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[O:4][CH2:3][CH2:2][NH:37][CH3:36])[CH2:13][CH2:12]4)[C:16]3=[O:35])[C:32]([CH3:33])=[C:31]([F:34])[CH:30]=2)[CH2:29][CH2:28]1
Reactant: CN
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCCl)CC2)c1=O
Solvent: C1COCCO1
Solvent: O
Product: CNCCOc1ccccc1C1(Nc2nccn(-c3cc(C(=O)NC4CC4)cc(F)c3C)c2=O)CC1

Procedure:
3-[3-[[1-[2-(2-chloroethoxy)phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-5-fluoro-4-methyl-benzamide (Preparation 1l, 0.5 g) and 40% methylamine in water (0.697 mL) were heated at 100° C. in dioxane (8 mL) in a sealed tube for 24 h. Purification of the cooled solution by preparative HPLC (Waters Xbridge column—acetonitrile/0.2% ammonia mobile phase) gave the title compound (270 mg).
Reaction SMILES: [CH3:1]COCC.C[Li].[O:8]=[C:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].[Cl-].[Ce+3].[Cl-].[Cl-]>O1CCCC1>[OH:8][C:9]1([CH3:1])[CH2:13][CH2:12][CH2:11][CH:10]1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NC1CCCC1=O
Reactant: CCOCC
Agent: [Ce+3]
Agent: [Cl-]
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCCC1(C)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 82 %

Procedure:
A 1.6 M ether solution of methyllithium (13.59 mL, 21.75 mmol) was added to a stirred suspension of tert-butyl 2-oxocyclopentylcarbamate (1.97 g, 9.89 mmol, from Step 2) and cerium(III) chloride (5.36 g, 21.75 mmol) in tetrahydrofuran (50 mL) at −78° C. under nitrogen. After 2.5 h at −78° C., the mixture was quenched with saturated ammonium chloride, allowed to warm to room temperature, and filtered through a short bed of Celite to remove insoluble cerium salt. The filter cake was rinsed with ethyl acetate. The filtrated was extracted with ethyl acetate three times. The combined ethyl acetate phase was washed with saturated ammonium chloride and brine respectively, dried (MgSO4), filtered and concentrated. Silica gel chromatography, eluting with 0 to 50% ethyl acetate in hexanes, gave tert-butyl 2-hydroxy-2-methylcyclopentylcarbamate as yellow solid (1.47 g, 82% yield). 1H NMR analysis indicated the presence of approximately a 3:1 diastereomeric mixture.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.[N:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:25][CH:24]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:17][C:10]1[CH:9]=[C:8]([C:18](=[O:20])[CH3:19])[C:7]([N:33]2[CH2:34][CH2:35][N:30]([CH2:29][C:26]3[CH:25]=[CH:24][N:23]=[CH:28][CH:27]=3)[CH2:31][CH2:32]2)=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2
Reactant: c1cc(CN2CCNCC2)ccn1
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(Cc2ccncc2)CC1
Temperature: 65 °C
Yield: 15.6 %

Procedure:
A stirred mixture of 7-acetyl-5-chloroquinolin-8-yl trifluoromethanesulfonate (0.12 g, 0.34 mmol, from Example 47, Step 2), 1-(pyridin-4-ylmethyl)piperazine (0.072 g, 0.41 mmol), palladium acetate (1.5 mg, 0.0067 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (6.3 mg, 0.010 mmol), and cesium carbonate (0.31 g, 0.95 mmol) in tetrahydrofuran (3 mL) was heated at 65° C. overnight. The mixture was cooled, diluted with dichloromethane and filtered. The filtrate was washed with brine, dried over MgSO4 and evaporated. The resulting residue was purified on silica gel (eluting with 0 to 10% methanol in dichloromethane) to give the desired product (20.2 mg, 16%). LCMS calculated for C21H22ClN4O (M+H)+: m/z=381.1; Found: 381.1.
Reaction SMILES: CN(C)[CH:3]=[C:4]1[CH2:8][CH2:7][CH:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:5]1=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([NH:38][C:39]([NH2:41])=[NH:40])[CH:29]=[CH:30][C:31]=1[N:32]1[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]1>>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([NH:38][C:39]2[N:41]=[CH:3][C:4]3[CH2:8][CH2:7][CH:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:5]=3[N:40]=2)[CH:29]=[CH:30][C:31]=1[N:32]1[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CCOC(=O)C1CCC(=CN(C)C)C1=O
Solvent: O=[N+]([O-])O
Product: CCOC(=O)C1CCc2cnc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)nc21

Procedure:
The title compound was prepared from crude ethyl 3-[1-dimethylamino-methylidene]-2-oxo-cyclopentanecarboxylate (70 mg, 0.3 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (83 mg, 0.22 mmol) using in analogous manner the procedure described in example 45b). Obtained as a pale-yellow solid (5 mg, 6%). MS ISP (m/e): 394.3 [(M+H)+]. mp 150-153° C.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([CH3:16])[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.[CH2:19](O)[CH3:20].C([O-])([O-])OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(N(CC)CC)C>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([CH3:16])[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]=[C:10]([O:11][CH2:19][CH3:20])[C:4]=2[CH:3]=1
Reactant: CCO
Reactant: CN1c2ccccc2CC(=O)c2cc(Br)ccc21
Agent: CCOC([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Product: CCOC1=Cc2ccccc2N(C)c2ccc(Br)cc21
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A suspension of 29.5 g of 2-bromo-5-methyl-10,11-dihydro [5H] dibenzo (b,f) azepine-11-one, 295 ml of ethanol and 29.5 ml of ethyl orthoformate was heated to 70°C and then 1 g of p-toluene sulfonic acid was added thereto in small fractions. The mixture was held at 70°C for 11/2 hours and then 15 ml of triethylamine were added dropwise while still hot and the mixture was then cooled. The product crystallized and the mixture was diluted with 300 ml of distilled water, was stirred at room temperature for 30 minutes and was vacuum filtered. The recovered precipitate was washed with water and dried to obtain 31.8 g of 2-bromo-5-methyl-11-ethoxy [5H] dibenzo (b,f) azepine as pale yellow crystals melting at 131°C.
Reaction SMILES: OS(O)(=O)=O.[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][N:7]=1.[Br:16]N1C(=O)CCC1=O.[NH4+].[OH-]>CCCCCCC>[Br:16][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[CH:9]=[CH:8][N:7]=[CH:6]2
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2cnccc2c1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CCCCCCC
Product: Brc1cccc2cnccc12
Temperature: -10 °C

Procedure:
Concentrated H2SO4 (260 mL) was cooled to −25° C. while stirring with a mechanical stirrer. Isoquinoline (30 mL, 0.25 mol) was added slowly so the temperature did not exceed 0° C. After the addition was complete the red solution was recooled to −25° C. and treated with N-bromosuccinimide (55.49 g, 0.31 mol) in small portions so that the temperature did not exceed −20° C. The reaction mixture was stirred for 5 hours keeping the temperature between −30° C. and −18° C. The reaction mixture was then allowed to warm to −10° C. and was poured carefully over 600 g of ice. The resulting slurry was adjusted to pH 10 using 25% NH4OH. The mixture was then extracted with diethyl ether (3×600 mL). The ether fractions were combined, filtered through a celite plug and the filtrate concentrated under reduced pressure. The residue was suspended in hot heptane (600 mL). The heptane was decanted. This procedure was repeated with hexane (2×200 mL). The combined heptane and hexane fractions were concentrated under reduced pressure to give a mustard yellow solid. The title compound was obtained by recrystallization from heptane (26.37 g, 50%). mp 78°-80° C.; MS (ESI+) m/z 209 (M+H)+; 1H NMR (DMSO, 300 MHz) δ 7.65 (t, J 7.9, 1H), 7.94 (d, J 8.1, 1H), 8.17 (dd, J 1.0, 7.4, 1H), 8.22 (d, J 8.1, 1H), 8.68 (d, J 6.1, 1H), 9.37 (s, 1H); Anal. Calcd for C9H6BrN: C, 51.96; H, 2.91; N, 6.73; Br, 38.41. Found: C, 51.24; H, 2.79; N, 6.52; Br, 38.81.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:10][S:11][CH2:12][CH2:13][CH2:14]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.O>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:14][CH2:13][CH2:12][S:11][CH3:10]
Reactant: CSCCCO
Reactant: Cc1c(O)cccc1Br
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: CSCCCOc1cccc(Br)c1C

Procedure:
3-Bromo-2-methylphenol (0.10 g), 3-(methylthio)propanol (0.055 mL), tri-n-butyl phosphine (0.12 g) and 1,1′-(azodicarbonyl)dipiperidine (0.15 g) are stirred in tetrahydrofurane for 16 hours. Water is added and the mixture extracted with diethyl ether. The organic layer is washed with brine, dried (Na2SO4) and volatiles removed under reduced pressure. The product (80 mg) is obtained after column chromatography (silica gel, n-hexane/ethyl acetate gradient 100:0 to 50:50).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[Mg].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[O:19][C:18](=[O:20])[C@H:17]([CH2:21][CH:22]([CH3:24])[CH3:23])[O:16]2)=[CH:11][CH:10]=1.[NH4+].[Cl-]>CCOCC.[Cl-].[Zn+2].[Cl-]>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:15]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)[O:16][C@@H:17]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:18]([OH:20])=[O:19])=[CH:13][CH:14]=1
Reactant: Brc1cccs1
Reactant: CC(C)C[C@@H]1OC(c2ccc(Br)cc2)OC1=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)C[C@H](O[C@@H](c1ccc(Br)cc1)c1cccs1)C(=O)O
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-bromothiophene (326 mg, 2.0 mmol) in ether (8 mL) was added magnesium turnings (51 mg, 2.1 mmol). The mixture was heated at 50° C. for 1 hour, under a nitrogen atmosphere. The grignard solution was then cooled down to −40° C. and aged until addition. In a second flask, cooled at −40° C., a 0.2M solution of (5S)-2-(4-bromophenyl)-5-isobutyl-1,3-dioxolan-4-one in ether, from step 1 (5.0 mL, 1.0 mmol) was added dropwise to a 1.0M solution of zinc chloride in ether (5.0 mL, 5 mmol). Finally, the grignard solution was added dropwise to the zinc chloride mixture and the reaction was aged for 30 minutes at −40° C. The mixture was allowed to warm to 0° C. and aged for 4 hours. The reaction was then poured into a saturated aqueous solution of NH4Cl and the resulting mixture was extracted 3 times with Et2O. The organic layers were washed with brine, dried and evaporated. The crude product was chromatographed on silica gel using 30% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:17][CH3:18])=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:7]=1.[N+:19]([O-])([O-:21])=[O:20].[K+]>S(=O)(=O)(O)O>[N+:19]([C:7]1[C:2]([OH:1])=[C:3]([O:17][CH3:18])[CH:4]=[C:5]([N+:14]([O-:16])=[O:15])[C:6]=1[CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])([O-:21])=[O:20]
Reactant: COc1cc([N+](=O)[O-])c(CCCC(=O)O)cc1O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COc1cc([N+](=O)[O-])c(CCCC(=O)O)c([N+](=O)[O-])c1O
Temperature: -15 °C

Procedure:
The product from Example 1 (0.77 g) was dissolved in concentrated sulfuric acid and cooled to -15° C. Potassium nitrate (0.31 g) was gradually added to this solution while maintaining the reaction temperature between -15 and -10° C. The resultant mixture was stirred at -15° C. for half an hour and then poured into ice. The solid was washed with water and dried.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[CH3:2].S(Cl)(Cl)=O.[CH3:16]O>>[CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH3:16])=[O:8])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CO
Reactant: CCc1ccc(C(=O)O)cc1
Solvent: O=S(Cl)Cl
Product: CCc1ccc(C(=O)OC)cc1
Reaction time: 3 h

Procedure:
A mixture of 4-ethylbenzoic acid (5.12 g), thionyl chloride (3.0 ml) and methanol (150 ml) was heated and refluxed. After 3 hours, the mixture was concentrated under reduced pressure to give methyl 4-ethylbenzoate (5.59 g). this product was used in the subsequent step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([N:27]([CH2:32][C:33]([OH:35])=[O:34])[CH2:28][C:29]([OH:31])=[O:30])[CH2:10][N:11]([CH2:16][CH2:17][N:18]([CH2:23][C:24]([OH:26])=[O:25])[CH2:19][C:20]([OH:22])=[O:21])[CH2:12][C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1.[C:36](Cl)(Cl)=[S:37].C(Cl)(Cl)Cl>O>[C:33]([CH2:32][N:27]([CH2:28][C:29]([OH:31])=[O:30])[CH:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]=[C:36]=[S:37])=[CH:3][CH:4]=1)[CH2:10][N:11]([CH2:16][CH2:17][N:18]([CH2:19][C:20]([OH:22])=[O:21])[CH2:23][C:24]([OH:26])=[O:25])[CH2:12][C:13]([OH:15])=[O:14])([OH:35])=[O:34]
Reactant: Nc1ccc(CC(CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O)N(CC(=O)O)CC(=O)O)cc1
Reactant: S=C(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(O)CN(CCN(CC(=O)O)CC(Cc1ccc(N=C=S)cc1)N(CC(=O)O)CC(=O)O)CC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a solution of 6a (10 mg, 0.0155 mmol) in water (100 μL) was added dropwise 1M thiophosgene in CHCl3 (18.6 μL, 0.0186 mmol). The resulting mixture was stirred at room temperature for 3 h. The aqueous layer was concentrated in vacuo to provide pure 7a (10 mg, 99%) as a light yellowish solid. 1H NMR (MeOD, 300 MHz) δ 2.50-4.55 (m, 24H), 7.10-70 (m, 4H).
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25]([OH:27])=O)[CH:20]=4)[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.[N:35]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=[N:36]1.C(OC(C)(C)C)(=O)NN>C(N(CC)CC)C>[CH:1]1([CH2:7][NH:8][C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25]([NH:35][NH2:36])=[O:27])[CH:20]=4)[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cc(Oc2ccc3nc(NCC4CCCCC4)oc3c2)ccn1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CC(C)(C)OC(=O)NN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: NNC(=O)c1cc(Oc2ccc3nc(NCC4CCCCC4)oc3c2)ccn1

Procedure:
In Scheme 5, 4-(2-(methylsulfinyl)benzo[d]oxazol-6-yloxy)-N-methylpyridine-2-carboxamide is aminated with cyclohexylmethanamine. The resulting 4-(2-(cyclohexylmethylamino)benzo[d]oxazol-6-yloxy)-N-methylpyridine-2-carboxamide is then hydrolyzed to form 4-[2-(cyclohexylmethyl-amino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic acid. 4-[2-(Cyclohexylmethyl-amino)-benzooxazol-6-yloxy]-pyridine-2-carboxylic acid then reacts with benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate, tert-butyl carbazate, and triethyl amine to form 4-(2-(cyclohexylmethylamino)benzo[d]oxazol-6-yloxy)pyridine-2-carbohydrazide. 4-(2-(Cyclohexylmethylamino)benzo[d]oxazol-6-yloxy)pyridine-2-carbohydrazide then reacts with trimethyl orthoformate to form a compound of the embodiments.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:34]=[CH:33][C:8]2=[N:9][N:10]([C:12]3[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:15]=[C:14]([C:22]([CH3:31])([CH3:30])[C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)[C:13]=3[OH:32])[N:11]=[C:7]2[CH:6]=1)=[O:4].[OH:35][C:36]([CH3:51])([CH3:50])[CH2:37][O:38][N:39]1[C:44]([CH3:46])([CH3:45])[CH2:43]C(O)[CH2:41][C:40]1([CH3:49])[CH3:48]>>[OH:35][C:36]([CH3:51])([CH3:50])[CH2:37][O:38][N:39]1[C:44]([CH3:46])([CH3:45])[CH2:43][CH:1]([O:2][C:3]([C:5]2[CH:34]=[CH:33][C:8]3=[N:9][N:10]([C:12]4[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:15]=[C:14]([C:22]([CH3:31])([CH3:30])[C:23]5[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=5)[C:13]=4[OH:32])[N:11]=[C:7]3[CH:6]=2)=[O:4])[CH2:41][C:40]1([CH3:49])[CH3:48]
Reactant: CC(C)(O)CON1C(C)(C)CC(O)CC1(C)C
Reactant: COC(=O)c1ccc2nn(-c3cc(C(C)(C)C)cc(C(C)(C)c4ccc(Cl)cc4)c3O)nc2c1
Product: CC(C)(O)CON1C(C)(C)CC(OC(=O)c2ccc3nn(-c4cc(C(C)(C)C)cc(C(C)(C)c5ccc(Cl)cc5)c4O)nc3c2)CC1(C)C

Procedure:
5-Methoxycarbonyl2-[2-hydroxy-3-(4-chloro-α,α-dimethylbenzyl)-5-tert-butyl-phenyl]-2H-benzotriazole (3.89 g, 0.0081 mol) and 1-(2-hydroxy-2-methylpropoxy)-2,2,6,6-tetramethyl-4-hydroxypiperidine (2.41 g, 0.0098 mol) are reacted together according to the procedure of Example 1. The title compound is obtained in a yield of 2.26 g (40.2%) as a yellow solid, melting at 80-90° C., whose structure is consistent with 1Hmnr and mass spectrometry. The compound has a molar absorptivity of 17,411 l/mole cm.
Reaction SMILES: [Cl-:1].[Mn+2:2].[Cl-:3].[C:4]1([CH:10]2[CH2:24][NH:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][NH:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>>[Cl:1][C:10]1([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:24][NH:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][N:11]1[Cl:3].[Mn+2:2]
Reactant: c1ccc(C2CNCCNCCNCCNCCN2)cc1
Reactant: [Cl-]
Agent: [Mn+2]
Product: ClN1CCNCCNCCNCCNCC1(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a methanolic solution (50 ml) at low reflux containing anhydrous manganese(II) chloride (150 mg, 1.19 mmol) was added a methanolic solution of 2-phenyl-1,4,7,10,13-pentaazacyclopentadecane prepared as in Example 31E (0.35 g, 1.2 mmol). The reaction was refluxed for 3 h under a dry nitrogen atmosphere and was then allowed to stir at room temperature overnight. The yellow solution was then filtered through celite and taken to dryness. The solid glassy oil was washed with hot ethyl ether (30 ml) and then dissolved in hot EtOH. The EtOH solution was filtered and then evaporated. The solid was recrystallized from acetone/CH3CN to give 255 mg (52% yield) of a white microcrystalline solid: FAB mass spectrum (NBA) m/z (relative intensity); 416 (M+, 2), 381/383 [(M-Cl)+, 100/32] Anal. calcd. for C16H29N5MnCl2 : C, 46.05; H, 7.01; N, 16.78. Found: C, 46.23; H, 7.04; N, 16.62.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[C:33]([O:40]C)[CH:34]=[CH:35][CH:36]=4)[N:31]=3)[CH2:26][CH2:25]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].B(Br)(Br)Br>ClCCl>[F:43][C:2]([F:1])([F:42])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][N:27]([C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[C:33]([OH:40])[CH:34]=[CH:35][CH:36]=4)[N:31]=3)[CH2:28][CH2:29]2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[C:14]2[C:19]1=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:6]
Reactant: COc1cccc2ccc(N3CCN(CCCCC4(C(=O)NCC(F)(F)F)c5ccccc5-c5ccccc54)CC3)nc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc4cccc(O)c4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
A solution of 0.2 g (0.34 mmol) of 9-{4-[4-(8-methoxy-quinolin-2-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 0.16 ml (1.7 mmol) of boron tribromide in 20 ml of dichloromethane is stirred for 48 hours at ambient temperature. The reaction solution is extracted with water and dichloromethane, dried over sodium sulphate and the solvent is distilled off. The product is purified by column chromatography on silica gel (eluant: ethyl acetate/methanol=50:1).
Reaction SMILES: [C:1]([C:4]1[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]=[C:7]1[C:11](=[O:12])[O:10]C(C2C=CC=CC=2)=N1)([OH:3])=[O:2].O1C=CNC1=O.[OH-].[Na+].Cl>O>[CH3:24][O:23][C:22]1[C:4]2[C:1](=[O:3])[O:2][C:7]([C:11]([OH:10])=[O:12])=[CH:6][C:5]=2[CH:19]=[CH:20][CH:21]=1
Reactant: COc1cccc(C=C2N=C(c3ccccc3)OC2=O)c1C(=O)O
Agent: Cl
Agent: O=c1[nH]cco1
Agent: [Na+]
Solvent: O
Product: COc1cccc2cc(C(=O)O)oc(=O)c12

Procedure:
A solution of the oxazolone of Example 4 (1.80 g., 5.57 mM) and 3.06 g. of sodium hydroxide in 15.2 ml. of water is refluxed under nitrogen for two hours. The resulting solution is cooled, acidified with concentrated hydrochloric acid, and refluxed for 0.5 hour. The solution is cooled and filtered to separate the precipitated solids. The dried solid is triturated with 2 ml. of cold methanol (to remove benzoic acid) and filtered to separate the product, m.p. 251°-253°. Recrystallization from 12 ml. of methanol (charcoal) gives 8-methoxy-1-oxo-1H-2-benzopyran-3-carboxylic acid as a white solid, m.p. 255°-256°.
Reaction SMILES: [F:1][C:2]1([F:19])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[C:3]1([F:18])[F:17].FC(F)(F)C(O)=[O:23]>[O-2].[O-2].[O-2].[Cr+6].C(O)(=O)C>[F:1][C:2]1([F:19])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[O:23])[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[C:3]1([F:17])[F:18]
Reactant: FC1(F)c2ccccc2Cc2ccccc2C1(F)F
Reactant: O=C(O)C(F)(F)F
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(F)(F)C(F)(F)c2ccccc21

Procedure:
A mixture of 1.45 g. (0.00544 mole) of 10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene, 0.73 g. (0.0073 mole) of chromium trioxide, 25 ml. of trifluoroacetic acid and 2 ml. of glacial acetic acid is stirred at reflux for 21/4 hours. During this period, almost all of the chromium trioxide dissolves. Solvents are evaporated under reduced pressure and the residue is partitioned between benzene and water. The aqueous layer is separated and re-extracted twice with benzene. The combined benzene extracts are washed thoroughly with water, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure. The crude product is left as the residual oily solid and is purified by column chromatography on 75 g. of silica gel, eluting the product with 1:1 benzene-carbon tetrachloride. The fractions that show one spot of Rf 0.75 on a silica thin layer plate developed with benzene are combined. Evaporation of the solvent under reduced pressure leaves the white crystalline product, m.p. 70°-75°C.