Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=2.[H-].[Na+].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:28]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:23][CH:22]=1>CN(C=O)C>[C:36]([O:35][C:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:3]2[C:4]3[C:9](=[CH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=3)[C:10]([CH3:11])=[C:2]2[CH3:1])=[CH:22][CH:23]=1)=[O:34])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCOC(=O)c1ccc2[nH]c(C)c(C)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of ethyl 2,3-dimethyl-1H-indole-5-carboxylate (1.493 g, 6.87 mmol) in dry DMF (10 mL) at 0° C. under argon was added NaH (0.3 g, 60% dispersion in mineral oil, 7.56 mmol) in portions. The reaction mixture was stirred at rt for 30 min and then re-cooled to 0° C. Tert-butyl 4′-(bromomethyl)biphenyl-2-carboxylate (2.62 g, 7.56 mmol) in DMF (2 mL) was slowly added. The reaction mixture was stirred at rt for another 1 h. The completion of the reaction was monitored by anal. HPLC. The reaction was quenched with MeOH, and then the solvent was removed in vacuo. The crude was dissolved in AcOEt, washed with saturated aqueous NaHCO3, brine and dried over Na2 SO4 and filtered. The filtrate was evaporated in vacuo to obtain the crude which was purified by flash chromatography (AcOEt/Hex 10→100%) to obtain the title compound. ESI-MS (m/z): 484 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]3[C:17](=[O:18])[NH:16][S:15][C:8]=3[N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:20].[C:21]([N:24]1[CH2:29][CH:28]=[C:27]([Sn](CCCC)(CCCC)CCCC)[CH2:26][CH2:25]1)(=[O:23])[CH3:22]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C)C=O>[C:21]([N:24]1[CH2:25][CH:26]=[C:27]([C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:19])[C:7]4[C:17](=[O:18])[NH:16][S:15][C:8]=4[N:9]3[CH:12]3[CH2:14][CH2:13]3)=[CH:4][C:3]=2[F:20])[CH2:28][CH2:29]1)(=[O:23])[CH3:22]
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCN(C(C)=O)CC1
Reactant: O=c1[nH]sc2c1c(=O)c1cc(F)c(Br)cc1n2C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(=O)N1CC=C(c2cc3c(cc2F)c(=O)c2c(=O)[nH]sc2n3C2CC2)CC1
Yield: 98 %

Procedure:
A mixture containing 7-bromo-9-cyclopropyl-6-fluoro-9H-isothiazolo[5,4-b]quinoline-3,4-dione (7, 100.0 mg, 0.28 mmol), 1-acetyl-4-tributylstannyl-1,2,3,6-tetrahydropyridine (190.0 mg, 0.46 mmol), tetrakis(triphenylphosphine)palladium(0) (16.0 mg, 0.014 mmol), and dimethylformamide (6.0 mL) Is sparged with argon gas and irradiated with microwaves (5×10 min irradiations at 130° C.). (For cross-coupling experiments described previously using C with conventional thermal heating, see: (a) Laborde, E.; Kiely, J. S.; Culbertson, T. P.; Lesheski, L. E. J. Med. Chem. 1993, 36, 1964-1970. (b) Kiely, J. S.; Laborde, E.; Lesheski, L. E.; Bucsh, R. A. J. Heterocyclic Chem. 1991, 28, 1581-1585. (c) Laborde, E.; Kiely, J. S.; Lesheski, L. E.; Schroeder, M. C. J Heterocyclic Chem. 1990, 28, 191-198) The resulting yellow solution is evaporated to dryness under reduced pressure (−6 mm Hg, 60° C.). The recovered solid is dissolved in a mixture containing 10% methanol in methylene chloride (10 mL), precipitated via addition of hexanes (100 mL), and collected by filtration. This process is repeated once. The product is purified further by flash column chromatography (eluting with 10% methanol in methylene chloride, Rf 0.50) to give pure 26 as a yellow solid (98% purity by HPLC). mp 243-244° C. 1H NMR (CDC3/CD3OD (12:1 v/v), 50° C.): δ 1.32 (m, 2H, c-Pr CH2), 1.45 (m, 2H, c-Pr CH2), 2.18 (s, 3H, NC(O)CH3), 2.65 (m, 2H, NCH2CH2), 3.45 (m, 1H, c-Pr CH), 3.73 (m, 1H, NCH2CH2), 3.87 (m, 1H, NCH2CH2), 4.23 (m, 1H, NCH2CH), 4.31 (m, 1H, NCH2CH), 6.19 (m, 1H, NCH2CH), 7.88 (d, JH-F=6.0 Hz, 1H, quinolone H-8), 8.08 (d, JH-F=11.0 Hz, 1H, quinolone H-5). 19F{1H} NMR (CDCl3/CD3OD (12:1 v/v), 50° C.): δ −119.4 (s). NMR spectroscopic data collected at room temperature indicated that two conformational isomers were present. LCMS m/z calcd for C20H18FN3O3S ([M]+) 399. Found 400 ([M+H]+). HRMS m/z calcd for C20H18FN3NaO3S ([M+Na]+) 422.0951. Found 422.0951.
Reaction SMILES: Cl.C(N(C1C=CC=CC=1)S(C1C=NC(N2C(=O)C(CC3C=NC=CC=3)=C(C)N2)=CC=1)(=O)=O)C.[CH3:34][O:35][CH2:36][C:37]1[CH:38]=[C:39]([CH2:43]O)[CH:40]=[CH:41][CH:42]=1.P(Br)(Br)[Br:46].CO>CCOCC>[Br:46][CH2:43][C:39]1[CH:40]=[CH:41][CH:42]=[C:37]([CH2:36][O:35][CH3:34])[CH:38]=1
Reactant: BrP(Br)Br
Reactant: COCc1cccc(CO)c1
Agent: CCN(c1ccccc1)S(=O)(=O)c1ccc(-n2[nH]c(C)c(Cc3cccnc3)c2=O)nc1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COCc1cccc(CBr)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 39 %

Procedure:
To a solution of 5.91 g (38.8 mmol) of 2 [3-(methoxymethyl)phenyl]methanol in 75 mL of Et2O are added dropwise, at 0° C., 9.1 mL (97.1 mmol) of phosphorus tribromide. The reaction mixture is allowed to warm slowly to room temperature and stirring is continued for 4 hours. The crude reaction mixture is then poured cautiously into a mixture of 100 g of ice and 100 mL of MeOH. After evaporating off the MeOH under reduced pressure, the aqueous phase is extracted with DCM (2×200 mL). The organic phases are combined, dried over Na2SO4, filtered and then concentrated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, eluting with a cyclohexane/EtOAc gradient of 0 to 20% EtOAc. 3.25 g of 1-(bromomethyl)-3-(methoxymethyl)benzene are thus obtained in the form of an oil.
Reaction SMILES: [C:1]1([S:11]([O-:14])(=[O:13])=[O:12])[C:10]2[C:4]([CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:3][CH:2]=1.[Na+].C(O)(=O)CCCCCCCCCCCCCCCCC>>[C:1]1([S:11]([OH:14])(=[O:12])=[O:13])[C:10]2[C:4]([CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:3][CH:2]=1
Reactant: O=S(=O)([O-])c1ccc2cccccc1-2
Agent: CCCCCCCCCCCCCCCCCC(=O)O
Agent: [Na+]
Product: O=S(=O)(O)c1ccc2cccccc1-2
Temperature: 80 °C
Yield: 0 %

Procedure:
Sodium azulenesulfonate (12 g), 186 g of hydroxypropylcellulose-M and 282 g of stearic acid were granulated by the same way as in Example 5. Each 160 mg of it was filled in a capsule No. 3. The capsules were placed in a fluidized bed granulator-drier, fluidized by heating with air (intake temperature: 80° C.) for 15 minutes, the heater was turned off and allowed to cool with air of the room temperature to give capsules each containing 4 mg of azulenesulfonic acid.
Reaction SMILES: [N:1]1([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:2]1[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].[H-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[N:1]1([C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:2]1[C:3]([N:5]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:4]
Reactant: O=C(Nc1ccccc1)[C@H]1CCCCN1C(=O)OCc1ccccc1
Reactant: CCOC(=O)CBr
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CN(C(=O)[C@H]1CCCCN1C(=O)OCc1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 95.1 %

Procedure:
To a solution of Cbz-D-hPro-NHC6H5 (7.7 g, 22.8 mmol) in tetrahydrofuran (300 mL) was added ethyl bromoacetate (12.6 mL, 113.8 mmol). The solution was cooled to 0° C. and NaH 60% suspension (2 g, 50 mmol) was added in small portions over 20 minutes, with gas evolution. After gas evolution had ceased, the cold bath was left unattended and the mixture was allowed to warm slowly to room temperature. After 18 hours, 1N citric acid (50 mL) was added slowly with cooling. The mixture was partitioned between ethyl acetate (300 mL) and 1N citric acid (300 mL). The organic layer was washed twice with 1N citric acid (200 mL), twice with saturated aqueous NaHCO3, and twice with saturated aqueous sodium chloride solution. The ethyl acetate layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed over silica gel, eluting with a step gradient of hexanes through 50% ethyl acetate/hexanes. Fractions containing product (as judged by TLC) were combined and concentrated in vacuo to give a yellow oil (9.2 g, 96%).
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=[C:13]([O:16][CH2:17][C:18]([O-:20])=[O:19])[CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[OH-].[K+].O.[CH2:24](O)[CH3:25]>>[O:1]=[C:2]1[C:15]2[CH:14]=[C:13]([O:16][CH2:17][C:18]([O:20][CH2:24][CH3:25])=[O:19])[CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: O=C([O-])COc1ccc2oc3ccccc3c(=O)c2c1
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)COc1ccc2oc3ccccc3c(=O)c2c1
Reaction time: 0.58 h

Procedure:
Ethyl (9-oxoxanthen-2-oxyacetate (10 g, 33 mmol) prepared as described above, was dissolved in 95% ethanol (150 mL), and 4 N aqueous KOH (30 mL, 0.12 mol) and water (15 mL) were added. The mixture was stirred for 35 minutes at 35°-40° C., cooled, and the solid precipitate which formed was collected by filtration, washed with absolute ether (3'20 mL), and air-dried. The structure of the potassium salt is shown below. Yield: 9.25 g (96%). TLC, Rf 0.90 [MeOH-H2O(4:1)]. NMR data in accordance with structure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:17][N:14]1[CH2:15][CH2:16][CH:11]([S:8][C:4]2[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=2)[CH2:12][CH2:13]1
Reactant: Nc1cccc(S)c1
Reactant: CN1CCC(Cl)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN1CCC(Sc2cccc(N)c2)CC1
Temperature: 80 °C
Reaction time: 18 h
Yield: 58.1 %

Procedure:
Combine 3-amino-benzenethiol (1.87 mL, 17.83 mmol), 4-chloro-1-methyl-piperidine hydrochloride (2.0 g, 11.76 mmol), cesium carbonate (8.42 g, 25.87 mmol), and dimethylformamide (60 mL), stir and heat at 80° C. After 18 hr., cool to ambient temperature and filter. Wash the filtrate with water (3×20 mL) and extract with diethyl ether (2×30 mL). Combine the organic layers, dry over magnesium sulfate, filter and concentrate. Purify through a plug of silica gel using dichloromethane/2.0 M ammonia in methanol (20:1 mixture ratio) to give the title compound as a pale orange oil (1.52 g, 58%): Mass spectrum (ion spray): m/z=223.1 (M+1), 1H NMR (free base, CDCl3): 7.10 (t, J=7.8 Hz, 1H), 6.84-6.80 (m, 1H), 6.77 (t, J=2.0 Hz, 1H), 6.58 (ddd, J=0.8, 2.2, 8.0 Hz, 1H), 3.69 (bs, 2H), 3.09 (bs, 1H), 2.85 (m, 2H), 2.31 (s, 3H), 2.16-1.99 (m, 4H), 1.79-1.64 (m, 2H). 13C NMR (free base, CDCl3): 146.7, 135.2, 129.4, 122.0, 118.4, 113.7, 55.1, 46.1, 43.6, 32.5.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:9]1([NH:12][C:13]([C:15]2[CH:16]=[CH:17][C:18]([CH3:34])=[C:19]([NH:21][C:22](=[O:33])[C:23]3[CH:28]=[C:27](F)[CH:26]=[CH:25][C:24]=3[N+:30]([O-:32])=[O:31])[CH:20]=2)=[O:14])[CH2:11][CH2:10]1>>[CH:9]1([NH:12][C:13]([C:15]2[CH:16]=[CH:17][C:18]([CH3:34])=[C:19]([NH:21][C:22](=[O:33])[C:23]3[CH:28]=[C:27]([N:5]4[CH2:6][CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][CH2:4]4)[CH:26]=[CH:25][C:24]=3[N+:30]([O-:32])=[O:31])[CH:20]=2)=[O:14])[CH2:11][CH2:10]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: CN1CCCNCC1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(N2CCCN(C)CC2)ccc1[N+](=O)[O-]

Procedure:
Using an analogous procedure to that described paragraph (A) in the portion of Example 13 which is concerned with the preparation of starting materials 1-methylhomopiperazine was reacted with N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-fluoro-2-nitrobenzamide to give N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-(4-methyl-1,4-diazepan-1-yl)-2-nitrobenzamide; NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.67 (m, 2H), 1.91 (m, 2H), 2.26 (s, 3H), 2.29 (s, 3H), 2.44 (m, 2H), 2.64 (m, 2H), 2.82 (m, 1H), 3.61 (m, 2H), 3.66 (m, 2H), 6.81 (s, 1H), 6.88 (d, 1H), 7.28 (d, 1H), 7.55 (d, 1H), 7.96 (s, 1H), 8.03 (d, 1H), 8.36 (s, 1H), 9.88 (s, 1H); Mass Spectrum: M+H+ 452.
Reaction SMILES: [CH3:1][C:2](C)([O-:4])[CH3:3].[K+].[Cl:7][C:8]1[C:17]([CH:18]=O)=[C:16]([Cl:20])[CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11].[Cl-].O=C(C)C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>O1CCCC1>[Cl:7][C:8]1[C:17]([CH:18]=[CH:1][C:2](=[O:4])[CH3:3])=[C:16]([Cl:20])[CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1ccc(Cl)c(C=O)c1Cl
Agent: CC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(C=CC(C)=O)c1Cl
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 87.9 %

Procedure:
At room temperature, first 14.0 g (125 mmol) of potassium t-butoxide and then, after 30 minutes, 23.3 g (100 mmol) of methyl 2,4-dichloro-3-formylbenzoate in 200 ml of tetrahydrofuran were added to 53.2 g (150 mmol) of (2-oxopropyl)triphenylphosphonium chloride in 300 ml of tetrahydrofuran. The mixture was stirred at room temperature for 4.5 hours and 400 ml of water were then added, the organic phase was separated off and the aqueous phase was extracted with methyl t-butyl ether. The combined organic phases were dried and concentrated and the resulting residue was chromatographed over silica gel (eluent: cyclohexane:ethyl acetate=9:1). 24.0 g (88% of theory) of methyl 2,4-dichloro-3-(2-oxobut-3-en-4-yl)benzoate were obtained.
Reaction SMILES: CO.CN1[C:8](=[O:9])CCC1.[H-].[Na+].Br[C:13]1[N:18]=[C:17]2[N:19]([C@H:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH3:24])[C:20]([OH:22])=[N:21][C:16]2=[N:15][CH:14]=1>CCOC(C)=O>[CH3:8][O:9][C:13]1[N:18]=[C:17]2[N:19]([C@H:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH3:24])[C:20]([OH:22])=[N:21][C:16]2=[N:15][CH:14]=1
Reactant: CN1CCCC1=O
Reactant: C[C@@H](c1ccccc1)n1c(O)nc2ncc(Br)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cnc2nc(O)n([C@@H](C)c3ccccc3)c2n1
Temperature: 200 °C
Yield: 29 %

Procedure:
A thick-walled microwave bottle equipped with a stirbar was charged with MeOH (2.0 equiv) and NMP (20 volume equivalents). To the resulting solution was added NaH (2.0 equiv), resulting in gas evolution. (S)-6-Bromo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2-ol (1.0 equiv) was then added to the reaction, and the resulting mixture was immediately fitted with a septum and cap and heated to 200° C. in a microwave for 30 min. The reaction was then diluted with EtOAc, washed twice with saturated aq. NaHCO3 and once with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Reverse-phase preparative HPLC provided the title compound (29%) as a white solid. LCMS m/z (APCI)=271.1 (M+H).
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:19]=[CH:18][C:5]3[CH2:6][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:9][O:10][C:4]=3[CH:3]=2)=[CH:23][CH:22]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCOc2cc(Br)ccc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2cc(-c3ccc(Cl)cc3)ccc2C1
Yield: 96.5 %

Procedure:
A mixture of tert-butyl 8-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), a solution of 4-chlorophenylboronic acid (143 mg, 0.912 mmol) in ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml), and tetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0730 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (210 mg, 95.9%) as an oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@H:14]([NH:17][CH2:18][C:19]2[CH:28]=[CH:27][C:22]3[O:23][CH2:24][CH2:25][O:26][C:21]=3[CH:20]=2)[CH2:13][CH2:12]1)=O>O1CCCC1>[O:23]1[C:22]2[CH:27]=[CH:28][C:19]([CH2:18][NH:17][C@H:14]3[CH2:15][CH2:16][C@H:11]([CH2:9][OH:8])[CH2:12][CH2:13]3)=[CH:20][C:21]=2[O:26][CH2:25][CH2:24]1
Reactant: COC(=O)[C@H]1CC[C@H](NCc2ccc3c(c2)OCCO3)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC[C@H]1CC[C@H](NCc2ccc3c(c2)OCCO3)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Lithium aluminium hydride (1.0 M solution in tetrahydrofuran, 2.20 mL, 2.20 mmol, 2.0 eq) is added at 0° C. to a stirred solution of trans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexanecarboxylic acid methyl ester (355 mg, 1.10 mmol, 1.0 eq) in tetrahydrofuran (30 mL). After 2 hours stirring at 0° C., the reaction mixture is cautiously quenched with ice-water (6 mL). Tetrahydrofuran is evaporated and the crude is extracted with ethyl acetate (3×50 mL) and water (50 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford {trans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexyl}-methanol as an orange oil (322 mg, 99% yield).
Reaction SMILES: COC([C:5]1[C:10]([CH2:11][CH2:12][C:13]([O:15]C)=O)=[CH:9][C:8]([CH3:17])=[CH:7][N:6]=1)=O.C[O-].[Na+]>C1COCC1>[CH3:17][C:8]1[CH:9]=[C:10]2[CH2:11][CH2:12][C:13](=[O:15])[C:5]2=[N:6][CH:7]=1
Reactant: COC(=O)CCc1cc(C)cnc1C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cnc2c(c1)CCC2=O
Yield: 117.6 %

Procedure:
3-(2-Methoxycarbonyl-ethyl)-5-methyl-pyridine-2-carboxylic acid methyl ester (2.33 g, 9.82 mmol) was dissolved in THF (70 ml). NaOMe (0.796 g, 14.7 mmol) was added and the reaction was heated at reflux temperature for 2 h. The solvents were evaporated under reduced pressure. The residue was taken into 4.5 N aqueous hydrochloric acid (24 ml) and the mixture was heated at reflux temperature for 2 h. After cooling to it solid potassium carbonate was added carefully in portions until pH >8. The mixture was extracted with DCM, the combined organic layers were washed with aq Na2CO3 and aq ammonium chloride solution, dried over sodium sulfate, and the solvent was evaporated at reduced pressure. The residue was purified by chromatography on silica (Flashmaster, hes/EtOAc 1/1 to EtOAc over 15 min, EtOAc to EtOAc/MeOH 9/1 over 10 min) to obtain the product as off-white solid (1.7 g, 81%). [1H-NMR (DMSO-d6, 600 MHz) δ 8.57 (s, 1H), 7.87 (s, 1H), 3.06 (t, 2H), 2.65 (t, 2H), 2.42 (s, 3H); LCMS RtI=2.460 min; [M+H]+=148.0]
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[Cl:15][C:16]1[CH:29]=[CH:28][C:19]([C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:21])=[CH:18][CH:17]=1.[C:30]1([C:32](=[CH:34][CH:35]=[CH:36][CH:37]=1)O)[OH:31]>C1C=CC=CC=1>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C:20]1([C:19]2[CH:18]=[CH:17][C:16]([Cl:15])=[CH:29][CH:28]=2)[O:31][C:30]2[CH:32]=[CH:34][CH:35]=[CH:36][C:37]=2[O:21]1)[CH3:27]
Reactant: Oc1ccccc1O
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: c1ccccc1
Product: CCOC(=O)CC1(c2ccc(Cl)cc2)Oc2ccccc2O1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
98.9 g of P2O5 is added to a mixture of 64 g of ethyl p-chlorobenzoylacetate and 90.4 g of pyrocatechol, heated at 80°C in portions over about 1/2 hour. After 15 minutes the heating is interrupted and 1000 cc of benzene are added. The organic phase is decanted. The latter is repeatedly washed first with NaHCO3 and subsequently with H2O until same is rendered neutral and finally dried with Na2SO4. The solvent is removed in vacuum and the residual oil fractionated, b.p. 150°-155°C (0.4 mm.Hg).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])[NH:10][C:9]=2[C:8]([OH:22])=[CH:7][CH:6]=1)=[O:4].O[Li].O>C1COCC1.CO.O>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[C:11]1[NH:10][C:9]2[C:8]([OH:22])=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=2[N:12]=1
Reactant: COC(=O)c1ccc(O)c2[nH]c(-c3ccc(F)cc3F)nc12
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(O)c2[nH]c(-c3ccc(F)cc3F)nc12
Temperature: 25 °C
Yield: 89.4 %

Procedure:
Wang resin-supported 2-(2,4-difluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methyl ester (570 mg, 0.47 mmol) obtained in step 5 was dissolved in THF, LiOH.H2O (99 mg, 2.35 mmol) in MeOH—H2O was added thereto and the resulting mixture was refluxed for 5 hours. The resulting solution was cooled to room temperature and filtered. The filtrate was washed with MeOH and CH2Cl2, and dried to obtain the title compound (551 mg, 0.42 mmol) in a yield of 90%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:32](=[O:33])[C:11]2=[CH:12][N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[CH:30][CH:29]=[N:28]4)=[CH:23][CH:22]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1.C(N(C(C)C)CC)(C)C.[CH3:43][CH:44]([CH3:49])[CH2:45][C:46](Cl)=[O:47]>ClCCl>[CH3:43][CH:44]([CH3:49])[CH2:45][C:46]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:32](=[O:33])[C:11]2=[CH:12][N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[CH:30][CH:29]=[N:28]4)=[CH:23][CH:22]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1)=[O:47]
Reactant: Nc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Reactant: CC(C)CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)CC(=O)Nc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Reaction time: 0.25 h

Procedure:
2-(2-Aminophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 626, 30 mg, 0.069 mmol) and diisopropylethylamine (30 μL, 0.17 mmol, 2.5 equiv) were combined in dichloromethane (1 mL) and treated with 3-methylbutanoyl chloride (9.2 mg, 0.076 mmol, 1.1 equiv). After 15 minutes at ambient temperature, the mixture was concentrated in vacuo and the residue was purified by preparative reverse phase HPLC (eluting 80:20 to 5:95; water containing 0.1% trifluoroacetic acid:acetonitrile containing 0.1% trifluoroacetic acid), providing the title compound; 1H-NMR (400 MHz, d6-DMSO) δ 9.72 (1H, br s), 9.33 (1H, s), 8.47 (1H, d, J=2.3 Hz), 8.28 (1H, d, J=7.7 Hz), 7.93 (1H, d, 8.0 Hz), 7.84 (1H, d, J=8.9 Hz), 7.83 (2H, d, J=8.5 Hz), 7.72 (1H, br s), 7.69-7.64 (2H, m), 7.59 (1H, t, J=7.3 Hz), 7.47 (2H, d, J=8.4 Hz), 7.37 (1H, t, J=7.5 Hz), 7.27 (1H, t, J=7.5 Hz), 6.53 (1H, m), 5.83 (2H, s), 2.15 (2H, d, J=7.3 Hz), 2.09-1.94 (1H, m), 0.86 (6H, d, J=6.6 Hz) ppm; high resolution mass spectrometry (ES+) m/z 517.2391 [(M+H)+; calculated for C31H29N6O2: 517.2347].
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=O.[CH2:14]([NH2:16])[CH3:15]>>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH2:4][NH:16][CH2:14][CH3:15]
Reactant: O=Cc1cc(C(F)(F)F)ccc1Br
Reactant: CCN
Product: CCNCc1cc(C(F)(F)F)ccc1Br

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using the following starting materials: 2-bromo-5-(trifluoromethyl)benzaldehyde and ethylamine (2M in THF).