Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1.[NH2:16][C@@H:17]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1)[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29].C(N(CC)C(C)C)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:16][C@@H:17]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)[CH2:18][N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1
Reactant: N[C@@H](Cc1cccc(F)c1)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1nccc1-c1cc(C(=O)O)sc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1nccc1-c1cc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a 500 mL round-bottomed flask was added 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (4.2 g, 17.31 mmol), 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (6.37 g, 19.04 mmol) [prepared according to the procedure of Preparation 6], N,N-diisopropyl ethylamine (4.53 ml, 26.0 mmol) and Pybrop (12.05 g, 26.0 mmol) in dichloromethane (DCM) (150 ml). After stirring at RT for 12 h, the reaction solution was washed with H2O (2×100 mL) and the organic layer was dried Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and was eluted with [EtOAc/hexanes, 1:1] to give the product [7.8 g, 86%] as a white solid: LCMS (ES) m/z 524 (M+H)+.
Reaction SMILES: Cl.[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[N+](C1C=CC=CC=1)([O-])=O.[Br:21]Br.Cl>>[Br:21][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=[N:3][CH:4]=1
Reactant: c1ccc2cnccc2c1
Reactant: BrBr
Agent: Cl
Solvent: O=[N+]([O-])c1ccccc1
Product: Brc1cncc2ccccc12
Temperature: 180 °C
Reaction time: 3 h

Procedure:
The same general procedure set forth in Example 1 above was followed. In a flask equipped with a reflux condenser, dropping funnel, thermometer, and stirrer was placed 33.3 g. (0.20 mole) of isoquinoline hydrochloride, together with 50 ml. of nitrobenzene, and the mixture was stirred and heated to about 180°C. to give a clear yellow solution. To this solution was added dropwise, via the dropping funnel, over a period of 1 hour and 13 minutes, 35.2 g. (0.22 mole) of bromine. The evolution of hydrogen chloride was smooth from the start to the completion of the addition of the bromine. After all the bromine had been added, the reaction mixture was of a single phase, amber red in color. Heating at about 180°C. and stirring were continued after addition of the bromine had been completed. An hour later, a few crystals of a solid material started to collect in the flask near the condenser. After 3 hours and 15 minutes of heating and stirring a very thin slurry of crystals had begun to form and hydrogen chloride evolution had become very slow. After 4 hours and 45 minutes of heating and stirring, the evolution of hydrogen chloride had practically ceased.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]([NH:20][C@H:21]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[CH3:22])=[O:19])[N:16]=[C:12]3[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:37][O:38][CH2:39][CH2:40]Br>CC(=O)CC.C(Cl)Cl>[CH3:37][O:38][CH2:39][CH2:40][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]([NH:20][C@H:21]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[CH3:22])=[O:19])[N:16]=[C:12]3[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc([C@H](C)NC(=O)Nc2nc3nccc(-c4ccc(O)cc4)n3n2)c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCC(C)=O
Product: COCCOc1ccc(-c2ccnc3nc(NC(=O)N[C@@H](C)c4cccc(OC)c4)nn23)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
(S)-1-[7-(4-hydroxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]-3-[1-(3-methoxyphenyl)ethyl]urea (the compound obtained in Example 223; 20.3 mg) was suspended in 2-butanone (2 ml). Thereafter, potassium carbonate (69.4 mg) and 2-methoxyethyl bromide (47.2 μl) were added to the suspension, and the obtained mixture was stirred at 80° C. for 5 hours. Thereafter, the reaction solution was diluted with methylene chloride (5 ml), and the resultant product was then washed with 1 M hydrochloric acid (5 ml×3), saturated sodium bicarbonate (5 ml×2), and distilled water (5 ml×2). The organic layer was concentrated under a reduced pressure, and the obtained residue was purified by reverse phase liquid chromatography (Inertsil PREP-ODS; 20 Φ×250 mm; eluted with water-containing acetonitrile) to obtain the captioned compound (10.7 mg).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([C:6]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])=[O:5].[Cl:21][CH2:22][CH:23]1[O:25][CH2:24]1.[OH-].[NH4+]>C1(C)C=CC=CC=1>[CH3:11][O:10][C:8](=[O:9])[C:7]1[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:6]=1[C:4]1([C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=2[F:1])[O:25][CH:23]([CH2:22][Cl:21])[CH2:24][O:5]1
Reactant: ClCC1CO1
Reactant: COC(=O)c1ccc(Cl)cc1C(=O)c1ccccc1F
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Cl)cc1C1(c2ccccc2F)OCC(CCl)O1
Reaction time: 0.5 h

Procedure:
To a solution of 47 g (0.16 mol) of the end product of Example 6 in 350 ml of dry toluene was added 21.4 ml (0.18 mol) of stannic chloride, and after 5 hrs a solution of 24 ml (0.308 mol) of 1-chloro-2,3-epoxypropane in 25 ml of toluene was added with stirring over a 30 min period. After 18 hrs an additional 12 ml (0.154 mol) of 1-chloro-2,3-epoxypropane was added over a 15 min period. After 4 hrs the reaction was cooled in an ice bath and made basic with concentrated ammonium hydroxide. The reaction was filtered through celite, and the celite was washed with toluene. The combined filtrates were washed with 200 ml of water, dried over sodium sulfate, and evaporated. The resulting oil was dissolved in 100 ml of dichloromethane and chromatographed through 500 g of alumina. The column was eluted with 4 l of dichloromethane/petrol (2/1 ) to give an oil, which was about 90-95% pure by TLC. A sample was crystallized and recrystallized from ether/petrol to give white prisms: mp 117°-122° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:21])[CH:16](OCC)O)=[CH:11][C:10]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24])C1C=CC=CC=1.[O:27]1[C:31]2[CH:32]=[CH:33][C:34]([C:36]3[N:40]=[C:39]([CH3:41])[N:38]([CH2:42][CH2:43][C:44]([NH2:47])([CH3:46])[CH3:45])[N:37]=3)=[CH:35][C:30]=2[O:29][CH2:28]1>>[O:27]1[C:31]2[CH:32]=[CH:33][C:34]([C:36]3[N:40]=[C:39]([CH3:41])[N:38]([CH2:42][CH2:43][C:44]([NH:47][CH2:16][CH:15]([C:12]4[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([NH:22][S:23]([CH3:26])(=[O:24])=[O:25])[CH:11]=4)[OH:21])([CH3:45])[CH3:46])[N:37]=3)=[CH:35][C:30]=2[O:29][CH2:28]1
Reactant: CCOC(O)C(=O)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Reactant: Cc1nc(-c2ccc3c(c2)OCO3)nn1CCC(C)(C)N
Product: Cc1nc(-c2ccc3c(c2)OCO3)nn1CCC(C)(C)NCC(O)c1ccc(O)c(NS(C)(=O)=O)c1

Procedure:
Analogously to the method described for Example 7, 379 mg (1 mmol) N-[2-benzyloxy-5-[2-ethoxy-2-hydroxy-acetyl)-phenyl]-methanesulphonamide and 288 mg (1 mmol) 3-(3-benzo[1,3]dioxol-5-yl-5-methyl-[1,2,4]triazol-1-yl)-1,1-dimethyl-propylamine are reacted with one another. The subsequent debenzylation yields the target compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8]S(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[CH2:24](O)[CH2:25][CH2:26][CH3:27].C1CCN2C(=NCCC2)CC1>COCCOC>[CH2:24]([O:8][C:6]1[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=[C:2]([NH2:1])[N:7]=1)[CH2:25][CH2:26][CH3:27]
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Reactant: CCCCO
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CCCCOc1nc(N)nc(-c2ccco2)c1[N+](=O)[O-]

Procedure:
From trifluoro-methanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester, butanol and DBU in DME. EI-MS m/e (%): 278 (M+, 24), 249 ([M—C2H5]+, 28), 193 (70), 177 (100), 150 (48), 108 (86), 94 (62), 70 (48), 69 (46), 43 (68), 41 (62), 29 (45).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=1>CN1CCCC1=O.C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(Cl)ccn1
Reactant: Oc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: Cc1cc(Oc2ccc(Br)cc2)ccn1
Temperature: 250 °C
Reaction time: 0.17 h

Procedure:
4-Bromophenol (1.0 g, 5.78 mmol) was added to a solution of sodium hydride (0.3 g, 7.51 mmol) in N-methylpyrrolidone (10 ml). After stiffing for 10 minutes, 4-chloro-2-methylpyridine (0.96 g, 7.51 mmol) was added. The reaction mixture was heated at 250° C. for 45 minutes under microwave irradiation. After cooling to room temperature the mixture was diluted with diethyl ether and washed with water. The solution was then extracted with additional diethyl ether, the organic layer dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate D10 (1.34 g, 88%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:19]1[CH2:25][C:23](=[O:24])[NH:22][C:20]1=[S:21].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12](/[CH:13]=[C:25]2/[C:23](=[O:24])[NH:22][C:20](=[S:21])[S:19]/2)=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(/C=C2\SC(=S)NC2=O)ccc1OCc1ccccc1

Procedure:
4-Benzyloxy-3-methoxy-benzaldehyde (29 g) was dissolved in acetic acid (16 g) and then rhodanine (16 g) and sodium acetate (36 g) added into. The solution was refluxed for one hour. The reaction solution was poured into water. The solid was filtered, washed with water and dried under vacuum.
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]([CH2:17][CH3:18])[C:11](=[O:16])[C:12]([O:14]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[CH2:1]([O:8][N:9]=[C:10]([CH2:17][CH3:18])[C:11](=[O:16])[C:12]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: CCC(=NOCc1ccccc1)C(=O)C(=O)OC
Product: CCC(=NOCc1ccccc1)C(=O)C(=O)N1CCOCC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
10.0 g (0.04 mol) of methyl 3-benzyloxyimino-2-oxovalerate and 20 ml of morpholine were combined and the mixture was stirred for 3 hours at 100° C. After distilling the morpholine off under reduced pressure, 100 ml of water was added and the mixture was extracted three times with 100 ml of diethylether. After washing with water and a saturated aqueous sodium chloride followed by anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a residue, which was purified by a column chromatography on a silica gel (n-hexanelethyl acetate) to obtain 6.78 g (yield: 56%) of 4-(3-benzyloxyimino-2-oxovaleryl)morpholine as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[N:7]=1)[CH3:2].[CH:22]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:1]([C:3]1[S:4][C:5]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:28]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:29])[CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[N:7]=1)[CH3:2]
Reactant: O=C(Cl)C1CCCCC1
Reactant: CCc1nc(-c2cccc(C)c2)c(-c2ccnc(N)c2)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1nc(-c2cccc(C)c2)c(-c2ccnc(NC(=O)C3CCCCC3)c2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
To a solution of 4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine (0.80 g, 2.7 mmol) in tetrahydrofuran (10 mL) were added cyclohexanecarbonyl chloride (0.40 mL, 3.0 mmol) and triethylamine (0.39 mL, 2.8 mmol) sequentially, and the mixture was stirred for 1 hour at room temperature. To the reaction mixture was added an aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extracts were washed with an aqueous sodium hydrogen carbonate solution, then, dried and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=20:1 to 4:1) to obtain a crystal. This crystal was washed with hexane to obtain a title compound (0.83 g, yield 75%).
Reaction SMILES: [C:1](O)([CH3:4])([CH3:3])C.C[C:7]([CH3:10])([O-])[CH3:8].[K+]>C1COCC1.O>[CH2:4]=[CH:1][CH:3]=[CH:10][CH2:7][CH2:8][CH2:8][CH2:7][CH:10]=[CH:3][CH:1]=[CH2:4]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC=CCCCCC=CC=C
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
The latter compound (2.0 g) was dissolved in 50 mL of 1:4 THF:tert-butanol and added dropwise to an ice cold solution of potassium tert-butoxide (3.00 g) in 100 mL of 1:4 THF:tert-butanol. The reaction mixture was stirred in ice for 0.5 hours and at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with pentane. The combined organic layer was washed with water. The organic layer was separated, dried with anhydrous magnesium sulfate, filtered and the solvent removed in vacuo to give an oil. Distillation gave 0.34 g (48% yield) of 1,3,9,11-dodecatetraene as established by proton and carbon-13 NMR and IR analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][C:3]=1[NH:18][C:19]([CH3:38])([CH2:21][CH2:22][N:23]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH3:20].[C:39]([O:43][CH2:44]C)(=[O:42])[CH:40]=O.C1(C)C=CC=CC=1>CO>[CH3:44][O:43][C:39]([C:40]1[N:18]([C:19]([CH3:38])([CH2:21][CH2:22][N:23]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH3:20])[C:3]2[CH:4]=[C:5]([C:6]([O:8][CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:7])[CH:16]=[CH:17][C:2]=2[N:1]=1)=[O:42]
Reactant: CC(C)(CCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)Nc1cc(C(=O)OCc2ccccc2)ccc1N
Reactant: CCOC(=O)C=O
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1nc2ccc(C(=O)OCc3ccccc3)cc2n1C(C)(C)CCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 99 %

Procedure:
To a stirred solution of crude benzyl 4-amino-3-({4-[bis(tert-butoxycarbonyl)amino]-2-methylbutan-2-yl}amino)benzoate (250 mg, 0.47 mmol) in methanol (10 mL) is added a 50% solution of ethyl glyoxalate in toluene (0.38 mL, 1.90 mmol). After 16 h, the solvent is evaporated to afford the title compound (295 mg, >99%), which is used in the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][C:8]=2[CH3:17])=[C:5]([CH3:18])[O:4][N:3]=1.[OH-].[Na+]>CCO.O>[CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=2[CH3:17])=[C:5]([CH3:18])[O:4][N:3]=1
Reactant: COC(=O)c1ccc(-c2c(C)noc2C)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(C(=O)O)ccc1-c1c(C)noc1C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Methyl 4-bromo-3-methylbenzoate (Intermediate 17, step 1) (4 g; 17.46 mmol; 1 eq.), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)isoxazole (4.28 g; 19.21 mmol; 1.10 eq.), potassium carbonate (12.07 g; 87.31 mmol; 5 eq.), tetrakis(triphenylphosphine)palladium(0) (2.02 g; 1.75 mmol; 0.10 eq.) were taken in Toluene (20 mL) and water (20 mL) under N2 atmosphere. The reaction mixture was degassed with N2 and then refluxed for 4 hours. The reaction mixture was cooled to RT, filtered over a pad of celite and washed with toluene (200 mL). The filtrate was concentrated to afford a brown oil which was taken up in EtOAc (250 mL). The organic layer was washed with a saturated aqueous solution of NaHCO3 solution (100 mL), water (100 mL) and brine (100 mL), dried over MgSO4 and concentrated affording methyl 4-(3,5-dimethylisoxazol-4-yl)-3-methylbenzoate (4.2 g, 99%, HPLC (Method A) Rt 3.93 min) as an orange solid, which was used without further purification. A solution of methyl 4-(3,5-dimethylisoxazol-4-yl)-3-methylbenzoate (3 g; 12.23 mmol; 1 eq.) in EtOH (90 mL) at RT was treated with sodium hydroxide (7.34 mL; 5 M; 36.69 mmol; 3 eq.). The reaction mixture was stirred at 60° C. for 1 hour. The reaction mixture was concentrated to give a brown solid which was taken up in water (100 mL) and the aqueous phase was washed twice with EtOAc. The aqueous phase was acidified with HCl cc to pH 2. Then it was concentrated until precipitation (volume divided by 2). The suspension was filtered affording the title compound as a brown solid. It was washed with diethyl ether affording the title compound as a beige solid. 1H NMR (DMSO-d6, 300 MHz) δ 13.03 (br s, 1H), 7.95 (s, 1H), 7.86-7.84 (dd, J=7.88, 1.31 Hz, 1H), 7.34-7.32 (d, J=7.88 Hz, 1H), 2.26 (s, 3H), 2.19 (s, 3H), 2.07 (s, 3H). HPLC (Method A) Rt 3.13 min (Purity: 97.1%).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:19][CH3:20])[CH:14]=[C:15]([CH2:16][O:17][CH3:18])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([O:19][CH3:20])[CH:14]=[C:15]([CH2:16][O:17][CH3:18])[C:7]=2[CH:6]([CH2:5][C:4]([OH:21])=[O:3])[O:10]1
Reactant: CCOC(=O)CC1OB(O)c2cc(OC)cc(COC)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COCc1cc(OC)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of (1-hydroxy-6-methoxy-4-methoxymethyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (60 g, 0.20 mmol) in THF (3 mL) and H2O (2 mL) was added LiOH (0.048 g) at 0° C. The resulting mixture was stirred at room temperature for 2 hours then cooled to 0° C. and acidified to pH 3 with 6N HCl. The mixture was concentrated in vacuo and the residue purified by silica gel flash column chromatography to give (1-hydroxy-6-methoxy-4-methoxymethyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid (0.050 g, 90%). 1H NMR (400 MHz, DMSO-d6) δ 7.12 (s, 1H), 6.94 (s, 1H), 5.56 (m, 1H), 4.40 (m, 2H), 3.75 (s, 3H), 3.26 (s, 3H), 3.00 (m, 1H), 2.02 (m, 1H). MS (ESI) m/z: 235 [M−1]−. HPLC purity: 86% (220 nm), 96% (Maxplot).
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].Cl[C:12]1[N:13]=[CH:14][C:15]([C:18]([NH:20][C:21]2[NH:22][N:23]=[C:24]([CH2:26][CH2:27][C:28]3[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[CH:29]=3)[CH:25]=2)=[O:19])=[N:16][CH:17]=1>CS(C)=O.CO>[CH3:35][O:34][C:32]1[CH:33]=[C:28]([CH2:27][CH2:26][C:24]2[CH:25]=[C:21]([NH:20][C:18]([C:15]3[CH:14]=[N:13][C:12]([N:7]4[CH2:8][CH2:9][CH2:10][N:4]([CH2:1][CH:2]=[CH2:3])[CH2:5][CH2:6]4)=[CH:17][N:16]=3)=[O:19])[NH:22][N:23]=2)[CH:29]=[C:30]([O:36][CH3:37])[CH:31]=1
Reactant: COc1cc(CCc2cc(NC(=O)c3cnc(Cl)cn3)[nH]n2)cc(OC)c1
Reactant: C=CCN1CCCNCC1
Solvent: CO
Solvent: CS(C)=O
Product: C=CCN1CCCN(c2cnc(C(=O)Nc3cc(CCc4cc(OC)cc(OC)c4)n[nH]3)cn2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.9 %

Procedure:
1-Prop-2-enyl-1,4-diazepane (224 mg, 1.60 mmol) was added to 5-chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (310 mg, 0.80 mmol) in DMSO (4.00 ml) at 25° C. The resulting solution was stirred at room temperature for 3 h. The reaction mixture was diluted with MeOH (5 ml) and the crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford crude product as an orange oil. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (271 mg, 69%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1([F:35])[CH2:8][N:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]2[N:17]=[C:18]([NH:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=3[O:31][CH3:32])[N:19]=[CH:20][C:5]=2[N:4]([CH3:33])[C:3]1=[O:34].C([N:38](C(C)C)C(C)C)C.[Cl-].[NH4+]>CN(C)C=O>[F:35][C:2]1([F:1])[CH2:8][N:7]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:6]2[N:17]=[C:18]([NH:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH2:38])=[O:28])=[CH:24][C:23]=3[O:31][CH3:32])[N:19]=[CH:20][C:5]=2[N:4]([CH3:33])[C:3]1=[O:34]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(CCc1ccccc1)CC(F)(F)C(=O)N2C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1cc(C(N)=O)ccc1Nc1ncc2c(n1)N(CCc1ccccc1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
To a mixture of 0.08 g (0.17 mmole) of 4-(7,7-difluoro-5-methyl-6-oxo-9-phenethyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-275), 0.12 mL (0.64 mmole) of ethyldiisopropyl amine and 0.018 g (0.34 mmole) of ammonium chloride in 2.0 mL of dimethylformamide was added 0.079 g (0.19 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The mixture was extracted with dichloromethane 3 times. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-90:10) gave 0.052 g of 4-(7,7-difluoro-5-methyl-6-oxo-9-phenethyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzamide (I-277) as a white solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[CH2:4][NH:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[Cl:17][C:18]1[CH:19]=[C:20]([NH:25][CH:26]([CH3:30])[C:27](O)=[O:28])[CH:21]=[CH:22][C:23]=1[Cl:24].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:17][C:18]1[CH:19]=[C:20]([NH:25][CH:26]([CH3:30])[C:27]([N:5]([CH2:4][CH:3]([O:15][CH3:16])[O:2][CH3:1])[CH2:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:28])[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: COC(CNCCCN1CCCCC1)OC
Reactant: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(CN(CCCN1CCCCC1)C(=O)C(C)Nc1ccc(Cl)c(Cl)c1)OC
Yield: 70.2 %

Procedure:
To a solution of (2,2-dimethoxy-ethyl)-(3-piperidin-1-yl-propyl)-amine (400 mg, 1.74 mmol) in N,N-dimethylformamide (4 mL) were added 2-(3,4-dichloro-phenylamino)-propionic acid (intermediate 11; 337 mg, 1.91 mmol), 4-methylmorpholine (527 mg, 5.21 mmol) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (990 mg, 2.61 mmol) at RT, then after 2 h the reaction mixture was partitioned between EtOAc and sat. aq. NaHCO3 solution. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2; CH2Cl2/MeOH/25% aq. ammonia solution 90:10:0.25) afforded the title compound (545 mg, 70%). Yellow viscous oil, MS: 446.2 (M+H)+.