Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:14])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:4]=2[O:3]1.COCCO[AlH2-]OCCOC.[Na+].[OH-].[Na+]>C1(C)C=CC=CC=1>[F:14][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][OH:12])=[CH:10][C:4]=2[O:3]1
Reactant: O=C(O)c1ccc2c(c1)OC(F)(F)O2
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: OCc1ccc2c(c1)OC(F)(F)O2
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
Commercially available 2,2-difluoro-1,3-benzodioxole-5-carboxylic acid (1.0 eq) is slurried in toluene (10 vol). Vitride® (2 eq) is added via addition funnel at a rate to maintain the temperature at 15-25° C. At the end of addition the temperature is increased to 40° C. for 2 h then 10% (w/w) aq. NaOH (4.0 eq) is carefully added via addition funnel maintaining the temperature at 40-50° C. After stirring for an additional 30 minutes, the layers are allowed to separate at 40° C. The organic phase is cooled to 20° C. then washed with water (2×1.5 vol), dried (Na2SO4), filtered, and concentrated to afford crude (2,2-difluoro-1,3-benzodioxol-5-yl)-methanol that is used directly in the next step.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24]>S(=O)(=O)(O)O.C(O)(=O)C.ClCCl>[Cl:9][C:10]1[CH:15]=[C:14]([I:1])[C:13]([O:16][CH3:17])=[CH:12][C:11]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24]
Reactant: COc1ccc(Cl)c(-c2ccccc2F)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(-c2ccccc2F)c(Cl)cc1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.9 %

Procedure:
N-Iodosuccinimide (683 mg, 3.04 mmol) was added to a solution of 2-chloro-2′-fluoro-5-methoxybiphenyl (Preparation 96, 749 mg, 3.16 mmol) in concentrated sulfuric acid (0.09 mL), acetic acid (4.7 mL) and dichloromethane (4.7 mL). The resulting mixture was stirred at room temperature for 18 hours and then partitioned between dichloromethane (30 mL) and water (5 mL). The organic phase was separated and washed with water (2×5 mL), brine (5 mL), dried over MgSO4, filtered and evaporated to give a red oil. Column chromatography purification on silica, eluting with dichloromethane:heptanes (1:9) gave the title compound (671 mg, 58%) as a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[C:24]3[C:19](=[C:20]([OH:27])[CH:21]=[C:22]([C:25]#[N:26])[CH:23]=3)[CH:18]=[N:17]2)[CH:5]=[CH:6][C:7]=1[O:8]CC1C=CC=CC=1>C(O)C.C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([N:16]2[C:24]3[C:19](=[C:20]([OH:27])[CH:21]=[C:22]([C:25]#[N:26])[CH:23]=3)[CH:18]=[N:17]2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: N#Cc1cc(O)c2cnn(-c3ccc(OCc4ccccc4)c(F)c3)c2c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#Cc1cc(O)c2cnn(-c3ccc(O)c(F)c3)c2c1
Yield: 42.3 %

Procedure:
A solution of 1-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-4-hydroxy-1H-indazole-6-carbonitrile (D6) (308 mg, 0.86 mmol) in ethanol (10 mL) and ethyl acetate (10 mL) was hydrogenated in an H-cube over a 10% palladium on charcoal catalyst. The resulting solution was concentrated, dissolved in ethanol then the product purified by silica gel chromatography eluting with 10-100% ethyl acetate in hexane to yield the title compound (E3) (98 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[S:5][CH:6]=1.S(=O)(=O)(O)O.[CH3:15]O>>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:15])=[O:8])[S:5][CH:6]=1
Reactant: O=C(O)c1cc(Br)cs1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)cs1
Temperature: 50 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
To a solution of 4-bromo-2-thiophenecarboxylic acid (25 g, 121 mmol) in methanol (241 ml) was added sulfuric acid (32.2 ml, 604 mmol). The resulting solution stirred at 50° C. over 12 h. The solution was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and used directly without further purification providing methyl 4-bromo-2-thiophenecarboxylate (26 g, 118 mmol, 97% yield), LCMS (ES) m/e 222 (M+H)+.
Reaction SMILES: [OH-].[Li+].[C:3]([N:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:13]=2)[N:9]([CH2:26][C:27]([O:29]CC2C=CC=CC=2)=[O:28])[C:8](=[O:37])[C@H:7]1[CH:38]([CH3:40])[CH3:39])(=[O:5])[CH3:4].C(OCC)C.Cl>C(O)C>[C:3]([N:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:13]=2)[N:9]([CH2:26][C:27]([OH:29])=[O:28])[C:8](=[O:37])[C@H:7]1[CH:38]([CH3:40])[CH3:39])(=[O:5])[CH3:4]
Reactant: CC(=O)N1C=C(c2cccc(OCc3ccccc3)c2)N(CC(=O)OCc2ccccc2)C(=O)[C@H]1C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: CC(=O)N1C=C(c2cccc(OCc3ccccc3)c2)N(CC(=O)O)C(=O)[C@H]1C(C)C

Procedure:
A 4 N aqueous lithium hydroxide solution (1.5 ml) is added to a solution of benzyl {(3R)-4-acetyl-6-(3-benzyloxyphenyl)-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}acetate (276 mg, Reference compound No. 63-1) in ethanol (8 ml)/diethyl ether (2 ml), and the mixture is stirred overnight. To the reaction mixture is added 6 N hydrochloric acid to acidify the system, and the whole is extracted with ethyl acetate. The extract is washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the titled reference compound (215 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH:5]([N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1)[C:6](=[O:12])[C:7]([CH3:11])([CH3:10])[CH2:8][F:9].[BH4-].[Na+].Cl>CO>[ClH:1].[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH:5]([N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1)[CH:6]([OH:12])[C:7]([CH3:11])([CH3:10])[CH2:8][F:9]
Reactant: CC(C)(CF)C(=O)C(Oc1ccc(Cl)cc1Cl)n1ccnc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(CF)C(O)C(Oc1ccc(Cl)cc1Cl)n1ccnc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 115.3 %

Procedure:
44 g (0.1275 mol) of 1-(2,4-dichlorophenoxy)-3,3-dimethyl-4-fluoro-1-(imidazol-1-yl)-2-butanone were dissolved in 300 ml of methanol, and 6.3 g of sodium borohydride were added at 0° to 5° C. The mixture was subsequently stirred at room temperature for 15 hours, 60 ml of concentrated hydrochloric acid were added dropwise, while cooling with ice, the mixture was stirred at room temperature for 10 hours and the solvent was distilled off under a waterpump vacuum. The residue was taken up in 250 ml of methylene chloride, the methylene chloride mixture was stirred in 500 ml of aqueous, saturated sodium bicarbonate solution, the methylene chloride phase was separated off and washed three times with 100 ml of water each time, the organic phase was dried over sodium sulphate and the solvent was distilled off. The oil which remained was taken up in 200 ml of ether, 50 ml of ethereal hydrochloric acid were added and the solvent was distilled off. 28.2 g (58% of theory) of 1-(2,4-dichlorophenoxy)-3,3-dimethyl-4-fluoro-1-(imidazol-1-yl)-2-butanol hydrochloride of melting point 184°-210° C. were obtained. ##STR85##
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]([CH2:40][CH3:41])[C:6]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[CH2:17][N:18]([CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=1)[C:19]1[N:20]=[N:21][N:22]([CH3:24])[N:23]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH3:4].[CH3:42]I>CN(C=O)C>[CH2:40]([N:5]([CH2:3][CH3:4])[C:6]([C:8]1[N:9]([CH3:42])[C:10]2[C:15]([C:16]=1[CH2:17][N:18]([CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=1)[C:19]1[N:20]=[N:21][N:22]([CH3:24])[N:23]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH3:41]
Reactant: CCN(CC)C(=O)c1[nH]c2ccccc2c1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1c(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2ccccc2n1C
Reaction time: 0.25 h
Yield: 68.5 %

Procedure:
To a suspension of NaH (0.01 g, 0.36 mmol) in DMF (5ml) was added 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-1H-indole-2-carboxylic acid diethylamide (0.1 g, 0.18 mmol), obtained in Example 131, at 0° C., and stirred for 15 min. Methyl iodide (0.031 g, 0.216 mmol) was added to this at the same temperature. The reaction was stirred for 6 h and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over sodium sulphate and then concentrated under vacuum to afford the crude residue which was purified by column chromatography over 100-200 mesh silica gel using 15% ethyl acetate and petroleum ether to afford 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-1-methyl-1H-indole-2-carboxylic acid diethylamide (0.07 g, 60%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:31](=[O:32])[N:30]([CH2:33][CH3:34])[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([N:23]5[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]5)=[CH:19][CH:18]=4)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[C:4]([Cl:35])[CH:3]=1.[CH3:36][C:37]1[S:41][C:40]([Sn](CCCC)(CCCC)CCCC)=[N:39][CH:38]=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.C1(C)C=CC=CC=1>[Cl:35][C:4]1[CH:3]=[C:2]([C:40]2[S:41][C:37]([CH3:36])=[CH:38][N:39]=2)[CH:7]=[CH:6][C:5]=1[C:8]1[C:31](=[O:32])[N:30]([CH2:33][CH3:34])[C:11]2[N:12]=[C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:14]=[CH:15][C:10]=2[CH:9]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncc(C)s1
Reactant: CCn1c(=O)c(-c2ccc(Br)cc2Cl)cc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCn1c(=O)c(-c2ccc(-c3ncc(C)s3)cc2Cl)cc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Temperature: 140 °C

Procedure:
6-(4-Bromo-2-chlorophenyl)-8-ethyl-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (12, 194 mg, 0.35 mmol), 5-methyl-2-(tributylstannyl)-thiazole (171 mg, 0.44 mmol), Pd(PPh3)4 (50 mg) and toluene (15 mL) were placed in a microwave tube and oxygen was removed by a stream of argon. The reaction was heated by microwave at 140° C. for 1.5 h and was monitored by LC/MS. The reaction mixture was evaporated and the solid was extracted with chloroform (100 mL). The solids were removed and the filtrate was evaporated and purified by silica gel chromatography (CHCl3+5% MeOH). Yield 17 mg, 0.03 mmol, 8% as yellow solid. LCMS m/z 572 (M+H)+Rt 1.74 min; 1H NMR (400 MHz, CDCl3) δ ppm 8.56 (s, 1H), 8.04 (s, 1H), 7.81-7.83 (d, 1H), 7.54-7.61 (m, 4H), 7.46-7.48 (d, 1H), 7.32-7.37 (s, 1H), 6.97-7.00 (d, 2H), 4.48-4.54 (q, 2H), 3.24-3.26 (m, 4H), 2.63-2.65 (m, 4H), 2.54 (s, 3H), 2.40 (s, 3H), 1.38-1.42 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:14])[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N+:6]([O-])[CH:7]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:18]>CN(C)C=O>[Br:1][C:2]1[C:7](=[O:18])[NH:6][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([F:14])[CH:3]=1
Reactant: CCOC(=O)c1c(F)cc(Br)c[n+]1[O-]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]c(=O)c(Br)cc1F
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a stirred solution of ethyl 5-bromo-3-fluoro-1-oxido-pyridin-1-ium-2-carboxylate (3, 0.85 g, 3.21 mmol) in dimethylformamide (15 mL) was added trifluoroacetic anhydride (1.35 g, 6.42 mmol) at 0° C. The reaction mixture was warmed to 50° C. and stirred for 1 h, quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (2×100 mL). The organic layers were separated, dried with magnesium sulfate, filtered and concentrated to dryness under vacuum to afford ethyl 5-bromo-3-fluoro-6-oxo-1H-pyridine-2-carboxylate (4) as a yellow solid. Yield: 0.8 g, 94%; MS (ESI) m/z 264 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 7.86 (m, 1H), 4.47 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:11]([CH3:12])=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[CH3:13].[CH2:14]([N:21]1[C:29]2[C:28](Cl)=[N:27][C:26]([NH2:31])=[N:25][C:24]=2[CH:23]=[CH:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN1C(=O)CCC1.O>[NH2:31][C:26]1[N:27]=[C:28]([O:3][C:4]2[C:5]([CH3:13])=[CH:6][C:7]([C:8]#[N:9])=[CH:10][C:11]=2[CH3:12])[C:29]2[N:21]([CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:22]=[CH:23][C:24]=2[N:25]=1
Reactant: Nc1nc(Cl)c2c(ccn2Cc2ccccc2)n1
Reactant: Cc1cc(C#N)cc(C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(C#N)cc(C)c1Oc1nc(N)nc2ccn(Cc3ccccc3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
To a stirred suspension of NaH (155 mg, 6.47 mmol) in dry NMP (4 mL) was added 4-hydroxy-3,5-dimethylbenzonitrile (570 mg, 3.88 mmol), and the mixture was stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 5-benzyl-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine (400 mg, 1.55 mmol) in dry NMP (4 mL) and heated at 160° C. for 16 h. After completion of the reaction, the resulting mixture was diluted with water and washed with EtOAc. The combined organic layers were washed with water, 2% NaOH, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (2:1-1:4) to give the product as a light yellow solid (342 mg, 60%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:8]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[Cl-].[Cl-].[Cl-].[Al+3].[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23].Cl>ClCCl>[CH3:1][O:2][C:3]([C:5]1[C:8]2[CH:9]=[C:10]([O:13][CH3:14])[C:11]([C:22](=[O:23])[C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[F:19])=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: O=C(Cl)c1ccccc1F
Reactant: COC(=O)C1=Cc2ccc(OC)cc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C1=Cc2cc(C(=O)c3ccccc3F)c(OC)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
While stirring at from 0 to 3°, 9.61 g of 5-methoxybenzocyclobutene-1-carboxylic acid methyl ester are added dropwise to a suspension, cooled to 0°, of 26.6 g of aluminium trichloride in 60 ml of dichloromethane. The whole is stirred for 30 minutes at 0°, 15.9 g of o-fluorobenzoyl chloride are added dropwise thereto and stirring is carried out for 2 hours at from 0° to 3°. The whole is then poured into a mixture of 100 g of ice-water and 5 ml of concentrated hydrochloric acid, extracted by shaking twice with 100 ml of dichloromethane each time, washed with water, dried over magnesium sulphate and concentrated to dryness by evaporation. The residue is taken up in a small amount of dichloromethane, petroleum ether is added until a precipitate begins to form and the whole is then cooled. The precipitate that has formed is filtered off with suction and the filtrate is concentrated by evaporation and chromatographed over silica gel using dichloromethane as eluant. After a small number of first runnings, 4-(o-fluorobenzoyl)-5-methoxybenzocyclobutene-1-carboxylic acid methyl ester is obtained having a melting point of 73°-74°.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]([F:15])[F:14])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]([F:14])[F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:35](=[O:38])[CH2:36][CH3:37])[CH2:33][CH2:34]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: CCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f60) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1([F:36])[CH2:8][N:7]([C@@H:9]2[CH2:11][C@H:10]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[N:18]=[C:19]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=3[O:32][CH3:33])[N:20]=[CH:21][C:5]=2[N:4]([CH3:34])[C:3]1=[O:35].C(N(C(C)C)C(C)C)C.[CH3:46][N:47]([CH3:52])[CH2:48][CH2:49][CH2:50][NH2:51]>CN(C)C=O>[F:1][C:2]1([F:36])[CH2:8][N:7]([C@@H:9]2[CH2:11][C@H:10]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[N:18]=[C:19]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH:51][CH2:50][CH2:49][CH2:48][N:47]([CH3:52])[CH3:46])=[O:29])=[CH:25][C:24]=3[O:32][CH3:33])[N:20]=[CH:21][C:5]=2[N:4]([CH3:34])[C:3]1=[O:35]
Reactant: CN(C)CCCN
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N([C@@H]1C[C@H]1c1ccccc1)CC(F)(F)C(=O)N2C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NCCCN(C)C)ccc1Nc1ncc2c(n1)N([C@@H]1C[C@H]1c1ccccc1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
To a mixture of 0.074 g (0.15 mmole) of 4-[7,7-difluoro-5-methyl-6-oxo-9-(trans-2-phenyl-cyclopropyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-3-methoxy-benzoic acid (I-287), 0.11 mL (0.6 mmole) of ethyldiisopropyl amine and 0.016 g (0.30 mmole) of N,N-dimethyl-propane-1,3-diamine in 2.0 mL of dimethylformamide was added 0.071 g (0.17 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 three times with dichloromethane. 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, 100:0-0:100) gave 0.063 g of 4-[7,7-difluoro-5-methyl-6-oxo-9-(trans-2-phenyl-cyclopropyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-N-(3-dimethylamino-propyl)-3-methoxy-benzamide (I-290) as a white solid.
Reaction SMILES: NC[C:3]1[CH:17]=[CH:16][C:6]([C:7]([NH:9]C2C=NC=CC=2)=[O:8])=[CH:5][CH:4]=1.CN1C(S(Cl)(=O)=O)=CN=C1C>N1C=CC=CC=1>[C:7]([NH2:9])(=[O:8])[C:6]1[CH:16]=[CH:17][CH:3]=[CH:4][CH:5]=1
Reactant: NCc1ccc(C(=O)Nc2cccnc2)cc1
Agent: Cc1ncc(S(=O)(=O)Cl)n1C
Solvent: c1ccncc1
Product: NC(=O)c1ccccc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(aminomethyl)-N-(3-pyridinyl)benzamide (33) (341 mg, 1.5 mmol) and 1,2-dimethyl-1H-imidazole-5-sulfonyl chloride (292 mg, 1.5 mmol) in dry pyridine (10 mL) was stirred at 20° C. for 16 h. The solvent was evaporated and the residue stirred in ice/water (20 mL) for 1 h. The precipitate was filtered, washed with water (5 mL) and dried. The crude solid was purified by column chromatography, eluting with a gradient (0-20%) of MeOH/EtOAc, to give benzamide I-6 (201 mg, 35%) as a white powder: mp (MeOH/EtOAc) 238-240° C.; 1H NMR δ 10.37 (s, 1H, CONH), 8.92 (br s, 1H, H-2′), 8.31 (dd, J=4.7, 1.5 Hz, 1H, H-6′), 8.18 (ddd, J=8.3, 2.5, 1.5 Hz, 1H, H-4′), 7.97 (br s, 1H, NHSO2), 7.91 (br dd, J=8.3, 1.7 Hz, 2H, H-2, H-6), 7.61 (s, 1H, H-5″), 7.44 (br d, J=8.3 Hz, 2H, H-3, H-5), 7.39 (ddd, J=8.3, 4.6, 0.6 Hz, 1H, H-5′), 4.10 (br d, J=6.0 Hz, 2H, CH2N), 3.58 (s, 3H, NCH3), 2.30 (s, 3H, CH3); 13C NMR δ 165.7, 146.4, 144.5, 142.5, 142.0, 137.1, 135.8, 132.9, 127.5 (2), 127.4 (2), 127.3, 124.7, 123.5, 45.7, 32.8, 12.4; MS m/z 386.6 (MH+, 100%). Anal. calcd for C18H19N5O3S: C, 56.09; H, 4.97; N, 18.17. Found: C, 56.15; H, 5.08; N, 18.00%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=3)[NH:10][CH:9]=2)[CH:5]=[C:4]([Cl:19])[N:3]=1.[NH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]1>C(#N)C.CCO>[Cl:19][C:4]1[N:3]=[C:2]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]2)[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=3)[NH:10][CH:9]=2)[CH:5]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: COc1cnc2[nH]cc(-c3cc(Cl)nc(Cl)c3)c2c1
Solvent: CCO
Solvent: CC#N
Product: COc1cnc2[nH]cc(-c3cc(Cl)nc(N[C@H]4CC[C@H](O)CC4)c3)c2c1

Procedure:
A mixture of Example 149e (43.9 mg, 0.146 mmol) and trans-4-aminocyclohexanol (0.337 g, 2.92 mmol) in acetonitrile (1.5 mL) and EtOH (1.5 mL) was heated at 190° C. for 3 hours in a Biotage microwave reactor. The solvent was evaporated. The residue was treated with 5% citric acid and brine, and extracted with EtOAc (2×). The combined organic layers were dried over MgSO4, filtered, concentrated, and purified on a 12 g column using the ISCO Companion flash system eluting with CH2Cl2/EtOAc (5:95) to 100% EtOAc to give 22.0 mg of the title compound. 1H NMR (500 MHz, DMSO-d6) ppm 1.15-1.33 (m, 3H), 1.84 (d, J=10.98 Hz, 2H), 1.96 (d, J=11.29 Hz, 2H), 2.07 (m, 1H), 3.40 (m, 1H), 3.59 (m, 1H), 3.89 (s, 3H), 6.76-6.90 (m, 2H), 7.78 (d, J=2.75 Hz, 1H), 8.07 (dd, J=6.71, 2.75 Hz, 2H), 12.03 (s, 1H). MS (APCI+) m/z 373.4 (M+H)+.
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[C:24]([N:25]([CH:27]([CH3:29])[CH3:28])[CH3:26])=[N:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:30]([OH:32])=[O:31])[CH:21]=3)[N:16]=2)=[CH:11][CH:10]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[C:24]([N:25]([CH:27]([CH3:29])[CH3:28])[CH3:26])=[N:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:30]([OH:32])=[O:31])[CH:21]=3)[N:16]=2)=[CH:11][CH:10]=1
Reactant: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc(NC(=O)OC(C)(C)C)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc(N)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
To a solution of 2-(6-(tert-butoxycarbonylamino)pyridin-3-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid (140.0 mg, 0.32 mmol) in dichloromethane (50 mL) was added CF3COOH (182.6 mg, 1.60 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (10 mL) and adjusted to pH 6 with sodium bicarbonate. The product were collected by filtration to afford 2-(6-aminopyridin-3-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a light yellow solid (88.6 mg, 78%).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:18](OC(=O)C)(=[O:20])[CH3:19].O>ClCCl>[CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:18](=[O:20])[CH3:19])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)Nc1ccc(N(C)C)cc1
Reaction time: 0.25 h
Yield: 69 %

Procedure:
To a solution of N,N-dimethylbenzene-1,4-diamine (1.0 eq) in dichloromethane, triethylamine (2.2 eq) was added at 0° C. and stirred for 15 min. To the above mixture was then added a solution of acetic anhydride (1.0 eq) in dichloromethane at 0° C., after addition the reaction was continued at room temperature for 5 hrs. Water was added and the organic layer was separated, dried over anhydrous Na2SO4, concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the desired N-[4-(dimethylamino)phenyl]acetamide. (Yield=69%)