Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[NH:8]2.[CH3:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[F:22][C:20]1[CH:19]=[CH:18][C:17]([O:23][CH3:24])=[C:16]([C:4]2[C:3]([CH2:2][NH:30][C:29]3[CH:31]=[CH:32][C:26]([CH3:25])=[CH:27][CH:28]=3)=[C:12]3[C:7]([NH:8][C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[NH:11]3)=[CH:6][CH:5]=2)[CH:21]=1
Reactant: COc1ccc(F)cc1-c1ccc2c(c1CCl)NC(=O)C(C)(C)N2
Reactant: Cc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(F)cc1-c1ccc2c(c1CNc1ccc(C)cc1)NC(=O)C(C)(C)N2
Temperature: 80 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A mixture of 8-chloromethyl-7-(5-fluoro-2-methoxyphenyl)-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 4-2, 50.7 mg, mmol), 4-methylaniline (19.3 mg, 0.18 mmol), and potassium carbonate (60.6 mg, 0.44 mmol) was suspended in anhydrous N,N-dimethylformamide (1 mL) and stirred at 80° C. overnight. After cooling down, ethyl acetate (30 mL) and water (30 mL) were added and partitioned. The organic layer was washed with water (30 mL) and saturated brine (30 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (48.2 mg) as a pale yellow solid. (Yield 80%)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[CH3:28])[CH2:9]/[C:10](/[C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH:42]=[CH:41][C:40]([S:43]([NH2:46])(=[O:45])=[O:44])=[CH:39][CH:38]=2)O1>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([C:37]3[CH:42]=[CH:41][C:40]([S:43]([NH2:46])(=[O:45])=[O:44])=[CH:39][CH:38]=3)=[CH:7][CH:6]=2)[CH2:9]/[C:10](=[N:11]\[OH:12])/[C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[C:22]([CH3:28])[CH:23]=1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Reactant: Cc1cc(F)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Product: Cc1cc(F)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(-c2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
The title compound was prepared in analogy to example 166, from (−)-5-{3-(4-bromo-phenyl)-3-(4-fluoro-2-methyl-phenyl)-1-[(E)-hydroxyimino]-propyl}-1-methyl-1H-pyridin-2-one (example 404) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (CAS RN 214360-51-7). The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of dichloromethane:methanol (100:0 to 90:10). Light brown solid. MS (ESI+): m/z=520.2 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[N:6][CH:7]=1.[CH3:12][C@@H:13]([OH:17])[CH2:14][CH:15]=[CH2:16].C(N(CC)CC)C.C(#N)C>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH:9]([O:8][C:4]1[CH:3]=[C:2](/[CH:16]=[CH:15]/[CH2:14][C@H:13]([OH:17])[CH3:12])[CH:7]=[N:6][CH:5]=1)([CH3:11])[CH3:10]
Reactant: C=CC[C@@H](C)O
Reactant: CC(C)Oc1cncc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)Oc1cncc(/C=C/C[C@@H](C)O)c1
Temperature: 140 °C
Yield: 84.9 %

Procedure:
A mixture of 5-bromo-3-isopropoxypyridine (10.26 g, 47.50 mmol), (2R)-4-penten-2-ol (4.91 g, 57.00 mmol), palladium(II) acetate (106 mg, 0.47 mmol), tri-o-tolylphosphine (578 mg, 1.90 mmol), triethylamine (28.46 mL, 204.25 mmol), and acetonitrile (30 mL) was heated in a sealed glass tube at 140° C. for 14 h. The reaction mixture was cooled to ambient temperature, diluted with water, and extracted with chloroform (3×200 mL). The combined chloroform extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation to give a pale-yellow oil (8.92 g, 85.0%).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(#N)C>[CH2:1]([N:8]([CH2:9][P:10]([O:14][CH2:15][CH3:16])([O:11][CH2:12][CH3:13])=[O:17])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOP(=O)(CNCc1ccccc1)OCC
Reactant: CCOC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CN(Cc1ccccc1)CP(=O)(OCC)OCC
Temperature: 25 °C

Procedure:
Into a 500-mL 3-necked round-bottom flask, was placed a solution of diethyl (benzylamino)methylphosphonate (intermediate 5.2) (12 g, 46.69 mmol, 1.00 equiv) in acetonitrile (150 mL), DIEA (12 g, 2.00 equiv). This was followed by the addition of ethyl 2-bromoacetate (8.4 g, 50.30 mmol, 1.10 equiv) dropwise with stirring. The mixture was stirred for 30 min at room temperature. The resulting solution was heated to reflux for 6 hr. The resulting mixture was cooled to room temperature and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20 to 1:5). This resulted in 8.0 g (50%) of ethyl 2-(benzyl((diethoxyphosphoryl)methyl)amino)acetate as yellow oil.
Reaction SMILES: F[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([F:14])[C:3]=1[C:4]([OH:6])=[O:5].CCN(CC)CC.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>CCO.O>[F:14][C:7]1[C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1c(F)ccc([N+](=O)[O-])c1F
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(O)c1c(F)ccc([N+](=O)[O-])c1Nc1ccccc1
Temperature: 70 °C
Yield: 88.3 %

Procedure:
To a solution of 2,6-difluoro-3-nitrobenzoic acid (5 g, 24.6 mmol) in EtOH (25 mL) and water (25 mL) at 0° C. were added Et3N (6.2 mL, 44.3 mmol) and aniline (2.3 g, 24.6 mmol). The reaction mixture was heated at 70° C. for 4 h under a nitrogen atmosphere. After cooling to RT, the pH of the solution was adjusted to 1 by addition of 1N HCl. A precipitate formed and this solid was collected by filtration, washed with water to afford the title compound (6.0 g, 88%). 1H NMR (DMSO-d6, 400 MHz): δ 9.02 (1H, s), 8.18 (1H, dd, J=9.29, 5.78 Hz), 7.25-7.16 (2H, m), 7.05 (1H, t, J=9.07 Hz), 7.00-6.91 (3H, m)
Reaction SMILES: C[O:2][C:3]([CH2:5][S:6][S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=O.CC(C[AlH]CC(C)C)C.O>C(OCC)C>[CH:3]([CH2:5][S:6][S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:2]
Reactant: CCCCCCCCSSCC(=O)OC
Agent: CC(C)C[AlH]CC(C)C
Solvent: O
Solvent: CCOCC
Product: CCCCCCCCSSCC=O
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 97 %

Procedure:
MeOC(O)CH2SSC8H17 (1.85 g, 7.39 mmol) was dissolved in dry diethyl ether (40 mL) in a N2 purged flask. The solution was cooled to −78° C., and DIBAL-H (8.87 mL, 1.0 M in cyclohexane, 8.87 mmol) was added to the cold solution dropwise via syringe. The reaction was stirred at −78° C. for 1 h 45 min, after which H2O (5 mL) was added, the cold bath removed and the solution was allowed to slowly warm to room temperature. Additional diethyl ether (60 mL) was added, and the organic phase was washed with 1N HCl (3×100 mL), dried over MgSO4, and concentrated to yield HC(O)CH2SSC8H17 (1.58 g, 97.02%) as a milky oil.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C@H:8]([NH:15][S@@](C(C)(C)C)=O)[C:9]1[S:10][C:11]([CH3:14])=[CH:12][N:13]=1)(C)(C)C.[ClH:24].O1CCOCC1>CO>[ClH:24].[NH2:15][C@H:8]([C:9]1[S:10][C:11]([CH3:14])=[CH:12][N:13]=1)[CH2:7][OH:6]
Reactant: Cc1cnc([C@H](CO[Si](C)(C)C(C)(C)C)N[S@](=O)C(C)(C)C)s1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cnc([C@@H](N)CO)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 184 mg of (R)—N-[(1S)-2-{[tert-butyl (dimethyl)silyl]oxy}-1-(5-methyl-1,3-thiazol-2-yl)ethyl]-2-methylpropane-2-sulfinamide in 2 ml of methanol was added 2 ml of a 4 M hydrogen chloride/1,4-dioxane solution, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and 1 M hydrochloric acid was added thereto, followed by washing with ethyl acetate. The aqueous layer was concentrated under reduced pressure to obtain 112 mg of (2S)-2-amino-2-(5-methyl-1,3-thiazol-2-yl)ethanol hydrochloride.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][C:10]=1[OH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl[CH2:29][O:30][CH3:31].[Cl-].[NH4+]>ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][C:10]=1[O:18][CH2:29][O:30][CH3:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(O)c1
Reactant: COCCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1cc(C(C)=O)ccc1OCc1ccccc1
Reaction time: 0.17 h

Procedure:
To a solution of 3′,4′-dihydroxyacetophenone (2.00 g) in N,N-dimethylformamide (40 ml) were added lithium carbonate (2.44 g) and benzyl bromide (4.0 ml), and the mixture was stirred for 14.5 hours at 50° C. To the reaction mixture was added 1N hydrochloric acid, and the resulting mixture was extracted with a mixed solution of diethyl ether and ethyl acetate (3/1). The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, purification of the residue by flash column chromatography on silica gel (eluent: hexane/ethyl acetate=4/1) gave 4′-benzyloxy-3′-hydroxyacetophenone (2.00 g). To a stirred solution of the obtained 4′-benzyloxy-3′-hydroxyacetophenone (2.00 g) in dichloromethane (25 ml) was added N,N-diisopropylethylamine (2.2 ml) under ice-cooling, and the mixture was stirred for 10 minutes. Chloromethylmethyl ether (1.2 ml) was added to the mixture, and the resulting mixture was stirred for 5.5 hours at room temperature. The reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted with dichloromethane. The extract was washed with brine and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, purification of the residue by flash column chromatography on silica gel (eluent: hexane/ethyl acetate=3/1) gave 4′-benzyloxy-3′-methoxymethoxyacetophenone (2.28 g).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:5]=[C:6]([CH3:20])[C:7]2[CH:13]=[CH:12][C:11](=[O:14])[N:10]([CH2:15][CH2:16][CH2:17][O:18][CH3:19])[C:8]=2[N:9]=1)[CH3:2].C(O)(=O)C.[Br:25]Br>C(Cl)Cl.O>[Br:25][C:12]1[C:11](=[O:14])[N:10]([CH2:15][CH2:16][CH2:17][O:18][CH3:19])[C:8]2[N:9]=[C:4]([NH:3][CH2:1][CH3:2])[N:5]=[C:6]([CH3:20])[C:7]=2[CH:13]=1
Reactant: BrBr
Reactant: CCNc1nc(C)c2ccc(=O)n(CCCOC)c2n1
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CCNc1nc(C)c2cc(Br)c(=O)n(CCCOC)c2n1
Reaction time: 0.08 h
Yield: 56.3 %

Procedure:
To a solution of 2-(ethylamino)-8-(3-methoxypropyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (0.18 g, 0.65 mmol), acetic acid (5 mL) and dichloromethane (3 mL) was added bromine (36 ul, 0.7 mmol). The mixture was stirred for 5 minutes, and then diluted with DCM and water. The organic layer was washed with sat. sodium bicarbonate (3 times), brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography to gave 0.13 g (56% yield) of 6-bromo-2-(ethylamino)-8-(3-methoxypropyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one. 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 5.44 (Br. s, 1H), 4.55 (m, 2H), 3.54-3.47 (m, 4H), 3.33 (s, 3H), 2.53 (s, 3H), 2.05-2.00 (m, 2H), 1.30-1.23 (m, 3H); MS (E) for C14H19BrN4O2: 355 (MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][N:11]([C:16]3[CH:17]=[C:18]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:19]([NH:21][CH:22]3[CH2:24][CH2:23]3)=[O:20])[C:12]2=[O:15])=[CH:7][CH:6]=1.[I-].[K+].Cl.[O:32]1[CH2:38][CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O.C(OCC)(=O)C>[CH:22]1([NH:21][C:19](=[O:20])[C:18]2[CH:25]=[CH:26][C:27]([CH3:28])=[C:16]([N:11]3[CH:10]=[CH:9][C:8]4[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:35]5[CH2:36][CH2:37][CH2:38][O:32][CH2:33][CH2:34]5)=[CH:6][CH:7]=4)[C:12]3=[O:15])[CH:17]=2)[CH2:24][CH2:23]1
Reactant: C1CNCCOC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccc2ccc(OCCCl)cc2c1=O
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccc2ccc(OCCN3CCCOCC3)cc2c1=O
Temperature: 150 °C
Yield: 65.3 %

Procedure:
3-[7-(2-Chloroethoxy)-1-oxoisoquinolin-2(1H)-yl]-N-cyclopropyl-4-methylbenzamide (0.15 g), potassium iodide (0.13 g), 1,4-oxazepane hydrochloride (0.34 g), and N,N′-diisopropylethylamine (0.8 ml) were stirred in DMA (3 ml) and heated under microwave irradiation conditions (Personal Chemistry Emrys Optimizer with 300 W magnetron) at 150° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water (×5), brine (×2), dried (magnesium sulfate) and concentrated. Purification by column chromatography on a silica column eluting using a gradient of ethyl acetate to 15% methanol/ethyl acetate gave N-cyclopropyl-4-methyl-3-[7-[2-(1,4-oxazepan-4-yl)ethoxy]-1-oxoisoquinolin-2(1H)-yl]benzamide (0.114 g) as a white solid; NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.69 (m, 2H), 1.80 (m, 2H), 2.10 (s, 3H), 2.76 (m, 4H), 2.85 (m, 1H), 2.92 (t, 2H), 3.61 (m, 2H), 3.66 (t, 2H), 4.19 (m, 2H), 6.72 (d, 1H), 7.21 (d, 1H), 7.41 (d, 1H), 7.49 (d, 1H), 7.69 (s, 1H), 7.71 (d, 1H), 7.74 (s, 1H), 7.88 (d, 1H), 8.43 (d, 1H); Mass Spectrum: M+H+ 462.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][NH:9][C:10](=[O:15])[C:11]([F:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=[C:4]([Cl:16])[C:3]=1[NH:17][C:18]1[N:22]([CH3:23])[C:21]2[CH:24]=[C:25]([N:31]3[CH2:36][CH2:35][CH:34]([C:37]([F:40])([F:39])[F:38])[CH2:33][CH2:32]3)[C:26]([C:28](O)=[O:29])=[CH:27][C:20]=2[N:19]=1.ClC(N(C)C)=C(C)C.CCN(C(C)C)C(C)C.[Cl:58][C:59]1[CH:60]=[C:61]([CH:63]=[CH:64][C:65]=1[F:66])[NH2:62]>CC#N>[Cl:58][C:59]1[CH:60]=[C:61]([NH:62][C:28]([C:26]2[C:25]([N:31]3[CH2:36][CH2:35][CH:34]([C:37]([F:40])([F:38])[F:39])[CH2:33][CH2:32]3)=[CH:24][C:21]3[N:22]([CH3:23])[C:18]([NH:17][C:3]4[C:4]([Cl:16])=[CH:5][CH:6]=[C:7]([CH2:8][NH:9][C:10](=[O:15])[C:11]([F:14])([CH3:13])[CH3:12])[C:2]=4[Cl:1])=[N:19][C:20]=3[CH:27]=2)=[O:29])[CH:63]=[CH:64][C:65]=1[F:66]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)F)c2Cl)nc2cc(C(=O)O)c(N3CCC(C(F)(F)F)CC3)cc21
Agent: CC(C)=C(Cl)N(C)C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)F)c2Cl)nc2cc(C(=O)Nc3ccc(F)c(Cl)c3)c(N3CCC(C(F)(F)F)CC3)cc21
Reaction time: 0.33 h

Procedure:
A mixture of 2-{2,6-dichloro-3-[(2-fluoro-2-methyl-propionylamino)-methyl]-phenylamino}-6-[4-trifluoromethyl-piperidinyl]-1-methyl-1H-benzimidazole-5-carboxylic acid (60 mg, 0.100 mmol), (1-chloro-2-methyl-propenyl)-dimethylamine (33 mg, 0.25 mmol), DIPEA (86 μL, 0.50 mmol) and MeCN (2 mL) is stirred for 20 min. This mixture is added to 3-chloro-4-fluoro-aniline (0.200 mmol) and it is stirred overnight at rt. The mixture is directly purified via reverse phase HPLC. Yield: 39 mg. HPLC Rt=0.607 min (method F). MS m/z: 731 [M+H]+.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]2[O:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14][CH2:13]2)(=O)=O)=CC=1.FC(F)(F)C(O)=O.[NH2:30][C:31]1[C:36]([C:37]([NH:39][CH2:40][CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[O:38])=[CH:35][CH:34]=[CH:33][N:32]=1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)/C=C\C(O)=O>C(#N)C>[NH2:30][C:31]1[C:36]([C:37]([NH:39][CH2:40][CH:41]2[CH2:46][CH2:45][N:44]([CH2:11][CH:12]3[O:17][C:16]4[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=4[O:14][CH2:13]3)[CH2:43][CH2:42]2)=[O:38])=[CH:35][CH:34]=[CH:33][N:32]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccccc3O2)cc1
Reactant: Nc1ncccc1C(=O)NCC1CCNCC1
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Nc1ncccc1C(=O)NCC1CCN(CC2COc3ccccc3O2)CC1

Procedure:
A stirred mixture of 1,4-benzodioxan-2-ylmethyl toluene4-sulphonate (0.82 g), 2-amino-N-(4-piperidylmethyl)pyridine-3-carboxamide trifluoroacetate (0.905 g; prepared in a similar manner to that described in Example 2) and potassium carbonate (1.4 g) in acetonitrile (50 ml) was heated under reflux for 6 hours. After cooling, the solvent was removed in vacuo, water (60 ml) was added to the residue, and the product was extracted with dichloromethane (2×30 ml). The extracts were dried over magnesium sulphate and the solvent was removed in vacuo to give an oil. The oil was purified by flash chromatography on silica eluting with a 9:1 then 1:1 mixture of dichloromethane and methanol. Appropriate fractions were combined and the solvents removed in vacuo to give an oil. Ethereal maleic acid (20 ml) was added to yield a white solid. The solid was collected by filtration, washed with ether and the solvent removed in vacuo to yield 2-amino-N-{[1-(1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide 0.5 maleate (95 mg) m.p. 104-106° C.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[N:15]12[CH2:23][CH2:22][CH:19]([CH2:20][CH2:21]1)[CH2:18][CH2:17][CH2:16]2.[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26].CO>C(OCC)(=O)C>[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][CH:16]3[CH2:17][CH2:18][CH:19]4[CH2:22][CH2:23][N:15]3[CH2:21][CH2:20]4)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: C1CC2CCN(C1)CC2
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CC1CCC2CCN1CC2

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-azabicyclo[3.2.2]nonane. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 85% overall yield. FDMS m/e=314 (M+ of free base). α[D]589 =-20.39 (c=0.48, methanol).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[C:17]([CH2:25][CH3:26])[CH:18]=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:27]>CO.O1CCOCC1>[ClH:27].[ClH:27].[N:11]1([C:15]2[CH:16]=[C:17]([CH2:25][CH3:26])[CH:18]=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CCc1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)c2ncccc2c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCc1cc(N2CCCNCC2)c2ncccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(6-Ethylquinolin-8-yl)-[1,4]-diazepan-1-carboxylic acid tert-butyl ester (1.0 g, 1.0 equiv) was dissolved in MeOH (5 mL) and 1.0 M HCl in 1,4-dioxane (10 mL) was added to the mixture. After stirring at room temperature for 1 hour, the mixture was concentrated to dryness to afford the title compound (1.0 g). MS (ES) m/z 256.1 (M+H+).
Reaction SMILES: [C:1]([N:4]1[C:8](=[O:9])[CH:7]=[CH:6][C:5]1=[O:10])(=[O:3])[NH2:2].[CH2:11](O)[CH2:12][CH2:13][CH3:14].[OH2:16]>[Cl-].[Zn+2].[Cl-].CC#N.O>[C:5]([O:10][CH2:11][CH2:12][CH2:13][CH3:14])(=[O:16])/[CH:6]=[CH:7]\[C:8](=[O:9])[NH:4][C:1](=[O:3])[NH2:2]
Reactant: NC(=O)N1C(=O)C=CC1=O
Reactant: CCCCO
Reactant: O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC#N
Product: CCCCOC(=O)/C=C\C(=O)NC(N)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
A mixture of 140 g of N-carbamylmaleimide (1 mole), 1.36 g of zinc chloride (0.01 moles) and 150 g of n-butanol (2 moles) was heated to reflux. After 4 hours, the mixture was poured into 400 mL of water and cooled to room temperature. The butyl maleurate was filtered, washed with water and dried to afford 200 g (93% yield). M.P.: 97°-90° C.; 1H NMR (CDCl3): δ10.6 (brs, 1H), 8.2 (brs, 1H), 6.3 (AB, 2H), 5.9 (brs, 1H), 4.2 (t, 2H), 1.6 (m, 2H), 1.4 (m, 2H), 0.9 (t, 3H); HPLC (20 to 40% CH3CN/H2O over 20 minutes, C8): Rt=9.4 minutes.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:44])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:24]=[CH:25][C:26]4[N:32]([CH3:33])[C:31](=[O:34])[C:30]([F:36])([F:35])[CH2:29][N:28]([CH:37]5[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]5)[C:27]=4[N:43]=3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:37]1([N:28]2[CH2:29][C:30]([F:35])([F:36])[C:31](=[O:34])[N:32]([CH3:33])[C:26]3[CH:25]=[N:24][C:23]([NH:22][C:19]4[CH:20]=[CH:21][C:16]([C:15]([NH:14][CH:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[O:44])=[CH:17][CH:18]=4)=[N:43][C:27]2=3)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)NC4CCNCC4)cc3)ncc21
Reaction time: 1 h
Yield: 80.5 %

Procedure:
A mixture of 0.095 g (0.15 mmole) of 4-[4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (I-259) 1 mL of trifluoroacetic acid and 5 mL of dichloromethane was stirred for 1 hour and then concentrated under reduced pressure. The residue was taken up in 30 mL of ethyl acetate, washed twice with 30 mL of saturated aqueous sodium bicarbonate and then brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with ether, to give 0.062 g of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-piperidin-4-yl-benzamide (I-260).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:21]([OH:23])=O)=[CH:19][NH:20][C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:24][C:25]([NH2:29])([C:27]#[CH:28])[CH3:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:21]([NH:29][C:25]([CH3:26])([C:27]#[CH:28])[CH3:24])=[O:23])=[CH:19][NH:20][C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)N
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C#CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.6 %

Procedure:
A mixture of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (70 mg, 0.225 mmol), 2-methylbut-3-yn-2-amine (28 mg, 0.338 mmol), HATU (171 mg, 0.45 mmol) and DIEA (58 mg, 0.45 mmol) in DMF (3 mL) was stirred at room temperature for 16 hours. Then the mixture was poured into water and filtered to give the crude product. The crude compound was then washed with MeOH to give 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-N-(2-methylbut-3-yn-2-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (20 mg, 23.5%).