Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([C:11]([NH:13][C:14]1[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[NH:16][N:15]=1)=[O:12])[CH2:5]2.C([Sn](CCCC)(CCCC)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)CCC.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[Cl-].[Li+]>CN1CCCC1=O>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([C:17]2[NH:16][N:15]=[C:14]([NH:13][C:11]([CH:6]3[CH2:5][C:4]4[C:8](=[CH:9][CH:10]=[C:2]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH:3]=4)[CH2:7]3)=[O:12])[CH:18]=2)=[CH:24][CH:23]=1
Reactant: COc1ccc(-c2cc(NC(=O)C3Cc4ccc(Br)cc4C3)n[nH]2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CN1CCCC1=O
Product: COc1ccc(-c2cc(NC(=O)C3Cc4ccc(-c5ccccc5)cc4C3)n[nH]2)cc1
Temperature: 85 °C

Procedure:
3-(5-Bromoindan-2-yl)carbonylamino-5-(4-methoxyphenyl)pyrazole (50 mg), tributylphenyltin (0.12 ml), a tris(dibenzylideneacetone)dipalladium chloroform complex (6 mg), tri-2-furylphosphine (11 mg) and lithium chloride (25 mg) were dissolved in N-methylpyrrolidone (1 ml) with heating, and the mixture was heated at 85° C. overnight. After allowing to cool, the reaction solution was concentrated under a reduced pressure. The residue was dissolved in ethyl acetate-hexane (1:1, 30 ml) and the solution was washed with saturated aqueous potassium fluoride solution and dried over anhydrous magnesium sulfate. The solvent was distilled away under a reduced pressure. The resultant residue was purified by preparative thin layer chromatography (chloroform: methanol=20:1) to obtain the title compound (4.4 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2)#[N:2].[Cl:13][C:14]1[N:19]=[CH:18][C:17]([S:20]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:25][CH2:24]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[ClH:13].[OH:12][C:7]1[NH:8][C:9]2[C:5]([C:6]=1[C:14]1[CH:15]=[CH:16][C:17]([S:20]([N:23]3[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:25][CH2:24]3)(=[O:22])=[O:21])=[CH:18][N:19]=1)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Reactant: CC(C)CCN1CCN(S(=O)(=O)c2ccc(Cl)nc2)CC1
Product: CC(C)CCN1CCN(S(=O)(=O)c2ccc(-c3c(O)[nH]c4ccc(C#N)cc34)nc2)CC1
Product: Cl
Yield: 5 %

Procedure:
The title compound was prepared as described for Example 82 using 5-cyanooxindole and 1-[(6-chloropyridin-3-yl)sulfonyl]-4-(3-methylbutyl)piperazine. Yield: 5% of the title compound as a yellow solid: 1H NMR (DMSO-d6, 400 MHz) δ 11.15 (br s, 1 H), 10.63 (br s, 1 H), 8.57 (s, 1 H), 8.02 (s, 1 H), 7.94-7.81 (m, 1 H), 7.73 (d, J=9 Hz, 1 H), 7.41 (d, J=8 Hz, 1 H), 7.05 (d, J=8 Hz, 1 H), 3.82-3.67 (m, 2 H), 3.62-3.34 (m, 2 H), 3.20-2.92 (m, 6 H), 1.64-1.46 (m, 3 H), 0.86 (d, J=6 Hz, 6 H); MS (ES) m/z 454 (M++1).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]([C:23]([NH2:25])=[O:24])[CH2:17]2>C(Cl)Cl>[C:8]([N:19]1[C:20]2[C:16](=[CH:15][C:14]([O:13][CH3:12])=[CH:22][CH:21]=2)[CH2:17][CH:18]1[C:23]([NH2:25])=[O:24])(=[O:10])[CH3:9]
Reactant: CC(=O)Cl
Reactant: COc1ccc2c(c1)CC(C(N)=O)N2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(c1)CC(C(N)=O)N2C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
Triethylamine (0.0106 mole) then acetyl chloride (0.0106 mole) were added to a solution of intermediate (21) (0.0032 mole) in DCM (40 ml) cooled in an ice bath under argon. The mixture was allowed to slowly warm to room temperature and stir overnight. The mixture was cooled in an ice bath and ice cold water (30 ml) was added. After stirring for 10 minutes, the mixture was filtered, and the solid was allowed to dry overnight. The residue was suspended in 50 ml water. The suspension was allowed to stir for 30 minutes, filtered, and dried overnight, yielding 0.40 g of 1-acetyl-2,3-dihydro-5-methoxy-1H-indole-2-carboxamide (intermediate 22, mp. 196–197° C.).
Reaction SMILES: [N+](C1C=C(C=CC=1)C=O)([O-])=O.[NH2:12][C@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1.[Cl:18][C:19]1[C:20](F)=[C:21]([F:36])[CH:22]=[C:23]2[C:28]=1[N:27]([CH:29]1[CH2:31][CH2:30]1)[CH:26]=[C:25]([C:32]([OH:34])=[O:33])[C:24]2=[O:35]>>[ClH:18].[NH2:12][C@H:13]1[CH2:17][CH2:16][N:15]([C:20]2[C:19]([Cl:18])=[C:28]3[C:23]([C:24](=[O:35])[C:25]([C:32]([OH:34])=[O:33])=[CH:26][N:27]3[CH:29]3[CH2:31][CH2:30]3)=[CH:22][C:21]=2[F:36])[CH2:14]1
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: N[C@H]1CCNC1
Agent: O=Cc1cccc([N+](=O)[O-])c1
Product: Cl
Product: N[C@H]1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Cl)C1

Procedure:
If, for example, the reaction mixture of 3-nitrobenzaldehyde and (S)-3-aminopyrrolidine is reacted with 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in a one-pot reaction, the course of the reaction via the intermediately formed 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-[(S)-3-(3-nitrobenzylideneamino)-1-pyrrolidinyl]-4-oxo-3-qninolinecarboxylic acid to give 7-[(S)-3-amino-1-pyrrolidinyl]-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride can be represented by the following equation: ##STR22##
Reaction SMILES: [C:1]([O:4][C@@H:5]([CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[NH:17][C:16]([CH2:21][OH:22])=[N:15][C:14]=2[N:13]([CH3:23])[C:11]1=[O:12])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C)C=O>[C:1]([O:4][C@@H:5]([CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:16]([CH2:21][OH:22])=[N:15][C:14]=2[N:13]([CH3:23])[C:11]1=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H](C)CCCCn1c(=O)c2[nH]c(CO)nc2n(C)c1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)O[C@@H](C)CCCCn1c(=O)c2c(nc(CO)n2Cc2ccccc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
To a suspension of (5)-1-(5-acetoxyhexyl)-8-hydroxymethyl-3-methylxanthine (prepared as described for synthesis of (R )-1-(5-hydroxyhexyl)-8-aminomethyl-3,7-dimethylxanthine libraries) (10.5 g, 31 mmol) and potassium carbonate (8.6 g, 62 mmol) in dimethylformamide (100 ml) was added benzyl bromide (8.67 g, 39 mmol). After stirring at room temperature overnight, the mixture was poured into ice water (250 ml) and stirred at 0-5° C. for 1 hour. The precipitate was filtered, rinsed with water (4x 50 ml) and dried under vacuum to provide (S)-1-(5-acetoxyhexyl)-7-benzyl-8-hydroxymethyl-3-methylxanthine (9.8 g, 74% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)[CH:5]=1.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:47](=[O:51])[CH:48]([CH3:50])[CH3:49].O>O1CCCC1>[CH3:1][O:2][C:3]([C:4]1[C:5]2[CH:47]([OH:51])[C:48]([CH3:50])([CH3:49])[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)[NH:11][C:6]=2[C:7]([F:10])=[CH:8][CH:9]=1)=[O:20]
Reactant: COC(=O)c1ccc(F)c(N=Cc2cccc(Br)c2)c1
Reactant: CC(C)C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(F)c2c1C(O)C(C)(C)C(c1cccc(Br)c1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.3 %

Procedure:
To a stirred mixture solution of 3-[(3-bromo-benzylidene)-amino]-4-fluoro-benzoic acid methyl ester (51.7 g, 153.8 mmol) and ytterbium(III) triflate hydrate (14.3 g, 23.1 mmol) in dry tetrahydrofuran (100 mL) at 25° C. was added isobutyraldehyde (14 mL, 153.8 mmol) and water (2.8 mL, 153.8 mmol) dropwise. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-phenyl)-8-fluoro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (63.0 g, quant.) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C19H19BrFNO3 (M+H)+: 409.27, observed: 390.0 & 392.0.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:7])[S:5][CH:6]=1.[Br:8][CH:9]([CH3:17])[C:10](=O)[CH2:11][C:12](OC)=[O:13].[OH-].[Na+]>C(Cl)Cl>[Br:8][CH:9]([C:10]1[N:7]=[C:4]2[S:5][CH:6]=[C:2]([CH3:1])[N:3]2[C:12](=[O:13])[CH:11]=1)[CH3:17]
Reactant: COC(=O)CC(=O)C(C)Br
Reactant: Cc1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1csc2nc(C(C)Br)cc(=O)n12
Temperature: 110 °C
Reaction time: 5 h
Yield: 42.4 %

Procedure:
To a manually stirred polyphosphoric acid (80 g, 800 mmol) in a 1000 mL beaker was added 4-methyl-1,3-thiazol-2-amine (Aldrich, 16 g, 140 mmol), followed by methyl 4-bromo-3-oxopentanoate (34.9 g, 167 mmol). The mixture was heated with stirring at 110° C. for 5 h. After cooling, the dark slurry was transferred into 300 g of ice. The pH of the mixture was adjust to 6-7 with 10% sodium hydroxide. The aqueous layer was discarded and the dark oil layer was diluted with methylene chloride and washed with 1N NaOH, brine, dried over magnesium sulfate, and evaporated to dryness to yield the desired product (16.2 g, 42.6%). LCMS calculated for C9H10BrN2OS (M+H)+: m/z=273.0. Found: 273.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2].[H-].[Na+].Br[CH2:19][C:20]#[C:21][CH3:22].O>O1CCCC1.CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[C:13]([O:15][CH2:19][C:20]#[C:21][CH3:22])[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(O)cc2o1
Reactant: CC#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC#CCOc1ccc2cc(C(=O)OCC)oc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a mixed solution of 6-hydroxy-benzofuran-2-carboxylic acid ethyl ester (250 mg, 1.21 mmol) in tetrahydrofuran (5 mL) and N,N-dimethylformamide (5 mL) were added sodium hydride (58 mg, 2.42 mmol) and 1-bromo-2-butyne (127 μL) at room temperature, which was stirred at room temperature for 1 hour. Water was added to the reaction solution followed by extraction with ethyl acetate. The organic layer was washed with water and sat. NaCl followed by drying over anhydrous magnesium sulfate and filtering. The filtrate was concentrated under a reduced pressure and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=5:1) to obtain the title compound (254 mg, 81%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19].CCOC(C)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:4][C:3]=1[CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(O)ccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(OS(C)(=O)=O)ccc1Cl
Temperature: 25 °C

Procedure:
To a solution of 4-chloro-3-methylphenol (35.0 g, 277 mmol) in 100 mL of methylene chloride at 0° C. was added triethylamine (77.0 mL, 554 mmol), followed by methanesulfonyl chloride (32.2 mL, 416 mmol). The reaction was allowed to warm to room temperature for 1 hr. The solution was poured into EtOAc, washed with H2O and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting yellow solid product was used without further purification.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:19])([F:18])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][O:16][CH3:17])=[CH:10][N:9]=1)([OH:7])[CH3:6].[CH3:20][S:21](Cl)(=[O:23])=[O:22].C([O-])(O)=O.[Na+]>C1COCC1.O>[F:19][C:4]([F:3])([F:18])[C:5]([O:7][S:21]([CH3:20])(=[O:23])=[O:22])([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][O:16][CH3:17])=[CH:10][N:9]=1)[CH3:6]
Reactant: COCOc1ccc(C(C)(O)C(F)(F)F)nc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1ccc(C(C)(OS(C)(=O)=O)C(F)(F)F)nc1
Reaction time: 3 h

Procedure:
To a stirred mixture of 0.213 g (8.44 mmol) sodium hydride in 6 ml dry THF, 1.06 g (4.22 mmol) 1,1,1-trifluoro-2-(5-methoxymethoxy-pyridin-2-yl)-propan-2-ol (dissolved in 4.9 ml dry THF) was added dropwise at 0° C. After completion of the addition, stirring was continued for 3 h at room temperature. Then methanesulfonyl chloride (dissolved in 7.3 ml dry THF) was added at room temperature and stirring was continued for another 2 h. Then water and sat. NaHCO3 soln. were added. This mixture was extracted 2 times with EtOAc. The combinded organic layers were washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo to afford 1.7 g of the title compound, which was used directly in the next step. LCMS (method L): tR=0.96 min, M+H=330.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.CI.[H-].[Na+].[C:35](=O)([O-])O.[Na+]>C(OCC)(=O)C.CN(C)C=O>[CH3:35][NH:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(Nc2ncccc2N)c1)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: CNc1cccnc1Nc1cccc(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 21 %

Procedure:
To a mixture of the compound (88.5 mg) obtained in Example 3, methyl iodide (15 μl) and dimethylformamide (2 ml), sodium hydride (content=60%; 10 mg) was added and the resulting mixture was stirred at room temperature for 4 days. To the reaction mixture, ethyl acetate and a saturated aqueous sodium hydrogencarbonate solution were added. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=2:3) to give 19.3 mg of the titled compound (yield, 21%).
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][C:3]=1[Br:11].C(N1C=CN=C1)(N1[CH:18]=[CH:17]N=C1)=O.C(O)C>C(#N)C>[CH2:17]([O:9][C:8](=[O:10])[C:7]1[C:2]([Br:1])=[C:3]([Br:11])[CH:4]=[N:5][CH:6]=1)[CH3:18]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1cncc(Br)c1Br
Solvent: CCO
Solvent: CC#N
Product: CCOC(=O)c1cncc(Br)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.9 %

Procedure:
A suspension of 4,5-dibromonicotinic acid (10 g, 36 mmol) in acetonitrile (160 mL) under nitrogen was treated with 1,1′-carbonyldiimidazole (8.65 g, 53.4 mmol) in portions over 10 min. The resulting mixture was stirred for 3 h at room temperature. Ethanol (24 mL) was added and the mixture was heated to 55° C. for 16 h. The solution was then filtered and the filtrate evaporated in vacuo. The residual oil was dissolved in ethyl acetate and the solution was washed with water followed by brine. The organic fraction was then dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography to afford 9 g (82%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 8.70 (s, 1H), 8.74 (s, 1H), 4.44 (q, J=7.1 Hz, 2H), 1.42 (t, J=7.1 Hz, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH2:9]Cl)=[CH:5][CH:6]=[CH:7][CH:8]=1.C(=O)(OC)[O:12]C.O>CN(C)C=O>[CH2:2]1[O:12][CH2:9][C:4]2[C:3]1=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: ClCc1ccccc1CCl
Reactant: COC(=O)OC
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2c(c1)COC2
Reaction time: 22 h
Yield: 37 %

Procedure:
The procedure described in Example 1 was followed in reacting 0.05 g mole of α,α'-dichloro-o-xylene with 0.06 g mole of dimethyl carbonate in 50 ml of N,N-dimethylformamide. After 22 hours, the reaction mixture was poured into 100 ml of water and the organic portion was extracted from the mixture with three 5050 ml portions of hexane. The combined extracts were dried over MgSO4 and the hexane was distilled off. The residue was distilled under reduced pressure to obtain 2.29 g (37 percent yield) of phthalan (1,3-dihydroisobenzofuran), b.p. 95° C./30 mm.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:26][CH3:27])=[C:16]([CH2:19][NH:20][C@@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.CC[O:31][C:32]([C@H:34](OS(C(F)(F)F)(=O)=O)[CH3:35])=[O:33]>>[Cl:1][C:2]1[C:3]([F:28])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:26][CH3:27])=[C:16]([CH2:19][N:20]([C@@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[C@H:34]([C:32]([OH:33])=[O:31])[CH3:35])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@@H](C)OS(=O)(=O)C(F)(F)F
Reactant: COC[C@H](C)NCc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC
Product: COC[C@H](C)N(Cc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC)[C@@H](C)C(=O)O

Procedure:
N-(3-Chloro-2-fluorophenyl)-7-methoxy-6-({[(1S)-2-methoxy-1-methylethyl]amino}methyl)quinazolin-4-amine (prepared as described in Example 52) was coupled with ethyl O-trifluoromethanesulfonyl-D-lactate and hydrolysed using analogous methods to those described for the equivalent steps in Example 46 to give N-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N-[(1S)-2-methoxy-1-methylethyl]-L-alanine; 1H NMR Spectrum: (DMSO-d6) 1.08 (d, 3H); 1.30 (d, 3H); 3.09 (m, 1H); 3.16 (s, 3H); 3.23 (dd, 1H); 3.39 (dd, 1H); 3.06 (q, 1H); 3.97 (s, 3H); 3.98 (d, 1H); 4.10 (d, 1H); 7.19 (s, 1H); 7.29 (t, 1H); 7.49 (m, 1H); 7.61 (m, 1H); 8.39 (s, 1H); 8.43 (s, 1H); 9.57 (brs, 1H); 12.13 (brs, 1H); Mass Spectrum: (M+H)+ 477.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10](=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[CH:18]2.C(O)(=O)C.C(=O)([O-])O.[Na+]>CO>[CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[NH:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[CH:18]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)C1
Reactant: Nc1ccc2[nH]ncc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: c1ccc(CN2CCCC2Nc2ccc3[nH]ncc3c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.3 %

Procedure:
1-Benzyl-3-pyrrolidinone (105 mg), 5-aminoindazole (67 mg), and acetic acid (0.02 ml) were dissolved in methanol (1 ml), and a borane-pyridine complex (0.06 ml) was added dropwise to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was then added thereto, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC [chloroform/methanol] to give the title compound (49 mg, yield 34%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([O-:14])=O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[NH2:15][C:16]1[C:21]([CH:22]=O)=[CH:20][N:19]=[C:18]([S:24][CH3:25])[N:17]=1.[C:26](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([C:11]2[C:12](=[O:14])[N:15]([CH3:26])[C:16]3[N:17]=[C:18]([S:24][CH3:25])[N:19]=[CH:20][C:21]=3[CH:22]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CSc1ncc(C=O)c(N)n1
Reactant: COc1cc(CC(=O)[O-])cc(OC)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)cc(-c2cc3cnc(SC)nc3n(C)c2=O)c1
Yield: 82.9 %

Procedure:
A solution of 2-(3,5-dimethoxyphenyl)acetate (6) (440 mg, 2.40 mmol), 4-amino-2-(methylthio)pyrimidine-5-carbaldehyde (4) (605 mg, 2.88 mmol) and potassium carbonate (662 mg, 4.8 mmol) in DMF (30 mL) was stirred at 110° C. for 3 hours. The reaction was monitored by LCMS. The reaction mixture was diluted with H2O (30 mL), and extracted by EtOAc (3×40 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/EtOAc=2:1) to afford 6-(3,5-dimethoxyphenyl)-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (7) (683 mg, 83%) as a white solid. MS (ES+) C17H17N3O5S requires: 343. found: 344 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Cl:34][CH2:35][C:36](Cl)=[O:37]>C(Cl)Cl>[Cl:34][CH2:35][C:36]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:24])[C:10]2[CH:11]=[C:12]([C:20]([F:21])([F:22])[F:23])[CH:13]=[C:14]([C:16]([F:18])([F:19])[F:17])[CH:15]=2)[CH2:3][CH2:2]1)=[O:37]
Reactant: O=C(NCC1CCNCC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCN(C(=O)CCl)CC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 8 h
Yield: 82 %

Procedure:
A solution of N-(piperidin-4-ylmethyl)-3,5-bis(trifluoromethyl)benzamide (2.0 g, 5.66 mmol) and DIPEA (1.2 mL) in CH2Cl2 (10 mL) was added 2-chloroacetyl chloride (0.64, 5.66 mmol) dropwise, the mixture was stirred overnight. The mixture was washed with water, dried with Na2SO4, filtered, and the solvent was removed in vacuo. The residue was purified by automated flash chromatography to yield the product (2.0 g, 82%).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.[CH3:12][N:13](C)[CH2:14][CH2:15][CH2:16]N=C=NCC.[CH2:23]([O:25][C:26]([C@@H:28]1[CH2:30][C@H:29]1[C:31]([OH:33])=O)=[O:27])[CH3:24].C(N(CC)CC)C.CNCCC>CN(C)C=O>[CH2:23]([O:25][C:26]([C@@H:28]1[CH2:30][C@H:29]1[C:31](=[O:33])[N:13]([CH3:12])[CH2:14][CH2:15][CH3:16])=[O:27])[CH3:24]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCOC(=O)[C@@H]1C[C@H]1C(=O)O
Agent: CCCNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCN(C)C(=O)[C@@H]1C[C@H]1C(=O)OCC
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
Add 1-hydroxybenzotriazole (HOBT) (1.46 g, 10.8118 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (2.07 g, 10.8118 mmol) to a solution of crude trans-cyclopropane-1,2-dicarboxylic acid monoethyl ester (1.71 g, 10.8118 mmol) in N,N-dimethylformamide (11 mL). Stir for 30 minutes. Add triethylamine (2.26 mL, 16.2177 mmol) and methylpropylamine (1.11 mL, 10.8118 mmol) and stir for 16 hours. Quench with 10% aqueous potassium carbonate (10 mL) and extract with ethyl acetate (3×50 mL). Combine the organic extracts, wash with 0.1 N aqueous citric acid (30 mL) and 1 N lithium chloride, dry (magnesium sulfate), concentrate and crystallize with xylenes to give the desired compound (1.02 g, 50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]([NH2:9])=[N:7][CH:8]=1.[C:10](Cl)(=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].NCC(O)=O>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]([NH:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[N:7][CH:8]=1
Reactant: COc1cnc(N)nc1
Reactant: CCCCCC(=O)Cl
Agent: NCC(=O)O
Solvent: c1ccncc1
Product: CCCCCC(=O)Nc1ncc(OC)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
5-Methoxypyrimidin-2-amine (12.3 g, 98.3 mmol) was dissolved in pyridine (123 mL), the solution was added with hexanoyl chloride (14.5 g, 108 mmol) on an ice bath, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was added with 1 M aqueous glycine (98.3 mL) at 0° C., and the mixture was stirred for 1 hour, and then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, and the resulting residue was azeotroped with toluene. The resulting residue was recrystallized from chloroform-hexane to obtain N-(5-methoxypyrimidin-2-yl)hexanamide (18.4 g, 84%) as colorless solid.