Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:15]([OH:17])=O)=[CH:14][C:6]1=2.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[F:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:15]([N:27]3[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]3)=[O:17])=[CH:14][C:6]1=2
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cnc2c(c1)N(Cc1cc(F)ccc1F)CCN2
Product: CN1CCN(C(=O)c2cnc3c(c2)N(Cc2cc(F)ccc2F)CCN3)CC1
Yield: 65 %

Procedure:
1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid (40 mg) was reacted with 1-methyl piperazine as in General Procedure 8 to give the title compound as an orange foam (65% yield). M.p. (foam), LCMS: m/z=388.08 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.28 (s, 3H), 2.32-2.38 (m, 4H), 3.41 (t, J=5.0 Hz, 2H), 3.53-3.61 (m, 4H), 3.62-3.65 (m, 2H), 4.44 (s, 2H), 5.07 (bs, 1H), 6.61 (s, 1H), 6.89-6.94 (m, 2H), 6.98-7.04 (m, 1H), 7.59 (d, J=1.5 Hz, 1H).
Reaction SMILES: CI.[Br:3][C:4]1[CH:5]=[C:6]([C:10]2[NH:14][N:13]=[N:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.[C:15](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[N:12][N:13]([CH3:15])[N:14]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Brc1cccc(-c2cnn[nH]2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1ncc(-c2cccc(Br)c2)n1
Reaction time: 8 h
Yield: 41.8 %

Procedure:
Methyl iodide (323 μl, 5.2 mmol) was added to a stirred mixture of 5-(3-bromophenyl)-1H-[1,2,3]triazole (776 mg, 3.46 mmol) and potassium carbonate (1.19 g, 8.6 mmol) in DMF (20 ml) at room temperature under nitrogen. The reaction mixture was stirred overnight and then concentrated under reduced pressure. Water (50 ml) was added and then the mixture was extracted with ethyl acetate (3×50 ml). The combined organic extracts were concentrated under reduced pressure while dry loading onto silica gel. The residue was purified by column chromatography (silica gel, 50% Et2O/isohexane) to yield first 4-(3-bromophenyl)-2-methyl-2H-[1,2,3]triazole (344 mg, 42%), the solvent polarity was increased to 80% Et2O/isohexanes to yield 5-(3-bromophenyl)-1-methyl-1H-[1,2,3]triazole (15 mg, 2%), and then the solvent polarity was increased to 100% Et2O to yield 4-(3-bromophenyl)-1-methyl-1H-[1,2,3]triazole (147 mg, 18%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4].CN(C)C=O.[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>O>[NH:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH2:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4]
Reactant: c1c[nH]cn1
Reactant: O=C(CBr)C12CC3CC(CC(C3)C1)C2
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1ncc[nH]1)C12CC3CC(CC(C3)C1)C2

Procedure:
A solution of 5 g. of 1-adamantyl bromomethyl ketone in 10 ml. of dimethylformamide is added dropwise with stirring and ice-cooling to 7 g. imidazole in 10 ml. dimethylformamide. The resulting solution is stirred overnight at room temperature and then poured into 250 ml. water. The precipitate which forms is filtered off, washed with water and air dried. Thereafter the resulting residue is chromatographed on silica gel to effect purification. Elution with 10% acetone in dichloromethane yields 1-adamantyl 1-imidazolylmethyl ketone, M.P. 128.5°-129.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[NH2:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[N:25][N:26]2[C:31]1[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=1)[C:34]([O:36][CH3:37])=[O:35]>CS(C)=O.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]([OH:11])([C:13]([F:16])([F:15])[F:14])[CH2:12][NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[CH:24]=[N:25][N:26]3[C:31]2[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=2)[C:34]([O:36][CH3:37])=[O:35])[CH:7]=1
Reactant: COC(=O)c1cccc(-n2ncc3c(N)cccc32)c1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Solvent: CS(C)=O
Solvent: CO
Product: COC(=O)c1cccc(-n2ncc3c(NCC(O)(CC(C)(C)c4cc(F)ccc4OC)C(F)(F)F)cccc32)c1
Temperature: 170 °C
Yield: 24.9 %

Procedure:
A mixture of racemic 2-{2-[5-fluoro-2-(methyloxy)phenyl]-2-methylpropyl}-2-(trifluoromethyl)oxirane (which may be prepared according to WO 04/063163, 35 mg, 0.12 mmol) and methyl 3-(4-amino-1H-indazol-1-yl)benzoate (Intermediate 9) (32.7 mg, 0.12 mmol) was heated by microwave (250 W) at 170° C. for 45 minutes. The crude product was cooled, dissolved in DMSO/MeOH and purified by mass-directed autopreparation. The appropriate fractions were evaporated, dissolved in DCM, washed with aqueous sodium bicarbonate, passed through a hydrophobic frit and evaporated to give the title compound (16.7 mg).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:19][CH2:20][N:21]([CH2:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:22][CH2:23]1
Reactant: ICC1CCCC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCNCC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCN(CC4CCCC4)CC3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(4-piperidinyl)propyl]-9H-purin-6-amine and (iodomethyl)cyclopentane.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([CH3:16])=[C:11]([F:17])[CH:10]=1)CCC.[OH-].[Na+]>CO.O>[F:15][C:13]1[CH:14]=[C:9]([CH2:8][CH2:7][C:6]([OH:18])=[O:5])[CH:10]=[C:11]([F:17])[C:12]=1[CH3:16]
Reactant: CCCCOC(=O)CCc1cc(F)c(C)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(F)cc(CCC(=O)O)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(3,5-difluoro-4-methyl-phenyl)-propionic acid butyl ester (6.960 g; 27.157 mmol) in MeOH (150 ml) and water (25 ml) was added at rt aq. 1N NaOH (68 ml; 68 mmol). The resulting solution was further stirred at rt for 1 h. MeOH was then removed under reduced pressure. Water (25 ml) was added, and the mixture was acidified with aq. 1N HCl (68 ml) in order to reach pH=2. DCM (150 ml) was added, and the layers were shaken and separated. The aq. layer was further extracted with DCM (50 ml). The mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. The product 3-(3,5-difluoro-4-methyl-phenyl)-propionic acid was obtained as a pale yellow solid which was further dried under HV (5.090 g; 94%). LC-MS: tR=0.86 min.; [M+H]+: no ionisation.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[CH3:18]CCCC=C>>[CH3:18][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=CCCCC
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: C=O
Product: CN(Cc1ccccc1)Cc1ccccc1
Yield: 254.6 %

Procedure:
In a similar manner to Example 1, 197.3 g (1.0 mol) of dibenzylamine and 165.1 g (1.6 mol) of formaldehyde (29.1%) are reacted in a 1 l autoclave; a maximum pressure of 1.8 MPa is established at a temperature of 160° C. After the end of the reaction, 30 g of hexene-1 are added and the organic phase is removed from the aqueous phase. The remaining organic phase is subsequently distilled. 191.8 g of N-methyldibenzylamine having a purity of 93.8% are isolated, corresponding to a yield of 85.1% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=S)=[CH:4][CH:3]=1.[N:21]#[C:22][NH2:23].C1(N=C=NC2CCCCC2)CCCCC1.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH2:7][CH2:8][NH:9][C:10]([NH:23][C:22]#[N:21])=[N:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: N#CN
Reactant: S=C(NCCOc1ccc(Cl)cc1)Nc1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#CNC(=Nc1cccnc1)NCCOc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
N-(2-p-Chlorophenoxyethyl)-N'-3-pyridylthiourea (1.05 g) was suspended in acetonitrile (10 ml), and cyanamide (285 mg), N,N'-dicyclohexylcarbodiimide (1.40 g) and triethylamine (0.04 ml) were added. The mixture was kept with stirring at room temperature for a week, when it was filtered, washed with acetonitrile and with ether. The solid mixture of the crude product and N,N'-dicyclohexylthiourea was extracted with chloroform (15 ml) to leave the pure product, which was collected by filtration and washed with chloroform and ether.
Reaction SMILES: [Na+].[Cl:2][C:3]1[N:8]=[CH:7][C:6]([S:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.N1C=CC=CC=1.Br[C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C=O)C>[CH2:23]([O:22][C:20](=[O:21])[C:19]([S:9]([C:6]1[CH:7]=[N:8][C:3]([Cl:2])=[CH:4][CH:5]=1)(=[O:11])=[O:10])([CH3:26])[CH3:25])[CH3:24]
Reactant: O=S([O-])c1ccc(Cl)nc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)S(=O)(=O)c1ccc(Cl)nc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
The crude 6-chloro-pyridine-3-sulfinic acid sodium salt (4.7 mmol) was suspended in DMF (20 mL). Pyridine (0.8 mL) and ethyl α-bromoisobutyrate (1 mL) were added. The reaction was stirred at 50° C. under nitrogen for 18 h. The reaction mixture was partitioned between diethyl ether (100 mL) and water (50 mL). The organic layer was washed with brine (50 mL) and dried over Na2SO4. Filtration, concentration under reduced pressure, followed by column chromatography (silica, eluent heptanes, 0-25% ethyl acetate) afforded 0.83 g of 2-(6-chloro-pyridine-3-sulfonyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [CH3:1][N:2]([CH2:9][CH:10]([OH:31])[CH2:11][NH:12][CH:13]([CH3:30])[CH2:14][O:15][C:16]1[CH:29]=[CH:28][C:19]([CH2:20][CH:21]2[S:25][C:24](=[O:26])[NH:23][C:22]2=[O:27])=[CH:18][CH:17]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CN(C)[CH:34]=[O:35]>>[CH3:1][N:2]([CH2:9][CH:10]1[O:31][C:34](=[O:35])[N:12]([CH:13]([CH3:30])[CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:20][CH:21]3[S:25][C:24](=[O:26])[NH:23][C:22]3=[O:27])=[CH:28][CH:29]=2)[CH2:11]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(COc1ccc(CC2SC(=O)NC2=O)cc1)NCC(O)CN(C)c1ccccc1
Reactant: CN(C)C=O
Product: CC(COc1ccc(CC2SC(=O)NC2=O)cc1)N1CC(CN(C)c2ccccc2)OC1=O

Procedure:
A procedure similar to that described in Example 4 was repeated, except that 0.9 g of 5-[4-{2-[3-(N-methyl-N-phenylamino)-2-hydroxypropylamino]propoxy}-benzyl]thiazolidine-2,4-dione (prepared as described in Example 39), 0.36 g of N,N'-carbonyldiimidazole and 20 ml of anhydrous dimethylformamide were used, to give 0.6 g of the title compound having an Rf value of 0.24 (on silica gel thin layer chromatography, using a 1:1 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: CC([N:5]([CH2:9][C:10]([NH:12][N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[Cl:18])=[O:11])C(=O)[O-])(C)C.Cl>CCOC(C)=O.CCOCC>[ClH:18].[NH2:5][CH2:9][C:10]([NH:12][N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[Cl:18])=[O:11]
Reactant: CC(C)(C)N(CC(=O)Nn1cccc1Cl)C(=O)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: NCC(=O)Nn1cccc1Cl
Reaction time: 19 h
Yield: 62.8 %

Procedure:
To a stirred solution of 1,1-dimethylethyl-[2-(2-chloro-1H-pyrrol-1-ylamino)-2oxoethyl]carbamate (3.1 g) in EtOAc (20 ml) and ether (20 ml) was added ethereal HCl (excess) at room temperature. The reaction mixture was allowed to stir for 19 hours at which time the precipitated product was filtered and washed with EtOAc. Recrystallization from ethanol/ether afforded 0.75 g of the product as a solid, m.p. 220° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=O)[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:4]1[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:2]([CH3:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: CCOC(=O)c1c(C)c2ccccc2[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(Cl)nc2ccccc2c1C

Procedure:
A suspension of ethyl 4-methyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate (obtained according to 3.a, 15.2 g, 0.066 mol) in phosphoryl chloride (243 ml) is taken to reflux for 6 hours. The phosphoryl chloride is evaporated under reduced pressure without taking to dryness, and the viscous residue is poured into ice cold water (300 ml). The precipitate obtained in this way is filtered, washed with water to a neutral pH, then washed with ethanol and with diethyl ether in order to produce after drying 8.8 g (53%) of a white solid, m.p. 110° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:12])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[I-].C[N+]1C=CN([C:20](=[O:29])[N:21]([CH3:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)C=1.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:20](=[O:29])[N:21]([CH3:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Reactant: Oc1ccnc2cc(Cl)ccc12
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C(=O)Oc1ccnc2cc(Cl)ccc12)c1ccccc1
Yield: 92.7 %

Procedure:
A solution of 7-chloro-4-hydroxyquinoline (0.54 g, 3.00 mmol), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (40:60)) yielding the title compound (0.87 g, 93% yield) as a colourless oil which solidified upon standing.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:28].[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1B(O)O.CC(C)([O-])C.[K+]>COCCOC.O.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>[CH3:25][C@H:20]1[NH:21][C@@H:22]([CH3:24])[CH2:23][N:18]([C:16]2[CH:15]=[CH:14][C:13]([O:26][CH3:27])=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([C:30]4[S:29][CH:33]=[CH:32][CH:31]=4)=[C:3]([F:28])[CH:4]=3)(=[O:10])=[O:9])[CH:17]=2)[CH2:19]1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)c(F)c1
Reactant: OB(O)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2cccs2)c(F)c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]-3-fluorobenzenesulfonamide (E105) (100 mg, 0.21 mmol) and 2-thienylboronic acid (54 mg, 0.42 mmol) in DME (3 ml) was added potassium tert-butoxide (212 mg, 1.89 mmol) and tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.01 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. Additional 2-thienylboronic acid (27 mg, 0.21 mmol) and tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.01 mmol) were then added and the mixture stirred in a microwave (set at high absorbance) at 100° C. for a further 45 minutes. The solvent was evaporated with addition of a few drops of toluene and the residue passed through an SCX column eluting with methanol followed by 2M ammonia in methanol. The abasic fractions were combined and the solvent evaporated. The crude product was purified by mass directed autoprep HPLC, the relevant fractions collected and solvent evaporated to afford the title compound (E114). MS (ES+) m/e 476 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([N+:9]([O-])=O)=[C:7]([CH3:12])[C:6]([O:13][C:14](=[O:16])[CH3:15])=[C:5]([CH3:17])[C:4]=1[CH3:18].[H][H]>C(O)C.C(OCC)(=O)C.[Pt]=O>[C:14]([O:13][C:6]1[C:5]([CH3:17])=[C:4]([CH3:18])[C:3]([NH:2][CH3:1])=[C:8]([NH2:9])[C:7]=1[CH3:12])(=[O:16])[CH3:15]
Reactant: CNc1c(C)c(C)c(OC(C)=O)c(C)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNc1c(C)c(C)c(OC(C)=O)c(C)c1N
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 55.7 %

Procedure:
A solution of 2.65 g of N-methyl-4-acetoxy-2,3,5-trimethyl-6-nitroaniline (prepared as described in Preparation 18) in a mixture of 20 ml ethanol and 20 ml of ethyl acetate was shaken at room temperature for 3.5 hours and then at 40° C. for 3 hours in an atmosphere of hydrogen and in the presence of 0.2 g of platinum oxide. At the end of this time, the reaction mixture was filtered to remove the platinum oxide and the filtrate was freed from the solvent by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of ethyl acetate and hexane as the eluent, to give 1.3 g of title compound, melting at 113°-116° C.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:25]([N:32]1[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>C(O)(C)C>[CH2:25]([N:32]1[CH2:36][CH2:35][C@H:34]([NH:37][C:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:33]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc3ccccc23)CC1
Reactant: N[C@H]1CCN(Cc2ccccc2)C1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2nc(N[C@H]3CCN(Cc4ccccc4)C3)nc3ccccc23)CC1
Yield: 62.5 %

Procedure:
A mixture of t-butyl 4-(2-chloroquinazolin-4-yl)piperazine-1-carboxylate (30 g) synthesized in the same manner as in Example 1, (S)-1-benzyl-3-aminopyrrolidine (15 g), triethylamine (8.7 g), and isopropyl alcohol (43 mL) was heated to reflux for 40 h. The reaction mixture was concentrated under reduced pressure, then water was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried with anhydrous magnesium sulfate, concentrated, and then purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=4:1) to obtain t-butyl 4-(2-((S)-1-benzylpyrrolidin-3-ylamino)quinazolin-4-yl)piperazine-1-carboxylate (26 g).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:20])(=[O:3])[CH3:2].[CH3:21][CH2:22][O:23][C:24](OCC)(OCC)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:10][CH:11]=2)[C:6](=[C:24]([O:23][CH2:22][CH3:21])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:5]1=[O:20])(=[O:3])[CH3:2]
Reactant: CCOC(OCC)(OCC)c1ccccc1
Reactant: CCCCCC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Product: CCCCCC(=O)c1ccc2c(c1)C(=C(OCC)c1ccccc1)C(=O)N2C(C)=O

Procedure:
Prepared from 1-acetyl-5-hexanoyl-2-indolinone and triethyl orthobenzoate
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:12]([OH:14])=O)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[CH3:22][O:23][C:24]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([O:33][CH3:34])[C:25]=1[NH2:26]>S(Cl)(Cl)=O.C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10][CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:12]([NH:26][C:25]2[C:27]([O:33][CH3:34])=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:24]=2[O:23][CH3:22])=[O:14])=[CH:8][CH:9]=1)[CH2:2][CH3:3]
Reactant: COc1cc(OC)c(N)c(OC)c1
Reactant: CCCCCCCC(Sc1ccc(CCC)cc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCCCCCCC(Sc1ccc(CCC)cc1)C(=O)Nc1c(OC)cc(OC)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
1.54 g (5 mmole) of the title compound of Example 3 in 20 ml of thionyl chloride was refluxed for 3 hours and then concentrated to dryness in vacuo. 523 mg (1.6 mmole) of the resulting acid chloride was dissolved in 20 ml methylene chloride and to the solution was added 292 mg (1.6. mmole) 2,4,6-trimethoxyaniline and 195 mg (1.6 mmole) 4-dimethylaminopyridine. The resulting solution was stirred at room temperature overnight and then concentrated in vacuo. The residue was partitioned between 60 ml ethyl acetate and 20 ml 1N aqueous hydrochloric acid solution. The ethyl acetate layer was washed with 50 ml water and 50 ml saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was chromatographed on 100 g silica gel, eluting with 1:1 hexane/ethyl acetate to yield 370 mg (49% yield) of the title compound as a whitish solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]([OH:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.FC(F)(F)C(O)=O.[OH-].[Na+].[Br:26][CH2:27][CH2:28]O>>[Br:26][CH2:27][CH2:28][O:16][CH:14]1[C:15]2[C:10](=[N:9][C:8]3[C:3]([C:2]=2[NH2:1])=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:11][CH2:12][CH2:13]1
Reactant: OCCBr
Reactant: Nc1c2c(nc3ccccc13)CCCC2O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: Nc1c2c(nc3ccccc13)CCCC2OCCBr
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
To a suspension of 9-amino-1,2,3,4-tetrahydroacridin-1-ol (7.55 g) in 40 ml of 2-bromoethanol was added 9.9 ml of trifluoroacetic acid. The reaction mixture was stirred at ambient temperature for 18 hrs, added to iced sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with water, saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and evaporated. The residue was purified by flash chromatography (ethyl acetate→2% triethylamine/ethyl acetate) to give 7.6 g (67%) of a product. Recrystallization from methanol/water gave the analytical sample, mp 163.5°-164.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][C:20]([N:22]([CH3:27])[CH2:23][CH2:24][O:25][CH3:26])=[O:21])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:35]([O:37][CH2:38][CH2:39][NH2:40])[CH3:36]>>[CH2:35]([O:37][CH2:38][CH2:39][NH:40][C:29]([C:14]1[C:15](=[O:28])[N:16]([CH2:19][C:20]([N:22]([CH3:27])[CH2:23][CH2:24][O:25][CH3:26])=[O:21])[C:17]2[C:12]([C:13]=1[OH:34])=[N:11][CH:10]=[C:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:18]=2)=[O:30])[CH3:36]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)CCOC)c1=O
Reactant: CCOCCN
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)CCOC)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-(2-{methyl[2-(methyloxy)ethyl]amino}-2-oxoethyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-ethoxyethylamine employing methods similar to those described in Example 9 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as an off-white solid: 1H NMR (CDCl3) mixture of rotamers δ 10.20 (1H, br), 8.56 and 8.52 (1H, s), 7.38 and 7.10 (1H, s), 7.16-7.09 (2H, m), 7.04-6.98 (2H, m), 5.21 and 4.98 (2H, s), 4.11 (2H, s), 3.74-3.50 (10H, m), 3.34 and 3.32 (3H, s), 3.18 and 2.97 (3H, s), 1.22 and 1.23 (3H, t, J=7 Hz); HRMS calcd for C26H31FN4O6+H+: 515.2306. Found: 515.2293.