Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].[CH3:11][N:12]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[CH3:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[N:15]1[CH2:16][CH2:17][CH2:18][N:12]([CH3:11])[CH2:13][CH2:14]1)[C:6]#[N:7]
Reactant: CN1CCCNCC1
Reactant: Cc1cc(C#N)ccc1F
Product: Cc1cc(C#N)ccc1N1CCCN(C)CC1

Procedure:
7.00 g (51.8 mmol) 4-fluoro-3-methyl-benzonitrile are heated to 110° C. together with 1-N-methyl-[1,4]diazepan for 1 week with stirring. After evaporation i. vac. the residue is separated on aluminium oxide (eluant: dichloromethane) and the corresponding fractions are again purified on silica gel (eluting gradient: dichloromethane/methanol 100:1->9:1).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:13][CH2:14][O:15][CH2:16][CH3:17].O>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][CH2:13][CH2:14][O:15][CH2:16][CH3:17])=[CH:4][CH:3]=1
Reactant: OCc1ccc(Br)cc1
Reactant: CCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCOCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.6 %

Procedure:
In DMF (120 ml) was dissolved 4-bromobenzyl alcohol (15 g). To the mixture was added under ice-cooling 65% sodium hydride (3.0 g), and the mixture was stirred at room temperature for 3 hours. To the mixture was added dropwise at room temperature 2-bromoethylethyl ether (11.4 g), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=10/1) to give 1-bromo-4-[(2-ethoxyethoxy)methyl]benzene (9.0 g). In THF (104 ml) was dissolved 1-bromo-4-[2-ethoxyethoxy)methyl)]benzene (8.7 g). To the mixture was added dropwise at −78° C. 1.6M n-butyllithium/hexane (23 ml), and the mixture was stirred for 1 hour. To the mixture was added dropwise trimethyl borate (8.7 g), and the mixture was stirred for 30 minutes and warmed to room temperature. To the mixture was added 5% sulfuric acid (35 ml), and the mixture was stirred for 15 minutes. The reaction mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=1/2) to give 4-[(2-ethoxyethoxy)methyl]phenyl borate (2.1 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2F)=[CH:10][CH:9]=1)[OH:7]>C1C=CC=CC=1.C(OCC)(=O)C>[OH:1][CH2:2][CH2:3][S:4][CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[OH:7]
Reactant: OCCSCC(O)c1ccc(-c2ccccc2F)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: OCCSCC(O)c1ccc(-c2ccccc2)cc1

Procedure:
2-Hydroxyethyl-[2-(2'-fluoro-4-biphenylyl)-2-hydroxyethyl]-sulfide, an oil, Rf -value: 0.3 on silicagel-polygram-plates with benzene/ethyl acetate = 1:1 as the eluant, was prepared in analogous manner.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: Oc1cccc(Br)c1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(C)(C)Oc1cccc(Br)c1
Yield: 89 %

Procedure:
25 g (144.5 mmol) of 3-bromophenol are placed in the presence of K2CO3 (21 g, 152 mmol) in 75 ml of ethyl 2-bromoisobutyrate and heated to reflux for 7 h. After elimination of K2CO3 by filtration, the reaction medium is dry concentrated. After purification by flash chromatography on silica (petroleum ether:AcOEt 90:10), 37 g of intermediate 10d are collected in the form of clear oil (yield=89%). TLC silica gel 60 F 254 Merck, petroleum ether:AcOEt 90:10, Rf=0.40.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27]([CH:28]([O:30][CH2:31][CH3:32])[CH3:29])[N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]([CH:33]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][N:42]([CH2:45][CH3:46])[CH2:43][CH3:44])[N:36]=2)[OH:34])=[C:7]([Cl:47])[N:6]=1)[CH2:2][CH2:3][CH3:4]>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27]([CH:28]([O:30][CH2:31][CH3:32])[CH3:29])[N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]([C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][N:42]([CH2:45][CH3:46])[CH2:43][CH3:44])[N:36]=2)=[O:34])=[C:7]([Cl:47])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C(O)c2cccc(CN(CC)CC)n2)n1Cc1ccc(-c2ccccc2-c2nnnn2C(C)OCC)cc1
Solvent: ClCCl
Product: CCCCc1nc(Cl)c(C(=O)c2cccc(CN(CC)CC)n2)n1Cc1ccc(-c2ccccc2-c2nnnn2C(C)OCC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
50 mg (0.076 mmole) of the compound obtained in step 1 of Example 12 was dissolved in 3 ml of methylene chloride and to the resulting solution was added 64.5 mg (0.152 mmole) of Des-Martin reagent. The resultant was stirred for 2 hours at room temperature and 10 ml of methylene chloride was added additionally thereto. The reaction mixture was washed with 5 ml of aqueous sodium bicarbonate solution, dried over anhydrous Na2SO4, concentrated under reduced pressure and purified with silica gel column chromatography to obtain 43.7 mg of the title compound (yield 87.8%).
Reaction SMILES: C1(C)C=CC=CC=1.C([N:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31]([OH:33])=[O:32])[C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:23])C1C=CC=CC=1>ClC1C=CC=CC=1Cl>[Cl:22][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:23])[C:16]=1[NH:15][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31]([OH:33])=[O:32]
Reactant: O=C(O)Cc1ccccc1N(Cc1ccccc1)c1c(Cl)cccc1Cl
Solvent: Clc1ccccc1Cl
Solvent: Cc1ccccc1
Product: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Reaction time: 1.5 h
Yield: 91.3 %

Procedure:
In an autoclave, 55 ml of toluene, 4 ml of o-dichlorobenzene, 10.0 g of N-benzyl-o-(2,6-dichloroanilino)phenylacetic acid and 2.0 g of 5% Pd-alumina were charged and it was purged with hydrogen gas and hydrogen gas was fed at 70° to 75° C. under a pressure of 10 to 20 cm H2O for 1.5 hours. The reaction mixture at the same temperature was filtered to remove 5% Pd-alumina and catalyst was washed with 35 ml of THF. The filtrate and the washing were combined and THF and toluene were distilled off. The residue was admixed with 200 ml of n-hexane and cooled to obtain 7.0 g of o-(2,6-dichloroanilino)phenylacetic acid as colorless crystals. Yield: 91.2%
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][C:13]=2[O:22][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])=[N:4][N:3]=1.[C:30]1([C@H:36]([NH2:38])[CH3:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:30]1([C@H:36]([NH:38][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][C:13]=3[O:22][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])=[N:4][N:3]=2)[CH3:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: O=S(=O)(Oc1ccc2ccccc2c1-c1nnc(Cl)c2ccccc12)C(F)(F)F
Product: C[C@@H](Nc1nnc(-c2c(OS(=O)(=O)C(F)(F)F)ccc3ccccc23)c2ccccc12)c1ccccc1
Temperature: 23 °C
Yield: 93.8 %

Procedure:
A solution of trifluoromethanesulfonic acid 1-(4-chlorophthalazin-1-yl)-naphthalen-2-yl ester (4.9 g, 11 mmol) in (R)-1-phenylethylamine (7.2 ml, 56 mmol) was stirred for 4 hrs at 120° C., then cooled to 23° C. The resulting viscous mixture was purified by flash chromatography on silica gel (toluene/EtOAc 7:1) to give 5.4 g of the title compound as a light brown solid as a 1:1 mixture of diastereomers. (yield: 93%)
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:11]([OH:13])=[O:12])=[CH:9][O:10][C:6]=2[CH2:5][CH2:4][CH2:3]1.[C:14](Cl)(=O)[CH3:15]>C(O)C>[O:1]=[C:2]1[C:7]2[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][O:10][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: CC(=O)Cl
Reactant: O=C(O)c1coc2c1C(=O)CCC2
Solvent: CCO
Product: CCOC(=O)c1coc2c1C(=O)CCC2
Reaction time: 1 h

Procedure:
To a stirred suspension of 4-oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid (28.2 g, 157 mmol) in ethyl alcohol (500 mL) under nitrogen at ambient temperature was added acetyl chloride(56 mL, 783 mmol) dropwise. After stirring 1 h, the solution was then heated at reflux for 1 h. The solution was cooled and concentrated in vacuo. The residue was taken up into dichloromethane, washed with aqueous sodium bicarbonate, washed quickly with 1N sodium hydroxide, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford ethyl 4-oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylate as an oil. A mixture of this ester (24.46 g, 117 mmol) and ammonium acetate (15.85 g, 206 mmol) in N,N-dimethylformamide (225 mL) was heated at 100° C. under Nitrogen for 1.25 h. The mixture was cooled, poured into ice water, and extracted two times with dichloromethane. The combined organic extracts were washed with water, dried over magnesium sulfate, filtered, concentrated in vacuo, and the residue triturated with ether to give ethyl 4-oxo-4,5,6,7-tetrahydroindole-3-carboxylate. A mixture of this ester (11.31 g, 55 mmol) in 5N sodium hydroxide (200 mL) and ethanol (20 mL) was heated at reflux for 1h. After cooling in an ice bath, the mixture was acidified with concentrated hydrochloric acid, the precipitate filtered, rinsed with ice water, and dried in vacuo to afford 4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid. m.p. 269°-270° C.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH2:3][C@H:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].ClCCl.[C:23]([O:27][C:28]([NH:30][C@@H:31]([CH3:35])[C:32](Cl)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(N(CC)CC)C>[C:23]([O:27][C:28]([NH:30][C@@H:31]([CH3:35])[C:32]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C(OCc1ccccc1)[C@@H]1CC2=C(CCCC2)N1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccccc2C[C@H]1C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
Introduce 200 g of benzyl (2S)-2,3,4,5,6,7-hexahydro-1H-indole-2-carboxylate and 1.5 liters of dichloromethane into a reactor, then bring the temperature of the reaction mixture to 0° C. and add 107 ml of triethylamine and then 162 g of (2S)-2-[(tert-butoxycarbonyl)amino]propionyl chloride. Subsequently, bring the mixture to ambient temperature. After stirring for 1 hour at that temperature, wash the mixture with water and then with a dilute acetic acid solution. The benzyl (2S)-1-{(2S)-2-[(tert-butoxycarbonyl)amino]propionyl}-2,3-dihydro-1H-indole-2-carboxylate solution so obtained is used as it is in the following Step.
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:6]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[C:10]([F:19])[C:9]([O:20][CH2:21][CH3:22])=[C:8]([CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([N:30]4[CH2:39][CH2:38][C:37]5[N:36]=[C:35]([CH3:40])[C:34]([C:41]([O:43]C)=[O:42])=[CH:33][C:32]=5[C:31]4=[O:45])[CH2:26][CH2:25]3)[CH:7]=2)[CH2:5][CH2:4]1.Cl>CO>[CH:3]1([C:6]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[C:10]([F:19])[C:9]([O:20][CH2:21][CH3:22])=[C:8]([CH2:23][N:24]3[CH2:25][CH2:26][CH:27]([N:30]4[CH2:39][CH2:38][C:37]5[N:36]=[C:35]([CH3:40])[C:34]([C:41]([OH:43])=[O:42])=[CH:33][C:32]=5[C:31]4=[O:45])[CH2:28][CH2:29]3)[CH:7]=2)[CH2:5][CH2:4]1
Reactant: CCOc1c(CN2CCC(N3CCc4nc(C)c(C(=O)OC)cc4C3=O)CC2)cc(C2CC2)c(-c2ccc(F)cc2)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOc1c(CN2CCC(N3CCc4nc(C)c(C(=O)O)cc4C3=O)CC2)cc(C2CC2)c(-c2ccc(F)cc2)c1F
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
A 2 M aqueous sodium hydroxide solution (1.0 mL) was added at room temperature to a methanol (4 mL) solution of methyl 6-(1-((6-cyclopropyl-3-ethoxy-2,4′-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-2-methyl-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate (460 mg), and the mixture was stirred at 50° C. for 30 minutes. The reaction mixture was neutralized with hydrochloric acid at room temperature and then stirred at room temperature for 2 hours, and then, the deposited solid was collected by filtration. The obtained solid was recrystallized (DMSO/ethanol/water) to obtain the title compound (385 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[Cl:23])[C:7]([CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[N:12](N)[C:11]([CH3:19])([CH3:18])[CH2:10]1)=[O:8])([O-:3])=[O:2].[C:24]([O:27]C(=O)C)(=O)[CH3:25].C([N:33](CC)CC)C>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[Cl:23])[C:7]([CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([C:24](=[O:27])[CH3:25])[C:11]([CH3:19])([CH3:18])[CH:10]1[NH2:33])=[O:8])([O-:3])=[O:2]
Reactant: CC1(C)CC(C(=O)c2ccc(Cl)c([N+](=O)[O-])c2)CC(C)(C)N1N
Reactant: CC(=O)OC(C)=O
Reactant: CCN(CC)CC
Product: CC(=O)N1C(C)(C)CC(C(=O)c2ccc(Cl)c([N+](=O)[O-])c2)C(N)C1(C)C
Reaction time: 16 h

Procedure:
68 Parts of 4-(3'-nitro-4'-chlorobenzoyl)-amino-2,2,6,6-tetramethylpiperidine are added to 250 parts of acetic anhydride. After the addition of 21 parts of triethylamine, the suspension is stirred for 16 hours at toom temperature and then for 3 hours at 100°-110°. In order to complete precipitation of the acetyl derivative, 1500 parts by volume of cold water are added and stirred at room temperature until all the excess acetic anhydride is destroyed. The precipitate is then filtered, washed neutral with water and dried. 72 parts of 4-(3'-nitro-4'-chlorobenzoyl)-amino-1-acetyl-2,2,6,6-tetramethyl-piperidine having a melting point of 198°-200° results.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=O)[CH2:3]2.[I:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>>[I:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][CH:4]2[CH:5]3[CH2:8][CH2:9][N:2]([CH2:7][CH2:6]3)[CH2:3]2)=[CH:14][CH:13]=1
Reactant: Nc1ccc(I)cc1
Reactant: O=C1CN2CCC1CC2
Agent: Cl
Product: Ic1ccc(NC2CN3CCC2CC3)cc1

Procedure:
3-Quinuclidinone hydrochloride (Aldrich, 3.22 g, 20 mmol) was treated with 4-iodo-aniline (2.19 g, 10 mmol) according to the procedure of Example 30A. The title product was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:2, Rf. 0.10) as oil (3.24 g, yield, 98%). 1H NMR (MeOH-d4, 300 MHz) δ 1.70–1.81 (m, 1H), 1.93–2.04 (m, 2H), 2.08–2.24 (m, 2H), 2.89 (ddd, J=12.9, 5.1, 2.7 Hz, 1H), 3.12–3.28 (m, 4H), 3.64 (ddd, J=12.9, 9.5, 2.4 Hz, 1H), 3.79–3.85 (m, 1H), 6.46 (dt, J=9.0, 2.7 Hz, 2H), 7.39 (dt, J=9.1, 2.7 Hz, 2H) ppm. MS (DCl/NH3) m/z 329 (M+H)+.
Reaction SMILES: [S:1]([N:11]1[C:15]2[N:16]=[CH:17][N:18]=[C:19]([NH:20][C@@H:21]3[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[H-].[Na+].[CH2:36](Br)[CH:37]=[CH2:38].O>CN(C=O)C>[CH2:38]([N:20]([C:19]1[C:14]2[CH:13]=[CH:12][N:11]([S:1]([C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=3)(=[O:3])=[O:2])[C:15]=2[N:16]=[CH:17][N:18]=1)[C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)[CH:37]=[CH2:36]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)ncnc32)cc1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN(c1ncnc2c1ccn2S(=O)(=O)c1ccc(C)cc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 1 h
Yield: 83.8 %

Procedure:
To a solution of (R)-tert-butyl 3-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidine-1-carboxylate (1.0 g, 2.1 mmol) in DMF (5 mL), NaH (60% suspension in mineral oil, 100 mg, 2.5 mmol) was added at 0° C. and the reaction mixture was stirred for 1 h. To the reaction mixture was added allyl bromide (308 mg, 2.12 mmol) and the reaction mixture was stirred for 6 h. The solution was diluted with ice-cooled water and stirred for 15 min, the solution was then extracted with EtOAc, dried over Na2SO4 and concentrated in vacuo to give the crude product that was purified by column chromatography (silica gel, gradient, EtOAc in hexanes) to give (0.9 g, 83%) of the titled compound. 1H NMR (400 MHz, CDCl3): δ 8.42 (s, 1H), 8.06 (d, J=8.0 Hz, 2H), 7.43 (d, J=3.2 Hz, 1H), 7.31 (d, J=8.0 Hz, 2H), 6.57 (d, J=3.2 Hz, 1H), 5.98-5.90 (m, 1H), 5.26-5.19 (m, 2H), 4.62-4.51 (m, 1H), 4.29-4.09 (m, 4H), 2.85 (t, J=11.6 Hz, 1H), 2.68-2.60 (m, 1H), 2.41 (s, 3H), 1.97-1.93 (m, 1H), 1.83-1.72 (m, 2H), 1.65-1.58 (m, 1H), 1.42 (s, 9H). LCMS [M+1]: 512.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=3[CH3:21])[N+:8]([O-:13])=[C:9]2[CH3:12])=[CH:4][N:3]=1.[CH:22]1([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.ClCCl.CO>[CH:22]1([C:25]([NH:27][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([C:14]4[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=4[CH3:21])[N+:8]([O-:13])=[C:9]3[CH3:12])=[CH:4][N:3]=2)=[O:26])[CH2:24][CH2:23]1
Reactant: NC(=O)C1CC1
Reactant: Cc1ccc(F)cc1-c1cc2cnc(Cl)cc2c(C)[n+]1[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccc(F)cc1-c1cc2cnc(NC(=O)C3CC3)cc2c(C)[n+]1[O-]
Temperature: 90 °C
Yield: 94.9 %

Procedure:
A mixture of 7-chloro-3-(5-fluoro-2-methylphenyl)-1-methyl-2,6-naphthyridine 2-oxide (350 mg, 1.2 mmol), cyclopropanecarboxamide (295 mg, 3.5 mmol), Chloro[2-(dicyclohexylphosphino)-3-,6-dimethoxy-2,4′-6′-tri-i-pr-1,1′-biphenyl)][2-(2-aminoethyl) Ph]Pd(II) (46 mg, 0.06 mmol), (dicyclohexylphosphino)-3-,6-dimethoxy-2,4′-6′-tri-i-pr-1,1′-biphenyl (120 mg, 0.2 mmol), and cesium carbonate (750 mg, 2.3 mmol) in 1,4-dioxane (5 mL) was heated at 90° C. for 4 hours. The cooled reaction mixture was diluted with dichloromethane (200 mL) and methanol (100 mL), mixed with Celite, filtered, the solids washed with 15% methanol/dichloromethane (2×100 mL), and the filtrate was dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 40 g, ISCO, 0-10% methanol in dichloromethane) to afford the title compound as an off-white solid (400 mg, 100%). 1H NMR (400 MHz, DMSO) δ 11.16 (s, 1H), 9.11 (s, 1H), 8.56 (s, 1H), 8.02 (s, 1H), 7.41-7.31 (m, 1H), 7.22 (m, 2H), 2.66 (s, 3H), 2.10 (m, 1H), 2.08 (s, 3H), 0.94-0.81 (m, 4H). LCMS (Method D): RT=11.358 min, M+H+=352.1.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:25])=[C:16]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH:17]=1)[N:5]=2.[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:25][C:15]1[CH:14]=[CH:13][C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:29]([CH:26]4[CH2:28][CH2:27]4)=[O:30])=[N:10][C:9]3=[CH:8][CH:7]=2)=[CH:17][C:16]=1[NH:18][C:19](=[O:24])[C:20]([F:22])([F:21])[F:23]
Reactant: Nc1nc2ccc(Oc3ccc(Cl)c(NC(=O)C(F)(F)F)c3)nc2s1
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(Nc1nc2ccc(Oc3ccc(Cl)c(NC(=O)C(F)(F)F)c3)nc2s1)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
N-{5-[(2-Amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2-chlorophenyl}-2,2,2-trifluoroacetamide (5.0 g, 12.9 mmol) was dissolved in pyridine (25 mL), cyclopropanecarbonyl chloride (1.28 ml, 14.2 mmol) was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was treated with aqueous sodium hydrogen carbonate solution (100 mL), and diluted with ethyl acetate (100 mL). The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residual solid was crystallized from ethyl acetate (30 mL), collected by filtration, and dried to give the title compound (3.46 g, 59%) as a colorless powder.
Reaction SMILES: O=S(Cl)Cl.[CH3:5][S:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9]Cl.[C:15]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[CH3:5][S:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:15]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CSc1ccccc1CCl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(Cc1ccccc1SC)C(=O)OCC

Procedure:
By reacting thiosalicylic acid with dimethyl sulfate in the presence of tetrabutylammonium bromide, there was obtained methyl 2-(methylthio)benzoate, melting point 64° C. Reduction with lithium aluminum hydride in dry tetrahydrofuran yielded 2-(methylthio)benzyl alcohol which was converted by reaction with SOCl2 into 2-(methylthio)benzyl chloride, boiling point 90° C./0.3 Torr. Reaction of diethyl malonate with 2-(methylthio)benzyl chloride yielded diethyl 2-(methylthio)benzyl-malonate, boiling point 130° C./0.05 Torr. Condensation with formamidine yielded 5-[o-(methylthio)benzyl]-6-hydroxy-4(3H)-pyrimidinone which was converted into 4,6-dichloro-5-[o-(methylthio)benzyl]pyrimidine, melting point 91° C. From 4,6-dichloro-5-(o-(methylthio)benzyl)pyrimidine and p-isopropylbenzenesulfonamide potassium, there was finally obtained N-[6-chloro-5-(o-(methylthio)benzyl)-4-pyrimidinyl]-p-isopropylbenzenesulfonamide, melting point 145°-146° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.[N+](C1C=CC(S(O[CH2:27][C@H:28]2[CH2:30][C:29]2([F:32])[F:31])(=O)=O)=CC=1)([O-])=O>>[Cl:1][C:2]1[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:5]=[C:6]([O:8][CH2:27][C@H:28]2[CH2:30][C:29]2([F:32])[F:31])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@H]2CC2(F)F)cc1
Reactant: CCOC(=O)c1ncc(O)cc1Cl
Product: CCOC(=O)c1ncc(OC[C@H]2CC2(F)F)cc1Cl

Procedure:
Using ethyl 3-chloro-5-hydroxypyridine-2-carboxylate and ((1R)-2,2-difluorocyclopropyl)methyl 4-nitrobenzenesulfonate, and in the same manner as in Example 5, the title compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11]1([CH3:23])[CH:16]=[CH:15][C:14]([S:17]([O:20]CC)(=[O:19])=[O:18])=[CH:13][CH:12]=1>CC(C)=O>[C:11]1([CH3:23])[CH:12]=[CH:13][C:14]([S:17]([O-:20])(=[O:18])=[O:19])=[CH:15][CH:16]=1.[CH2:11]([N+:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[S:3][C:2]=1[CH3:1])[CH3:12]
Reactant: Cc1nc2ccccc2s1
Reactant: CCOS(=O)(=O)c1ccc(C)cc1
Solvent: CC(C)=O
Product: CC[n+]1c(C)sc2ccccc21
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 150 °C
Reaction time: 0.17 h

Procedure:
300 g (2 mol) of 2-methylbenzothiazole and 440 g (2.2 mol) of ethyl p-toluenesulfonate (or a mixture of ethyl o- and p-toluenesulfonate) are heated with stirring to 150° C., the temperature rising to about 200° C. due to the exothermic reaction. After 10 minutes, the mixture is poured into two liters of acetone, and the product which has precipitated is filtered off with suction, washed with acetone and dried in vacuo. Yield 730 g (98%).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10](N)[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:13][O:14][CH3:15])[N:8]=2)[N:3]=1.C(O)(=[O:18])C>[OH-].[Na+]>[NH2:1][C:2]1[NH:11][C:10](=[O:18])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:13][O:14][CH3:15])[N:8]=2)[N:3]=1
Reactant: COCc1cnc2nc(N)nc(N)c2n1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: COCc1cnc2nc(N)[nH]c(=O)c2n1
Yield: 83 %

Procedure:
The diaminopteridine, vide supra, was hydrolyzed in 1N NaOH at 70° C. for 3 hr. The resulting basic solution was then acidified with acetic acid, and the yellow product was filtered, washed with 95% ethanol and ethyl ether, and dried under vacuum overnight to yield 0.5 g (83%) of 2-amino-6-methoxymethyl-4(3H)-pteridinone as a yellow powder: UV (0.1N NaOH) λmax 255 nm (22300), 277.5 nm sh (6200), 364 nm (7100); NMR (DMSO-d6) 3.36 δ(s, OMe), 4.53 (s, CH2O), 7.32 (brs, NH2), and 8.63 (s, 7-H). Anal. calcd. for C8H9N5O2.7/10H2O: C, 43.72; H, 4.77; N, 31.86. Found: C, 43.77; H, 4.77; N, 31.63.