Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CN(C=O)C.[NH:8]1[CH:12]=[CH:11][CH:10]=[N:9]1.Cl[C:14]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:18]([CH3:27])[N:17]=[N:16][C:15]=1[CH3:28]>C(OCC)(=O)C>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([C:19]2[C:14]([C:12]3[CH:11]=[CH:10][NH:9][N:8]=3)=[C:15]([CH3:28])[N:16]=[N:17][C:18]=2[CH3:27])=[CH:25][CH:24]=1
Reactant: c1cn[nH]c1
Reactant: Cc1nnc(C)c(-c2ccc(Cl)cc2)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nnc(C)c(-c2cc[nH]n2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
87 mg of sodium hydride (55% oil dispersion) was added to 5 ml of DMF. To this was added 0.14 g of pyrazole, and the mixture was stirred for 0.5 hours at room temperature. To the resultant mixture was added 0.25 g of 4-chloro-5-(4-chlorophenyl)-3,6-dimethylpyridazine, and the mixture was stirred for 3 hours on an oil bath of 80° C. To the reaction mixture was added ethyl acetate, and the mixture was washed with brine four times. The organic layer was dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.38 g of the resultant residue was subjected to silica gel column chromatography, to obtain 0.19 g of 5-(4-chloro-phenyl)-3,6-dimethyl-4-pyrazolylpyridazine (hereinafter, described as compound (6) of the present invention.).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[S:19][C:18]([CH2:20]Cl)=[CH:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:25][NH:26][CH2:27][C@H:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[OH:29].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[S:19][C:18]([CH2:20][N:26]([CH2:27][C@@H:28]([OH:29])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[CH3:25])=[CH:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CNC[C@@H](O)c1ccccn1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CCl)cc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cc2c(s1)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C)C[C@@H](O)c1ccccn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 65.7 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (113 mg, 0.30 mmol), (1R)-2-(methylamino)-1-pyridin-2-ylethanol (Preparation 28) (100 mg, 0.44 mmol) and diisopropylethylamine (230 μL, 1.32 mmol) in dry DMF (8 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 7 hours at that temperature. After cooling to room temperature, the solution was diluted with water (12 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight in the refrigerator. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile/water (dissolved with warming 5 mL of acetonitrile, then cooled to 0° C. and then diluted with 1 mL of water, left overnight) gave the title compound (98 mg) as a white solid.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][C:5](=[O:19])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([OH:18])[CH2:16][OH:17])=[CH:9][CH:8]=1.C[I:21].[CH3:22]COCC>CN(C)C=O>[I-:21].[OH:18][CH:15]([CH2:16][OH:17])[CH2:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:5]([CH2:4][CH2:3][S+:2]([CH3:22])[CH3:1])=[O:19])=[CH:8][CH:9]=1
Reactant: CI
Reactant: CSCCC(=O)Nc1ccc(OCC(O)CO)cc1
Reactant: CCOCC
Solvent: CN(C)C=O
Product: C[S+](C)CCC(=O)Nc1ccc(OCC(O)CO)cc1
Product: [I-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.8 %

Procedure:
Dissolved in 5 ml of dimethylformamide was 2.85 g of 2-{4-(2,3-dihydroxypropoxy)phenylcarbamoyl}ethyl methyl sulfide. To the solution was added 5.00 g of methyl iodide and the mixture was stirred at room temperature for 12 hours. Ether was added to the reaction mixture and the insoluble solid was filtered off, and recrystallized from methanol-ether, giving 4.05 g of 2-{4-(2,3-dihydroxypropoxy)phenylcarbamoyl}ethyldimethylsulfonium iodide (Compound 3) in 94.8% yield, M.P. 113° to 115° C.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13]([C:17]#[C:18][Si](C)(C)C)=[CH:12]2)=[O:5].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.ClCCl>[Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13]([C:17]#[CH:18])=[CH:12]2)=[O:5]
Reactant: C[Si](C)(C)C#Cc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C#Cc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a solution of 8-(2,6-dichlorobenzoylamino)-3-(trimethylsilylethynyl)quinoline (150 mg) in tetrahydrofuran (3 ml) was added 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.04 ml) under ice-cooling, and the mixture was stirred for 2 hours at the same temperature. The mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate:n-hexane, 1:4, v/v) to give 8-(2,6-dichlorobenzoylamino)-3-ethynylquinoline (111 mg).
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][C@H:13]1[CH2:18][CH2:17][C@@H:16]([NH:19][C:20]2[N:29]=[C:28]([N:30]([CH3:32])[CH3:31])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)[CH2:15][CH2:14]1)C1C=CC=CC=1.C1CC=CCC=1>CCO.[Pd]>[NH2:10][CH2:11][CH2:12][C@@H:13]1[CH2:14][CH2:15][C@H:16]([NH:19][C:20]2[N:29]=[C:28]([N:30]([CH3:31])[CH3:32])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)[CH2:17][CH2:18]1
Reactant: CN(C)c1nc(N[C@H]2CC[C@@H](CCNC(=O)OCc3ccccc3)CC2)nc2ccccc12
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCC=CC1
Product: CN(C)c1nc(N[C@H]2CC[C@@H](CCN)CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of cis-{2-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-ethyl}-carbamic acid benzyl ester (4.47 g, 10 mmol) in EtOH (20 mL) was added 1,4-cyclohexadiene (20 mL) and 200 mg of 10% Pd/C. The reaction mixture was stirred at ambient temperature for 18 hr, filtered through pad of celite, and concentrated. The residue was purified by column chromatography (silica gel, 5% to 15% 2 M NH3/MeOH in CH2Cl2) to give cis-N2-[4-(2-amino-ethyl)-cyclohexyl]-N4,N4-dimethyl-quinazoline-2,4-diamine (2.41 g, 77%) as a yellow oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][NH:6][CH2:5][C:4]2[S:8][CH:9]=[CH:10][C:3]1=2.[C:11]1([N:17]=[C:18]=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1C=CC=CC=1>[OH:1][CH:2]1[CH2:7][N:6]([C:18](=[O:19])[NH:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5][C:4]2[S:8][CH:9]=[CH:10][C:3]1=2
Reactant: OC1CNCc2sccc21
Reactant: O=C=Nc1ccccc1
Solvent: c1ccccc1
Product: O=C(Nc1ccccc1)N1Cc2sccc2C(O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To a solution of 4-hydroxy-4,5,6,7-tetrahydro-thieno[2,3-c]-pyridine (5.6 g; 36.2 mmoles) in benzene (40 cc), is added dropwise a mixture of phenyl isocyanate (4.3 g; 36.2 mmoles) in benzene (10 ml). After stirring during 2 hours at room temperature, the resulting precipitate is filtered off, washed with ether and dried in vacuo. On recrystallization from ethanol, the desired product is obtained in a yield of 65% (M.p. = 200° C).
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]([OH:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:24](Cl)(=[O:26])[CH3:25].C(Cl)[Cl:29]>>[C:24]([O:14][CH:7]([O:6][C:5]1[CH:15]=[CH:16][C:2]([Cl:29])=[CH:3][CH:4]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: ClCCl
Reactant: OC(Oc1ccc(F)cc1)c1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)OC(Oc1ccc(Cl)cc1)c1ccccc1
Reaction time: 18 h

Procedure:
To a solution of compound 26 (21.8 g, 0.1 M) and triethylamine (14 mL, 0.1 M) in 300 mL CH2Cl2, acetyl chloride (8 g, 0.102 M) was added at room temperature. The mixture was kept at room temperature for 18 h, then washed with water, dried over Na2SO4, concentrated to afford 27.3 g of 4-chlorophenoxybenzyl acetate 32 as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[CH:18][CH:17]=1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([Cl:46])[C:32]=1[OH:47].Cl>ClCCl.CO>[ClH:30].[Cl:30][C:31]1[CH:36]=[C:35]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[CH:20][CH:21]=2)[CH:34]=[C:33]([Cl:46])[C:32]=1[OH:47]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(CN2CCN(C)CC2)cc1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(CN2CCN(C)CC2)cc1
Yield: 121.2 %

Procedure:
Following general procedure F, 1-(6-bromo-4-(4-((4-methylpiperazin-1-yl)methyl)phenylamino)quinolin-3-yl)ethanone (6.0 g, 13.0 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (4.2 g, 15.0 mmol) to obtain the free base. The purified product was suspended in dichloromethane/methanol (1:1, 200 mL) after which HCl (36 mL, 1.25 M in methanol) was added to form a solution. The solution was concentrated to dryness and the resultant solid was triturated with dichloromethane. The mixture was filtered, washed with dichloromethane, and dried to obtain desired product (5.2 g, 66% over two steps) as a yellow solid: 1H NMR (300 MHz, CD3OD) δ 9.30 (s, 1H), 8.15 (dd, J=8.8, 1.9 Hz, 1H), 7.99 (d, J=8.8 Hz, 1H), 7.73 (d, J=2.0 Hz, 1H), 7.62 (d, J=8.0 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H), 7.10 (s, 2H), 3.81 (s, 2H), 3.55-3.31 (m, 2H), 3.29-2.89 (m, 4H), 2.89 (s, 3H), 2.82 (s, 3H), 2.80-2.35 (m, 2H); APCI MS m/z 535 [C29H28Cl2N4O2+H]+; HPLC>99% (AUC), tR=7.89 min.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:3]=1.[CH3:30][C:31]1[NH:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[N:32]=1>>[CH3:23][C:19]([N:16]1[CH2:15][CH2:14][N:13]([CH2:12][C:7]2[N:8]([CH3:11])[C:9]3[C:5]([N:6]=2)=[C:4]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[N:3]=[C:2]([N:32]2[C:33]4[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=4[N:35]=[C:31]2[CH3:30])[N:10]=3)[CH2:18][CH2:17]1)([CH3:22])[CH2:20][OH:21]
Reactant: Cc1nc2ccccc2[nH]1
Reactant: Cn1c(CN2CCN(C(C)(C)CO)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)(C)CO)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-(4-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperazin-1-yl)-2-methylpropan-1-ol and 2-methyl-1H-benzo[d]imidazole were reacted to give 264. LCMS m/z: 520.3 (MH+)
Reaction SMILES: [Cl-].O[NH3+].[C:4](=[O:7])([O-])[OH:5].[Na+].[CH2:9]([C:11]1[S:42][C:14]2[N:15]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=4)=[CH:30][CH:29]=3)[C:16](=[O:26])[N:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:13]=2[CH:12]=1)[CH3:10].[N:43]12CCCN=C1CCCCC2>C(Cl)(Cl)Cl.C(Cl)Cl.CS(C)=O>[CH2:9]([C:11]1[S:42][C:14]2[N:15]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]4[NH:43][C:4](=[O:7])[O:5][N:41]=4)=[CH:30][CH:29]=3)[C:16](=[O:26])[N:17]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[C:13]=2[CH:12]=1)[CH3:10]
Reactant: CCc1cc2c(s1)n(Cc1ccc(-c3ccccc3C#N)cc1)c(=O)n2Cc1ccc(F)cc1
Reactant: O=C([O-])O
Reactant: C1CCC2=NCCCN2CC1
Agent: [Cl-]
Agent: [NH3+]O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCc1cc2c(s1)n(Cc1ccc(-c3ccccc3-c3noc(=O)[nH]3)cc1)c(=O)n2Cc1ccc(F)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
A mixture of hydroxylammonium chloride (0.44 g), sodium hydrogencarbonate (0.65 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C. for 30 min, 4′-{[5-ethyl-1-(4-fluorobenzyl)-2-oxo-1,2-dihydro-3H-thieno[2,3-d]imidazol-3-yl]methyl}biphenyl-2-carbonitrile (0.36 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by silica gel column chromatography was dissolved in methylene chloride (30 mL), N,N′-carbonyldiimidazole (0.14 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.12 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.12 g, 29%).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[Na+].[CH3:13][CH:14]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1.Cl[O-].[Na+]>C(OCC)(=O)C.O>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][N:16]1[CH2:17][CH2:18][CH2:19][CH:14]([CH3:13])[CH2:15]1
Reactant: Sc1nc2ccccc2s1
Reactant: CC1CCCNC1
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC1CCCN(Sc2nc3ccccc3s2)C1
Reaction time: 2 h
Yield: 95.5 %

Procedure:
In a 500 ml volume flask, there are charged 2-mercaptobenzothiazole (UV absorption spectrum: 329 mμ) (41.28 g), sodium hydroxide (10 g) and water (180 ml), and the resultant mixture is stirred to form a solution. After the addition of 3-methylpiperidine (27.2 g) to the resulting solution, a 15 % by volume aqueous solution of sodium hypochlorite (138.5 ml) is dropwise added thereto in 2 hours, during which the inner temperature is kept below 70° C. The reaction mixture is allowed to stand at the same temperature for 1 hour and then shaken with ethyl acetate (150 ml). The ethyl acetate extract is washed with water and distilled under reduced pressure to give 1-(2-benzothiazolylthio)-3-methyl-piperidine (62.3 g).
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[C:5]([O:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20]([OH:22])=O)[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1.[F:30][C:31]([F:39])([F:38])[C:32]1[N:33]=[C:34]([NH2:37])[S:35][CH:36]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[F:29][CH:2]([F:1])[O:3][C:4]1[C:5]([O:23][CH2:24][CH2:25][CH:26]([CH3:27])[CH3:28])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20]([NH:37][C:34]2[S:35][CH:36]=[C:32]([C:31]([F:39])([F:38])[F:30])[N:33]=2)=[O:22])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1nc(C(F)(F)F)cs1
Reactant: CC(C)CCOc1c(/C=C/c2nc3sccn3c2C(=O)O)cccc1OC(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)CCOc1c(/C=C/c2nc3sccn3c2C(=O)Nc2nc(C(F)(F)F)cs2)cccc1OC(F)F

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 8 (300 mg, 0.710 mmol) with 4-(trifluoromethyl)-1,3-thiazol-2-amine (128 mg, 0.781 mmol) in the presence of EDCI hydrochloride (272 mg, 1.42 mmol), DMAP (80 mg, 0.710 mmol) in a mixture of THF and DMF (1:1, 6 mL) to give 35 mg of the product as an off-white solid; 1H NMR (300 MHz, CDCl3) δ 0.86 (d, J=6.6 Hz, 6H), 1.56-1.65 (m, 2H), 1.77-1.86 (m, 1H), 3.95 (t, J=6.3 Hz, 2H), 7.20 (t, J=74.4 Hz, 1H), 7.22-7.30 (m, 2H), 7.46 (s, 1H), 7.57-7.64 (m, 2H), 7.76 (d, J=15.9 Hz, 1H), 8.05-8.12 (m, 2H), 13.03 (br s, 1H); APCI-MS (m/z) 573.23 (MH)+.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([O:10][CH2:11][C:12]2[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[N:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][C:16]=3[CH3:22])=[N:3][CH:2]=1.C1C=C[NH+]=CC=1.Br[Br-]Br.CC(O)=[O:41]>CC(O)(C)C.[Zn]>[CH3:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[N:14]=[C:13]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])[C:12]([CH2:11][O:10][C:4]1[C:5]3[CH2:9][C:8](=[O:41])[NH:7][C:6]=3[N:1]=[CH:2][N:3]=1)=[CH:21]2
Reactant: CC(=O)O
Reactant: Cc1ccccc1-c1nc2c(C)cccc2cc1COc1ncnc2[nH]ccc12
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Product: Cc1ccccc1-c1nc2c(C)cccc2cc1COc1ncnc2c1CC(=O)N2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 3-((7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)methyl)-8-methyl-2-o-tolylquinoline (120 mg, 0.316 mmol) in AcOH (4 mL) and t-BuOH (2.43 mL) under N2 was added pyridinium bromide perbromide (303 mg, 0.947 mmol) in one portion. After stirring at room temperature for 5 h the solvents was removed, and the remaining solids suspended in H2O and extracted with ethyl acetate, after drying with brine and MgSO4 the crude dry solid was dissolved in THF (8 mL) followed by 5 mL of a saturated NH4Cl solution, this was followed in turn by Zn powder (528 mg, 26 mmol) and stirred at room temperature for 24 h. The mixture was then extracted with ethyl acetate and chromatographed {gradient elution DCM/89:9:1(DCM/MeOH/NH4OH)}. The solid was recrystallized from DCM to provide the pure product [PI3Kδ IC50=349 nM]. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.29 (1 H, s), 8.52 (1 H, s), 8.30 (1 H, s), 7.89 (1 H, d, J=7.8 Hz), 7.65 (1 H, d, J=7.0 Hz), 7.51-7.57 (1 H, m), 7.30-7.35 (3 H, m), 7.22-7.29 (1 H, m), 3.47 (2 H, s), 2.67 (3 H, s), 2.09 (3 H, s) Mass Spectrum (ESI) m/e=397.1 [M+1].
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6](Cl)[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].O.[NH2:20][NH2:21]>O>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([NH:20][NH2:21])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: COc1c(Cl)nc(SC)nc1Cl
Reactant: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1c(Cl)nc(SC)nc1NN
Reaction time: 0.5 h

Procedure:
A mixture of 48.1 g (0.21 mol) of 4,6-di-chloro-2-methylthio-5-methoxypyrimidine, 29.5 g (0.21 mol) of potassium carbonate, 80 ml of hydrazine monohydrate, and 80 ml of water was prepared and heated at reflux with stirring for about 30 min at which time the reaction appeared by high pressure liquid chromatography to be complete. The mixture was allowed to cool and was extracted with methylene chloride. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was mixed with hexane and the solids removed by filtration and dried to obtain 34,7 g of the title compound as a tan solid melting at 118° C.-119° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[Na+].[CH2:12]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1)[CH3:13].O>CO>[CH2:12]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[OH:19])=[CH:16][CH:15]=1)[CH3:13]
Reactant: CCc1ccc(C=O)cc1
Reactant: c1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1ccc(C(O)c2c[nH]c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 16.3 %

Procedure:
To a solution of indole (6.00 g) in methanol (60 ml) were added sodium hydroxide (2.25 g) and 4-ethylbenzaldehyde (7.56 g), and the mixture was stirred at room temperature for 3 days under argon atmosphere. Added thereto was water, and methanol was evaporated under reduced pressure. The residue was extracted with diethyl ether, and the extract was washed with water, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=98:2-70:30) to give 4-ethylphenyl-(1H-indol-3-yl)methanol (2.10 g) as a colorless solid. APCI-Mass m/Z 234 (M+H−H2O).
Reaction SMILES: Cl[O-:2].[Na+].[OH-].[Na+].[C:6]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:19][CH3:20])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1)(=[O:8])C>>[C:6]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:19][CH3:20])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1)([OH:8])=[O:2]
Reactant: CCC(C(=O)O)c1ccc(C(C)=O)cc1
Reactant: [O-]Cl
Agent: [Na+]
Agent: [OH-]
Product: CCC(C(=O)O)c1ccc(C(=O)O)cc1
Temperature: 55 °C
Reaction time: 20 h
Yield: 94.9 %

Procedure:
Part D--To a solution of sodium hypochlorite (330 mL, 17.32 g, 0.234 mol) in a solution of sodium hydroxide (50%, 172 mL), warmed to 55° C., was added, portionwise as a solid, 4-acetylphenylbutyric acid (16.0 g, 0.078 mol) while keeping the temperature between 60°-70° C. All was stirred at 55° C. over 20 hours. The cooled solution was quenched by the dropwise addition of a solution of sodium bisulfite (25%, 330 mL). The mixture was then transferred to a beaker and acidified by the careful addition of concentrated hydrochloric acid. The resulting solid was collected, washed with water and dried, then triturated sequentially with chlorobutane and hexane to give 4-carboxyphenylbutyric acid (15.31 g, 0.074 mol, 95%) as a white solid. mp=190°-195° C.; 1H NMR (DMSO) d 12.55 (bs, 1H), 8.1 (s, 1H), 7.85 (d, 2H, J=8.1 Hz), 7.3 (d, 2H, J=8.1 Hz), 2.7 (t, 2H, J=7.5 Hz), 2.2 (t, 2H, J=7.4 Hz), 1.8 (quintet, 2H, J=7.5 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:12])=[N:4][C:5](Cl)=[CH:6][C:7]=1[CH2:8][CH2:9][CH3:10].[H][H]>CO.O.[Pd]>[NH2:1][C:2]1[C:3]([Cl:12])=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH3:10]
Reactant: CCCc1cc(Cl)nc(Cl)c1N
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CCCc1ccnc(Cl)c1N

Procedure:
In a 1 liter stirred autoclave 150.0 g of 3-amino-2,6-dichloro-4-n-propylpyridine and 5.0 g of 10% palladium/carbon are suspended in a mixture of 450.0 ml of methanol and 150.0 ml of water and hydrogenated under 3 bars of hydrogen at 50°-70° C. until the uptake of gas has ceased.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]([OH:21])[C@H:12]([NH:15][C:16]([CH:18]([Cl:20])[Cl:19])=[O:17])[CH2:13][F:14])=[CH:9][CH:10]=1)(=[O:4])=[O:3].Cl(O)(=O)(=O)=[O:23]>C(OC(=O)CCCCC)(=O)CCCCC>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]([OH:21])[C@H:12]([NH:15][C:16]([CH:18]([Cl:20])[Cl:19])=[O:17])[CH2:13][F:14])=[CH:9][CH:10]=1)(=[O:4])=[O:3].[C:11]([O-:21])(=[O:23])[CH2:8][CH2:7][CH2:6][CH2:5][CH3:10]
Reactant: [O-][Cl+3]([O-])([O-])O
Agent: CCCCCC(=O)OC(=O)CCCCC
Agent: CS(=O)(=O)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Product: CCCCCC(=O)[O-]
Reaction time: 3 h

Procedure:
100 g of florfenicol was suspended in 500 g of hexanoic anhydride in one liter round bottom flask equipped with an overhead stirrer and a drying tube. To this suspension was added 3 ml of perchloric acid, while stirring vigorously, with a pipette. A clear solution was obtained in a few minutes. Stirring was continued for another 3 hours during which the product, florfenicol hexanoate pro-drug was recrystallized. The solid product was filtered using Buckner fimnel under vacuum, washed thoroughly with hexane. The product was finally recrystallized in ethanol and the recrystallized product was washed with hexane and dried to obtain around 117 g of solid florfenicol hexanoate.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.O.O.[Sn](Cl)Cl.[BH4-].[Na+].C(OCC)(=O)C>CC(O)(C)C>[Cl:11][C:5]1[CH:6]=[C:7]([NH2:8])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(Cl)cnc1N

Procedure:
A procedure similar to that described in Preparation 42 was repeated, except that 12.5 g of 2-amino-5-chloro-3-nitropyridine (prepared as described in Preparation 61) 82.0 g of tin(II) chloride dihydrate, 1.35 g of sodium borohydride and 300 ml of a 9:1 by volume mixture of ethyl acetate and 2-methyl-2-propanol were used, to give the title compound as a crude product. This crude product was crystallized by trituration with a mixture of ethyl acetate and hexane, to give 8.14 g of the title compound, melting at 164°-165° C.