Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.[Li]C(C)(C)C.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23](=[O:27])[CH2:24][CH2:25][CH:26]=2)=[CH:18][CH:17]=1>CCOCC>[CH3:9][S:8][C:5]1[CH:6]=[CH:7][C:2]([C:23]2([OH:27])[CH2:24][CH2:25][CH:26]=[C:22]2[C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)=[CH:3][CH:4]=1
Reactant: O=C1CCC=C1c1ccc(F)cc1
Reactant: CSc1ccc(Br)cc1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CSc1ccc(C2(O)CCC=C2c2ccc(F)cc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 89.4 %

Procedure:
To a solution of 3.86 g (19 mmol) of 4-bromothioanisole in 90 mL of Et2O cooled at -78° C., was added 22 mL of 1.7 M solution of t-BuLi in penlane (38 mmol) dropwise. The reaction mixture was stirred for 15 min at -78° C. and a solution of 2.23 g of 2-(4-Fluorophenyl)-2-cyclopenten-1-one in 10 mL of Et2O was added. After stirring for 15 min at -78° C., the reaction mixture was warmed to 0° C., and quenched with 50 mL of sat. NH4Cl. The product was extracted with 100 mL EtOAc, dried over Na2SO4, and purified by flash chromatography, eluted with 4:1 hexane/EtOAc to give 3.4 g of the desired product.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)=[O:5].[CH2:13]([O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)[CH2:14][CH2:15][CH2:16][CH3:17].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:13]([O:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([NH:2][CH2:3][C:4]([C:6]2[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=2)=[O:5])=[O:24])=[CH:26][CH:27]=1)[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCOc1ccc(C(=O)O)cc1
Reactant: NCC(=O)c1ccc(Br)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCCCOc1ccc(C(=O)NCC(=O)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.9 %

Procedure:
To a solution of 2-amino-4′-bromoacetophenone hydrochloride (8.2 g), 4-pentyloxybenzoic acid (6.8 g) and 1-hydroxybenzotriazole (4.42 g) in dichloromethane (80 ml) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (WSCD) (6.0 ml), and stirred for 3 hours at ambient temperature. The reaction mixture was diluted with dichloromethane (800 ml), and washed with 1N hydrochloric acid, saturated sodium hydrogen carbonate aqueous solution and brine. The organic layer was dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. The solids were slurried in ethyl acetate, and collected by filtration to give 2-(4-pentyloxybenzamido)-4′-bromoacetophenone (2.49 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:11](=[O:22])[C:12]2[C:17]([C:18](=[O:21])[C:19]=1[Cl:20])=[CH:16][CH:15]=[CH:14][CH:13]=2>C(O)C>[Cl:20][C:19]1[C:18](=[O:21])[C:17]2[C:12]([C:11](=[O:22])[C:10]=1[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)=[CH:13][CH:14]=[CH:15][CH:16]=2
Reactant: Cc1ccc(N)cc1
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Solvent: CCO
Product: Cc1ccc(NC2=C(Cl)C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C

Procedure:
p-Toluidin (1.4 g, 13.2 mmol) was added to the solution of 2,3-dichloro-1,4-naphthoquinone (1.0 g, 4.4 mmol) in ethanol (300 ml). The reaction mixture was allowed to stir at room temperature for over night. The precipitated product was filtered off and washed with cold ethanol. The product was purified by recrystallization with ethanol/CHCl3 (1:5) to afford the fine reddish needles. Yield: 0.642 g (53.8%), Mp: 295° C.
Reaction SMILES: [S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[CH:3]=[CH:2]1.C(N(CC)CC)C.[C:18]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:22][C:21]([C:24](Cl)=[O:25])=[CH:20][CH:19]=1.ClCl>>[C:18]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:19]=[CH:20][C:21]([C:24]([N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]3[S:1][CH:2]=[CH:3][C:4]2=3)=[O:25])=[CH:22][CH:23]=1
Reactant: c1cc2c(s1)CCCCN2
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: ClCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(-c2ccccc2)cc1)N1CCCCc2sccc21

Procedure:
As described for Example 1, a solution of 2 mmol of 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine, 5 mmol of triethylamine and 2.1 mmol of [1,1'-biphenyl]-4-carbonyl chloride in 10 ml of CH2 Cl2 is stirred at room temperature for 16 hours to give the product as a solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[C:10]([S:14][C:15](=[O:20])[CH2:16][C:17](=[O:19])[CH3:18])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([S:14][C:15](=[O:20])[CH:16]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1)[C:17](=[O:19])[CH3:18])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(=O)CC(=O)SC(C)(C)C
Reactant: Fc1ccc(CBr)cc1
Product: CC(=O)C(Cc1ccc(F)cc1)C(=O)SC(C)(C)C

Procedure:
The title compound was prepared by the method of Preparation 34a using 1-bromomethyl-4-fluorobenzene and 3-oxothiobutyric acid S-tert-butyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:16]=[C:15]([CH2:17][C:18]([NH:20][C@H:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:19])[CH:14]=[CH:13][C:5]=1[C:6]([O:8]C(C)(C)C)=[O:7])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:16]=[C:15]([CH2:17][C:18]([NH:20][C@H:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:19])[CH:14]=[CH:13][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOc1cc(CC(=O)N[C@@H](CC(C)C)c2ccccc2N2CCCCC2)ccc1C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCOc1cc(CC(=O)N[C@@H](CC(C)C)c2ccccc2N2CCCCC2)ccc1C(=O)O

Procedure:
102 mg (0.20 mMol) of tert.butyl (S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoate (melting point: 122-123° C.; [α]D20 =+8.7°; c=1 in methanol) are refluxed in 5 ml of benzene together with a few crystals of p-toluenesulphonic acid hydrate, for half a day. The desired product is then obtained, according to thin layer chromatography, according to the Rf value and mass spectrum.
Reaction SMILES: [OH:1][C:2]([CH3:23])([CH3:22])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14](SC)=[N:13][C:12]2=[O:19])=[CH:7][C:6]=1[O:20][CH3:21].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][OH:32])=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1.C(Cl)Cl>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][O:32][C:14]2[CH:15]=[CH:16][N:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][C:2]([OH:1])([CH3:23])[CH3:22])=[C:6]([O:20][CH3:21])[CH:7]=3)[C:12](=[O:19])[N:13]=2)=[CH:27][CH:26]=1
Reactant: COc1cc(-n2ccc(SC)nc2=O)ccc1OCC(C)(C)O
Reactant: OCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: COc1cc(-n2ccc(OCc3ccc(Cl)cc3)nc2=O)ccc1OCC(C)(C)O
Temperature: 145 °C

Procedure:
A stirred mixture of 1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)-4-(methylthio)pyrimidin-2(1H)-one Part C of Procedure 1 (10 mg, 0.03 mmol), (4-chlorophenyl)methanol (85 mg, 0.6 mmol) and K2CO3 (12 mg, 0.09 mmol) in NMP (0.1 mL) was heated at 145° C. for 60 min, diluted with CH2Cl2, washed with water, dried (MgSO4), and concentrated. The residue was purified by flash chromatography (silica gel/hexane-EtOAc 100:0:0 to 0:100 gradient) to afford the title compound 4-(4-chlorobenzyloxy)-1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrimidin-2(1H)-one A-8 (5 mg, 36% yield) as a white solid. LC/MS 431 (M+H)+, tR 0.9 min (method 5); 1H NMR (400 MHz, chloroform-D) δ 7.53 (1H, d, J=7.03 Hz), 7.40 (2H, d, J=8.53 Hz), 7.37 (2H, d, J=8.78 Hz), 6.96 (1H, d, J=8.53 Hz), 6.91 (1H, d, J=2.26 Hz), 6.85 (1H, dd, J=8.53, 2.51 Hz), 6.00 (1H, d, J=7.03 Hz), 5.45 (2H, s), 3.86 (3H, s), 3.85 (2H, s), 1.35 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=O)[C:6]3([F:16])[CH2:13][CH2:14][CH2:15][CH:5]3[C:4]=2[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1COCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[S:26])[C:6]3([F:16])[CH2:13][CH2:14][CH2:15][CH:5]3[C:4]=2[CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1Nc2ccc(Cl)cc2C2CCCC12F
Solvent: C1CCOC1
Product: FC12CCCC1c1cc(Cl)ccc1NC2=S

Procedure:
A solution of 0.83 g (3.5 mmol) of 8-chloro-3a-fluoro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one in 100 ml of THF is refluxed with 2.86 g (7.1 mmol) of Lawesson's reagent for 1.5 hours. Then, the reaction mixture is concentrated by evaporation, and the residue is purified by column chromatography on silica gel with hexane-ethyl acetate: 0.86 g of product.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=[C:5]([CH2:17][CH3:18])[C:4]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][C:27]2[CH:40]=[CH:39][C:30]3[C@H:31]([CH2:34][C:35]([O:37]C)=[O:36])[CH2:32][O:33][C:29]=3[CH:28]=2)[CH:20]=1)[CH3:2].CO.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.O1CCCC1>[CH2:17]([C:5]1[CH:6]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][C:27]2[CH:40]=[CH:39][C:30]3[C@H:31]([CH2:34][C:35]([OH:37])=[O:36])[CH2:32][O:33][C:29]=3[CH:28]=2)[CH:20]=1)[CH3:18]
Reactant: CCc1cc(OCCCS(C)(=O)=O)cc(CC)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)OC)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(OCCCS(C)(=O)=O)cc(CC)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 81.3 %

Procedure:
To a solution of methyl [(3S)-6-({2′,6′-diethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetate (0.521 g, 0.919 mmol) in a mixed solvent of methanol (2 mL) and tetrahydrofuran (4 mL) was added 2 M aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at 50° C. for 1.5 hr. The reaction mixture was diluted with water, acidified with 10% aqueous citric acid solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitated crystals were recrystallized from heptane-ethyl acetate to give the title compound (0.413 g, yield 81%) as colorless crystals.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:5]([OH:7])=[O:6])[CH3:4].[CH2:8](O)[CH3:9]>>[ClH:1].[CH2:8]([O:6][C:5](=[O:7])[C@H:3]([CH3:4])[NH2:2])[CH3:9]
Reactant: CCO
Reactant: C[C@H](N)C(=O)O
Agent: Cl
Product: CCOC(=O)[C@H](C)N

Procedure:
Hydrogen chloride gas was bubbled into a suspension of L-alanine (1) (100 g, 1.12 mol) in dry ethanol (800 ml) and the solution was refluxed for 2 hours. After concentration in vacuo the compound was recrystallised from ethanol-diethyl ether giving the title ester (2) (168.2g, 98%) as a white solid. δH (200 MHz; D2O) 1.11 (3H, t, J=7.1, CH2 CH3), 1.37 (3H, d, J=7.4, CHCH3), 4.03 (1H, q, J=7.2, CHCH3), 4.09 (2H, q, J=7.2, CH2CH3), 4.16 (2H, s, NH2); δC (125 MHz; D2O) 13.98 (CH3), 15.90 (CH3), 49.65 (CH), 64.29 (CH2), 171.57 (CO).
Reaction SMILES: I[C:2]1[C:3](=[O:21])[N:4]([CH3:20])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCCC1.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>[CH3:20][N:4]1[C:3](=[O:21])[C:2]([C:24]2[CH:25]=[CH:26][S:22][CH:23]=2)=[C:7]([CH3:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:5]1=[O:19]
Reactant: Cc1c(I)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)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: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(-c2ccsc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Yield: 50.9 %

Procedure:
To a solution of 5-iodo-3,6-dimethyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 60) (60.0 mg), 2-thiophen boronic acid (84.6 mg), sodium carbonate (84.6 mg) in tetrahydrofuran (2.0 ml)/water (0.3 ml) was added tetrakis(triphenylphosphine)palladium (25.2 mg) and the resulting mixture was stirred with heating under reflux for five hours. The reaction mixture was filtered through Celite (trade mark) and thereto was added water (10 ml), and the resulting mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) and further purified by silica gel column chromatography (eluent: chloroform/methanol) to afford 3,6-dimethyl-5-(thiophen-3-yl)-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (27.3 mg).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[C:16]([C:19]1[N:20]=[C:21]([CH3:27])[N:22]2[CH:26]=[CH:25][S:24][C:23]=12)(=[O:18])[CH3:17].C([Li])CCC.CCCCCC.[CH2:39]([Sn:43](Cl)([CH2:48][CH2:49][CH2:50][CH3:51])[CH2:44][CH2:45][CH2:46][CH3:47])[CH2:40][CH2:41][CH3:42].[Cl-].[NH4+]>C1COCC1>[C:16]([C:19]1[N:20]=[C:21]([CH3:27])[N:22]2[CH:26]=[C:25]([Sn:43]([CH2:44][CH2:45][CH2:46][CH3:47])([CH2:48][CH2:49][CH2:50][CH3:51])[CH2:39][CH2:40][CH2:41][CH3:42])[S:24][C:23]=12)(=[O:18])[CH3:17]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(=O)c1nc(C)n2ccsc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2c(C)nc(C(C)=O)c2s1
Reaction time: 0.83 h

Procedure:
A 1.0 N lithiumbis(trimethylsilyl)amide/THF solution (3.75 ml) was added dropwise to a solution of 613 mg of 7-acetyl-5-methylimidazo[5,1-b]thiazole in 34 ml of THF in an argon atmosphere at −73° C. The mixture was stirred at the same temperature for 50 min. A 1.59 N n-butyllithium/n-hexane solution (4.71 ml) was added dropwise thereto. The mixture was stirred at the same temperature for 50 min. Tri-n-butylstannyl chloride (1.16 ml) was added dropwise thereto. The mixture was further stirred at the same temperature for 40 min. An ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate and washing with brine. The extract was dried over anhydrous magnesium sulfate and then filtered. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to give 1.40 g of the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7]4=[C:8]([C:17](=[O:20])[NH:18][N:19]=[C:6]4[C:5]=2[CH:4]=1)[CH:9]=[CH:10][CH:11]=3.[P:21]([O-])([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>CN(C=O)C>[O:20]=[C:17]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[O:13][C:14]4[CH:15]=[CH:16][C:3]([CH2:2][O:1][P:21](=[O:22])([O:31][CH2:32][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[O:23][CH2:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[CH:4][C:5]=4[C:6]([C:7]=23)=[N:19][NH:18]1
Reactant: O=P([O-])(OCc1ccccc1)OCc1ccccc1
Reactant: O=c1[nH]nc2c3c(cccc13)Oc1ccc(CO)cc1-2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=c1[nH]nc2c3c(cccc13)Oc1ccc(COP(=O)(OCc3ccccc3)OCc3ccccc3)cc1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
To a solution of compound 57 (0.25 mmol) in anhydrous DMF was added dibenzyl phosphate (0.80 mmol) and triphenylphosphine (0.80 mmol). The reaction mixture was stirred while diisopropyl azodicarboxylate was added slowly. The reaction mixture was stirred at room temperature for 3 hours. Solvent was removed in vacuo. To the residue, 100 mL of ethyl acetate was added. The organic layer was washed with water and brine, then dried with MgSO4. The Solvents were removed to afford a yellow oil. The oil was re-crystallized in EtOAc/Hexanes to afford an off-white solid 60 in 40% yield. MS (ES+): 527; Mp: 223-225° C.; 1H-NMR (CDCl3, 400 MHz): 9.91 (s, 1H), 8.13 (d, J=2.0 Hz, 1H), 8.11 (dd, J=8.0 and 1.0 Hz, 1H), 7.85 (t, J=8.0 Hz, 1H), 7.59 (dd, J=8.0 and 1.0 Hz, 1H), 7.45 (dd, J=8.5 and 1.0 Hz, 1H), 7.36-7.26 (m, 11H), 5.08 (m, 6H). Anal. Calcd. for C29H23N2O6P.(0.15hydrazine): C, 65.56; H, 4.48; N, 6.06. Found: C, 65.55; H, 4.33; N, 6.09.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.ClC1C=C(C=CC=1)N>O>[N:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([OH:10])=[O:9])[CH:2]=1
Reactant: O=C(O)c1cccnc1Cl
Solvent: O
Solvent: Nc1cccc(Cl)c1
Product: O=C(O)c1cccnc1
Reaction time: 1 h
Yield: 188.5 %

Procedure:
A mixture of 2-chloro-3-pyridinecarboxylic acid (78.75 g, 0.500 mol), 3-chloroaniline (127.6 g, 1.00 mol), paratoluenesulfonic acid. H2O (8.5 g, 45 mmol), and H2O (500 mL) was refluxed 4 hrs. The solids dissolved, and after 1 hr, the solution gave a precipitate. The cooled mixture was filtered, and the collected yellow solid was washed with cold H2O and was dried (60°) to give 2-[3-chlorophenyl)amino]-3-pyridinecarboxylic acid (116.0 g, 93.3%), mp 197°-199° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[NH2:8].[C:15]1([CH3:24])[C:16]([N:21]=[C:22]=S)=[CH:17][CH:18]=[CH:19][CH:20]=1.C(N=C=NC(C)C)(C)C>C(O)C>[C:15]1([CH3:24])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]1[NH:1][C:2]2[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=2[N:8]=1
Reactant: CCOC(=O)Cc1ccc(N)c(N)c1
Reactant: Cc1ccccc1N=C=S
Agent: CC(C)N=C=NC(C)C
Solvent: CCO
Product: CCOC(=O)Cc1ccc2nc(Nc3ccccc3C)[nH]c2c1

Procedure:
A mixture of ethyl 3,4-diaminophenylacetate (5.8 g, prepared according to the procedure of Mederski et al, Bioorg Med Chem Left, 1998, 8, pages 17-22) and o-tolylisothiocyanate (4.9 g) in ethanol (100 mL) was kept at room temperature overnight then treated with diisopropylcarbodiimide (7.6 g). The mixture was stirred at reflux for 5 hours then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of 10% methanol and ether (1:9, v/v) to give the title compound (5.2 g) as a yellow gum.
Reaction SMILES: [C:1]([OH:6])(=O)[C@@H:2]([CH3:4])[OH:3].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.[CH2:37]([N:41]1[C:49]([N:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)=[N:48][C:47]2[C:42]1=[N:43][C:44]([C:62]1[CH:63]=[N:64][C:65]([NH2:68])=[N:66][CH:67]=1)=[N:45][C:46]=2[N:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1)[CH:38]([CH3:40])[CH3:39]>C(Cl)Cl.CO.CN(C)C=O>[NH2:68][C:65]1[N:64]=[CH:63][C:62]([C:44]2[N:43]=[C:42]3[C:47]([N:48]=[C:49]([N:50]4[CH2:51][CH2:52][N:53]([C:1](=[O:6])[C@H:2]([OH:3])[CH3:4])[CH2:54][CH2:55]4)[N:41]3[CH2:37][CH:38]([CH3:40])[CH3:39])=[C:46]([N:56]3[CH2:61][CH2:60][O:59][CH2:58][CH2:57]3)[N:45]=2)=[CH:67][N:66]=1
Reactant: CC(C)Cn1c(N2CCNCC2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reactant: C[C@@H](O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: CC(C)Cn1c(N2CCN(C(=O)[C@@H](C)O)CC2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reaction time: 96 h
Yield: 73.4 %

Procedure:
D-Lactic acid (26.3 mg, 0.29 mmol), 1-hydroxybenzotriazole monohydrate (37.2 mg, 0.24 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (69.8 mg, 0.36 mmol), and triethylamine (50.8 μl, 0.36 mmol) were added to an N,N-dimethylformamide suspension (2.0 ml) of 5-[9-(isobutyl)-6-morpholin-4-yl-8-piperazin-1-yl-9H-purin-2-yl]pyrimidin-2-amine (106.5 mg, 0.24 mmol) at room temperature. The resulting mixture was stirred for 4 days and then the reaction mixture was poured into methylene chloride-methanol (10:1), washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by preparative thin layer silica gel chromatography (methylene chloride:methanol=10:1) to give the title compound (89.9 mg, 73%) as a pale yellow solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:13][CH:12]=1)C.[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.O>[C:17]1([C:14]2[N:13]=[CH:12][C:11]([CH2:10][OH:9])=[CH:16][CH:15]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1ccc(-c2ccccc2)nc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.3 %

Procedure:
Lithium aluminum hydride (3.50 g) was suspended in tetrahydrofuran (200 mL), 6-phenylnicotinic acid ethyl ester (21.0 g) synthesized in Reference Example 19 was added under ice-cooling, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was ice-cooled, water (5 mL) and aqueous sodium hydroxide solution (1 mol/L, 10 mL) were successively added dropwise. After warming to room temperature, the mixture was stirred for 1 hr. Anhydrous sodium sulfate was added to the reaction mixture, the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 1:3) to give the title compound (17.0 g) as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[CH:24]=[CH:23][CH:22]=[CH:21][C:9]=1[NH:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1>[Pd].C(O)(=O)C>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][C:8]1[CH:24]=[CH:23][CH:22]=[CH:21][C:9]=1[NH:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2Cc2ccccn2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc(C(=O)Nc2ccccc2CC2CCCCN2)cc1

Procedure:
Reduction of 2'-(2-pyridylmethyl)-p-anisanilide (4.65 g., 0.0146 mole) according to the procedure of Walker, J. Org. Chem., 27, 2966 (1962), in 150 ml. of acetic acid with 2.35 g. of 10% palladium on carbon catalyst affords 2'-(2-piperidylmethyl)-p-anisanilide, m.p. 108°-109°C. (corr.), from benzene-hexane.
Reaction SMILES: Cl[C:2]1[C:12](Cl)=[CH:11][C:5]2[O:6][C:7]([F:10])([F:9])[O:8][C:4]=2[C:3]=1[N+:14]([O-])=O.C(=O)([O-])[O-].[K+].[K+].[H][H]>CO.[C].[Pd]>[NH2:14][C:3]1[C:4]2[O:8][C:7]([F:10])([F:9])[O:6][C:5]=2[CH:11]=[CH:12][CH:2]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1c(Cl)c(Cl)cc2c1OC(F)(F)O2
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Nc1cccc2c1OC(F)(F)O2

Procedure:
68 g (250 mmol) of 5,6-dichloro-4-nitro-2,2-difluoro-benzo(1.3)dioxole, 69 g (500 mmol) of potassium carbonate and 5 g of palladium-carbon (10% strength) are stirred at 50° C. and a hydrogen pressure of 90 bar in 500 ml of methanol in an autoclave for 20 hours. The reaction mixture is filtered, the filtrate is mixed with 500 ml of water and extracted thoroughly with ether, the extract is dried over sodium sulphate and the ether is removed in a rotary evaporator. By distillation, 35 g (81% of theory) of 4-amino-2,2-difluoro-benzo(1.3)dioxole are obtained having a boiling point of 84° to 86° C./16 mm and a refractive index of nD21 : 1.4995.