Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]([C:14]#[N:15])=[N:8][C:7]2[N:6]=[C:5]([C:16]3[CH:17]=[N:18][N:19]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)[CH:20]=3)[NH:4][C:3]1=2.[OH-].[Na+].C([OH:36])C.O>C(Cl)Cl>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]([C:14]([NH2:15])=[O:36])=[N:8][C:7]2[N:6]=[C:5]([C:16]3[CH:17]=[N:18][N:19]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)[CH:20]=3)[NH:4][C:3]1=2
Reactant: CCCn1c(C#N)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCCn1c(C(N)=O)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Temperature: 50 °C
Reaction time: 18 h
Yield: 78 %

Procedure:
A mixture of 6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purine-2-carbonitrile (40 mg, 0.0934 mmol), NaOH (6 mg, 0.140 mmol) and Ethanol:water (3:1) (2 ml) were stirred at 50° C. for 18 hours. Reaction mixture was cooled and organic volatiles were evaporated and the residue obtained was dissolved in DCM (10 ml) and washed with brine (10 ml). Organic layer was dried over Na2SO4 and evaporated to obtain pure 6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purine-2-carboxylic acid amide (32 mg, 78%) as an off white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:11])[CH2:9][OH:10])=[CH:4][CH:3]=1.[C:12](N1C=CN=C1)(N1C=CN=C1)=[O:13]>C(#N)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][O:10][C:12](=[O:13])[O:11]2)=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OCC(O)c1ccc(Br)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C1OCC(c2ccc(Br)cc2)O1
Temperature: 40 °C
Yield: 56.6 %

Procedure:
1-(4-bromophenyl)ethane-1,2-diol (0.15 g, 0.69 mmol) was dissolved in 7 mls of dry acetonitrile, followed by the addition of carbonyldiimidazole (0.17 g, 1.04 mmol). This mixture was warmed to 40° C. for 1.5 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with saturated ammonium chloride solution, water, dried over sodium sulfate and concentrated under reduced pressure. 10 g Sep Pak purification (1:1 EtOAc:Hexanes) afforded 0.095 g of 4-(4-bromophenyl)-1,3-dioxolan-2-one (57%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH:18]([CH2:23][CH:24]=[CH2:25])[C:19]([O:21][CH3:22])=[O:20])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O.ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([NH:17][CH:18]([CH2:23][CH:24]3[O:35][CH2:25]3)[C:19]([O:21][CH3:22])=[O:20])(=[O:16])=[O:15])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCC(NS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1)C(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Reaction time: 72 h

Procedure:
To a solution of methyl 2-[(4′-chloro[1,1′-biphenyl]-4-yl)-sulfonylamino]-pent-4-eneoate 12c (9.2 g, 24.1 mmol) in CH2Cl2 (175 mL), NaHCO3 (4.2 g, 50 mmol) and water (100 mL) at 0 C., is slowly added m-chloroperbenzoic acid (57-86%) (19.4 g, ˜80 mmol). The reaction is stirred for 72 hours. The mixture is diluted with aqueous NaHCO3 and this mixture is extracted with ethyl acetate (3×100 mL). The combined ethyl acetate layer is washed with brine, dried over MgSO4, filtered and concentrated to an oil. Purification of this compound is accomplished by column chromatography with 40% ethyl acetate in hexanes as the eluent to give the desired product.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([C:13]3([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1B(O)O>>[CH3:19][C:13]1([C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:21]4[S:20][CH:24]=[CH:23][CH:22]=4)[N:3]=3)[NH:8][CH:9]=2)=[O:12])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: OB(O)c1cccs1
Reactant: CC1(C(=O)c2c[nH]c3ncc(Br)nc23)CCCCC1
Product: CC1(C(=O)c2c[nH]c3ncc(-c4cccs4)nc23)CCCCC1

Procedure:
(1-Methyl-cyclohexyl)-(2-thiophen-2-yl-5H-pyrrolo[2,3-b]pyrazin-7-yl)-methanone was prepared starting from (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1-methyl-cyclohexyl)-methanone and thiophene-2-boronic acid following general procedures described in these Examples. MP 224-225° C., M+H=326.
Reaction SMILES: C(O[CH2:4][CH2:5][CH2:6][CH2:7][O:8]C=C)=C.C#C.[C:13]1(=O)[NH:19][CH2:18][CH2:17]CC[CH2:14]1>>[CH:18]([N:19]1[CH2:13][CH2:14][CH2:4][CH2:5][CH2:6][C:7]1=[O:8])=[CH2:17]
Reactant: O=C1CCCCCN1
Reactant: C=COCCCCOC=C
Agent: C#C
Product: C=CN1CCCCCC1=O
Yield: 85 %

Procedure:
Example 3 was carried out by adding 1% by weight of 1,4-divinyloxybutane as cocatalyst. The amount of ethyne taken up was 0.97 mol per mole of ε-caprolactam. The distillative workup yielded N-vinyl-ε-caprolactam in a yield of 85.0%. A liquid distillation residue was obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1([OH:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].I[CH:26]([CH2:28][CH3:29])[CH3:27]>C(#N)C>[CH:26]([N:15]1[CH2:16][CH2:17][C:12]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:10])([F:11])[F:9])[C:2]=2[F:1])([OH:18])[CH2:13][CH2:14]1)([CH2:28][CH3:29])[CH3:27]
Reactant: CCC(C)I
Reactant: OC1(c2cccc(C(F)(F)F)c2F)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCC(C)N1CCC(O)(c2cccc(C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 2: 4-[2-fluoro-3-(trifluoromethyl)phenyl]piperidin-4-ol (0.02 g, 0.076 mmol), acetonitrile (2 ml), potassium carbonate (0.02 g, 0.14 mmol), 2-iodobutane (0.009 ml, 0.082 mmol). MS m/z (relative intensity, 70.eV) 319 (M+, 2), 290 (72), 191 (28), 177 (14), 56 (bp).
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[CH2:4][CH2:3][C:2]1=[O:12].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[CH2:4][CH2:3][C:2]1=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCC2=C(CCCC2=O)N1
Product: O=C1CCCC2=C1CCC(=O)N2Cc1ccccc1

Procedure:
Prepared analogously to Example H from 3,4,7,8- tetrahydro-2,5(1H,6H)-quinolinedione and benzyl bromide.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C@@H:8]2[CH2:12][CH2:11][CH:10]([OH:13])[O:9]2)=[CH:4][CH:3]=1.N1C=CN=C1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>C(Cl)Cl>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH:8]2[CH2:12][CH2:11][CH:10]([O:13][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[O:9]2)=[CH:4][CH:3]=1
Reactant: OC1CC[C@@H](COc2ccc(F)cc2)O1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCC(COc2ccc(F)cc2)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3.47 g of (2S)-(4-fluorophenoxymethyl)-5-hydroxytetrahydrofuran 7 in 30 mL of CH2Cl2 was taken in an 100 mL round bottom flask equipped with a magnetic stir bar and nitrogen inlet. That solution was cooled in an ice-water bath and 2.18 g (0.032 mol) of imidazole was added, followed by a solution of 3.6 g (0.024 mol) of tert-butyldimethylsilylchloride (TBDMSCl) in 30 mL of CH2Cl2. The reaction mixture then was stirred at room temperature for 3 hours, and the reaction then quenched with ice water, the organic layer separated, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography using light petroleum ether:ethyl acetate (9:1) to yield (2S) (4-fluorophenoxymethyl)-5-(tert-butyldimethylsiloxy)-tetrahydrofuran) 8 as an oil (5.1 g, 95%). 1H NMR (200 MHz, CDCl3): δ0.09 (s, 6H), 0.88 (s, 9H), 1.72-2.34 (m, 4H), 3.76=4.08 (m, 2H), 4.28-4.54 (m, 1H), 5.47. (s, 1/3H), 5.54 (d, J=4.5 Hz, 2/3H), 6.75-7.0 (m, 4H).
Reaction SMILES: [H-].[Na+].[CH:3]1([NH:6][S:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)(=[O:9])=[O:8])[CH2:5][CH2:4]1.Br[CH2:22][C:23]#[N:24].O>CN(C)C=O>[CH:3]1([N:6]([CH2:22][C:23]#[N:24])[S:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=2)(=[O:9])=[O:8])[CH2:5][CH2:4]1
Reactant: O=S(=O)(Cc1cccc(C(F)(F)F)c1)NC1CC1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCN(C1CC1)S(=O)(=O)Cc1cccc(C(F)(F)F)c1
Reaction time: 0.25 h
Yield: 28.3 %

Procedure:
0.26 g of sodium hydride was added portion-wise to a solution containing 2.79 g of N-cyclopropyl-3-trifluoromethylbenzylsulfonamide in 50 ml of dimethylformamide over an ice bath. The mixture was stirred 15 minutes at 0l° C. and then 1.26 g of bromoacetonitrile was added drop-wise with cooling. The mixture was stirred overnight at room temperature. Water was then added resulting in the formation of a precipitate and oil. Addition of water was continued until no further precipitate or oil was formed. (About 150 ml of water was used.) The mix was cooled over an ice bath and then filtered. The filter cake was dissolved in hot cyclohexane and then recrystallized affording 0.9 g of the title compound as a solid m.p. 70.1°-71.0° C.
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[N:21]=[C:20]([S:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=3[F:39])[N:19]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:39][C:33]1[C:34]([F:38])=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][S:30][C:20]1[N:19]=[C:18]([NH:17][S:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)(=[O:15])=[O:16])[CH:23]=[C:22]([O:24][CH2:25][C:26]([F:29])([F:27])[F:28])[N:21]=1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)Nc2cc(OCC(F)(F)F)nc(SCc3cccc(F)c3F)n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1cc(OCC(F)(F)F)nc(SCc2cccc(F)c2F)n1)N1CCNCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-[[[2-[[(2,3-difluorophenyl)methyl]thio)-6-(2,2,2-trifluoroethoxy)-4-pyrimidinyl]amino]sulfonyl]-1-piperazinecarboxylic acid-1,1-dimethylethyl ester (the product from step i) (0.21 g) in DCM (2 mL) was added trifluoroacetic acid (2 mL) and the reaction mixture was stirred at ambient temperature for 4 h. The reaction mixture was evaporated, the residue was azeotroped with Et2O (×2) and then purified by reverse phase HPLC eluting with acetonitrile/aq. 0.2% trifluoroacetic acid mixtures to give title compound as a white solid. Yield: 0.14 g
Reaction SMILES: C(N1C=C(I)C=N1)C1C=CC=CC=1.[C:14]([C:16]1[CH:17]=[N:18][N:19]([CH2:21][C:22]2[CH:27]=[CH:26][C:25](OC)=[CH:24][CH:23]=2)[CH:20]=1)#[CH:15].C[Si](C#C)(C)C>>[CH2:21]([N:19]1[CH:20]=[C:16]([C:14]#[CH:15])[CH:17]=[N:18]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: C#Cc1cnn(Cc2ccc(OC)cc2)c1
Agent: C#C[Si](C)(C)C
Agent: Ic1cnn(Cc2ccccc2)c1
Product: C#Cc1cnn(Cc2ccccc2)c1
Reaction time: 5 h
Yield: 83 %

Procedure:
This compound was prepared from 1-benzyl-4-iodo-1H-pyrazole using a similar procedure to that employed in the preparation of 4-ethynyl-1-(4-methoxy-benzyl)-1H-pyrazole (see a)(ii) above). The reaction time was extended to 5 h and 1.6 equivalents of trimethylsilylacetylene were added. Silica-gel flash chromatography of the crude reaction mixture afforded the product as a white solid (83% yield over two steps).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([N+:32]([O-])=O)[CH2:13][CH2:14][CH2:15][C:16]([C:30]#[N:31])([CH:27]([CH3:29])[CH3:28])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH2:32])[CH2:13][CH2:14][CH2:15][C:16]([C:30]#[N:31])([CH:27]([CH3:29])[CH3:28])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC(CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)[N+](=O)[O-])cc1OC
Solvent: CO
Product: COc1ccc(CC(N)CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
A mixture of 1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane (10, 58.7 g, 0.125 mol) and methanol (950 mL) was added to a flask, and evacuated to remove oxygen. The catalyst, 5% Pd in carbon (50% water, 19 g, Engelhard Co.), was added under an N2 atmosphere. After stirring for 10 minutes at room temperature, solid HCO2NH4 (65 g, Aldrich) was added, and the resulting mixture stirred for 1 hour. The mixture was then slowly heated to 50° C. for 48 hours, then cooled to room temperature and filtered through Celite (50 g). The solids were washed with methanol (50 mL), the filtrates concentrated in vacuo, and the resulting solid dissolved in CH2Cl2. The solution was extracted with saturated aqueous NH4Cl (500 mL) and saturated aqueous NaHCO3 (300 mL), and the organic layer evaporated to yield 1-(3,4-dimethoxyphenyl)-2-amino-6 -cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane (11, 52.3 g, MS m/e 440(M+)) as a pale yellow oil.
Reaction SMILES: [N:1]1([C:6]2([C:10]#[N:11])[CH2:9]O[CH2:7]2)[CH2:5]CC[CH2:2]1.[C:12]1(=O)CCC1.Cl.CNC>>[CH3:5][N:1]([CH3:2])[C:6]1([C:10]#[N:11])[CH2:7][CH2:12][CH2:9]1
Reactant: N#CC1(N2CCCC2)COC1
Reactant: O=C1CCC1
Agent: CNC
Agent: Cl
Product: CN(C)C1(C#N)CCC1

Procedure:
The title compound, colorless liquid, MS: m/e=125.1 [(M+H)+], was prepared in accordance with the general method of intermediate A from cyclobutanone and dimethylamine hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[C:6]=1C(OCC)=O.[OH-].[K+]>C(O)C>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([C:5]2[CH:6]=[C:2]([NH2:1])[S:3][CH:4]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1c(-c2cccc(OC)c2)csc1N
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(-c2csc(N)c2)c1
Temperature: 110 °C
Yield: 49.4 %

Procedure:
A mixture of ethyl 2-amino-4-[3-(methyloxy)phenyl]-3-thiophene carboxylate (Description 39) (5 g, 18.03 mmol) and 20% aqueous solution of potassium hydroxide (100 mL, 18.03 mmol) in ethanol (100 mL) was heated at 110° C. for 24 h. After cooling to RT the ethanol was removed under reduced pressure. The residue was poured into water (100 mL) and extracted with ethyl acetate (50 mL×3). The organic layers were combined, washed with brine (100 mL), dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by chromatography on silica, eluting with a gradient of 0-25% ethyl acetate in cyclohexane, to give the title compound (1.83 g). LCMS (A) m/z: 206 [M+1]+, Rt 1.14 min (acidic).
Reaction SMILES: [F:1][C:2]1[C:3]([C:17]2[S:21][C:20]3[C:22](B4OC(C)(C)C(C)(C)O4)=[CH:23][CH:24]=[CH:25][C:19]=3[CH:18]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])=[N:6][CH:7]=1.[F:35][C:36]1[CH:41]=[C:40](I)[C:39]([CH2:43][F:44])=[CH:38][N:37]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(Cl)(Cl)Cl.C(O)(C)C>[F:1][C:2]1[C:3]([C:17]2[S:21][C:20]3[C:22]([C:40]4[C:39]([CH2:43][F:44])=[CH:38][N:37]=[C:36]([F:35])[CH:41]=4)=[CH:23][CH:24]=[CH:25][C:19]=3[CH:18]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])=[N:6][CH:7]=1
Reactant: CC1(C)OB(c2cccc3cc(-c4nc(NCCN5CCNC5=O)ncc4F)sc23)OC1(C)C
Reactant: FCc1cnc(F)cc1I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: O=C1NCCN1CCNc1ncc(F)c(-c2cc3cccc(-c4cc(F)ncc4CF)c3s2)n1
Temperature: 100 °C
Yield: 58.2 %

Procedure:
Combine 1-(2-{5-fluoro-4-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzo[b]thiophen-2-yl]-pyrimidin-2-ylamino}-ethyl)-imidazolidin-2-one (120 mg, 248.26 μmol), 2-fluoro-5-fluoromethyl-4-iodo-pyridine (100 mg, 392.15 μmol) tris(dibenzylideneacetone)dipalladium (0) (11.37 mg, 12.41 μmol) tricyclohexylphosphine (2.09 mg, 7.45 μmol), potassium phosphate (105.39 mg, 496.51 μmol) in 5 mL of dioxane in a sealed pressure tube. Heat the mixture at 100° C. for 3 hours in the oil bath. LC-MS shows a peak at 485. Cool the reaction mixture down to room temperature and dilute it with chloroform-isopropyl alcohol (3/1). Wash the organic solution with saturated aqueous sodium chloride, dry it over sodium sulfate and concentrate it to crude. Purify the crude by flash chromatography (10% methanol in dichloromethane) to give the target product (70 mg, 58.2%). MS (ES) m/z 485 [M+1]+.
Reaction SMILES: [C:1]1(C)C(C)=CC=CC=1.[CH3:9][C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[O:11]>>[CH3:1][CH2:16][O:15][CH2:14][CH2:13][O:12][C:10]([CH3:9])=[O:11]
Reactant: COCCOC(C)=O
Reactant: Cc1ccccc1C
Product: CCOCCOC(C)=O

Procedure:
When the polyamide-imide resin obtained in this invention is made into a varnish, there may be used as auxiliary solvents xylene, NISSEKI HISOL-100, 150 (trade names, mfd. by Nippon Petrochemicals Co., Ltd., aromatic hydrocarbons obtained from petroleum, b.p. 80°-300° C.), methyl Cellosolve acetate, ethyl Cellosolve acetate, γ-butyrolacetone and the like in combination with the basic organic solvents described above.
Reaction SMILES: [ClH:1].[C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]([CH3:41])[N:14]([C:33]3[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=3)[C:15](=[O:32])[C:16]=2[C:17]([N:19]2[CH2:24][CH2:23][CH:22]([O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:21][CH2:20]2)=[O:18])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[NH4+:46].[NH4+]>C(O)C>[ClH:1].[C:39]([C:36]1[CH:35]=[CH:34][C:33]([N:14]2[C:15](=[O:32])[C:16]([C:17]([N:19]3[CH2:20][CH2:21][CH:22]([O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][CH2:24]3)=[O:18])=[C:12]([C:9]3[CH:8]=[CH:7][C:6]([C:2]([CH3:3])([CH3:4])[CH3:5])=[CH:11][CH:10]=3)[N:13]2[CH3:41])=[CH:38][CH:37]=1)(=[NH:46])[NH2:40]
Reactant: CCOC(=O)COC1CCN(C(=O)c2c(-c3ccc(C(C)(C)C)cc3)n(C)n(-c3ccc(C#N)cc3)c2=O)CC1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)COC1CCN(C(=O)c2c(-c3ccc(C(C)(C)C)cc3)n(C)n(-c3ccc(C(=N)N)cc3)c2=O)CC1

Procedure:
Dry hydrogen chloride was introduced into a mixture of 1.19 g of 3-(4-t-butylphenyl)-4-{[4-(ethoxycarbonylmethyloxy)-1-piperidinyl]carbonyl}-1-(4-cyanophenyl)-2-methyl-2H-pyrazol-5-one and 15 ml of absolute ethanol under cooling with ice for 2 hours, and the mixture was stirred under cooling with ice for another 15 hours. 38.5 g of ammonium carbonate was added to adjust the pH to 7-8, and the reaction solution was stirred at room temperature for 22 hours. The precipitated insolubles were filtered off, and hydrochloric acid in ethanol was added to the mother liquor to adjust the pH to 3. The precipitated crystals were filtered off, and the mother liquor was concentrated under reduced pressure. The residue was purified by C-18 reverse phase silica gel chromatography (water/methanol=2:1). The resulting crude crystals were recrystallized in methanol-chloroform-ethyl acetate to give 543 mg of the title compound as colorless crystals.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([N:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([NH:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[N:26]=2)=[CH:21][C:20]1=[O:38])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C@H:10]([N:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][CH:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[N:26]=3)=[CH:21][C:20]2=[O:38])[CH2:9][OH:8])=[CH:12][C:13]=1[F:18]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(Cl)c(F)c1)n1ccc(-c2ccnc(NC3CCOCC3)n2)cc1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=c1cc(-c2ccnc(NC3CCOCC3)n2)ccn1[C@H](CO)c1ccc(Cl)c(F)c1

Procedure:
A solution of (S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one (6.00 g, 10.7 mmol) in THF (20 mL) was treated with tetrabutyl ammonium fluoride (12.9 mL, 12.9 mmol) at room temperature for 30 minutes. The reaction mixture was concentrated, and the residue was taken up with ethyl acetate and water. The organic layer was washed with water (1×). The combined organics were dried, filtered and concentrated. The crude product was purified via column chromatography, eluting with ethyl acetate to give (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((tetrahydro-2H-pyran-4-ylamino))pyrimidin-4-yl)pyridin-2(1H)-one as a solid (4.14 g, 87%; 96% enantiomeric excess (“e.e.”) by chiral HPLC (Chiral Tech, column OJ-H, 4.6 mm×250 mm, 5 u, 30% ethanol/70% hexanes, 1 mL/minute)). 1H NMR (400 MHz, CDCl3) δ 8.38 (d, J=5.0 Hz, 1H), 7.40 (m, 2H), 7.20 (m, 2H), 7.10 (d, J=8.2 Hz, 1H), 6.88 (d, J=5.0 Hz, 1H), 6.78 (m, 1H), 6.20 (m, 1H), 5.16 (d, J=8.0 Hz, 1H), 4.31 (m, 2H), 4.10 (m, 1H), 4.00 (m, 2H), 3.55 (m, 2H), 2.74 (br, s, 1H), 2.06 (m, 2H), 1.58 (m, 2H); m/z (APCI-pos) M+1=445.1, 447.0.
Reaction SMILES: [C:1]([NH:20][C@H:21]([C:25]([O:27][CH2:28][CH:29]([CH2:32][CH:33]=[CH2:34])[CH2:30][OH:31])=[O:26])[CH:22]([CH3:24])[CH3:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:41](Cl)(=[O:59])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58]>ClCCl>[C:1]([NH:20][C@H:21]([C:25]([O:27][CH2:28][CH:29]([CH2:32][CH:33]=[CH2:34])[CH:30]([C:41](=[O:59])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[OH:31])=[O:26])[CH:22]([CH3:24])[CH3:23])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCC(CO)COC(=O)[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)C
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCC(COC(=O)[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)C)C(O)C(=O)CCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-O-(N-trityl-L-valyl)-2-allyl-1,3-propandiol (1.83 g, 4 mmol) in dichloromethane (40 ml) and pyridine (3.2 ml, 40 mmol) at 0° C. was added dropwise stearoyl chloride (3.62 g, 12 mmol) in dichloromethane. The solution was warmed up to room temperature, and kept for 3 hr. It was then washed with sodium hydrogen carbonate aqueous solution and dried. The product was isolated by silica gel column chromatography. 1.9 g
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][CH2:13][CH2:14][CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:23]=[CH:24][C:25]3[S:30][CH2:29][C:28](=[O:31])[NH:27][C:26]=3[CH:32]=2)[CH2:17]1>>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH:12][CH2:13][CH2:14][CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:23]=[CH:24][C:25]3[S:30][CH2:29][C:28](=[O:31])[NH:27][C:26]=3[CH:32]=2)[CH2:17]1)=[O:6]
Reactant: NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Product: Nc1ccc(Cl)cc1C(=O)NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Yield: 73 %

Procedure:
Starting from 2-amino-5-chlorobenzoic acid and 6-[(R)-5-(3-amino-propyl)-2-oxo-oxazolidin-3-yl]-4H-benzo[1,4]thiazin-3-one (described in WO 2010/041219) and using Procedure D, the title compound was obtained as a beige solid (158 mg; 73% yield).