Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)O[C:6](=O)[CH2:5][C:4](=O)[O:3]1.C(OC)(OC)OC.[Cl:18][C:19]1[CH:25]=[C:24]([CH3:26])[C:22]([NH2:23])=[CH:21][CH:20]=1.O>CN(C=O)C>[Cl:18][C:19]1[CH:20]=[C:21]2[C:22](=[C:24]([CH3:26])[CH:25]=1)[N:23]=[CH:6][CH:5]=[C:4]2[OH:3]
Reactant: Cc1cc(Cl)ccc1N
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: CN(C)C=O
Solvent: COC(OC)OC
Solvent: O
Product: Cc1cc(Cl)cc2c(O)ccnc12
Temperature: 25 °C

Procedure:
A solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (1.58 g, 11.0 mmol) in trimethyl orthoformate (10 mL, 90 mmol) was refluxed for one hour. The mixture was cooled slightly, then a solution of 4-chloro-6-methylaniline (1.4 g, 10 mmol) in DMF (10 mL) was added. The mixture was refluxed for 2 hours then cooled to room temperature. The mixture was poured into cold water (150 mL) then extracted with EtOAc. The organic phase was washed with water then saturated NaCl (aq), dried over Na2SO4, filtered, then concentrated. The resulting light yellow, crystalline solid was used directly for the following step. LC4: 2.14 min. (M+H) 296.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]([CH2:24][CH2:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[C:22]#[N:23])[CH:17]=[CH:18][C:19]=1[Cl:20].[CH2:33]([O:35][C:36](=[O:39])[CH2:37]Br)[CH3:34]>O1CCCC1.O>[C:22]([C:21]([C:16]1[CH:17]=[CH:18][C:19]([Cl:20])=[C:14]([Cl:13])[CH:15]=1)([CH2:24][CH2:25][O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[CH2:37][C:36]([O:35][CH2:33][CH3:34])=[O:39])#[N:23]
Reactant: N#CC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)CBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: CCOC(=O)CC(C#N)(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of diisopropylamine (25.9 ml, 1 mol. equiv.) in tetrahydrofuran (200 ml) at −78° C. under nitrogen was added n-butyllithium (73.9 ml of a 2.5M solution, 1 mol. equiv.). The solution was allowed to warm to room temperature over two hours. A solution of 2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butanenitrile (PREPARATION 17) (58 g, 158 mmol) in tetrahydrofuran (200 ml) was then added and the solution was stirred for one hour. A solution of ethyl-2-bromoacetate (20.5 ml, 1 mol. equiv.) in tetrahydrofuran (50 ml) was then added and the reaction was heated to reflux for two hours. Water (10 ml) was then added and the solution was concentrated under reduced pressure. Water (300 ml) and brine (300 ml) were added and the mixture was extracted with ethyl acetate (2×300 ml). The combined organic layers were washed with water (2×300 ml), dried over anhydrous magnesium sulphate, filtered and the solvent was removed under reduced pressure. Chromatography using silica gel, eluting with diethyl ether:hexane using gradient elution (4:1 to 1:1 by volume), gave the title compound.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:12][CH:13]=[CH:14][N:15]=2)=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:31][CH2:32][C:33]1[C:34]([CH3:39])=[N:35][NH:36][C:37]=1[CH3:38]>C(#N)C>[CH3:39][C:34]1[C:33]([CH2:32][CH2:31][N:19]2[CH2:18][CH2:17][N:16]([C:11]3[C:10]([C:7]4[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=4)=[N:15][CH:14]=[CH:13][N:12]=3)[CH2:21][CH2:20]2)=[C:37]([CH3:38])[NH:36][N:35]=1
Reactant: Cc1n[nH]c(C)c1CCBr
Reactant: Fc1ccc(-c2nccnc2N2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: Cc1n[nH]c(C)c1CCN1CCN(c2nccnc2-c2ccc(F)cc2)CC1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
Dissolve 3′-(4-fluoro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl dihydrochloride (0.200 g, 0.604 mmol) in acetonitrile (12 mL). Add potassium carbonate (0.334 g, 2.415 mmol), potassium iodide (0.005 g, 0.030 mmol), and 4-(2-bromo-ethyl)-3,5-dimethyl-1H-pyrazole (0.135 g, 0.664 mmol). Heat reaction at reflux for 14 hr. under nitrogen. Cool to room temperature and filter over celite. Concentrate filtrate in vacuo and purify residue by flash chromatography eluting with DCM:acetone 6:4 to afford the freebase as a mixture. Purify by reverse phase chromatography (43 g C-18, CH3CN: 1% aqueous TFA 5 to 95% over 20 min.) to afford a mixture. Purify by flash chromatography eluting with chloroform:methanol 0-10% to afford 4-[2-(3,5-dimethyl-1H-pyrazol-4-yl)-ethyl]-3′-(4-fluoro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.150 mg). Dissolve the free base (0.150 g, 0.394 mmol) in acetonitrile (1 mL) and add aqueous 1N HCl (0.433 mL, 0.433 mmol). Stir for 1 h at room temperature. Remove organics and lyophilize to afford the title compound (0.144 g, 77% yield). MS (m/z)=381 [M+H]+.
Reaction SMILES: Cl.[NH2:2][OH:3].C[O-].[Na+].[Cl:7][C:8]1[S:32][C:11]2[NH:12][C:13]([C:15]([NH:17][CH:18]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH2:28][C:29]#[N:30])[C:19]3=[O:31])=[O:16])=[CH:14][C:10]=2[CH:9]=1>CO.C1COCC1.CCOC(C)=O>[NH2:30]/[C:29](=[N:2]\[OH:3])/[CH2:28][N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:27][CH:18]([NH:17][C:15]([C:13]2[NH:12][C:11]3[S:32][C:8]([Cl:7])=[CH:9][C:10]=3[CH:14]=2)=[O:16])[C:19]1=[O:31]
Reactant: NO
Reactant: N#CCN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N/C(CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21)=N\O
Reaction time: 18 h
Yield: 101.2 %

Procedure:
Hydroxylamine hydrochloride (181 mg, 2.60 mmol) in MeOH (5 mL) was added to a solution of NaOMe in MeOH (10.20 mL, 0.25M) under an inert atmosphere followed by 2-chloro-N-[1-(cyanomethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide (Example 27; 500 mg, 1.30 mmol) in THF (7 mL) then stirred for 18 hours. The mixture was diluted with EtOAc (100 mL) and washed with brine (25 mL), dried (Na2SO4), filtered and evaporated to afford the title product (550 mg, 100%) as a pale brown solid.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].C(N(C(C)C)C(C)C)C.[C:14]([O:18][C:19]([N:21]([CH3:33])[C@@H:22]([CH2:26][S:27][S:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:23]([OH:25])=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15].[Cl-].[NH4+]>CN(C)C=O>[C:14]([O:18][C:19]([N:21]([CH3:33])[C@@H:22]([CH2:26][S:27][S:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:23]([O:25][CH2:2][C:3]#[N:4])=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: N#CCBr
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CSSC(C)(C)C)C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)[C@@H](CSSC(C)(C)C)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
2-Bromoacetonitrile (0.200 ml, 2.87 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.183 ml, 1.05 mmol) were added to a solution of (R)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(tert-butyldisulfanyl)propanoic acid (Compound 2K-B) (309 mg, 0.955 mmol) in N,N-dimethylformamide (2.5 ml), and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution (3 ml) was added to the reaction mixture, after which the mixture was extracted with ethyl acetate and the organic layer was washed with water. The organic extract was then dried over magnesium sulfate. Following concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→70/30) to afford (R)-cyanomethyl 2-((tert-butoxycarbonyl)(methyl)amino)-3-(tert-butyldisulfanyl)propanoate (Compound 21-B) (272 mg, 78%).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11](=[O:54])[CH2:12][C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH:38]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[C:39]([CH3:42])([CH3:41])[CH3:40])=[C:32]([CH3:51])[CH:31]=3)([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:21][C:20]=2[CH3:52])[N:16]=[N:15][C:14]=1Cl)[CH3:9].[H][H]>C(O)C.C(OCC)C.[Pd]>[CH2:8]([O:10][C:11](=[O:54])[CH2:12][C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH:38]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[C:39]([CH3:42])([CH3:41])[CH3:40])=[C:32]([CH3:51])[CH:31]=3)([CH2:26][CH3:27])[CH2:28][CH3:29])=[CH:21][C:20]=2[CH3:52])[N:16]=[N:15][CH:14]=1)[CH3:9]
Reactant: [H][H]
Reactant: CCOC(=O)Cc1cc(-c2ccc(C(CC)(CC)c3ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c3)cc2C)nnc1Cl
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)Cc1cnnc(-c2ccc(C(CC)(CC)c3ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c3)cc2C)c1
Yield: 81.9 %

Procedure:
10% Pd-C (2 mg) and triethylamine (0.011 mL, 0.079 mmol) were added to a solution of {6-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-3-chloro-pyridazin-4-yl}acetic acid ethyl ester (Example 183-(2); 4.8 mg, 0.007 mmol) in ethanol (0.6 mL) at room temperature. After replacement with hydrogen, the mixture was stirred in a hydrogen atmosphere at room temperature for seven hours. The reaction mixture was diluted with diethyl ether and filtered. The filtrate was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=3/1) to give the title compound (3.7 mg, 82%).
Reaction SMILES: [I:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)=[N:4][NH:5][CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1.O>CN(C)C=O>[I:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)=[N:4][N:5]([CH2:28][C:27]2[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[CH:6]=1
Reactant: O=[N+]([O-])c1cccc(-c2n[nH]cc2I)c1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2cc(I)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
2 g (6.3 mmol) of 4-iodo-3-(3-nitrophenyl)-1H-pyrazole were dissolved in 20 ml of dry dimethylformamide and 2.46 g (7.5 mmol) of cesium carbonate and 0.85 ml (6.3 mmol) of p-methoxybenzyl chloride were added successively. The reaction mixture was heated at 70° C. under stirring for 5 hours. Water was then added and the product extracted with dichloromethane. The organic phase was dried over sodium sulphate and the solvent evaporated under reduced pressure. 2.4 g (86%) of the title compound crystallized from a mixture diethylether-diisopropylether.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[NH:23][CH:22]=[C:21]([C:24](O)=[O:25])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.[C:56]([O:60][C:61]([N:63]1[CH2:68][CH2:67][CH:66]([NH2:69])[CH2:65][CH2:64]1)=[O:62])([CH3:59])([CH3:58])[CH3:57]>ClCCl>[C:56]([O:60][C:61]([N:63]1[CH2:68][CH2:67][CH:66]([NH:69][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[C:8]5[O:12][CH2:11][O:10][C:9]=5[CH:13]=[CH:14][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:16]=3[NH:23][CH:22]=2)=[O:25])[CH2:65][CH2:64]1)=[O:62])([CH3:59])([CH3:57])[CH3:58]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(O)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To a suspension of 4-(5-cyclopropylmethoxy-1,3-benzodioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (3.53 g; 10.0 mmol) from example A67 in dry dichloromethane (50 mL) is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (12.0 mmol), triethylamine (15.0 mmol) and 1-hydroxybenzotriazole (10.0 mmol). The suspension is stirred at ambient temperature for one hour. To the resulting solution, 4-amino-piperidine-1-carboxylic acid tert-butyl ester (12.0 mmol) is added and stirring is continued overnight at ambient temperature. The reaction mixture is loaded onto a silica gel column and purified by flash chromatography using acetic acid ethyl ester/2-propanol (98:2 v/v). The eluate containing the product fraction is collected and evaporated. The product is triturated with n-hexane and dried in high vacuo at 50° C. to yield 3.85 g of the title compound as white solid.
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].BrC(Br)C.[CH:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[C:15]1=[O:24])[CH2:21]2.B(OC)(OC)OC.Cl>[Zn].C(OCC)(=O)C.O1CCCC1>[F:8][C:2]([F:9])([C:15]1([OH:24])[CH:16]2[CH2:22][CH:20]3[CH2:19][CH:18]([CH2:23][CH:14]1[CH2:21]3)[CH2:17]2)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: CC(Br)Br
Agent: COB(OC)OC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)C1(O)C2CC3CC(C2)CC1C3
Temperature: 80 °C
Reaction time: 10 h
Yield: 58 %

Procedure:
A mixture of 24 g of ethyl bromodifluoroacetate, 2.2 g of dibromoethane and 25 g of tetrahydrofuran was added dropwise to a mixture of 7.8 g of zinc, 15 g of 2-adamantanone, 30 mL of trimethyl borate, and 25 g of tetrahydrofuran at a temperature of 50° C., followed by stirring for 10 hours at 80° C. Thereafter, 50 g of 5 wt % hydrochloric acid was added to quench the reaction. Ethyl acetate, 20 g, was added to the reaction solution, from which the organic layer was extracted. The organic layer was washed with saturated sodium chloride water and then with water. The reaction solution after washing was concentrated under reduced pressure. Methyl isobutyl ketone was added to the concentrate, the resulting solution was concentrated under reduced pressure again, and n-hexane was added to the concentrate for crystallization. The resulting solid was dried in vacuum, obtaining 15 g of the target compound, ethyl difluoro-(2-hydroxyadamantan-2-yl)acetate as white crystals (yield 58%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([C:28]([C:30]2[CH:31]=[C:32]3[C:36](=[C:37]([CH3:39])[CH:38]=2)[NH:35][C:34](=[O:40])[CH2:33]3)=[O:29])[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(#N)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([C:28]([C:30]5[CH:31]=[C:32]6[C:36](=[C:37]([CH3:39])[CH:38]=5)[NH:35][C:34](=[O:40])[CH2:33]6)=[O:29])[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2c1NC(=O)C2
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)CC(=O)N5)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.12 g (0.42 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 0.12 g (0.42 mmol) 5-(6-chloro-pyrimidine-4-carbonyl)-7-methyl-1,3-dihydro-indol-2-one and 0.08 mL (0.46 mmol) DIPEA were combined in 2 mL DMF and shaken overnight at RT. Then the reaction mixture was taken up in acetonitrile/water and purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[N:13]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)=[C:5]([CH3:22])[N:4]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[C:3]1=[O:33].[Cl-:34].[Li+].[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[Ce].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.C(OCC)(=O)C.C(O)(=O)C>[Cl:34][C:10]1[CH:11]=[N:12][N:13]([C:14]2[CH:15]=[CH:16][C:17]([C:18]#[N:19])=[CH:20][CH:21]=2)[C:9]=1[C:6]1[C:7](=[O:8])[N:2]([CH3:1])[C:3](=[O:33])[N:4]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=2)[C:5]=1[CH3:22]
Reactant: [Cl-]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: O=S([O-])([O-])=S
Agent: [Ce]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CC(=O)O
Product: Cc1c(-c2c(Cl)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Yield: 107.9 %

Procedure:
To a solution of 4-(5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 1) (205 mg) in acetonitrile (10 ml) were added lithium chloride (23 mg), ammonium hexanitrato cerate(IV) (498 mg) and acetic acid (2.5 ml) and the resulting mixture was stirred with heating under reflux for five hours. To the reaction mixture was 10% aqueous sodium thiosulfate solution (10 ml) followed by an addition of ethyl acetate (20 ml×2) such that the intended products were extracted into an organic layer. 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) to afford 4-(4-chloro-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (238 mg). UPLC/MS 486 (M+H)/1.13 min (measurement condition 9)
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([O:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].O>CCCCCC.CC(O)C>[C:11]([O:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:8](=[O:10])[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:23][CH:22]=1)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)C(=O)OCCOc1ccccc1
Reactant: O=C(O)Cc1ccccc1
Solvent: CCCCCC
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)C(=O)OCCOc1ccc(C(=O)Cc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Polyphosphoric acid (PPA) (250 g) was charged to a reaction vessel and warmed to 50° C. (bath temperature) with mechanical stirring. 2-Phenylacetic acid (30.6 g, 0.225 mol) was added to PPA followed by 2-phenoxyethyl pivalate (50 g, 0.225 mol). After 3 hours TLC and HPLC indicated full conversion and water (1000 ml) was added. The mixture was stirred at room temperature for 2 h. The precipitated product was filtered and washed with water (300 ml). After drying in vacuo the crude product (65 g) was re-crystallized with hexane/i-PrOH 1:1 yielding the title compound as slightly yellow solid (51.49 g, 0.151 mol, 67%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.02 (2H, d, J=9.2 Hz, ArH), 7.32-7.22 (5H, m, ArH), 7.07 (2H, d, J=8.8 Hz, ArH), 4.37 (2H, m, CH2CH2OPiv), 4.31 (2H, s, ArCH2CO), 4.3 (2H, m, ArOCH2CH2), 1.12 (9H, s, 3×Me). 13C-NMR (100 MHz, DMSO-d6) δ (ppm): 196.4, 177.7, 162.6, 135.8, 131.2, 129.9, 129.8, 128.7, 126.8, 114.8, 66.5, 62.7, 44.8, 38.6, 27.2.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.C(=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCC.O1CCCC1>[OH:4][C:3]1[CH2:5][CH:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:7][C:1](=[O:6])[CH:2]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(c2ccccc2)O1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared as described in General Method 1 using 13.67 g methyl acetoacetate, 8.5 g of NaH 60% dispersion in oil, 73.6 mL of 1.6M n-butyl lithium in hexane, 10 g of benzaldehyde, and 300 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred 15 minutes at -78° C. then allowed to warm to room temperature overnight. A solid was filtered off after concentration (m.p. 145°-146° C.). 'H NMR (CDCl3) δ2.8-3.05 (m, 2H), 3.5 (d, 1H), 3.7 (d, 1H), 5.7 (dd, 1H), 7.3-7.5 (m, 5H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([SH:17])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=2)=[CH:13][CH:12]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: COc1cccc(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: COc1cccc(Sc2ccc(Cl)cc2)c1
Yield: 81 %

Procedure:
The general procedure in example 39 was followed. 3-Iodoanisole (234 mg, 1.0 mmol), 4-chlorothiophenol (145 mg, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-propanol (1.0 mL) were used to obtain the 3-methoxyphenyl 4-chlorophenyl sulfide (203 mg, 81% yield) as colorless liquid. Column chromatographic solvent (hexane/ethyl acetate=50/1). Rf=0.4 (hexane/ethyl acetate=40/1). 1H NMR (CDCl3, 300 MHz) δ 7.13-7.26 (m, 2 H), 6.88 (ddd, 2 H, J=1.2 Hz, 1.8 Hz, 7.8 Hz), 6.83 (t, 2 H, J=1.5 Hz), 6.78 (ddd, 2 H, J=0.9 Hz, 2.7 Hz, 8.1 Hz), 3.75 (s, 3 H). 13C NMR (CDCl3, 75 MHz) δ 160.2, 136.6, 134.3, 133.4, 132.5, 130.3, 129.5, 123.4, 116.4, 113.3, 55.7. IR (neat, cm−1) 3065, 3002, 2962, 2949, 2820. MS (E) m/z (relative intensity) 252 (30), 250 (100). Anal Cald for C13H11ClOS, Cald. C, 62.27; H, 4.42. Found C, 62.58; H, 4.46.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:6]=2[N:7]=1.[CH2:14]1[N:19]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)[CH2:18][CH2:17][O:16][CH2:15]1.NC1C=CC=CC=1>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:26][C:23]2[CH:22]=[CH:21][C:20]([N:19]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[CH:25][CH:24]=2)[C:5]2[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:6]=2[N:7]=1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: Cc1sc2nc(Cl)nc(Cl)c2c1C
Solvent: Nc1ccccc1
Solvent: CCO
Product: Cc1sc2nc(Cl)nc(Nc3ccc(N4CCOCC4)cc3)c2c1C
Yield: 112.5 %

Procedure:
To 240 mg (1.02 mmol of 2,4-dichloro-5,6-dimethyl-thieno[2,3-d]pyrimidine in 50 ml of ethyl alcohol were added 220.20 mg (1.23 mmol) of 4-(4-morpholino)aniline and 130.90 mg (1.23 mmol) of aniline, and then the mixture was stirred under reflux. After completion of the reaction, the reaction solvent, ethyl alcohol, was evaporated under reduced pressure, and the residue was crystallized from ethyl alcohol and filtered, yielding 430 mg (quantitative) of 2-chloro-5,6-dimethyl-thieno[2,3-d]pyrimidin-4-yl-4-morpholin-4-yl-phenylamine. 220 mg (0.53 mmol) of the obtained product was dissolved in 20 ml of 1-butanol in a sealed tube, and 223 μl (1.59 mmol) of triethylamine and 45.9 mg of piperazine were added thereto, and the mixture was stirred at 120° C. After completion of the reaction, the resulting solid was filtered and the filtrate was concentrated under reduced pressure and then crystallized from ethyl acetate, yielding 30 mg (15% yield) of 5,6-dimethyl-2-piperazin-1-yl-thieno[2,3-d]pyrimidin-4-yl-4-morpholin-4-yl-phenylamine. To 9 mg (0.02 mmol) of the obtained compound and 5,6-dimethyl-2-piperazin-1-yl-thieno[2,3-d]pyrimidin-4-yl-4-morpholin-4-yl-phenylamine in 5 ml of dimethyl chloride were added 3.5 μl (0.02 mmol) of triethylamine and 4.1 mg (0.02 mmol) of picolinoyl chloride hydrochloride, and then the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction solvent, dimethyl chloride, was evaporated under reduced pressure, and the residue was crystallized from dimethyl chloride, thus obtaining 6 mg (30% yield) of the title product.