Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][C:9]([C:11]2(Br)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:8][C:7]=1[CH2:18]Br)=[O:5])C.C[O-].[Na+].[C:23](O)(=[O:25])C>CO>[CH3:1][O:3][C:4]([C:6]1[O:10][C:9]([C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=2)=[N:8][C:7]=1[CH2:18][O:25][CH3:23])=[O:5]
Reactant: CCOC(=O)c1oc(C2(Br)CCCCC2)nc1CBr
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1nc(C2=CCCCC2)oc1C(=O)OC
Temperature: 65 °C
Reaction time: 1 h

Procedure:
14.7 g 2-(1-Bromo-cyclohexyl)-4-bromomethyl-oxazole-5-carboxylic acid ethyl ester were dissolved in 150 ml methanol. 6.03 g sodium methylate were added and the reaction mixture stirred at 65° C. for one hour. The cooled reaction mixture was acidified by addition of acetic acid (pH˜6). The solvent was removed in vacuo. The residue was dissolved in 250 ml ethyl acetate and washed with 80 ml water and brine, dried over MgSO4 and then the solvent was removed in vacuo. The residue was purified by reversed phase HPLC to obtain 5.30 g 2-Cyclohex-1-enyl-4-methoxymethyl-oxazole-5-carboxylic acid methyl ester as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[N:9]1[CH:13]=[CH:12][C:11]([CH3:14])=[N:10]1.C([Mg]Cl)(C)C.[F:20][C:21]([F:28])([F:27])[C:22](OCC)=[O:23].Cl>C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:22](=[O:23])[C:21]([F:28])([F:27])[F:20])=[C:3]([N:9]2[CH:13]=[CH:12][C:11]([CH3:14])=[N:10]2)[CH:4]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: Cc1ccn(-c2cc(Br)ccc2Br)n1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccn(-c2cc(Br)ccc2C(=O)C(F)(F)F)n1
Reaction time: 0.75 h

Procedure:
1-(2,5-dibromophenyl)-3-methyl-1H-pyrazole (23.0 g, 73 mmol) from Step 1 was dissolved in 200 mL of THF and cooled to 0° C. i-Propyl magnesium chloride (2.0 M in THF, 40 mL) was added dropwise and the reaction was stirred for 45 min, then ethyl trifluoroacetate (10.5 mL) was added. The reaction was stirred for 30 min at 0° C., then 10% HCl is added dropwise (400 mL). The reaction was extracted with water and EtOAc, washed with brine, dried over Na2SO4, filtered, and then concentrated in vacuo. Purification by normal phase silica gel column chromatography (EtOAc/heptane) provided 1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanone.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:18])[N:5]=[C:4]2[S:19][C:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:3]=12.C(=O)([O-])[O-].[K+].[K+].[C:32]1([CH3:41])[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(OCC)(=O)C>COCCOC.O.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>[CH3:18][C:6]1[N:5]=[C:4]2[S:19][C:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:3]2=[C:2]([C:35]2[CH:36]=[CH:37][C:32]([CH3:41])=[CH:33][CH:34]=2)[C:7]=1[CH:8]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1Cl)CCCC3
Reactant: Cc1ccc(B(O)O)cc1
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: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 54.3 %

Procedure:
To a solution of methyl 2-[4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate (0.069 g; 0.181 mmol) in a mixture of DME-water (3:1) (1 mL) were added potassium carbonate (0.100 g; 0.723 mmol), tetrakis(triphenylphosphine)palladium(0) (0.010 g; 0.009 mmol) and 4-tolylboronic acid (0.049 g; 0.361 mmol). The solution was stirred for 30 min at 140° C. under microwave irradiation. Ethyl acetate was added to the reaction mixture and the solution was washed with brine. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethylacetate (5-40%) in heptane furnished 0.043 g (44%) of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]([CH3:22])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH:17](OC)OC)[C:12](=[O:15])[C:13]=1[OH:14])=[O:8].FC(F)(F)C(O)=O.[N:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:36][CH:35]=1.C([BH3-])#N.[Na+]>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]([CH3:22])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][N:43]2[CH2:44][CH2:45][N:40]([C:37]3[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=3)[CH2:41][CH2:42]2)[C:12](=[O:15])[C:13]=1[OH:14])=[O:8]
Reactant: COC(CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O)OC
Reactant: c1cc(N2CCNCC2)ccn1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN2CCN(c3ccncc3)CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1.2 %

Procedure:
A solution of 1-(2,2-dimethoxy-ethyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide (0.29 g, 0.71 mmol) in acetonitrile/water (10 mL, 2.5:1) was stirred with trifluoroacetic acid (1 mL) overnight at room temp. The mixture was concentrated then dissolved in MeOH (3 mL). 1-(4-pyridyl)-piperazine (0.42 g, 2.6 mmol) was added and the resulting mixture was stirred at room temp 30 min. Sodium cyanoborohydride (0.013 g, 0.2 mmol) was added and the mixture was stirred an additional 5 h at room temp. The crude product was purified by preparative HPLC (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as an amber foam (0.0042 g, 12% yield). HRMS (M+H) calcd for C24H28N5Cl2O3: 504.15693; found: 504.1564.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]#[N:15])[C:11]3[N:16]=[N:17][N:18]([CH3:19])[C:10]=3[CH:9]=2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][CH:33](O)[CH2:32][CH2:31]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CN1C(=O)CCC1>[CH3:19][N:18]1[C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([O:1][CH:33]4[CH2:32][CH2:31][N:30]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=5)[CH2:35][CH2:34]4)=[C:3]([C:20]([F:23])([F:22])[F:21])[CH:4]=3)[N:13]=[C:12]([C:14]#[N:15])[C:11]=2[N:16]=[N:17]1
Reactant: Cn1nnc2c(C#N)nc(-c3ccc(O)c(C(F)(F)F)c3)cc21
Reactant: OC1CCN(c2ccccn2)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Product: Cn1nnc2c(C#N)nc(-c3ccc(OC4CCN(c5ccccn5)CC4)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-(4-hydroxy-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (0.940 mmol, 300 mg), 1-(pyridin-2-yl)piperidin-4-ol (1.410 mmol, 251 mg) and Triphenylphosphine (1.410 mmol, 370 mg) were suspended in NMP (1 ml) and DIAD (1.410 mmol, 0.278 ml, 285 mg) added. The mixture was stirred at room temperature overnight. The reaction mixture was passed down an SCX column to afford 1-methyl-6-(4-(1-(pyridin-2-yl)piperidin-4-yloxy)-3-(trifluoro-methyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile. (0.024 g)
Reaction SMILES: [CH3:1][C:2]1[C:9]([CH3:10])=[C:8]([CH3:11])[CH:7]=[C:6]([CH3:12])[C:3]=1[CH:4]=[O:5].C1(=[O:19])CCCCC1>C(O)(=O)C.C([O-])(=O)C.[Co+2].C([O-])(=O)C>[CH3:1][C:2]1[C:9]([CH3:10])=[C:8]([CH3:11])[CH:7]=[C:6]([CH3:12])[C:3]=1[C:4]([OH:19])=[O:5]
Reactant: O=C1CCCCC1
Reactant: Cc1cc(C)c(C=O)c(C)c1C
Agent: [Co+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: Cc1cc(C)c(C(=O)O)c(C)c1C
Yield: 58.4 %

Procedure:
To a flask equipped with an oxygen inlet, stirrer and condenser were added 2,3,4,6-tetramethylbenzaldehyde (8.10 g, 50 mmol), 20 mL (0.194 mol) of cyclohexanone and 4 mg of cobalt (II) acetate dissolved in several drops of acetic acid. Oxygen was bubbled in while the solution was rapidly stirred. After 21/2 hr at room temperature and 4 hr at 50° the solution was poured into a separatory funnel and extracted with 100 mL, then 50 mL, of 3% aqueous sodium bicarbonate solution. The combined aqueous extracts were rinsed with 50 mL of cyclohexane, then acidified to a pH of 2 with concentrated hydrochloric acid and the precipitated product was collected by filtration, washed with water and air dried. A total of 5.2 g (58% yield) of fluffy white 2,3,4,6-tetramethylbenzoic acid was obtained: mp 164°-167°.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1.[CH2:8](O)[CH2:9][OH:10]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[S:1]1[CH:5]=[CH:4][C:3]([CH:6]2[O:10][CH2:9][CH2:8][O:7]2)=[CH:2]1
Reactant: O=Cc1ccsc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: c1cc(C2OCCO2)cs1
Temperature: 0 °C
Yield: 95.9 %

Procedure:
To a solution of thiophene-3-carbaldehyde (25.00 g, 222.9 mmol) in toluene (250 ml) were added ethylene glycol (69.18 g, 1115 mmol) and p-toluenesulfonic acid (424.0 mg, 2.229 mmol). The mixture was heated under reflux for 4 hr while separating generated water using Dean-Stark trap. After cooling to 0° C., saturated aqueous sodium hydrogen carbonate solution (50 ml) was added, and the mixture was stirred, stood still and then partitioned. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure, filtered through silica gel pad (FUJI SILYSIA CHEMICAL LTD. BW-300SP 100 g), and washed with ethyl acetate/hexane mixed solvent (1:2, 1000 ml). The filtrate was concentrated under reduced pressure to give 2-(thiophen-3-yl)-1,3-dioxolane (33.40 g, 213.8 mmol, yield 95.9%) as a yellow oil.
Reaction SMILES: [O:1]1[CH2:5]CC[CH2:2]1.[Br:6][C:7]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([Br:17])[NH:9][N:8]=1.C(N(CC)C(C)C)(C)C.COCCl>O>[Br:17][C:10]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]([Br:6])[N:8]([CH2:2][O:1][CH3:5])[N:9]=1
Reactant: CCOC(=O)c1c(Br)n[nH]c1Br
Reactant: C1CCOC1
Agent: COCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c(Br)nn(COC)c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a tetrahydrofuran (262 mL) solution of ethyl 3,5-dibromo-1H-pyrazole-4-carboxylate (20.93 g, 703 mmol) was added N,N-diisopropylethylamine (24.5 mL, 141 mmol), and chloromethyl methyl ether (6.42 mL, 84.3 mmol) was added dropwise while cooling on ice, and stirred at room temperature for one hour. After the reaction was completed, water was added while cooling on ice, the reaction mixture was extracted with ethyl acetate, the organic layer was dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane/ethyl acetate=3/1) to obtain the title compound (23.4 g, 68.5 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([O:11]C)=[CH:6][C:3]=1[CH:4]=[O:5].Br>C(O)(=O)C>[Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([OH:11])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1cc(C=O)c(Br)cc1F
Agent: Br
Solvent: CC(=O)O
Product: O=Cc1cc(O)c(F)cc1Br
Yield: 64 %

Procedure:
A solution of 2-bromo-4-fluoro-5-methoxybenzaldehyde (1.19 g, 8.20 mmol), 48% HBr (57 mL) and glacier acetic acid (57 mL) were refluxed at 130° C. for 5 hours. The glacier acetic acid was removed under reduced pressure. The solution was neutralized using sodium carbonate. Water was added and the mixture was extracted using ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel column using Combiflash to give 2-bromo-4-fluoro-5-hydroxybenzaldehyde (1.15 g, 64% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:7]=1.[CH:18](O)=O>CO.[Fe]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:15]=[CH:18][N:8]([CH:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[C:6]=2[CH:7]=1
Reactant: O=CO
Reactant: O=[N+]([O-])c1ccc(Br)cc1NC1CCOCC1
Agent: [Fe]
Solvent: CO
Product: Brc1ccc2ncn(C3CCOCC3)c2c1
Reaction time: 4 h

Procedure:
To a solution of N-(5-bromo-2-nitrophenyl)tetrahydro-2H-pyran-4-amine (600 mg, 1.99 mmol) in HCOOH (10 mL) was added Fe powder (1.3 g, 23.2 mmol). After stirring for 4 h at reflux temperature, the mixture was diluted with MeOH (100 mL) and filtered over a Celite pad. The filtrate was concentrated to give the title compound which was directly used for next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:3]=1[C:4]#[N:5].[Cl:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:11])[CH:17]=2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: OB(O)c1cccc(Cl)c1
Reactant: N#Cc1cc(Br)ccc1N
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1cc(-c2cccc(Cl)c2)ccc1N
Temperature: 85 °C
Yield: 70 %

Procedure:
A mixture of 2-amino-5-bromobenzonitrile (log, 50 mmol), 3-chlorophenyl boronic acid (9.5 g, 60 mmol), tetrakis(triphenylphosphine)-palladium (0) (3.5 g, 3 mmol), and sodium carbonate (13 g, 120 mmol) in a mixture of DME and water (100 mL/25 mL) was degassed to remove the oxygen and then heated to 85° C. under a blanket of nitrogen for 5 hours. The reaction mixture was cooled to ambient temperature and quenched with a saturated aqueous ammonium chloride solution (80 mL). Ethyl acetate (200 mL) was added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with brine and dried with MgSO4. The solvent was removed in vacuo and the residue was purified by a silica gel flash chromatography (hexane:ethyl acetate/4:1) to afford 4-amino-3′-chloro-biphenyl-3-carbonitrile as an off-white solid (8 g, 87%): mp 118-119° C.; 1H-NMR (DMSO-d6)δ 7.80 (d, 1H, J=2.3 Hz), 7.65-7.72 (m, 2H), 7.57 (d, 1H, J=8.0 Hz), 7.42 (t, 1H, J=7.9 Hz), 7.31 (m, 1H), 6.87 (d, 1H, J=8.7 Hz), 6.29 (br, 2H); Anal. Calc. For C13H9ClN2: C, 68.28, H, 3.97, N, 12.25. Found: C, 67.68, H, 4.06, N, 11.89.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:22][O:23][C:24]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([C:34]2[N:35]([CH3:43])[C:36]3[C:41]([CH:42]=2)=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:28][C:25]=1[CH:26]=O>CO.C(Cl)Cl>[CH3:22][O:23][C:24]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([C:34]2[N:35]([CH3:43])[C:36]3[C:41]([CH:42]=2)=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:28][C:25]=1/[CH:26]=[CH:2]/[C:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])(=[O:11])=[O:12])=[CH:8][CH:9]=1)=[O:3]
Reactant: COc1cc(OC)c(-c2cc3ccccc3n2C)cc1C=O
Reactant: CC(=O)c1ccc(S(=O)(=O)NO[Si](C)(C)C(C)(C)C)cc1
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(-c2cc3ccccc3n2C)cc1/C=C/C(=O)c1ccc(S(=O)(=O)NO[Si](C)(C)C(C)(C)C)cc1
Yield: 19 %

Procedure:
The title compound was prepared in an analogous manner as Ex-1 using 4-acetyl-N-(tert-butyldimethylsiloxy)benzenesulfonamide (Ex-33A) and 2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)benzaldehyde (Ex-15A), 19% yield after preparative TLC (MeOH/CH2Cl2, 1:10), yellow solid, mp 129–131° C. 1H-NMR (300 MHz, CDCl3) δ 8.18 (d, J=15 Hz, 1H), 8.12 (d, J=8 Hz, 2H), 8.02 (d, J=8 Hz, 2H), 7.69 (s, 1H), 7.64 (d, J=8 Hz, 1H), 7.47 (d, J=15 Hz, 1H), 7.36 (d, J=7 Hz, 1H), 7.22–7.26 (m, 1H), 7.11–7.16 (m, 1H), 6.58 (s, 1H), 6.50–6.51 (m, 2H), 4.03 (s, 3H), 3.90 (s, 3H), 3.59 (s, 3H), 0.90 (s, 9H), 0.20 (s, 6H). HRMS (ESI) Calcd. for C32H39N2O6SSi: 607.2298 (M+H)+; Found: 607.2306.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[CH3:20][CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=[C:3]1[CH2:15][C:16]([N:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:29][CH:21]1[CH3:20])=[O:18]
Reactant: CC1Cc2ccccc2N1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC1Cc2ccccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)n1C
Yield: 5 %

Procedure:
The product is prepared according to the procedure described in example 68, using 550 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 400 mg of 2-methylindoline and 500 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 320 μl of pyridine and 8.0 ml of N,N-dimethylformamide. 37 mg of 3-methyl-2-[2-(2-methyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a pink powder, the characteristics of which are the following:
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:6][N:5]=[C:4]([S:18][CH3:19])[N:3]=1.ClC1C=CC=C(C(OO)=[O:28])C=1.O>CCOC(C)=O>[CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:6][N:5]=[C:4]([S:18]([CH3:19])=[O:28])[N:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ncc(C(=O)OCc2ccccc2)c(C)n1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc(S(C)=O)ncc1C(=O)OCc1ccccc1
Yield: 84 %

Procedure:
A solution of benzyl 4-methyl-2-(methylthio)-5-pyrimidinecarboxylate (3.6 g) and m-chloroperbenzoic acid (P=75%) (2.72 g) in AcOEt (30 ml) was stirred at ambient temperature for 2 hours. The reaction mixture was poured into a mixture of AcOEt and H2O and the organic layer was washed with saturated NaHCO3 solution, brine and dried over MgSO4. The solvent was evaporated in vacuo to give benzyl 4-methyl-2-(methylsulfinyl)-5-pyrimidinecarboxylate (3.2 g)
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[C:25]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[SH:35])([CH3:28])([CH3:27])[CH3:26]>CCCCO.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>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][N:12]([C:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([S:35][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[C:25]([CH3:28])([CH3:27])[CH3:26])[CH:11]=3)[CH:6]=[CH:7][N:8]=2)[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)c1ccccc1S
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc3ccc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCN(c2nccc3ccc(Sc4ccccc4C(C)(C)C)cc23)CC1
Temperature: 110 °C
Yield: 70.9 %

Procedure:
A mixture of 4-(7-bromo-isoquinoline-1-yl)-piperazine-1-carboxylic acid, tert-butyl ester (0.5 g, 1.3 mmol), 2-t-butyl-thiophenol (0.216 g, 1.3 mmol), Nat-BuO (0.44 g, 4.5 mmol), Pd(PPh3)4 (74 mg, 0.065 mmol) in n-BuOH (10 mL) was heated at 110° C., 3 h. The reaction mixture was filtered. The filtrate was concentrated and the residue was dissolved in ethyl acetate. The organic phase was washed with water (50 mL×3), separated and dried (MgSO4), filtered. The volatiles were evaporated and the residue was purified by flash column chromatography (SiO2, n-heptane: ethyl acetate 8:2) to give 440 mg of the title compound as colorless oil (yield 71%). 1H NMR (CDCl3) δ 8.00-8.10 (m, 2H), 7.15-7.65 (m, 7H), 3.60-3.70 (m, 1H), 3.30-3.45 (m, 4H), 3.05-3.20 (m, 3H), 1.55 (s, 9H), 1.50 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][C:12]=2[C:19]#[N:20])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Na+].Cl[C:24]1[CH:25]=[C:26]2[N:33]([CH3:34])[CH2:32][CH2:31][N:27]2[C:28](=[O:30])[N:29]=1>C1COCC1>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:24]3[CH:25]=[C:26]4[N:33]([CH3:34])[CH2:32][CH2:31][N:27]4[C:28](=[O:30])[N:29]=3)=[CH:13][C:12]=2[C:19]#[N:20])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: N#Cc1ccc(Oc2ccc(CO)cc2C#N)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCn2c1cc(OCc1ccc(Oc3ccc(C#N)c(Cl)c3)c(C#N)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using 2-chloro-4-(2-cyano-4-(hydroxymethyl)phenoxy)benzonitrile (60 mg, 0.211 mmol) in THF (S mL), sodium hydride (12.64 mg, 0.316 mmol) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (39.1 mg, 0.211 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.C1C=CC2N(O)[N:20]=[N:19]C=2C=1.CCN=C=NCCCN(C)C.Cl.NN.C1CCCCC=1>C(#N)C>[OH:1][C:2]1[CH:12]=[CH:11][C:5](/[CH:6]=[CH:7]/[C:8]([NH:19][NH2:20])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)C=Cc1ccc(O)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN
Solvent: CC#N
Solvent: C1=CCCCC1
Product: NNC(=O)/C=C/c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.5 %

Procedure:
To a stirred solution of 4-hydroxycinnamic acid (3.28 g, 20 mmol) in acetonitrile (40 ml) was added HOBt (3.24 g, 24 mmol) and EDC.HCl (4.6 g, 24 mmol). The mixture was stirred at room temperature for 2 h, and the resulting yellow suspension was cooled to 0° C. by an ice bath. A ice-cold solution of hydrazine (1.25 ml, 40 mmol) and cyclohexene (0.61 ml, 6 mmol) in acetonitrile (30 ml) was added into the suspension in one portion, and the mixture was stirred at 0° C. for 20 min, then all owed to warm to ambient temperature, with the stirring continued for additional 1 h. The yellow suspension was filtered off via suction, washed the solid successively with MeOH (3×30 ml), H2O (2×30 ml), saturated NaHCO3 (2×30 ml), H2O (2×20 ml) and EtOAc (2×20 ml), and air-dried to afford 133 (1.3 g, 36% yield) as yellow solid. 1H NMR (300 MHz, DMSO-d6): δ4.40 (brs, 3H), 6.32 (d, J=15.9 Hz, 1H), 6.76 (d, J=8.4 Hz, 2H), 7.33 (d, J=16.2 Hz, 1H), 7.36 (d, J=8.1 Hz, 2H), 9.21 (br s, 1H); 13C NMR (75 MHz, DMSO-d6): δ116.49, 117.21, 126.44, 129.83, 139.08, 159.72, 165.86; MS (ESI): m/z 179 (M+1).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](F)[N:13]=1>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([F:11])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cccc(F)n1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1cccc(OCc2ccccc2)n1
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 98 %

Procedure:
Benzylalcohol (1.88 g, 17.38 mmol) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 458 mg, 19.11 mmol) in tetrahydrofuran (15 mL) and the mixture was heated to 50° C. for 45 minutes. The reaction mixture was then cooled to room temperature, a solution of 2,6-difluoropyridine (2 g, 17.38 mmol) in tetrahydrofuran (4 mL) was added dropwise and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was then diluted with ethyl acetate, concentrated in vacuo and the residue was partitioned between ethyl acetate (50 mL) and water (20 mL). The organic layer was separated, washed with brine (20 mL), dried over magnesium sulfate and concentrated in vacuo. The residue was then concentrated in vacuo from dichloromethane to afford the title compound as a clear oil in 98% yield, 3.48 g. LRMS APCI m/z 204 [M+H]+.