Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:39]([C:36]4[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=4)(=[O:41])=[O:40])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccc(F)cc4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 4-fluoro-benzenesulfonyl chloride. Purity (ELSD, based on MW=579.6)=93%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:24][C:25]1[C:33]([OH:34])=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[C:28]([CH3:35])[NH:29]2>>[F:24][C:25]1[C:33]([O:34][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[C:28]([CH3:35])[NH:29]2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCCCC1
Yield: 83.6 %

Procedure:
Using an analogous procedure to that described in Example 237, 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (1.65 g, 4.89 mmol), (prepared as described for the starting material in Example 67), was reacted with 4-fluoro-5-hydroxy-2-methylindole (970 mg, 5.88 mmol), (prepared as described for the starting material in Example 237), to give 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline (1.9 g, 83%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.C([Li])CCC.O1CCCC1.[CH:22]([N:25]([CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[C:26](=[O:35])[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=1)([CH3:24])[CH3:23]>C(OCC)C.O1CCCC1.C(OCC)C.C(OCC)(=O)C.CCCCCC>[CH:36]1([N:25]([CH:22]([CH3:24])[CH3:23])[C:26](=[O:35])[C:27]2[CH:28]=[CH:29][C:30]([CH:31]([C:2]3[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=3)[OH:32])=[CH:33][CH:34]=2)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: COc1ccc(Br)cc1OC
Reactant: CC(C)N(C(=O)c1ccc(C=O)cc1)C1CCCCC1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2ccc(C(=O)N(C(C)C)C3CCCCC3)cc2)cc1OC
Temperature: -20 °C

Procedure:
To a stirred solution of 4-bromoveratrole (0.77 ml, 6.0 mmol) in ethyl ether (30 mL) at 0° C. under an argon atmosphere was added n-butyl lithium (3.75 mL of 1.6 M solution in hexane). A white precipitate formed and tetrahydrofuran (THF) (10 mL) was added. The reaction mixture was cooled to -20° C. and a solution of terephthalaldehydic acid N-isopropyl-N-cyclohexyl amide (0.82 g, 3.0 mmol) in THF: ethyl ether (4:3, 35 mL) was added rapidly. Thin layer chromatography (TLC) (50% ethyl acetate/hexane) after 5 min showed the reaction was nearly complete. The reaction was quenched at -15° C. by adding water (50 mL) and 1N HCl(20 mL). The reaction was further diluted with water (300 mL) and extracted three times with ethyl acetate (50 mL portions). The combined extracts were washed twice with saturated NaCl solution and dried (MgSCO4). The drying agent was filtered and the filtrate concentrated in vacuo to give the crude product. The crude product was chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the title compound as an amorphous solid.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][O:27][CH2:28][C:29](Cl)=[O:30]>C1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:29](=[O:30])[CH2:28][O:27][CH3:26])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Reactant: COCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COCC(=O)OC1CCN(C)C(=O)N1c1nnc(C(C)(C)C)s1

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)- 3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Methoxyacetyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol- 2-yl)-3-methyl-6-methoxyacetyloxy-2(1H)-pyrimidinone as the residue.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]([CH3:9])=[CH:7][CH:8]=1)(=[O:3])[CH3:2].O.[C:11]([O:14]CC)(=[O:13])[CH3:12]>>[CH3:9][C:6]1[O:5][C:4]([C:1](=[O:3])/[CH:2]=[CH:12]/[C:11]([OH:14])=[O:13])=[CH:8][CH:7]=1
Reactant: CCOC(C)=O
Reactant: CC(=O)c1ccc(C)o1
Solvent: O
Product: Cc1ccc(C(=O)/C=C/C(=O)O)o1

Procedure:
10 g of 2-acetyl 5-methyl furan (J. Am. Chem. Soc., 72 3695 (1950)), 7.4 g monohydrated glyoxylic acid and 5 cm3 water are heated to 120°-130° C. for 5 hours, while eliminating the water formed in the course of the reaction. After cooling, 60 cm3 ethyl acetate are added and extracted with a solution of sodium carbonate. The aqueous phase is acidified, extracted with ethyl acetate, dried, and concentrated to dryness. The residue is chromtographed on silica, then, the product is recrystallized in ethyl acetate. 2.2 g of the expected product are obtained. MP=159°-162° C.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[CH3:7][O:8][C:9]([C@@H:11]1[CH2:25][C@H:24]2[C@@H:14]([CH2:15][C:16]3[C:26]4[C:19](=[CH:20][CH:21]=[CH:22][C:23]2=4)[NH:18][CH:17]=3)[NH:13][CH2:12]1)=[O:10].O>N1C=CC=CC=1>[CH:1]1([C:4]([N:13]2[C@H:14]3[C@@H:24]([C:23]4[CH:22]=[CH:21][CH:20]=[C:19]5[C:26]=4[C:16]([CH2:15]3)=[CH:17][NH:18]5)[CH2:25][C@@H:11]([C:9]([O:8][CH3:7])=[O:10])[CH2:12]2)=[O:5])[CH2:3][CH2:2]1
Reactant: COC(=O)[C@H]1CN[C@@H]2Cc3c[nH]c4cccc(c34)[C@H]2C1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)[C@@H]1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C(=O)C2CC2)C1
Reaction time: 1 h

Procedure:
There were slowly added 6 ml of cyclopropanecarboxylic acid chloride to an iced solution of 15 g of 8β-methoxycarbonylergoline in 170 ml of pyridine. The reaction mixture was left at room temperature for 1 hr, then poured into cooled acid water. The precipitate was filtered and crystallized from methanol to give 16 g of 6-cyclopropanoyl-8β-methoxycarbonylergoline melting at 276°-278° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([N:10]=[C:11]=[S:12])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([CH3:35])[CH:29]=1.C1(C)C=CC=CC=1>C(O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:11]([NH:10][C:8](=[O:9])[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)=[S:12])=[C:30]([CH3:35])[CH:29]=1
Reactant: Cc1cccc(C(=O)N=C=S)c1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(C)c4)c(C)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
Commercially available 3-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (32 mg, yield 40%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([O:24]C)=[O:23])=[CH:15][CH:14]=1>>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:18]=1)=[O:5]
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)c1ccc(F)cc1F
Product: O=C(O)CCC(=O)c1ccc(NC(=O)c2ccc(F)cc2F)cc1
Yield: 76.8 %

Procedure:
In a manner similar to that described in Example 3, 2,4-difluoro-benzoyl chloride (0.059 g, 0.00033 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.064 g of 4-[4-(2,4-difluoro-benzoylamino)-phenyl]-4-oxo-butyric acid as an off-white solid; MS-(AP+) MH+334.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH2:11])[CH:10]=1)[C:5]([NH2:7])=[O:6].[CH3:12][O:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17]>>[CH3:12][O:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH:11][C:16](=[O:17])[C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[O:13][CH3:12])[CH:10]=1)[C:5]([NH2:7])=[O:6])=[O:17]
Reactant: NC(=O)c1cc(N)cc(N)c1
Reactant: COc1ccccc1C(=O)Cl
Product: COc1ccccc1C(=O)Nc1cc(NC(=O)c2ccccc2OC)cc(C(N)=O)c1

Procedure:
By the procedure similar to that described in Example 12, 3,5-diaminobenzamide was condensed with 2-methoxybenzoylchloride to obtain 3,5-bis(2'-methoxybenzamido)-benzamide having a melting point between 226° - 227°C.
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br.C(N(C(C)C)CC)(C)C>C(#N)C>[Br:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=2)[CH2:6][CH2:5]1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: BrCc1ccccc1Br
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc(N2CCN(Cc3ccccc3Br)CC2)cc1

Procedure:
A solution of EXAMPLE 4A (23.43 g, 100.0 mmol), 2-bromobenzyl bromide (26.24 g, 105.0 mmol) and diisopropylethylamine (20.94 mL, 120.0 mmol) in acetonitrile (200 mL) was stirred at room temperature for two hours. The resulting precipitate was collected by filtration to give the desired product, which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.CN(C=O)C.[NH:39]1[C:43]2[CH:44]=[CH:45][C:46]([NH2:48])=[CH:47][C:42]=2[N:41]=[N:40]1.Cl>CCO>[NH:39]1[C:43]2[CH:44]=[CH:45][C:46]([NH:48][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=6[F:32])[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)=[CH:47][C:42]=2[N:41]=[N:40]1
Reactant: Nc1ccc2[nH]nnc2c1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4[nH]nnc4c3)n2)c1)c1c(F)cccc1F
Temperature: 80 °C
Yield: 74.5 %

Procedure:
To a slurry of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide (103 mg, 0.223 mmol.) in 1 mL of EtOH/0.5 mL of DMF, 1H-1,2,3-benzotriazol-5-amine (32 mg, 0.245 mmol) and 5 μL of conc. HCl, the reaction contents were heated to 80° C. After heating for 18 h, the reaction mixture was cooled to rt and partitioned between DCM and sat. aq. NaHCO3. The layers were separated, extracted the aqueous layer with DCM (2×10 mL), the organic layers were pooled, dried over MgSO4, filtered, reduced in vacuo. Addition of TFA, followed by titration with Et2O afforded the desired product as a yellow solid 93 mg, 63% yield. 1H NMR (400 MHz, d6-DMSO): δ 10.91 (s, 1H); 9.91 (s, 1H); 8.54 (d, J=7 Hz, 1H); 8.52-8.49 (m, 2H); 8.31 (d, J=5 Hz, 1H); 7.99 (s, 1H); 7.82 (t, J1=10 Hz, 2H); 7.60-7.53 (m, 2H); 7.50-7.45 (m, 2H); 7.37 (d, J=8 Hz, 1H); 7.23 (t, J=9 Hz, 2H); 7.13 (t, J=7 Hz, 1H); 6.55 (d, J=5 Hz, 1H). HRMS calculated C30H20F2N9O [M+H]+ 560.1759, found 560.1763.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:11][CH2:10][CH:7]([CH2:8][CH2:9]1)[NH:6][CH2:5][CH2:4]2.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](O)=[O:19].C(N(C(C)C)CC)(C)C.O.ON1C2C=CC=CC=2N=N1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.CO.C(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[N:3]12[CH2:11][CH2:10][CH:7]([CH2:8][CH2:9]1)[N:6]([C:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=1)=[O:19])[CH2:5][CH2:4]2
Reactant: O=C(O)c1ccccn1
Reactant: C1CN2CCC(CC2)N1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(c1ccccn1)N1CCN2CCC1CC2
Reaction time: 12 h

Procedure:
To a stirred solution of 1,4-diazabicyclo[3.2.2]nonane dihydrochloride (120 mg, 0.60 mmol), picolinic acid (85 mg, 0.69 mmol), and diisopropylethylamine (0.45 mL, 2.6 mmol) in dry DMF (2 mL) at ambient temperature was added in succession 1-hydroxybenzotriazole hydrate (85 mg, 0.63 mmol) and TBTU (200 mg, 0.62 mmol). The resulting precipitous mixture was stirred for 12 hours, partitioned between water and chloroform, and extracted with chloroform (3×). The organic layers were combined, washed with water, brine, and dried. The resulting product obtained from concentration of the organic phases was subjected to chromatography on silica gel eluting with a chloroform (ammoniated) to 15% MeOH/chloroform gradient to give (1,4-diazabicyclo[3.2.2]non-4-yl)(pyridin-2-yl)methanone. MS (ES+) 232 (MH+).
Reaction SMILES: Br[C:2]1[C:7]([NH:8][S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[CH:6][C:5]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]2=[O:26])=[C:4]([F:27])[CH:3]=1.[C-]#N.[Na+].C(C1C=C[C:36](C)=[N:37]C=1)C>[Cl-].[Zn+2].[Cl-].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:36]([C:2]1[C:7]([NH:8][S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[CH:6][C:5]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[N:16]([CH3:25])[C:15]2=[O:26])=[C:4]([F:27])[CH:3]=1)#[N:37]
Reactant: CCS(=O)(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Br
Reactant: CCc1ccc(C)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Cl-]
Product: CCS(=O)(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1C#N
Temperature: 120 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
1.2 g (2.5 mmol) of 3-(4-bromo-5-ethylsulfonylamino-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)pyrimidinedione, 0.15 g of sodium cyanide and 0.04 g of zinc chloride were added to 5 ml of 5-ethyl-2-picoline and the mixture was stirred at 120° C. under an argon atmosphere for 1 hour. Next, 0.6 g of tetrakis(triphenylphosphine)palladium was added to the mixture, which was then heated with stirring for 10 hours. After the reaction was completed, the title compound was obtained with a yield of 90% as determined by the internal standard method in liquid chromatography.
Reaction SMILES: C(O)CCCCCCCCC(O)C.[OH:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]1>C(O)(=O)C>[OH:14][CH2:15][CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1
Reactant: OCC1CCC(O)CC1
Agent: CC(O)CCCCCCCCCO
Solvent: CC(=O)O
Product: O=C1CCC(CO)CC1
Temperature: 55 °C
Yield: 72.6 %

Procedure:
To acetic acid in which Ce (IV)/PFCP (50 mg, 0.027 mmole) and 200 mg of NaBrO3 were dispersed and dissolved, 1.0 mmole of 1,10-undecane diol and 1.0 mmole of 4-hydroxymethyl cyclohexanol were added, respectively. The reaction mixture was heated for three hours at 55° C. and the product was purified with a column chromatography to yield 154 mg (82% yield) of 10-undecane-1-ol and 93 mg (73% yield) of 4-hydroxymethyl cyclohexanone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.CN(C)C=O.[NH2:31][C@@H:32]([C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40]([OH:42])=[O:41])[CH2:33][C:34]([OH:36])=[O:35].CCN(CC)CC>CN(C=O)C>[C:34]([CH2:33][C@H:32]([C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40]([OH:42])=[O:41])[NH:31][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1)([OH:36])=[O:35]
Reactant: N[C@H](CC(=O)O)c1cccc(C(=O)O)c1
Reactant: COc1ccc(C(=O)O)cc1OC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N[C@H](CC(=O)O)c2cccc(C(=O)O)c2)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.8 %

Procedure:
Stir a solution of 3,4-dimethoxybenzoic acid (2.318 g, 12.59 mmol) and CDI (2.063 g, 12.59 mmol) in DMF (75 mL) at room temperature for 1 h. To this add 3-((R)-1-amino-2-carboxy-ethyl)-benzoic acid N,N-dimethyl-formamide complex HCl salt (1.606 g, 5.04 mmol) followed by Et3N (2.47 mL, 17.63 mmol), and stir the solution at room temperature for 24 h. Remove the DMF in vacuo at 40° C. and dry the residue to a gum. Redissolve in EtOAc (200 mL). Wash with 0.5 M HCl (200 mL) then water (200 mL) and brine (100 mL). Extract the aqueous layers with more EtOAc (200 mL), and dry the organics (Na2SO4) then concentrate to a gummy residue. Purify this by silica gel chromatography eluting with 50% hexane/EtOAc to 100% EtOAc. Pool fractions containing desired product (Rf=0.10 100% EtOAc) and triturate the residue in EtOAc/hexane to afford 693 mg 3-[(R)-2-carboxy-1-(3,4-dimethoxy-benzoylamino)-ethyl]-benzoic acid as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23]([O:25]C)=O)=[CH:14][C:12]=2[N:13]=1.[F:28][C:29]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:30]=1[NH2:31].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:21])([CH3:22])[O:20][C:16]=3[C:15]([C:23]([NH:31][C:30]3[CH:32]=[C:33]([F:37])[C:34]([F:36])=[CH:35][C:29]=3[F:28])=[O:25])=[CH:14][C:12]=2[N:13]=1
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cncc3Cl)[nH]c2c2c1OC(C)(C)C2
Reactant: Nc1cc(F)c(F)cc1F
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC1(C)Cc2c(c(C(=O)Nc3cc(F)c(F)cc3F)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Yield: 65.7 %

Procedure:
The title compound was prepared following the procedure described for Example-137 by using methyl 2-[(3,5-dichloropyridin-4-yl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylate (Step-1 of Intermediate-3, 0.250 g, 0.612 mmol), 2,4,5-trifluoroaniline (0.132 g, 0.9025 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL), dry toluene (10.0 mL) at room temperature to afford 0.210 g of the desired product. 1HNMR (DMSO-d6): δ 1.55 (s, 6H), 3.09 (s, 2H), 7.28 (s, 1H), 7.73 (q, J=10.2 Hz, 10.2 Hz, 1H), 8.43 (m, 3H), 10.02 (s, 1H), 11.00 (br s, 1H), 11.48 (br s, 1H); MS [M]+: 522.00.
Reaction SMILES: [CH3:1][C:2]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[CH:17][CH2:18][CH2:19][N:20]3[C:24](=O)C4=CC=CC=C4[C:21]3=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.O.NN.Cl>C(O)C>[CH3:1][C:2]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[CH:17][CH2:18][CH2:19][N:20]([CH3:24])[CH3:21])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c1C=Cc1ccccc1C2=CCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1cccc2c1C=Cc1ccccc1C2=CCCN(C)C

Procedure:
9.2 g. of 1-methyl-5-(3-phthalimidopropylidene)-5H-dibenzo[a,d]cycloheptene are dissolved in 100 ml. of ethanol, treated with 1.2 g. of hydrazine hydrate and heated for 6 hours under reflux conditions. An excess of concentrated hydrochloric acid is added, and the mixture is heated for an additional hour under reflux conditions. The reaction mixture is filtered warm. The solid residue is washed with warm ethanol, and the residual ethanol portions are evaporated to dryness. The residue is taken up in ether. The ethereal solution is washed with dilute sodium hydroxide solution, dried and evaporated whereby 1-methyl-5-(3-aminopropylidene)-5H-dibenzo[a,d]cycloheptene remains behind as a thick oil.
Reaction SMILES: [O:1]=[C:2]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:23][N:22]=[C:21]3[NH:31][CH:32]=[CH:33][C:20]=23)[CH2:15][CH2:14]1)[CH2:3][CH2:4][NH:5]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:5][CH2:4][CH2:3][C:2]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:23][N:22]=[C:21]3[NH:31][CH:32]=[CH:33][C:20]=23)[CH2:15][CH2:14]1)=[O:1]
Reactant: CC(C)(C)OC(=O)NCCC(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]ccc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCC(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 119.2 %

Procedure:
tert-Butyl 3-oxo-3-(4-(5-phenyl-1H-pyrrolo[2,3-b]pyri din-4-yl)piperazin-1-yl)propylcarbamate (0.054 g, 0.12 mmol) was placed in DCM (3 mL) at room temperature. TFA (0.3 mL) was added, and the reaction was stirred at room temperature for 1 hour. The reaction was then concentrated to dryness. The resulting residue was dissolved in minimal DCM and added to a stirring solution of 1M HCl in ether. The resulting solid was collected by filtration, washed with ether, and dried to give 3-amino-1-(4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)propan-1-one (0.050 g, 99% yield). MS ESI (+) m/z 350 detected.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH3:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=2)[CH:10]=1>F>[C:4]([C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[O:8][CH3:7])(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: COc1ccc2cc(OC)ccc2c1
Reactant: C=C1CC(=O)O1
Agent: F
Product: COc1ccc2c(C(=O)CC(C)=O)c(OC)ccc2c1
Reaction time: 8 h

Procedure:
33.6 g (0.4 mol) of diketene were added drop by drop, while stirring at -30°C, to 37.6 g (0.2 mol) of 2,6-dimethoxynaphthalene in 200 ml of anhydrous hydrofluoric acid and the mixture was stirred for another 8 hours at said temperature. The hydrogen fluoride was distilled off under reduced pressure at a temperature of the still of -30°C and the residue washed until it was free from acid. After sublimation of unreacted starting product (11 g = 71 % conversion) colorless crystals of 1-acetoacetyl-2,6-dimethoxynaphthalene melting at 88°C were obtained by column chromatography (silica gel, 0.065 - 0.2 mm, CH2Cl2) in an amount of 35 g (90 % calculated on 2,6-dimethoxynaphthalene).