Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1>>[CH2:25]([N:3]([CH2:1][CH3:2])[C:4](=[O:24])[C:5]1[CH:6]=[CH:7][C:8]([C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]2[CH2:13][CH2:14][N:15]([CH2:33][C:32]3[CH:35]=[CH:36][C:29]([O:28][CH3:27])=[CH:30][CH:31]=3)[CH2:16][CH2:17]2)=[CH:9][CH:10]=1)[CH3:26]
Reactant: COc1ccc(CCl)cc1
Reactant: CCN(CC)C(=O)c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Product: CCN(CC)C(=O)c1ccc(C(=C2CCN(Cc3ccc(OC)cc3)CC2)c2ccccc2)cc1
Yield: 68.6 %

Procedure:
Method as described for Example 4, using compound 6 (174 mg) and 4-methoxybenzyl chloride (78 mg) provided N,N-diethyl-4-[(N-4-methoxybenzyl)-phenyl-piperidin-4-ylidene-methyl]-benzamide (160 mg, 68%):
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10]([NH:11][NH2:12])=[CH:9][C:8](=[O:13])[N:7]([CH3:14])[C:6]2=[O:15])[CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][N:21]=[C:20]2[CH:26]=O.[CH:28]([C:30]1[N:34]([CH3:35])[CH:33]=[C:32]([C:36]([OH:38])=[O:37])[CH:31]=1)=O>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][N:21]=[C:20]2[CH2:26][N:12]1[C:28]([C:30]2[N:34]([CH3:35])[CH:33]=[C:32]([C:36]([OH:38])=[O:37])[CH:31]=2)=[C:9]2[C:10]([N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[C:6](=[O:15])[N:7]([CH3:14])[C:8]2=[O:13])=[N:11]1
Reactant: Cn1cc(C(=O)O)cc1C=O
Reactant: Cn1c(=O)cc(NN)n(CC2CC2)c1=O
Reactant: O=Cc1n[nH]c2ccc(Cl)cc12
Product: Cn1cc(C(=O)O)cc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1n[nH]c2ccc(Cl)cc12

Procedure:
This compound was made following the procedure described above, starting with 1-(cyclopropylmethyl)-6-hydrazino-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 5-chloro-1H-indazole-3-carbaldehyde, followed by 5-formyl-1-methyl-1H-pyrrole-3-carboxylic acid. Mass: 508.13 (M+H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[NH2:34][CH:35]([CH2:38][OH:39])[CH2:36][OH:37]>>[C:28]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:29]=[CH:30][C:31]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:34][CH:35]([CH2:38][OH:39])[CH2:36][OH:37])=[O:18])=[O:7])=[CH:32][CH:33]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: NC(CO)CO
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)NC(CO)CO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]4-carbonyl chloride, and 2-amino-1,3-propanediol, the title compound was obtained in 61% purity by HPLC. MS(ESI+): m/z=412.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:14][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([O:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([CH:12]=[O:13])=[CH:10]2
Reactant: Oc1ccccc1
Reactant: O=Cc1cc2cccc(Cl)c2nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc2cccc(Cl)c2nc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2,8-dichloroquinoline-3-carbaldehyde (1 eq) in DMF (0.25 M) was added phenol (1.5 eq) and K2CO3 (2.0 eq) at rt and the mixture was stirred for 3 h at rt. The mixture was diluted with water, extracted with EtOAc (2 times) and the combined organic layers were washed with water (2 times), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on a Redi-Sep™ column using 0 to 40% gradient of EtOAc in hexane to provide 8-chloro-2-phenoxyquinoline-3-carbaldehyde.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=O)[C:9]([CH3:12])([CH3:11])[CH3:10].[Li]CCCC.[NH4+].[Cl-]>C1COCC1>[C:9]([C:8]1[NH:7][C:2]2[C:1]([CH:14]=1)=[CH:6][CH:5]=[CH:4][CH:3]=2)([CH3:12])([CH3:11])[CH3:10]
Reactant: Cc1ccccc1NC(=O)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc2ccccc2[nH]1
Temperature: 15 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
To a solution of N-o-tolylpivalamide (30.0 g, 159 mmol) in dry THF (100 mL) was added dropwise n-BuLi (2.5 M in hexane, 190 mL) at 15° C. After addition, the mixture was stirred overnight at 15° C. The mixture was cooled in an ice-water bath and treated with saturated NH4Cl. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was purified by column chromatography on silica gel to give 2-tert-butyl-1H-indole (24 g, 88%). 1H NMR (300 MHz, CDCl3) δ 7.99 (br. s, 1H), 7.54 (d, J=7.2 Hz, 1H), 7.05 (d, J=7.8 Hz, 1H), 7.06-7.13 (m, 2H), 6.26 (s, 1H), 1.39 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([CH2:14][CH2:15][F:16])[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20].[C:21]([O:25][C:26]([NH:28][C@H:29]1[C@@H:33]([CH3:34])[CH2:32][NH:31][CH2:30]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:21]([O:25][C:26]([NH:28][C@H:29]1[C@@H:33]([CH3:34])[CH2:32][N:31]([C:11]2[C:10]([F:13])=[C:9]3[C:4]([C:5](=[O:20])[C:6]([C:17]([OH:19])=[O:18])=[CH:7][N:8]3[CH2:14][CH2:15][F:16])=[CH:3][C:2]=2[F:1])[CH2:30]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=C(O)c1cn(CCF)c2c(F)c(F)c(F)cc2c1=O
Reactant: C[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[C@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(CCF)c3c2F)C[C@H]1NC(=O)OC(C)(C)C
Yield: 62.8 %

Procedure:
A mixture of 6,7,8-trifluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.5 g), anhydrous acetonitrile (5 ml), cis-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.5 g) and DBU (0.27 g) was refluxed for an hour and then concentrated. The resulting residue was dissolved in chloroform and the solution was washed with 10% aqueous citric acid solution. After concentration of the chloroform layer, the resulting precipitate was triturated in water, and collected by filtration and washed with water, methanol and ether successively to give the title compound (0.51 g) as white powder, mp 217°-219° C.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH2:16])[CH:11]=[CH:12][C:13]=1[Cl:14].[CH:17]([Br:20])(Br)[Br:18]>O>[Br:18][C:17]1([Br:20])[CH2:16][CH:15]1[C:10]1[CH:11]=[CH:12][C:13]([Cl:14])=[C:8]([Cl:7])[CH:9]=1
Reactant: BrC(Br)Br
Reactant: C=Cc1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: Clc1ccc(C2CC2(Br)Br)cc1Cl
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
Potassium t-butoxide (5.1 g.) was added to a stirred mixture of 3,4-dichlorophenylethylene (6.1 g.), bromoform (8.9 g.) and petroleum ether (b.p. 60°-80° C.; 100 ml.) which was cooled to -30° C., and the mixture was stirred at that temperature for 30 minutes, then at laboratory temperature for 17 hours and then poured into water. The mixture was extracted with ethyl acetate and the extract was washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated to dryness under reduced pressure The residue was purified by chromatography on a silica gel column using petroleum ether (b.p. 40°-60° C.) as eluant, and there was thus obtained as an oil 1,1-dibromo-2-(3,4-dichlorophenyl)cyclopropane.
Reaction SMILES: O[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[Br-:19].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(O)C>[Br:19][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: [Br-]
Reactant: O=c1cc(-c2cccnc2)c2ccc(O)cc2o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Product: O=c1cc(-c2cccnc2)c2ccc(Br)cc2o1

Procedure:
Commercially available 7-hydroxy-4-(3-pyridyl)coumarin (1.48 g, 6.19 mmol) and triphenylphosphine dibromide (5.22 g, 12.4 mmol) are heated in a sand bath at 320-350° C. for 1.5 h. The cooled solid is taken up with ethanol (200 ml) and silica gel (100 g) and evaporated to dryness. Column chromatography (toluene/acetone; 80:20) affords 7-bromo-4-pyridin-3-yl-2H-chromen-2-one.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:13])[O:8][CH2:9][CH:10]([F:12])[F:11])[C@H:3]1[C:14]([OH:16])=[O:15].[C:18]([C@H:20](O)[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1)#[N:19]>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:17])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:13])[O:8][CH2:9][CH:10]([F:11])[F:12])[C@H:3]1[C:14]([O:16][C@@H:20]([C:18]#[N:19])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:22]=1)=[O:15]
Reactant: N#C[C@H](O)c1cccc(Oc2ccccc2)c1
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1/C=C\C(=O)OCC(F)F
Solvent: ClC(Cl)Cl
Product: CC1(C)[C@H](C(=O)O[C@@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)OCC(F)F

Procedure:
Using the procedure of Step F of Example 9, (1R,cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-(2,2-difluoroethoxy)-1 propenyl]-cyclopropane-carboxylic acid and (R)α-cyano-3-phenoxy-benzyl alcohol were reacted to obtain (R)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-(2,2-difluoroethoxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+117.5°±3° (c=0.6% in chloroform).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=O)=[C:4]([O:11][CH3:12])[CH:3]=1.[NH:13]([C:15](=[S:17])[NH2:16])[NH2:14].P(Cl)(Cl)(Cl)=O>>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:17][C:15]([NH2:16])=[N:13][N:14]=2)=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(I)ccc1C(=O)O
Reactant: NNC(N)=S
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(I)ccc1-c1nnc(N)s1
Temperature: 78 °C
Reaction time: 1 h
Yield: 16.2 %

Procedure:
To an ice cooled mixture of 4-iodo-2-methoxybenzoic acid (6.178 g, 22.22 mmol) and hydrazinecarbothioamide (2.43 g, 26.7 mmol) was added phosphorous oxychloride (6.21 mL, 66.7 mmol) slowly. The mixture was heated at 78° C. overnight. After cooling to 0° C., ice water was added and the mixture was vigorously stirred for 1 hour. The resulting precipitate was filtered, washed with water, and re-suspended in saturated NaHCO3(aq) and water (1:1) for 1 hour. The solid was filtered, washed with water, and dried in vacuo to afford the crude compound. The crude material was purified by flash chromatography (MeOH/CH2Cl2) to afford the title compound (1.2 g, 16% yield). MS m/z 334.0 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([CH:15](O)[CH3:16])[CH2:11][CH2:10]1.C(=O)([O-])[O-:19].[K+].[K+]>CS(C)=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][OH:19])[CH2:11][CH2:10]2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CC(O)C1CCNCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: OCCC1CCN(c2ccc(Br)cn2)CC1
Temperature: 160 °C

Procedure:
An autoclave is charged with 11 g (46.43 mmol) of 2,5-dibromopyridine, 6 g (46.43 mmol) of piperidin-4-ylethanol and 6.74 g (48.76 mmol) of potassium carbonate in 8 ml of DMSO. This charge is subsequently heated at 160° C. for 20 hours.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][OH:28])=[O:24])[C:5]1=[O:29].[CH:30]([N:33]([CH:36](C)C)[CH2:34]C)(C)C.CC[OH:41]>CN(C=O)C>[CH3:30][N:33]([CH3:36])[C:34]([NH:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][OH:28])=[O:24])[C:5]1=[O:29])=[O:41]
Reactant: NCCn1c(=O)c(C(=O)NCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Reactant: CCO
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)NCCn1c(=O)c(C(=O)NCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Reaction time: 2 h

Procedure:
A solution of 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(2-hydroxyethyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.019 g, 0.047 mmol) and diisopropyl ethylamine (0.15 mL, 0.86 mmol) in DMF (1.2 mL) under nitrogen was treated with N,N-dimethyl carbonyl chloride (0.0038 mL, 0.041 mmol) at ambient temperature. After 2 h, added EtOH (0.25 mL) and concentrated in vacuo. The resulting residue suspended in 1 N NaHSO4 the refrigerated overnight. Purified by reversed phase HPLC to provide the title compound from pure fraction concentrated in vacuo as an off-white solid: 1H NMR (300 MHz, DMSO-D6) δ ppm 2.7 (s, 6 H), 3.3 (s, 4 H), 3.4 (t, J=5.5 Hz, 2 H), 3.6 (t, J=5.3 Hz, 2 H), 4.1 (s, 2 H), 4.2 (t, J=6.0 Hz, 2 H), 4.9 (m, 1 H), 6.5 (m, 1 H), 7.1 (t, J=8.9 Hz, 2 H), 7.4 (m, 2 H), 8.3 (s, 1 H), 8.5 (s, 1 H), 10.4 (s, 1 H); ES− MS: 472 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][CH2:7][N:8]([C:17](=[O:25])[C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[N:12]=1.C(N(CC)CC)C.[CH3:33][C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36](Cl)=[O:37]>C(Cl)Cl>[CH3:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][CH2:7][N:8]([C:17]([C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:36](=[O:37])[C:35]4[CH:39]=[CH:40][CH:41]=[CH:42][C:34]=4[CH3:33])=[CH:22][CH:23]=3)=[O:25])[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[N:12]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Cc1ncc2c(n1)-c1ccccc1N(C(=O)c1ccc(N)cc1)CC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ncc2c(n1)-c1ccccc1N(C(=O)c1ccc(NC(=O)c3ccccc3C)cc1)CC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 0.216 mg of 6,7-dihydro-2-methyl-7-(4-aminobenzoyl)-5H-pyrimido[5,4-d][1]benzazepine in 6 ml of methylene chloride under argon is added 100 μl of triethylamine followed by a solution of 94 μl of 2-methylbenzoyl chloride in 1.5 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours, washed with water, saturated NaHCO3 and the separated organic layer treated with activated carbon and filtered through MgSO4. The filtrate is evaporated to a residue which is dissolved in ethyl acetate and evaporated in vacuo to give 300 mg of the desired product as a pale yellow foam. HR FABMS: Exact Mass (M+H):449.1974.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:11][C:12]1[CH:13]=[C:14]([CH2:18][CH2:19][NH2:20])[CH:15]=[CH:16][CH:17]=1)[CH2:8][CH2:9][CH3:10].[CH:21]1([CH:27]=[CH:28][C:29](Cl)=[O:30])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.O>C(#N)C>[CH:21]1([CH:27]=[CH:28][C:29]([NH:20][CH2:19][CH2:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH2:7][CH2:8][CH2:9][CH3:10])[CH:13]=2)=[O:30])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(Cl)C=CC1CCCCC1
Reactant: CCCCOc1cccc(CCN)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCCOc1cccc(CCNC(=O)C=CC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
Powdered potassium carbonate (4.5 g) was added to a solution of 2-(3-butyloxyphenyl)ethylamine (4.12 g) in acetonitrile (55 cm3). A solution of 3-cyclohexylacryloyl chloride (3.66 g) in acetonitrile (20 cm3) was added dropwise over fifteen minutes and the reaction mixture was then stirred at room temperature for 2 hours. Following treatment with distilled water (75 cm3) and SVM (3 cm3), a white precipitate was formed. This was filtered off and sucked dry to give the product (3.76 g) m.p. 67°-71° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=O)[CH3:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22]>CN(C)C=O>[F:1][C:2]1[C:3]2[C:9]([CH3:10])=[C:19]([C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[O:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1c(O)cccc1F
Reactant: CC(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)C(C)C)oc2cccc(F)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.4 %

Procedure:
To a solution (25 mL) of 1-(2-fluoro-6-hydroxyphenyl)ethanone (1.3 g) in N,N-dimethylformamide were added potassium carbonate (3.5 g) and 1-bromo-3-methylbutan-2-one (1.7 g) synthesized in Example A75(1) at room temperature, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was allowed to cool to room temperature, and filtered through celite. Water was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in N,N-dimethylformamide (15 mL) again, 1,8-diazabicyclo[5.4.0]undec-7-ene (1.3 mL) was added to the mixture, and the mixture was stirred at 110° C. for 1 hr with heating. After cooling to room temperature, the reaction mixture was quenched with 1N hydrochloric acid, and the mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure, and the precipitated compound was recrystallized from diisopropyl ether-hexane to give the title object compound (1.4 g, 77%) as a colorless solid.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:17][C:18]([C:20]2[C:29]3[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=3[CH:23]=[CH:22][CH:21]=2)=[O:19])[C@H:14]([CH3:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@@H:7]1[CH3:16])=[O:5])C.[OH-].[K+].O>CCO>[CH3:16][C@H:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:14]([CH3:15])[C:6]1([NH:17][C:18]([C:20]1[C:29]2[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=2[CH:23]=[CH:22][CH:21]=1)=[O:19])[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)C1(NC(=O)c2cccc3c2CCCC3)[C@H](C)c2ccccc2[C@@H]1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[C@@H]1c2ccccc2[C@H](C)C1(NC(=O)c1cccc2c1CCCC2)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.1 %

Procedure:
The mixture of (cis)-1,3-dimethyl-2-[(5,6,7,8-tetrahydro-naphthalene-1-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (76) (62 mg, 1.2 mmol) and KOH (300 mg, 5.4 mmol) is dissolved in EtOH (3 mL) and water (0.3 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until pH˜4. The precipitate is filtered to give a pure product (77) as white solid (44 mg, 75%).
Reaction SMILES: [SH:1][C:2]1[NH:10][C:9]2[C:4](=[N:5][CH:6]=[N:7][C:8]=2[NH2:11])[N:3]=1.CC1C=CC2C=CC3C=CC(C)=NC=3C=2N=1.O.O(C(C)(C)C)[Na].[Br:35][C:36]1[C:44](I)=[CH:43][C:39]2[O:40][CH2:41][O:42][C:38]=2[CH:37]=1>[Cu]I.CN(C=O)C>[Br:35][C:36]1[C:44]([S:1][C:2]2[NH:10][C:9]3[C:4](=[N:5][CH:6]=[N:7][C:8]=3[NH2:11])[N:3]=2)=[CH:43][C:39]2[O:40][CH2:41][O:42][C:38]=2[CH:37]=1
Reactant: Brc1cc2c(cc1I)OCO2
Reactant: Nc1ncnc2nc(S)[nH]c12
Agent: [Cu]I
Agent: CC(C)(C)O[Na]
Agent: Cc1ccc2ccc3ccc(C)nc3c2n1
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncnc2nc(Sc3cc4c(cc3Br)OCO4)[nH]c12
Temperature: 110 °C
Reaction time: 24 h
Yield: 97.9 %

Procedure:
8-Mercaptoadenine (602 mg, 3.6 mmol), neocuproine hydrate (81 mg, 0.36 mmol), CuI (69 mg, 0.36 mmol), NaO-t-Bu (692 mg, 7.2 mmol), 5-bromo-6-iodo-benzo[1,3]dioxole (3.53 g, 10.8 mmol) and anhydrous DMF (24 mL) were charged in a nitrogen box. The vessel was sealed with Teflon tape, placed in an oil bath (110° C.) and magnetically stirred for 24 h. The solvent was removed under high vacuum and the crude purified by column chromatography on silica gel (EtOAc:CH2Cl2:MeOH at 2:2:1) to provide the product (1.29 g, 97%). 1H NMR (400 MHz, acetone-d6) 8.07 (s, 1H), 7.28 (s, 1H), 7.15 (s, 1H), 7.08 (bs, 2H), 6.13 (s, 2H); MS m/z 366.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:12])[N:5]=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[ClH:1].[NH:13]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:12])[N:5]=[CH:4][N:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Clc1cccc2ncnc(Cl)c12
Reactant: Nc1ccccc1
Solvent: CCO
Product: Cl
Product: Clc1cccc2ncnc(Nc3ccccc3)c12
Yield: 41 %

Procedure:
A solution of 3.0 g of 4,5-dichloroquinazoline and 1.4 g of aniline in 20 ml of ethanol was heated, whereupon a violet reaction occurred and the reaction mixture solidified. After cooling, the solidified product was collected and recrystallized from ethanol to give 1.8 g (yield 46%) of the desired Compound No. 2 in the form of a pale yellow powder melting at 263°-267° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6](Cl)[N:5]2[N:15]=[CH:16][CH:17]=[C:4]2[N:3]=1.[CH3:18][O-:19].[Na+]>CO.ClCCl.O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([O:19][CH3:18])[N:5]2[N:15]=[CH:16][CH:17]=[C:4]2[N:3]=1
Reactant: Clc1nc2ccnn2c(Cl)c1-c1ccccc1
Reactant: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COc1c(-c2ccccc2)c(Cl)nc2ccnn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.00 g 5,7-dichloro-6-phenylpyrazolo[1,5-a]pyrimidine (prepared as described under example 19) are dissolved in 20 ml methanol and 20 ml dichlormethane. 1.2 g sodium methylate is added at 0° C. and stirred at room temperature for 2 h. The solution is diluted with water and dichloromethane. The organic phase separated and the water phase is extracted with dichloromethane. The combined organic layers are dried over Na2SO4 and the solvent is evaporated. The crude product is used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[CH2:9]([C:16]([C:18]([F:21])([F:20])[F:19])=O)[C:10]([C:12]([F:15])([F:14])[F:13])=O>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]2[C:4](=[N:8][C:10]([C:12]([F:13])([F:14])[F:15])=[CH:9][C:16]=2[C:18]([F:19])([F:21])[F:20])[N:3]=1
Reactant: Nc1cccc(N)n1
Reactant: O=C(CC(=O)C(F)(F)F)C(F)(F)F
Product: Nc1ccc2c(C(F)(F)F)cc(C(F)(F)F)nc2n1

Procedure:
A process as claimed in claim 1 wherein 2,6-diaminopyridine is reacted with 1,1,1,5,5,5-hexafluoroacetylacetone to provide 2-amino-5,7-di(trifluoromethyl)-1,8-naphthyridine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:7]#[N:8])([O-])=O.C(O)(=O)C.[Sn](Cl)Cl>CCO.O>[NH2:1][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=1)[C:7]#[N:8]
Reactant: N#Cc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: N#Cc1cc(N)cc(C(F)(F)F)c1
Temperature: 80 °C
Yield: 49.5 %

Procedure:
To a solution of 3-nitro-5-(trifluoromethyl)benzonitrile (500 mg, 2.31 mmol) and acetic acid (6.62 mL, 116 mmol) in EtOH (10 mL) and water (10 mL) is added tin (II) chloride (2.61 g, 11.6 mmol) and the reaction mixture is heated at 80° C. for 6 h. The solvent is removed in vacuo and then the residue is portioned between DCM and 4 N HCl solution. The organic layer separated and then dried over anhydrous Na2SO4, filtered and concentrated. The residue is then separated via FCC (10-100% EtOAc/heptane) to give the compound as a yellow oil (213 mg, 49%). MS (ESI) m/z 185.3 (M+1).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([O:21][C:22](=[O:46])[C:23]([CH3:45])([CH3:44])[C:24]([C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([O:36][Si](C(C)(C)C)(C)C)[CH:32]=2)[CH:27]=1)=[O:25])[CH3:20]>C1COCC1.C(OCC)(=O)C>[CH2:19]([O:21][C:22](=[O:46])[C:23]([CH3:45])([CH3:44])[C:24]([C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([OH:36])[CH:32]=2)[CH:27]=1)=[O:25])[CH3:20]
Reactant: CCOC(=O)C(C)(C)C(=O)c1ccc2cc(O[Si](C)(C)C(C)(C)C)ccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)C(=O)c1ccc2cc(O)ccc2c1

Procedure:
Tetrabutylammonium floride 1M in THF (78 mL, 78 mmol) was added to a solution of 3-[6-(tert-butyl-dimethyl-silanyloxy)-naphthalen-2-yl]-2,2-dimethyl-3-oxo-propionic acid ethyl ester (77.1 mmol) in THF (300 mL) at room temperature for 0.5 h. The reaction was taken up in ethyl acetate, washed with water (2×) and brine, dried over magnesium sulfate, and concentrated to give the 3-(6-Hydroxy-naphthalen-2-yl)-2,2-dimethyl-3-oxo-propionic acid ethyl ester as a crude oil.