Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.[CH3:32][N:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)N>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:33]([CH3:32])[C:35]3[C:40]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(F)c3)CC2)c1
Reactant: CN(N)c1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc(F)c4)n(C)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-methyl-1-phenylhydrazine: ESMS m/e: 512.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([C:11]1[CH:16]=[C:15]([NH2:17])[C:14]([CH3:18])=[CH:13][C:12]=1[Cl:19])C(OCC)=O)[CH3:2].[Cl-].[Li+]>CS(C)=O.O>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:11]1[CH:16]=[C:15]([NH2:17])[C:14]([CH3:18])=[CH:13][C:12]=1[Cl:19])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)c1cc(N)c(C)cc1Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)Cc1cc(N)c(C)cc1Cl
Temperature: 170 °C
Yield: 50.6 %

Procedure:
To a solution of 2-(5-amino-2-chloro-4-methyl-phenyl)-malonic acid diethyl ester (0.50 g, 2.17 mmol) in DMSO (3 ml) and water (0.078 ml) was added, followed by lithium chloride (0.138 g, 3.26 mmol). The mixture was heated to 170° C. for three hours, then cooled to room temperature. Water was added and the mixture was extracted with EtOAc. The combined extracts were washed with water and brine, dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Purification of the crude product by flash chromatography (hexanes:EtOAc 8:2) gave 0.250 g (50%) of (5-amino-2-chloro-4-methyl-phenyl)-acetic acid ethyl ester as a white foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:40])[NH:19][C@H:20]([C:36]([O:38][CH3:39])=[O:37])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)[CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:42])=[C:13]([NH2:41])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].Cl[CH:49]([C:53]1[CH:58]=[CH:57][C:56]([O:59][CH2:60][C:61]2[CH:66]=[CH:65][C:64]([Cl:67])=[C:63]([Cl:68])[CH:62]=2)=[CH:55][CH:54]=1)[C:50](Cl)=[O:51].C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O.O>[C:1]([O:5][C:6]([N:8]1[CH:17]([C:18](=[O:40])[NH:19][C@H:20]([C:36]([O:38][CH3:39])=[O:37])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:29]=[CH:30][C:31]([C:34]#[N:35])=[CH:32][CH:33]=3)=[CH:24][CH:23]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[C:12]([O:42][C@@H:49]([C:53]4[CH:58]=[CH:57][C:56]([O:59][CH2:60][C:61]5[CH:66]=[CH:65][C:64]([Cl:67])=[C:63]([Cl:68])[CH:62]=5)=[CH:55][CH:54]=4)[C:50](=[O:51])[NH:41]3)=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)C(Cl)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc(N)c(O)cc2CN1C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61.7 %

Procedure:
(S)-6-amino-3-[(S)-2-(4′-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-7-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.75 mmol) was dissolved in 5 mL EtOAc, 10 mL water and 15 g sodium bicarbonate added. 2-Chloro-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-acetyl chloride (1.93 mmol) in 5 mL EtOAc was added to the mixture. The resulting mixture stirred at r.t. for 1.5 h. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The resulting residue was dissolved in 5 mL DMF and potassium carbonate (8.75 mmol) added. The reaction stirred at r.t. for 3 h and was poured onto ethyl acetate and water. The organic was dried and concentrated. The residue was purified over silica gel (-hexanes-ethyl acetate) to provide (S)-7-[(S)-2-(4′-Cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylic acid tert-butyl ester (931 mg). LC-MS (m/z) 862.
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[CH:10]=[CH:9][C:8]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])=[CH:7][C:6]=1[N+:17]([O-:19])=[O:18]>CN(C)C=O.O>[N+:17]([C:6]1[CH:7]=[C:8]([S:11]([F:16])([F:12])([F:13])([F:14])[F:15])[CH:9]=[CH:10][C:5]=1[C:2]#[N:3])([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1cc(S(F)(F)(F)(F)F)ccc1Br
Reactant: N#C[Cu]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(S(F)(F)(F)(F)F)cc1[N+](=O)[O-]
Temperature: 14 °C
Reaction time: 1.25 h
Yield: 95.1 %

Procedure:
Copper (I) cyanide (5.05 g) was added to a stirred solution of 4-bromo-3-nitro-phenylsulphur pentafluoride (18.5 g) in N,N-dimethylformamide and heated at 14° C. for 4 hours. A mixture of ferric chloride (20.0 g),concentrated hydrochloric acid and water was added at 105° C. and heating continued for 1.25 hours. The cooled mixture was diluted with water, extracted (ether) and the organic phase washed (water), dried (magnesium sulphate) and evaporated to give 2-nitro-4-pentafluorosulphanylbenzonitrile (14.7 g), m.p.57-59° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:19]=O)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:23][Si](C[Mg]Cl)(C)C.S(Cl)(Cl)=O>C1COCC1.C(OCC)C>[F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:19]=[CH2:23])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: C[Si](C)(C)C[Mg]Cl
Reactant: O=Cc1ccccc1OS(=O)(=O)c1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: C=Cc1ccccc1OS(=O)(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 0.5 h

Procedure:
A dry, air-free, ice-cold solution of 2-formylphenyl 4-(trifluoromethyl)-benzenesulfonate (2.0 g, 6.1 mmol) in THF (7 mL) is treated with 6.8 mL of 1 M (trimethylsilylmethyl)magnesium chloride in diethyl ether. The reaction is stirred 30 minutes. Thionyl chloride (0.5 mL, 6.9 mmol) is added and the reaction is stirred at 0° C. for 1 h. The reaction is quenched with ice and extracted with ethyl acetate. The product is purified on silica gel in methylene chloride. A yield of 1.8 g of 2-vinylphenyl 4-(trifluoromethyl)benzenesulfonate is obtained.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][N:13]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]3[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][N:13]=3)[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=[N+]([O-])c1ccnc(N2CCN(C3CCCC3)CC2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccnc(N2CCN(C3CCCC3)CC2)c1
Yield: 95 %

Procedure:
A mixture of 2.85 g (10 mmol) 1-cyclopentyl-4-(4-nitro-pyridin-2-yl)-piperazine and 0.285 g Pd/C (10%) in 25 ml methanol was treated with 1 bar hydrogen at room temperature for 3 h. After filtration the mixture was evaporated to dryness to yield 2.34 g (92%) of the title compound as brownish solid. (m/e): 247.4 (MH+; 100%).
Reaction SMILES: [F:1][C:2]1[C:3]([C:18]2[NH:22][C:21]([CH3:23])=[C:20]([C:24]([O:26]CC)=[O:25])[CH:19]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([NH:13][C:14]1([CH3:17])[CH2:16][CH2:15]1)=[N:5]2.Cl>O.O1CCOCC1>[F:1][C:2]1[C:3]([C:18]2[NH:22][C:21]([CH3:23])=[C:20]([C:24]([OH:26])=[O:25])[CH:19]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([NH:13][C:14]1([CH3:17])[CH2:15][CH2:16]1)=[N:5]2
Reactant: CCOC(=O)c1cc(-c2c(F)ccc3nc(C)c(NC4(C)CC4)nc23)[nH]c1C
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc2ccc(F)c(-c3cc(C(=O)O)c(C)[nH]3)c2nc1NC1(C)CC1
Temperature: 80 °C
Yield: 15.2 %

Procedure:
A mixture of ethyl 5-(6-fluoro-2-methyl-3-((1-methyl-cyclopropyl)amino)quinoxalin-5-yl)-2-methyl-1H-pyrrole-3-carboxylate (417b) (0.555 g, 1.451 mmol), LiOH monohydrate (Sigma Aldrich, 365 mg, 8.71 mmol) in water (9 mL) and dioxane (18.00 mL) was heated to 80° C. overnight. Reaction mixture was then heated to 105° C. for an additional 4 h. Mixture was cooled back to RT and quenched with 4 M HCl in 1,4-dioxane (Sigma Aldrich, 2.177 mL, 8.71 mmol). Volatile solvents were removed by rotovap. The residue was loaded onto a silica gel samplet. Purification by Biotage (0-100% EtOAc/hexanes) produced 5-(6-fluoro-2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-2-methyl-1H-pyrrole-3-carboxylic acid (417c) (78 mg, 0.220 mmol, 15% yield). m/z (ESI, +ve) 355.0 (M+H).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:25]#[N:26])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1OC)[CH:9]=2)=[O:4].[NH2:27][C@H:28]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@@H:29]([OH:34])[C:30]([O:32][CH3:33])=[O:31].CCN(CC)CC>CO>[C:25]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:27][C@H:28]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@@H:29]([OH:34])[C:30]([O:32][CH3:33])=[O:31])=[O:4])[N:6]=1)#[N:26]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3OC)ccc2c1O
Reactant: COC(=O)[C@H](O)[C@H](N)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)[C@H](O)[C@@H](Cc1ccccc1)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 150 °C

Procedure:
A mixture of 1-cyano-4-hydroxy-7-(2-methoxy-phenoxy)-isoquinoline-3-carboxylic acid methyl ester (20 mg, 0.06 mmol), (2R,3R)-methyl 3-amino-2-hydroxy-4-phenylbutanoate (43 mg, 0.13 mmol) and Et3N (0.04 mL, 0.27 mmol) in MeOH (2 mL) was heated at 150° C. in a microwave for 3 hours. The solvent was removed in vacuo and the residue oil was purified by flash chromatography (0-10% EtOAc/CH2Cl2) to give the title compound in 7 mg. MS: (−) m/z 496.34 (M-1).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([NH2:10])[CH2:6][CH2:5]1.C(O[C:16]1[O:17][CH2:18][C:19](=[O:26])[C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])C>C(O)C>[O:26]=[C:19]1[CH2:18][O:17][C:16]([NH:10][N:7]2[CH2:8][CH2:9][N:4]([CH2:3][C:2]([F:1])([F:11])[F:12])[CH2:5][CH2:6]2)=[C:20]1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: NN1CCN(CC(F)(F)F)CC1
Reactant: CCOC(=O)C1=C(OCC)OCC1=O
Solvent: CCO
Product: CCOC(=O)C1=C(NN2CCN(CC(F)(F)F)CC2)OCC1=O
Reaction time: 2 h

Procedure:
To a solution of 4-(2,2,2-trifluoroethyl)piperazine-1-amine (4.72 g, 25.8 mmol) in ethanol (43 mL), ethyl 2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (4.70 g, 23.5 mmol) which similarly prepared according to the procedure described in the Example 74, Third step was added at ambient temperature. The mixture was stirred for 2 h. The precipitate was collected by filtration, washed with diethyl ether and hexane then dried to afford ethyl 4-oxo-2-{[4-(2,2,2-trifluoroethyl)piperazinyl]amino}-4,5-dihydrofuran-3-carboxylate as solid (5.64 g, y. 71%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[N:3]=1.[NH:21]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[N:22]1.O>C(Cl)Cl>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:24]3[CH:25]=[N:21][NH:22][CH:23]=3)[N:7]=[C:6]3[N:8]([CH3:11])[N:9]=[CH:10][C:5]=23)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc(Nc2nc(Cl)nc3c2cnn3C)c1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Solvent: O
Solvent: ClCCl
Product: COc1cccc(Nc2nc(-c3cn[nH]c3)nc3c2cnn3C)c1

Procedure:
6-Chloro-N-(3-methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 6 was reacted with pyrazole-4-boronic acid pinacol ester using General Procedure A. Addition of water and CH2Cl2 to the reaction, followed by sonication and filtration yielded 101. NMR: (CDCl3): 3.87 (s, 3H, CH3), 4.07 (s, 3H, CH3), 6.87 (dd, H, ArH, J=2.4, 8.37), 7.13 (d, H, ArH, J=7.85), 7.29 (m, H, ArH), 7.37 (t, H, ArH, J=8.13), 7.43 (s, H, ArH), 8.37 (s, 2H, 2×ArH). MS: (ESI+) MH+==322.23
Reaction SMILES: [CH:1]1([C:7]2[N:8]=[C:9]([NH:12][C:13]([C:15]([O:17]CC)=[O:16])=[O:14])[S:10][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH:1]1([C:7]2[N:8]=[C:9]([NH:12][C:13]([C:15]([OH:17])=[O:16])=[O:14])[S:10][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C(=O)Nc1nc(C2CCCCC2)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(O)C(=O)Nc1nc(C2CCCCC2)cs1
Reaction time: 0.17 h

Procedure:
Ethyl 4-cyclohexylthiazol-2-ylcarbamoylcarboxylate (1.41 g., 5 mmole) was combined with 40 ml. of water and 5 ml. of 1 N potassium carbonate (1 equivalent, 2.5 mmole) was heated on a steam bath for 15 minutes. After 10 minutes, tlc (chloroform-1% ethanol) indicated hydrolysis was almost complete. The hot reaction mixture was clarified by filtration, cooled in an ice-water bath and acidified with 10.5 ml. of 1 N hydrochloric acid. Product (1.02 g.) was recovered by filtration. Recrystallization from isopropyl alcohol gave purified 4-cyclohexylthiazol-2-ylcarbamoylcarboxylic acid [625 mg.; m.p. 198.5°-200.5° C. (dec)].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[CH:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][N:6]3[C:7]=2[C:3]=1[CH:4]=[C:5]3[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(N(CC)CC)C.CS(Cl)(=O)=O.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][N:6]3[C:7]=2[C:3]=1[CH:4]=[C:5]3[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)c1cc2c(Cl)ccc3c2n1CCCCC3O
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(Cl)ccc3c2n1CCCC=C3
Temperature: -20 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
A mixture of ethyl 5,6,7,8-tetrahydro-11-chloro-8-hydroxy-4H-azocino[3,2,1-hi]indole-2-carboxylate (0.70 g, 2.27 mmol), triethylamine (0.61 g, 6.00 mmol) and tetrahydrofuran (30 ml) was cooled to −20° C. with stirring, and methanesulfonyl chloride (0.31 g, 2.73 mmol) was added dropwise. After completion of the dropwise addition, the reaction temperature was raised to room temperature and the reaction mixture was allowed to stand overnight at room temperature. The reaction mixture was poured into an aqueous ammonium chloride solution and extracted twice with ethyl acetate, and the extract solution was washed with an aqueous sodium hydrogencarbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/98) to obtain 0.63 g of ethyl 5,6-dihydro-11-chloro-4H-azocino[3,2,1-hi]indole-2-carboxylate.
Reaction SMILES: CN(C)[CH:3]([N:20]([CH3:22])C)[CH:4]([O:7][C:8]1[CH:16]=[C:15]([CH3:17])[C:11]2[S:12][CH:13]=[CH:14][C:10]=2[C:9]=1[CH2:18][CH3:19])[C:5]#[N:6].Cl.N[C:26]1[CH:31]=[CH:30]C=[CH:28][CH:27]=1.Cl.NC(N)=N.C[O-].[Na+].NC(N)=N>C(O)C>[CH2:18]([C:9]1[C:10]2[CH:14]=[CH:13][S:12][C:11]=2[C:15]([CH3:17])=[CH:16][C:8]=1[O:7][C:4](=[CH:3][NH:20][C:22]1[CH:30]=[CH:31][CH:26]=[CH:27][CH:28]=1)[C:5]#[N:6])[CH3:19]
Reactant: Nc1ccccc1
Reactant: CCc1c(OC(C#N)C(N(C)C)N(C)C)cc(C)c2sccc12
Agent: C[O-]
Agent: Cl
Agent: N=C(N)N
Solvent: CCO
Product: CCc1c(OC(C#N)=CNc2ccccc2)cc(C)c2sccc12
Yield: 55 %

Procedure:
3,3-Bis-dimethylamino-2-(4-ethyl-7-methyl-benzo[b]thiophen-5-yloxy)-propionitrile (590 mg, 2 mmol) and aniline HCl (1.1 g, 9 mmol) in 5 mL absolute ethanol were heated at reflux for 2.0 hours. In a separate flask, guanidine HCl (0.850 mg., 9 mmol) and sodium methoxide solution (1.83 ml, 9 mmol, 4.9 molar solution in methanol) were mixed in 1 ml Ethanol. The guanidine solution was added to the reaction mixture via pipette, and the reaction mixture was heated to reflux for 5 hours, then cooled. Solvent was removed in vacuo, and the residue was, chromatographed (5% MeOH/methylene chloride/1% NH4OH) to give 368 mg 2-(4-Ethyl-7-methyl-benzo[b]thiophen-5-yloxy)-3-phenylamino-acrylonitrile, 61% . Also present was 50 mg of 5-(4-Ethyl-7-methyl-benzo[b]thiophen-5-yloxy)-pyrimidine-2,4-diamine, 9% .
Reaction SMILES: [CH3:1][C@H:2]([C:15]([OH:17])=[O:16])[C:3]1[CH:8]=[CH:7][C:6]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:5]=2[CH:4]=1.[F:18][C:19]([F:27])([C:23]([F:26])([F:25])[F:24])[CH:20](O)[CH3:21].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:14][O:13][C:10]1[CH:9]=[C:6]2[C:5](=[CH:12][CH:11]=1)[CH:4]=[C:3]([CH:2]([CH3:1])[C:15]([O:17][C@H:20]([C:19]([F:27])([F:18])[C:23]([F:26])([F:25])[F:24])[CH3:21])=[O:16])[CH:8]=[CH:7]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: CC(O)C(F)(F)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc2cc(C(C)C(=O)O[C@@H](C)C(F)(F)C(F)(F)F)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (S)-naproxen (9.23 g, 40.1 mmol), racemic 3,3,4,4,4-pentafluoro-2-butanol (6.58 g, 40.1 mmol), EDC (9 20 g, 48.0 mmol) and DMAP (4.89 g, 40.0 mmol) was dissolved in CH2Cl2 (40 mL) at room temperature. After stirring for 8 h at room temperature, the mixture was diluted with CH2Cl2, then washed successively with 1 N HCl, sat. NaHCO3, and brine. After drying over Na2SO4 and concentrating, a mixture of diastereomeric naproxen esters was obtained as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[N:9])[N:3]=1.[O-:10][CH2:11][CH3:12].[Na+]>O1CCCC1>[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:10][CH2:11][CH3:12])[N:3]=1)#[N:9]
Reactant: N#Cc1cccc(Cl)n1
Reactant: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1cccc(C#N)n1
Yield: 14.1 %

Procedure:
A mixture of 2-chloro-6-cyanopyridine (1.00 g, 7.2 mmol), sodium ethoxide (0.54 g, 7.9 mmol) and tetrahydrofuran (100 ml) was refluxed for 18 hrs. The reaction mixture was concentrated under reduced pressure, diluted with ice-water and extracted with ethyl acetate. The extract was washed with saturated brine and dried. The solvent was evaporated under reduced pressure. The residue was subjected to a silica gel column chromatography and eluted with hexane-ethyl acetate (5:1, v/v) to give the titled compound (0.15 g, 14%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].B>O1CCCC1>[Cl:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:7][CH:8]=[CH:9][C:10]=1[OH:11]
Reactant: O=C(O)c1cccc(O)c1Cl
Agent: B
Solvent: C1CCOC1
Product: OCc1cccc(O)c1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
A solution of 2-chloro-3-hydroxybenzoic acid (2.59 g, 15 mmol) in tetrahydrofuran was added dropwise to a solution of borane (48 mmol) in tetrahydrofuran (150 mL) at a temperature of 0° C. The reaction mixture was then warmed to 60° C. and allowed to stir overnight. Upon cooling, the mixture was quenched with water and made basic with 3M sodium hydroxide. The aqueous layer was separated, acidified with 3M hydrochloric acid, and extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. Recrystallization from ethanol/hexane gave 2-chloro-3-hydroxymethylphenol as a white crystalline solid (1.63 g, 64.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:28]=[C:27]4[C:18]([N:19]5[CH:24]([C:25](=[O:29])[NH:26]4)[CH2:23][NH:22][CH2:21][CH2:20]5)=[N:17][CH:16]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:30](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:15]3[CH:28]=[C:27]4[C:18]([N:19]5[CH:24]([C:25](=[O:29])[NH:26]4)[CH2:23][N:22]([CH3:30])[CH2:21][CH2:20]5)=[N:17][CH:16]=3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1Nc2cc(CN3CCN(c4ccc(Cl)cc4)CC3)cnc2N2CCNCC12
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1CCN2c3ncc(CN4CCN(c5ccc(Cl)cc5)CC4)cc3NC(=O)C2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 3.2 %

Procedure:
To a solution of 7-[4-(4-Chloro-phenyl)-piperazin-1-ylmethyl]-1,3,4,10a-tetrahydro-2H,9H-2,4a,5,9-tetraaza-phenanthren-10-one (139 mg, 0.337 mmol) in DMF (3.4 mL) cooled to 0° C. was added potassium carbonate (233 mg, 1.683 mmol) and methyl iodide (2 M in THF, 0.168 mL). The reaction was stirred 1 h at 0° C. and filtered through celite. The filtrate was purified via HPLC (55-90% acetonitrile in water, ammonium bicarbonate buffer). The fractions were combined and concentrated until a white solid precipitated. The precipitate was filtered off and dried in vacuum to afford the title compound (4.6 mg, 3.2%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.59 (s, 1H), 7.68 (d, J=1.8 Hz, 1H), 7.15-7.28 (m, 2H), 7.01 (d, J=2.0 Hz, 1H), 6.85-6.97 (m, 2H), 4.17-4.30 (m, 1H), 3.88 (dd, J=10.6, 3.3 Hz, 1H), 3.37 (s, 2H), 3.14-3.20 (m, 1H), 3.06-3.14 (m, 4H), 2.84 (d, J=11.6 Hz, 1H), 2.74 (td, J=12.4, 3.0 Hz, 1H), 2.44-2.48 (m, 4H), 2.26 (s, 3H), 1.91-2.02 (m, 2H). [M+H] calc'd for C22H27ClN6O, 427. found, 427.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=3)[CH:10]=[CH:9][C:8]2=[O:22])=[CH:4][CH:3]=1.[CH3:25][Mg]Br>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:21])([CH3:25])[CH3:20])=[CH:15][CH:14]=3)[CH:10]=[CH:9][C:8]2=[O:22])=[CH:23][CH:24]=1
Reactant: C[Mg]Br
Reactant: CC(=O)c1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3)c2)cc1
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3)c2)cc1
Temperature: -50 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
According to Scheme 20: To a solution of 1-(4-chlorobenzyl)-5-(4-acetylphenyl)pyridin-2(1H)-one (1 eq, 0.20 mmol, 80 mg) in THF (5 mL) at −50° C. was added a solution of methyl magnesium bromide (3M, 1.3 eq, 0.30 mmol, 0.04 g) and the reaction stirred at −50° C. for 1 hour. The reaction was quenched at −78° C. with saturated aqueous NH4Cl. The reaction was allowed to warm to room temperature and diluted with AcOEt and the organic phase extracted (×3). The combined organic fractions were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 25 g SiO2) using CH2Cl2/AcOEt 80/20 and was recrystallized from pentane/Et2O to afford 1-(4-chlorobenzyl)-5-(4-(2-hydroxypropan-2-yl)phenyl)pyridin-2(1H)-one (0.08 mmol, 30 mg, 36%) as a white solid.