Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=O)[CH:5]([Na])[C:6]([O:8]CC)=[O:7])C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:31])[C:21]2[CH:26]=C(Cl)[CH:24]=[CH:23][C:22]=2[N+:28]([O-:30])=[O:29])=[CH:16][CH:15]=1.O.C(O)(=O)C>C(OCC)(=O)CC(OCC)=O>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([C:21]2[CH:26]=[C:4]([CH2:5][C:6]([OH:8])=[O:7])[CH:24]=[CH:23][C:22]=2[N+:28]([O-:30])=[O:29])=[O:31])=[CH:18][CH:19]=1
Reactant: CCOC(=O)C([Na])C(=O)OCC
Reactant: O=C(c1ccc(Cl)cc1)c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CCOC(=O)CC(=O)OCC
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)Cc1ccc([N+](=O)[O-])c(C(=O)c2ccc(Cl)cc2)c1
Temperature: 90 °C

Procedure:
To a solution of 0.0175 mole of diethylsodiomalonate in 250 ml of diethyl malonate under nitrogen atmosphere at 80° C. was added 20.7 g (0.07 mole) of 4',5-dichloro-2-nitrobenzophenone. The mixture was heated at 90° C. for 2 hr, then poured into water and neutralized with glacial acetic acid. The mixture was extracted with diethyl ether and then washed and dried over sodium sulfate; extracts were concentrated and excess diethyl malonate removed by distillation. The residue was chromatographed eluting with 50-75% isopropyl ether in hexane and the appropriate fraction collected. This material was hydrolyzed by heating at reflux in a mixture of 150 ml of dioxane and 80 ml of 6N hydrochloric acid for 6 hr. The reaction mixture was diluted with water and extracted with diethyl ether. The ether extracts were washed with dilute sodium hydroxide and the basic washings were combined, acidified and extracted with diethyl ether-isopropyl ether to give after recrystallization from 80% aqueous methanol, 6.2 g of title compound as tan crystals, m.p. 182.0°-183.0° C.
Reaction SMILES: C(#N)C.N1C=CC=CC=1.F.[CH3:11][C:12]1[CH2:26][C@@H:25]([O:27][Si](C(C)(C)C)(C)C)[C@H:24](/[CH:35]=[CH:36]/[C@@H:37]([O:45][Si](C(C)(C)C)(C)C)[CH2:38][C@H:39]([CH3:44])[CH2:40][CH2:41][CH2:42][CH3:43])[C:13]=1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21]>N1C=CC=CC=1>[CH3:11][C:12]1[CH2:26][C@@H:25]([OH:27])[C@H:24](/[CH:35]=[CH:36]/[C@@H:37]([OH:45])[CH2:38][C@H:39]([CH3:44])[CH2:40][CH2:41][CH2:42][CH3:43])[C:13]=1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21]
Reactant: CCCC[C@@H](C)C[C@@H](/C=C/[C@@H]1C(CCCCCCC(=O)OC)=C(C)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: F
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCC[C@@H](C)C[C@H](O)/C=C/[C@@H]1C(CCCCCCC(=O)OC)=C(C)C[C@H]1O
Reaction time: 15 h
Yield: 10 %

Procedure:
To a solution of ice-cooled acetonitrile (2 ml) and pyridine (0.2 mL) was added hydrogen fluoride-pyridine (0.2 mL). To this solution was added a mixture (174 mg) containing methyl (11R,12R,13E,15S,17R)-9-methyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethylprosta-8,13-dienoate in pyridine (0.2 mL). The ice bath was removed and the solution was agitated for 15 hours while returning it to room temperature. The reaction solution was poured into a mixture of ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The desired product was extracted from this mixed solution with ethyl acetate. The extract was washed with brine, then dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, then was purified by silica gel column chromotography (30 to 50% ethyl acetate/hexane) and subjected to thin layer chromotography for separation (ethyl acetate:hexane=4:1) to obtain methyl (11R,12R,13E,15S,17R)-9-methyl-11,15-dihydroxy-17,20-dimethylprosta-8,13-dienoate (21 mg, 2 step 10%) and as a byproduct, methyl (11R,12R,13E,15S,17R)-9-trifluoromethanesulfonyloxy-11,15-dihydroxy-17,20-dimethylprosta-8,13-dienoate (48 mg, 2 step, 18%).
Reaction SMILES: C(O[C:6]([C:8]1[C:9]([OH:25])=[C:10]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[S:14][C:11]2=[CH:12][N:13]=1)=[O:7])CCC.[NH2:26][CH2:27][C:28]([OH:30])=[O:29]>C[O-].[Na+].CO.Cl>[OH:25][C:9]1[C:8]([C:6]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:7])=[N:13][CH:12]=[C:11]2[S:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[CH:16][C:10]=12
Reactant: CCCCOC(=O)c1ncc2sc(-c3ccc(OC)cc3)cc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-c2cc3c(O)c(C(=O)NCC(=O)O)ncc3s2)cc1

Procedure:
4-Hydroxy-2-(4-methoxy-phenyl)-thieno[2,3-c]pyridine-5-carboxylic acid butyl ester, example 3-d, (23 mg, 0.064 mmol) and glycine (63 mg, 0.64 mmol) were suspended in 1.3 mL of 0.5 N NaOMe in methanol. The reaction mixture was heated at reflux temperature for 16 hours, cooled, and diluted with 1 N HCl to precipitate out a white solid. The precipitate was collected on a fine glass fritted filter, washed twice with water, and dried under hi-vacuum to isolate 20 mg of the title compound. MS: (+) m/z 359.04 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1.Cl.[CH3:18][C:19](C)=[O:20].C(Cl)(=O)C>C(N(CC)CC)C>[C:19]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)(=[O:20])[CH3:18]
Reactant: CC(C)=O
Reactant: Nc1ccccc1N1CCc2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)Cl
Product: CC(=O)Nc1ccccc1N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred slurry, under N2, of 9.96 g of 1-(2-amino-phenyl)indoline.HCl and 300 ml of dry acetone is treated with 10.1 g of triethylamine over a 10 minute period. After cooling to 0°-5° C., 4.70 g of acetyl chloride is added dropwise over 0.5 hour. The mixture is stirred 18 hours at ambient temperature, then filtered. The filtrate is diluted with 100 ml of water and concentrated. When all the acetone is removed, the residue is filtered off, washed well with water, and dried to afford 1-(2-acetamidophenyl)indoline, m.p. 125°-128° C.
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH2:24][C:25]([OH:27])=O)=[C:17]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:16]=2)=[CH:11][N:10]=1)=O)(C)(C)C.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[NH2:8][C:9]1[N:10]=[CH:11][C:12]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH2:24][C:25]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[O:27])=[C:17]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[N:16]=2)=[CH:13][N:14]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncn(CC(=O)O)c3n2)cn1
Reactant: C1COCCN1
Product: Nc1ncc(-c2nc(N3CCOCC3)c3ncn(CC(=O)N4CCOCC4)c3n2)cn1

Procedure:
2-(2-(2-(Tert-butoxycarbonylamino)pyrimidin-5-yl)-6-morpholino-9H-purin-9-yl)acetic acid (35 mg) was reacted with morpholine via General Procedure F followed by Boc deprotection via General Procedure E and purified via reverse phase HPLC to give 3.2 mg 124 as a white solid. MS (Q1) 426.2 (M)+
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[C:10](Cl)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4].[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([F:26])[CH:25]=1)[CH2:21][OH:22]>>[CH2:1]([N:5]1[C:9]2=[C:10]([O:22][CH2:21][C:20]3[CH:19]=[C:18]([F:17])[CH:25]=[C:24]([F:26])[CH:23]=3)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4]
Reactant: CC=CCn1c(C)c(C)c2cnnc(Cl)c21
Reactant: OCc1cc(F)cc(F)c1
Product: CC=CCn1c(C)c(C)c2cnnc(OCc3cc(F)cc(F)c3)c21
Yield: 41.6 %

Procedure:
The title compound (cis/trans=29/71) was prepared as a white powder in 41.6% yield in a similar procedure to that described in Example 1 by using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine (cis/trans=24/76) and 3,5-difluorobenzyl alcohol.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([CH3:18])[N:16]=[C:15]([C:19](=O)[CH3:20])[C:14]=2[OH:22])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH:23]([C:25]([NH:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1)=[S:26])[NH2:24].CN(C)C=O>Cl.O>[CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([CH3:18])[N:16]=[C:15]([C:19](=[N:24][NH:23][C:25]([NH:27][C:28]3[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=3)=[S:26])[CH3:20])[C:14]=2[OH:22])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Reactant: CCCCCCc1ccc(-c2c(O)c(C(C)=O)nn2C)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCc1ccc(-c2c(O)c(C(C)=NNC(=S)Nc3ccc(C(=O)O)cc3)nn2C)cc1
Yield: 80.2 %

Procedure:
1-[5-(4-n-Hexylphenyl)-1-methyl-4-hydroxy-1H-pyrazol-3-yl]ethanone (0.117 mmol, 35.1 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.117 mmol, 24.7 mg) were stirred with dimethylformamide (2.3 mL) and three drops of concentrated hydrochloric acid at room temperature for 23.5 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. The resulting solid was stirred with chloroform/n-hexane for a while, then recovered by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (46.3 mg, yield 80%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[Br:15])=[O:5])[CH3:2].CC(C)([O-])C.[K+].[C:22]([O:26][C:27]([N:29]1[CH2:33][C@H:32]([CH3:34])OS1(=O)=O)=[O:28])([CH3:25])([CH3:24])[CH3:23]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C@H:32]([CH3:34])[CH2:33][NH:29][C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[Br:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cccc(Br)c2[nH]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cccc(Br)c2n1[C@H](C)CNC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
A solution of 8.1 g (30.1 mmol) 7-bromo-1H-indole-2-carboxylic acid ethyl ester in 120 ml N,N-dimethylformamide was cooled to 0° C. and 3.55 g (31.6 mmol) potassium tert-butoxide was added. After 30 min., 7.86 g (33.1 mmol) (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester were added and the cooling bath was removed. After 20 h the reaction mixture was poured on 10% aqueous citric acid solution and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and evaporated. The resulting yellow oil was chromatographed on silica gel (0.032-0.063 mm) with tert-butyl methyl ether: n-hexane (1:8) as eluant to give the desired compound as a yellow oil. ISP-MS: m/e=427.3 ([M+H+]).
Reaction SMILES: [C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:11][CH3:12])[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[C:36]([NH:35][C:31]1[CH:30]=[C:29]([CH:26]2[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][CH2:20][NH:19][C:8](=[O:9])[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH3:12])[CH2:24][CH2:25]2)[CH:34]=[CH:33][CH:32]=1)(=[O:40])[CH:37]([CH3:38])[CH3:39]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: CCC(C(=O)O)(c1ccccc1)c1ccccc1
Product: CCC(C(=O)NCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)(c1ccccc1)c1ccccc1

Procedure:
Example 12 was prepared from 2,2-diphenylbutanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methyl propanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.44–7.39 (m, 2H), 7.37–7.28 (m, 8H), 7.27–7.20 (m, 3H), 6.89 (d, 1H, J=7.4 Hz), 6.43 (t, 1H, J=4.5 Hz), 3.35–3.27 (m, 2H), 2.90–2.82 (m, 2H), 2.51 (septet, 1H, J=6.8 Hz), 2.49–2.35 (m, 4H), 2.24 (t, 2H, J=6.3 Hz), 1.89 (t, 2H, J=10.2 Hz), 1.75–1.68 (m, 2H), 1.66–1.58 (m, 2H), 1.57–1.45 (m, 2H), 1.24 (d, 6H, J=6.7 Hz), 1.27–1.23 (m, 2H); ESMS m/e: 526.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=3)[C:10]([CH:11]([OH:14])[C:12]#[CH:13])=[C:6]2[CH:5]=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=3)[C:10]([C:11](=[O:14])[C:12]#[CH:13])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: C#CC(O)c1c(-c2cccc(C)c2)nn2c(Cl)cccc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: C#CC(=O)c1c(-c2cccc(C)c2)nn2c(Cl)cccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.8 %

Procedure:
To a solution of 1-[7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol (11.3 g, 36.2 mmol) in chloroform (300 mL) was added manganese dioxide (78.9 g, 905 mmol). The reaction mixture was stirred at room temperature for 18 hours. The suspension was filtered through a pad of Celite and the filtrate was concentrated and purified by flash chromatography (7:3 hexanes:ethyl acetate). 1-[7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one (4.57 g, 41%) was obtained as a pale yellow crystalline. 1H NMR (CDCl3) δ 8.48 (d, 1H), 7.51 (m, 3H), 7.33 (t, 1H), 7.29 (d, 1H), 8.21 (dd, 1H), 2.89 (s, 1H), 2.42 (s, 3H); MS m/z 295 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9](=O)[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[N:17]1[C:21]([CH2:22][N:23]2C(=O)C3=CC=CC=C3C2=O)=[N:20][N:19]=[C:18]1[CH2:34][N:35]([CH3:37])[CH3:36].O.NN>C(O)C>[Cl:16][C:14]1[CH:13]=[CH:12][C:11]2[N:17]3[C:18]([CH2:34][N:35]([CH3:36])[CH3:37])=[N:19][N:20]=[C:21]3[CH2:22][N:23]=[C:9]([C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:10]=2[CH:15]=1
Reactant: CN(C)Cc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc(Cl)cc1C(=O)c1c(F)cccc1F
Agent: NN
Solvent: O
Solvent: CCO
Product: CN(C)Cc1nnc2n1-c1ccc(Cl)cc1C(c1c(F)cccc1F)=NC2

Procedure:
In the manner given in Example 27, 2',6'-difluoro-5-chloro-2-[3-[(dimethylamino)methyl]-5-(phthalimidomethyl)- 4H-1,2,4-triazol-4-yl]benzophenone is heated in ethanol with hydrazine hydrate to give 8-chloro-1[(dimethylamino)-methyl]-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine.
Reaction SMILES: [C:1](OCC)(OCC)(OCC)[CH3:2].[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:23]=[C:22]([CH2:24][NH:25][C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][N:34]=4)[N:29]=[CH:28][C:27]=3[NH2:36])[O:21][N:20]=2)=[CH:15][CH:14]=1>C1(C)C=CC=CC=1.Cl.N1C=CC=CC=1>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:23]=[C:22]([CH2:24][N:25]3[C:26]4[C:35]5[N:34]=[CH:33][CH:32]=[CH:31][C:30]=5[N:29]=[CH:28][C:27]=4[N:36]=[C:1]3[CH3:2])[O:21][N:20]=2)=[CH:17][CH:18]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: Nc1cnc2cccnc2c1NCc1cc(-c2ccc(F)cc2)no1
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1nc2cnc3cccnc3c2n1Cc1cc(-c2ccc(F)cc2)no1
Temperature: 110 °C
Yield: 31.7 %

Procedure:
Triethyl orthoacetate (2.8 mL, 15.2 mmol) was added to a solution of N4-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}[1,5]naphthyridine-3,4-diamine (prepared in Part B of Example 12, 3.4 g, 10.1 mmol) and pyridine hydrochloride (0.023 g, 0.20 mmol) in toluene (100 mL), and the reaction was heated at 110° C. under a nitrogen atmosphere for 15.5 hours. The reaction mixture was then concentrated under reduced pressure, and the residue was dissolved in dichloromethane. The work-up and purification procedures described in Part D of Example 12 were followed with the modification that the silica column was eluted with 5% methanol in ethyl acetate. 1-{[3-(4-Fluorophenyl)isoxazol-5-yl]methyl}-2-methyl-1H-imidazo[4,5-c][1,5]naphthyridine (1.15 g) was obtained as a light gray solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.C(Cl)Cl.[C-:15]#[N:16].[Na+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CCCCCC>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([C:15]#[N:16])=[O:8])=[CH:5][CH:4]=1
Reactant: [C-]#N
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCCCCC
Product: COc1ccc(C(=O)C#N)cc1
Temperature: 2.5 °C
Reaction time: 4 h

Procedure:
A mixture of p-methoxybenzoyl chloride (11.9 grams; 0.07 mole) and tetrabutylammonium bromide (0.10 gram) in 60 mls. of methylene dichloride is cooled to 0°-5° C. and a solution of sodium cyanide (3.63 grams; 0.074 mole) in 8 mls. of water is added thereto at 0-5° C. Upon completion of the addition of the sodium cyanide the reaction mixture is stirred at 0-5° C. for an additional period of about 11/4 hours and filtered. The filtrate is dried over magnesium sulfate, filtered to separate the magnesium sulfate and evaporated under vacuum to obtain an oil which solidifies. The solid is dissolved in hot hexane and the hexane solution is treated with activated carbon and filtered to separate the carbon. The filtrate is cooled to room temperature and later filtered to recover 6.2 grams of the desired product which melts at 51°-53° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([OH:13])[CH:9]=2)=[CH:4][CH:3]=1.[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23]O)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][O:13][C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[O:12][N:11]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: Oc1cc(-c2ccc(F)cc2)on1
Reactant: CC(C)(C)OC(=O)NCCO
Product: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc(F)cc2)on1
Yield: 74.1 %

Procedure:
5-(4-Fluorophenyl)-3-hydroxyisoxazole (0.06 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.06 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.08 g, 74%) as a colorless powder.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:5]2[N:6]=[CH:7][CH:8]=[C:9]([OH:10])[C:4]=2[CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1F.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1[O:10][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:11][C:2]([CH3:1])=[CH:3][C:4]=12
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: Cc1cc2c(O)ccnc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2[nH]1
Temperature: 50 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
A mixture of 2-methyl-1H-pyrrolo[2,3-b]pyridin-4-ol (90 mg, TFA salt, 0.34 mmol), 3,4-difluoronitrobenzene (0.05 mL) and potassium carbonate (100 mg, 0.72 mmol) in DMF (1 mL) was stirred at 50° C. for 2 h. The mixture was diluted with water and extracted with ethyl acetate (3×5 mL). The combined extracts were washed with water, dried (MgSO4) and concentrated in vacuo to afford the crude product, which was purified by preparative HPLC to give the title compound (45 mg, 46%). 1H NMR (CD3OD) δ 8.25 (dd, 2H, J=10.4, 2.6 Hz), 8.12 (m, 1H), 8.04 (d, 1H, J=5.5 Hz), 7.30 (t, 1H, J=8.3 Hz), 6.67 (d, 1H, J=5.5 Hz), 5.95 (s, 1H), 2.41 (s, 3H); MS(ESI+) m/z 288 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:14]3[CH:18]=[N:17][CH:16]=[N:15]3)([CH3:13])[CH3:12])[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:19]1([CH2:10][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)([OH:9])[C:11]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)([CH3:13])[CH3:12])[CH:23]=[N:22][CH:21]=[N:20]1
Reactant: c1nc[nH]n1
Reactant: CC(C)(n1cncn1)C1(c2ccc(F)cc2)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(n1cncn1)C(O)(Cn1cncn1)c1ccc(F)cc1
Reaction time: 19 h
Yield: 31.9 %

Procedure:
To a solution of 2-(4-fluorophenyl)-2-[2-(1H-1,2,4-triazol-1-yl)prop-2-yl]oxirane (1.0 g, 4.0 mMole) in dimethylformamide (50 ml) were added 1,2,4-triazole (0.56 g., 8.0 mMole) and anhydrous potassium carbonate (0.56 g, 4.0 mMole). Heating at 80°, with stirring, was carried out for 19 hours. The solvent was then evaporated, water (75 ml) was added, and the mixture was extracted with methylene chloride (3×50 ml.). The combined organic extracts were washed with water (3×30 ml), dried over anhydrous magnesium sulphate, and evaporated to an impure gum (1.15 g). Purification of the gum was carried out using a flash column of Merck "Kieselgel 60" (Trademark) 230-400 mesh silica eluting with methylene chloride and 5% methanol in methylene chloride. The appropriate fractions on evaporation gave a solid which was recrystallised from diisopropylether and isopropyl alcohol giving the title compound, 0.4 g., m.p. 156°-158° (31.9% yield).
Reaction SMILES: Cl.[CH:2]1([NH:6][C:7]([C:9]2[CH:18]=[CH:17][C:16]3[CH2:15][N:14]([CH2:19][C:20]([OH:22])=O)[CH2:13][CH2:12][C:11]=3[N:10]=2)=[O:8])[CH2:5][CH2:4][CH2:3]1.[CH:23]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:26][CH2:25][CH2:24]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH:2]1([NH:6][C:7]([C:9]2[CH:18]=[CH:17][C:16]3[CH2:15][N:14]([CH2:19][C:20]([N:30]4[CH2:31][CH2:32][N:27]([CH:23]5[CH2:26][CH2:25][CH2:24]5)[CH2:28][CH2:29]4)=[O:22])[CH2:13][CH2:12][C:11]=3[N:10]=2)=[O:8])[CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)CN1CCc2nc(C(=O)NC3CCC3)ccc2C1
Reactant: C1CC(N2CCNCC2)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: O=C(NC1CCC1)c1ccc2c(n1)CCN(CC(=O)N1CCN(C3CCC3)CC1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of {2-[(cyclobutylamino)carbonyl]-7,8-dihydro-1,6-naphthyridin-6(5H)-yl}acetic acid hydrochloride (37 mg, 0.11 mmol), 1-cyclobutylpiperazine (19 mg, 0.133 mmol), BOP (59 mg, 0.133 mmol) and TEA (0.075 ml, 0.532 mmol) in DCM (5 ml) is stirred at rt overnight. The solvent is removed in vacuo and the residue is partitioned between water (10 mL) and EtOAc (10 mL). The layers are separated and the aqueous layer is extracted with EtOAc (10 ml). The combined extracts are washed with brine (10 mL), dried and evaporated. The residue is purified by PTLC to give the title compound as a light yellow oil. MS (M+1): 412.4; 1H NMR (δ, CDCl3): 8.11 (d, 1H), 7.94 (d, 1H), 7.43 (d, 1H), 4.53-4.61 (m, 1H), 3.75 (s, 2H), 3.58-3.66 (m, 4H), 3.45 (t, 2H), 3.40 (s, 2H), 3.04 (t, 2H), 2.92 (t, 2H), 2.63-2.76 (m, 1H), 2.36-2.46 (m, 2H), 2.25-2.32 (m, 6H), 1.63-2.06 (m, 6H).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[I:22]I>O1CCCC1>[C:1]([NH:5][S:6]([C:9]1[C:10]([O:15][CH3:16])=[CH:11][CH:12]=[CH:13][C:14]=1[I:22])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccccc1S(=O)(=O)NC(C)(C)C
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(I)c1S(=O)(=O)NC(C)(C)C
Temperature: -30 °C
Reaction time: 8 h

Procedure:
A solution of 30.00 g (123.29 mmol) of N-(tert-butyl)-2-methoxybenzenesulfonamide in 400 ml of tetrahydrofuran is cooled to −70° C. and slowly admixed with a solution of 110.96 ml (277.41 mmol) of a 2.5 molar n-butyllithium solution in THF. The solution is subsequently warmed briefly to −30° C. and then cooled again to −60° C. At this temperature a solution of 31.29 g (123.29 mmol) of iodine in 200 ml of tetrahydrofuran is added dropwise. Subsequently the reaction solution is stirred at room temperature overnight. Following extraction with water, the organic phase is dried over sodium sulfate and evaporated to dryness. This gives 42.40 g (93% of theory) of N-(tert-butyl)-2-iodo-6-methoxybenzenesulfonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].Cl[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]([OH:35])=[O:34])[CH:28]=1.C(N(CC)CC)C>C(O)C>[C:33]([C:29]1[CH:28]=[C:27]([N:23]2[CH2:22][CH2:21][CH:20]([CH2:19][NH:18][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:17][C:6]=3[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=3)=[O:8])[CH2:25][CH2:24]2)[CH:32]=[CH:31][N:30]=1)([OH:35])=[O:34]
Reactant: O=C(O)c1cc(Cl)ccn1
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)ccc1NCC1CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(O)c1cc(N2CCC(CNc3ccc(Cl)cc3C(=O)Nc3ccc(Cl)cn3)CC2)ccn1
Yield: 81.8 %

Procedure:
Using a similar procedure to that described in Example 52, 5-chloro-N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethyl)aminobenzamide (166 mg, 0.44 mmol), 4-chloropicolinic acid (103 mg, 0.66 mmol), triethylamine (89 mg, 0.88 mmol, and ethanol (3 mL) yielded 180 mg (82%) of the title compound.