Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([Mg]Br)C.[F:13][C:14]([F:27])([F:26])[C:15]1[CH:23]=[C:22]2[C:18]([C:19](=[O:25])[C:20](=[O:24])[NH:21]2)=[CH:17][CH:16]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:19]2([OH:25])[C:18]3[C:22](=[CH:23][C:15]([C:14]([F:27])([F:13])[F:26])=[CH:16][CH:17]=3)[NH:21][C:20]2=[O:24])[CH:3]=1
Reactant: O=C1Nc2cc(C(F)(F)F)ccc2C1=O
Reactant: Oc1ccc(Cl)cc1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: O=C1Nc2cc(C(F)(F)F)ccc2C1(O)c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.7 %

Procedure:
To a solution of 4-chlorophenol (2.87 g, 22.3 mmol) in THF (30 mL) at 0° C., 1.0 M solution of ethyl magnesium bromide (22.3 mL, 22.3 mmol) in THF was added dropwise. The resulting white suspension was then concentrated to dryness and dissolved in CH2Cl2 (30 mL). Neat 6-(trifluoromethyl)isatin (4.0 g, 18.6 mmol) was then added at once. After stirring at room temperature for 4 hours, the reaction was quenched with 1N HCl solution. The organic layer was separated, washed with water and brine, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo to provide a dark red oil which was purified by flash column chromatography (silica gel, 1:1 hexanes/EtOAc) to afford the title compound as an orange solid (5.48 g, 86% yield). 1H NMR (DMSO-d6): δ10.61 (s, 1H), 9.73 (s, 1H), 7.73(d, J=2.7 Hz, 1H), 7.15-7.21 (m, 2H), 7.03-7.07 (m, 2H), 6.81 (s, 1H), 6.61 (d, J=8.6 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][C:2]2[CH:7]=[C:6]([N:8]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[N:5]=[C:4]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:3]=2)=[CH:24][CH:23]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: Clc1cc(N2CCCCCC2)nc(-c2ccccc2)n1
Product: Clc1ccc(Sc2cc(N3CCCCCC3)nc(-c3ccccc3)n2)cc1

Procedure:
A mixture of the above prepared 4-chloro-6-(hexahydroazepin-1-yl)-2-phenylpyrimidine is reacted with p-chlorothiophenol, as in Example X, to produce 4-(4-chlorophenylthio)-6-(hexahydroazepin-1-yl)-2-phenylpyrimidine.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:14])[C:4]([CH2:12][OH:13])=[CH:5][CH:6]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:8]=1.[H-].[Na+].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:22][CH2:23]I>CN(C)C=O.ClCCl>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:22][CH2:23][O:1][C:2]2[C:3](=[O:14])[C:4]([CH2:12][OH:13])=[CH:5][CH:6]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:8]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: COc1ccc(CCI)cc1OC
Reactant: CC(C)c1ccc(CO)c(=O)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(CCOc2cc(C(C)C)ccc(CO)c2=O)cc1OC
Temperature: 80 °C
Yield: 10.8 %

Procedure:
A solution of 2-hydroxy-7-hydroxymethyl-4-isopropyl-2,4,6-cycloheptatrien-1-one (844 mg, 4.35 mmol) in dimethylformamide (5 ml) was stirred while 60% oily sodium hydride (191 mg, 4.78 mg) in small portions were added thereto. Subsequently, 3,4-dimethoxyphenethyl iodide (2.54 mg, 8.70 mmol) was added, then the solution was heated at 80° C. for 7 hours. The solution was diluted with dichloromethane, washed with water and dried over sodium sulfate. After solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography [eluent: hexane/ethyl acetate (3:2)] to give 169 mg of 2-[2-(3,4-dimethoxyphenyl)ethoxy]-7-hydroxymethyl-4-isopropyl-2,4,6-cycloheptatrien-1-one as a yellowish brown oil (yield: 11%).
Reaction SMILES: [CH:1]([C:3]1[S:11][C:10]2[C:9](=[O:12])[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][NH:6][C:5]=2[C:4]=1[CH3:18])=[O:2].C(Cl)Cl.[BH4-].[Na+]>CO>[OH:12][C:9]1[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][N:6]=[C:5]2[C:4]([CH3:18])=[C:3]([CH2:1][OH:2])[S:11][C:10]=12
Reactant: CCOC(=O)c1c[nH]c2c(C)c(C=O)sc2c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1cnc2c(C)c(CO)sc2c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
A suspension of ethyl 2-formyl-3-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylate (Preparation 3)(1.50 g, 5.66 mmol) in 1:1 CH2Cl2:MeOH (15 mL) was chilled in an ice bath before the addition of sodium borohydride (0.214 g, 5.66 mmol). The reaction was stirred at 0° C. for one hour and then quenched by the addition of water (30 mL). While continuing to chill in an ice bath, the mixture was adjusted to pH 4 by the careful addition of 1 N HCl. The resulting thick mixture was stirred at 0° C. for one hour before filtering. The collected solid was washed with water and dried in vacuo, affording the title compound (0.90 g) as an off-white solid. The filtrate was concentrated in vacuo to a volume of about 50 mL, more water was added, and the mixture was again filtered after chilling in ice, giving an additional 0.29 g of the title product.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[C:8](=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][C:13]1=[O:21])[C:9]([OH:11])=O.[F:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26]>>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[C:8](=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][C:13]1=[O:21])[C:9]([NH:26][C:25]1[CH:27]=[CH:28][CH:29]=[C:23]([F:22])[CH:24]=1)=[O:11]
Reactant: Nc1cccc(F)c1
Reactant: Cc1cc(C)c(C(C(=O)O)=C2C(=O)Nc3ccccc32)[nH]1
Product: Cc1cc(C)c(C(C(=O)Nc2cccc(F)c2)=C2C(=O)Nc3ccccc32)[nH]1
Yield: 21.1 %

Procedure:
(3,5-Dimethyl-1H-pyrrol-2-yl)-(2-oxo-1,2-dihydroindol-3-ylidene)-acetic acid (90 mg) was reacted with 3-fluoroaniline (35 mg) using method B to give 25 mg (21%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][N:12]([CH3:14])[CH2:11][C:10]3[S:15][C:16]([CH3:18])=[CH:17][C:9]2=3)=[CH:4][CH:3]=1.BrN1[C:24](=[O:25])CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C[O-].[Na+]>C(Cl)(Cl)(Cl)Cl.CO.O>[CH3:24][O:25][CH2:18][C:16]1[S:15][C:10]2[CH2:11][N:12]([CH3:14])[CH2:13][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:9]=2[CH:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2c(s1)CN(C)CC2c1ccc(Cl)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: COCc1cc2c(s1)CN(C)CC2c1ccc(Cl)cc1

Procedure:
2.79 gm (0.01 -ol) of 4-(p-chloro-phenyl)-2,6-dimethyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine were dissolved in 50 ml of carbon tetrachloride, the solution was heated at its boiling point with 1.8 gm of N-bromo-succinimide and 0.1 gm of azo-bis-isobutyronitrile for several hours. The resulting succinimide was suction-filtered off, and the solvent was removed in a rotary evaporator. The residue was admixed with a solution of 0.01 mol of sodium methoxide in methanol, and the mixture was heated at its boiling point for a short time. Then, water was added, and the resulting mixture was extracted with ether. Upon addition of ethereal hydrochloric acid to the extract, the hydrochloride of the title compound crystallized out.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Cl)=[CH:8][N:9]=1)(=[O:3])[CH3:2].[SH:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ncc(Cl)s1
Reactant: Sc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(Sc2ccncc2)s1
Temperature: 120 °C
Yield: 83.5 %

Procedure:
A mixture of 2-acetylamino-5-chlorothiazole (5.3 g), 4-mercaptopyridine (3.4 g) and potassium carbonate in N,N-dimethylformamide (50 ml) was heated at 120° C. for 2.5 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was triturated with water. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-acetylamino-5-(4-pyridylthio)thiazole (6.3 g, yield: 83.7%). IR (Nujol): 3150, 1680, 1580, 1300 cm-1
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][CH2:7][CH2:6][C:5]2([C:13]([OH:15])=[O:14])[OH:12].CCCCCCC.C(OCC)(=O)C>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][CH2:7][CH2:6][C@@:5]2([C:13]([OH:15])=[O:14])[OH:12]
Reactant: O=C(O)C1(O)CCSc2ccc(Cl)cc21
Solvent: CCCCCCC
Solvent: O=CO
Solvent: CCOC(C)=O
Product: O=C(O)[C@@]1(O)CCSc2ccc(Cl)cc21

Procedure:
The enantiomers of 6-chloro-4-hydroxythiochromane-4-yl-carboxylic acid (1.4 g, 5.7 mmol; from step (iii) above) were separated using chiral chromatography (Kromasil TBB; heptane: ethyl acetate: formic acid) yielding 0.500 g (71%) of the slower moving sub-title compound.
Reaction SMILES: [OH-].[K+].Cl.NO.CC1[N:8]([C:13]2[CH:17]=[C:16]([C:18]([O:24][CH3:25])([CH3:23])[C:19]([F:22])([F:21])[F:20])[N:15]([CH3:26])[N:14]=2)C(C)=CC=1>O.C(O)C>[CH3:26][N:15]1[C:16]([C:18]([O:24][CH3:25])([CH3:23])[C:19]([F:20])([F:21])[F:22])=[CH:17][C:13]([NH2:8])=[N:14]1
Reactant: COC(C)(c1cc(-n2c(C)ccc2C)nn1C)C(F)(F)F
Agent: Cl
Agent: NO
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COC(C)(c1cc(N)nn1C)C(F)(F)F

Procedure:
A solution of potassium hydroxide (280 mg, 5 mmol) in water (6 mL) and ethanol (6 mL) is added to a slurry of hydroxylamine hydrochloride (700 mg, 10 mmol) in ethanol (9 mL). Then 3-(2,5-dimethyl-pyrrol-1-yl)-1-methyl-5-(2,2,2-trifluoro-1-methoxy-1-methyl-ethyl)-1H-pyrazole (500 mg, 1.7 mmol) is added and the mixture is refluxed for 24 hours. At this point the contents of the flask are concentrated under reduced pressure and the residue is partitioned in water and DCM and separated. The water layer is extracted with DCM and the organic layers are combined and concentrated to give the crude title compound. MS (ESI) m/z 224.2 (M+1).
Reaction SMILES: [C:1]([CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]2=[O:26])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[C:2]1([CH:1]([OH:8])[CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([N:16]3[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][C:17]3=[O:26])[CH2:14][CH2:15]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CN1CCC(N2Cc3ccccc3NC2=O)CC1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C1Nc2ccccc2CN1C1CCN(CC(O)c2ccccc2)CC1
Temperature: 25 °C
Yield: 63.5 %

Procedure:
In this example, 2.30 g of 1-benzoylmethyl-4-[3,4-dihydro-2(1H)-quinazolinon-3-yl]-piperidine and 100 ml of methanol are mixed and stirred at room temperature. To the stirred mixture, 1.5 g of sodium borohydride is added over a period of 5 hours. Then, the mixture is stirred overnight at room temperature. The white crystals deposited are separated by filtration, successively washed with methanol and water and dried to obtain 2.06 g of a crude product. The crude product is recrystallized from a mixed solvent of chloroform and ethanol to obtain 1.47 g of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[N:8][N:9]([C:11]2[CH:16]=[C:15]([S:17][CH2:18][C:19]([F:22])([F:21])[F:20])[C:14]([CH3:23])=[CH:13][C:12]=2[F:24])[CH:10]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[F:33][C:34]([O:38][C:39]([F:42])([F:41])[F:40])=[C:35]([F:37])[F:36].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25][C:35]([F:37])([F:36])[CH:34]([F:33])[O:38][C:39]([F:42])([F:41])[F:40])=[N:8][N:9]([C:11]2[CH:16]=[C:15]([S:17][CH2:18][C:19]([F:22])([F:21])[F:20])[C:14]([CH3:23])=[CH:13][C:12]=2[F:24])[CH:10]=1)=[O:5])[CH3:2]
Reactant: FC(F)=C(F)OC(F)(F)F
Reactant: CCOC(=O)c1cn(-c2cc(SCC(F)(F)F)c(C)cc2F)nc1O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(-c2cc(SCC(F)(F)F)c(C)cc2F)nc1OC(F)(F)C(F)OC(F)(F)F

Procedure:
1.20 g of ethyl-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-hydroxypyrazole-4-carboxylate was dissolved in 40 mL of N,N-dimethylformamide, 25 g of triethylamine was added, and stirring was carried out at 50° C. for 3 hours while trifluoromethyl trifluorovinyl ether was blown. To this solution, ethyl acetate was added, followed by washing with a saturated aqueous solution of citric acid, and then the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:4) to obtain 0.73 g of ethyl-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole-4-carboxylate (1H-NMR (CDCL3/TMS δ (ppm) value) δ: 1.36 (3H, t), 2.51 (3H, s), 3.41 (2H, q), 4.34 (2H, q), 6.21 (1H, dt), 7.16 (1H, d), 7.97 (1H, d), 8.38 (1H, d)).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].CO[C:14](OC)([N:16]([CH3:18])[CH3:17])[CH3:15]>CO>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([N:6]=[C:14]([N:16]([CH3:18])[CH3:17])[CH3:15])=[O:5]
Reactant: COC(C)(OC)N(C)C
Reactant: NC(=O)c1cc(F)ccc1Br
Solvent: CO
Product: CC(=NC(=O)c1cc(F)ccc1Br)N(C)C
Temperature: 120 °C
Yield: 75 %

Procedure:
A mixture of 2-bromo-5-fluorobenzamide (9.57 g, 43.89 mmol) and N,N-dimethylacetamide dimethyl acetal (20 ml) was heated under argon at 120° C. for 1.5 h. The methanol formed was collected through a reflux condenser. The reaction mixture was allowed to cool and the excess N,N-dimethylacetamide dimethyl acetal was removed under reduced pressure. The residual oil was crystallized from a mixture of ether (30 ml) and hexane (50 ml) to give 9.51 g (75% yield) of the title material as white crystals. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.43 (3H, s, CH3), 3.16 (3H, s, NCH3), 3.19 (3H, s, NCH3), 6.90-6.97 (1H, m, aromatic), 7.46 (1H, dd, J=3.1 Hz and J=9.1 Hz, aromatic), 7.53 (1H, dd, J=5.1 Hz and J=9.1 Hz, aromatic). MS (ESI+) m/e 287 [M+H+].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.Cl.[BH3-]C#N.[Na+]>CCO>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([CH2:2][CH2:3][CH2:4][NH:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: Clc1ccc2c(c1)NCCC2
Temperature: 60 °C
Reaction time: 18 h

Procedure:
Similar to the process reported by B. S. Rauckman, et. al., J. Med. Chemn., 1989, 32, 1927-1935, 4,7-dichloroquinoline (1.02 g, 5.1 mmol) was dissolved into anh. EtOH (30 mL) under N2 at RT. Concentrated HCl (1.76 mL, 20.4 mmol) was added, followed by the addition of the NaCNBH3 (1.28 g, 20.4 mmol). This produced vigorous gas and heat evolution. The reaction was heated to 60° C. for 2 h, then cooled and stirred at RT for an additional 18 h. The reaction was quenched by adjusting the pH to approximately 9 with 2 N NaOH. This mixture was extracted 3 times with EtOAc. The EtOAC extracts were washed brine, combined, dried over Na2SO4, filtered, and concentrated, then eluted through a 30×2.5 cm column of silica gel (3.75% EtOAc/Hexane) giving 7-chloro-1,2,3,4-tetrahydro-quinoline as an orange solid: MS m/z 168=[M+H]+. Calc'd for C9H10ClN: 167.05.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:24]([CH3:25])=[C:23]2[NH:26][C:4]=1[CH:5]=[C:6]1[N:10]=[C:9]([C:11]([CH:38]=[O:39])=[C:12]3[N:16]=[C:15]([CH:17]=[C:18]4[NH:27][C:21](=[CH:22]2)[C:20]([CH:28]=[CH2:29])=[C:19]4[CH3:30])[C@@H:14]([CH3:31])[C@@H:13]3[CH2:32][CH2:33][C:34]([O:36]C)=[O:35])[C:8]([C:40]([O:42]C)=[O:41])=[C:7]1[CH3:44].Cl>CC(C)=O>[CH3:1][CH2:2][C:3]1[C:24]([CH3:25])=[C:23]2[NH:26][C:4]=1[CH:5]=[C:6]1[N:10]=[C:9]([C:11]([CH:38]=[O:39])=[C:12]3[N:16]=[C:15]([CH:17]=[C:18]4[NH:27][C:21](=[CH:22]2)[C:20]([CH:28]=[CH2:29])=[C:19]4[CH3:30])[C@@H:14]([CH3:31])[C@@H:13]3[CH2:32][CH2:33][C:34]([OH:36])=[O:35])[C:8]([C:40]([OH:42])=[O:41])=[C:7]1[CH3:44]
Reactant: C=Cc1c(C)c2cc3nc(c(C=O)c4nc(cc5[nH]c(cc1[nH]2)c(C)c5CC)C(C)=C4C(=O)OC)[C@@H](CCC(=O)OC)[C@@H]3C
Agent: Cl
Solvent: CC(C)=O
Product: C=Cc1c(C)c2cc3nc(c(C=O)c4nc(cc5[nH]c(cc1[nH]2)c(C)c5CC)C(C)=C4C(=O)O)[C@@H](CCC(=O)O)[C@@H]3C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Purpurin 5 dimethyl ester is dissolved in acetone and concentrated hydrochloric acid (37%) is added in the ratio 1:2. The mixture is stirred for 2 hours at 25° C., neutralised, purpurin 5 is filtered out, washed with water, dissolved in 10 % N-methyl-D-glucamine solution and gel filtrated on a Sephadex G10 column with the use of 1% N-methyl-D-glucamine solution as an eluent, the second fraction is collected, neutralised, a precipitate is filtered out, washed with water, dried over phosphorus pentoxide till the weight becomes constant to give purpurin 5 (5.2% calculating to the dry reaction mass taken for esterification).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:30])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:19]=2)=[CH:12][C:11]=1[NH:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(N(C)C)=O>O>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:30])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:19]=2)=[CH:12][C:11]=1[NH:31][C:32](=[O:40])[C:33]1[CH:34]=[CH:35][C:36]([O:39][C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=2)=[CH:37][CH:38]=1
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1ccc(O)cc1
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1ccc(Oc2cc(Cl)ncn2)cc1
Yield: 53.2 %

Procedure:
4,6-Dichloropyrimidine (0.103 g) was added to a stirred mixture of N-[2-methyl-5-(3-morpholinobenzamido)phenyl]-4-hydroxybenzamide (0.3 g), caesium carbonate (0.453 g) and DMA (7.5 ml) and the resultant solution was stirred at ambient temperature for 18 hours. The mixture was poured into water (200 ml) and extracted with ethyl acetate. The organic phase was washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. The material so obtained was triturated under diethyl ether. The resultant solid was isolated, washed with diethyl ether and dried under vacuum at 60° C. There was thus obtained the title compound (0.2 g); NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 3.2 (t, 4H), 3.74 (t, 4H), 7.12 (m, 1H), 7.23 (m, 1H), 7.41 (m, 6H), 7.58 (m, 1H), 7.82 (d, 3H); 8.06 (d, 2H), 8.67 (s, 1H), 9.93 (s, 1H), 10.12 (s, 1H); Mass Spectrum: M+H+ 544.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:11][C:10]=1[C:20]1[CH:21]=[C:22]([CH:37]=[CH:38][N:39]=1)[C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1)=[O:24])=[O:7].C(=O)([S:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][O:69][CH3:70])C.C[O-].[Na+].CO.[C:77]([OH:83])([C:79]([F:82])([F:81])[F:80])=[O:78]>CN(C=O)C.O>[C:77]([OH:83])([C:79]([F:82])([F:81])[F:80])=[O:78].[CH3:70][O:69][CH2:68][CH2:67][O:66][CH2:65][CH2:64][O:63][CH2:62][CH2:61][O:60][CH2:59][CH2:58][O:57][CH2:56][CH2:55][O:54][CH2:53][CH2:52][O:51][CH2:50][CH2:49][O:48][CH2:47][CH2:46][S:45][CH2:2][C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:11][C:10]=1[C:20]1[CH:21]=[C:22]([CH:37]=[CH:38][N:39]=1)[C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1)=[O:24])=[O:7]
Reactant: COCCOCCOCCOCCOCCOCCOCCOCCSC(C)=O
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(CCl)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(NC(=O)c2cccc(CSCCOCCOCCOCCOCCOCCOCCOCCOC)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(2-(3-(chloromethyl)benzamido)-5-(diethylamino)phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide 143a (715 mg, 1.2 mmol) and S-2,5,8,11,14,17,20,23-octaoxapentacosan-25-yl ethanethioate 135c.3 (590 mg, 1.33 mmol) in DMF (10 mL) was added 4.3 M NaOMe in MeOH (0.37 mL, 1.6 mmol) and stirred at room temperature for 15 minutes. The reaction mixture was added to water (35 mL) and extracted with DCM (3×50 mL). The combined organic layers were washed with water (25 mL), dried (Na2SO4) and concentrated at reduced pressure. The residue was purified by flash chromatography on silica gel (1% to 5% MeOH in DCM). The purified product was dissolved in 50% ACN/water and TFA (410 mg, 3.6 mmol) was added. Lyophilization gave a TFA salt of the title compound (1.34 g) as a light yellow oil. MS (ES, m/z): 959.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([F:13])=[C:11]([F:14])[C:10]([C:15]([F:18])([F:17])[F:16])=[C:9]([F:19])[C:8]=2[F:20])[N:5]=[CH:4][C:3]=1[C:21]#[N:22].[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:23]([NH:1][C:2]1[N:6]([C:7]2[C:12]([F:13])=[C:11]([F:14])[C:10]([C:15]([F:18])([F:17])[F:16])=[C:9]([F:19])[C:8]=2[F:20])[N:5]=[CH:4][C:3]=1[C:21]#[N:22])(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1cnn(-c2c(F)c(F)c(C(F)(F)F)c(F)c2F)c1N
Product: CC(=O)Nc1c(C#N)cnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F

Procedure:
5-Amino-4-cyano-1-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl)pyrazole (6.5 g) in acetic anhydride (30 ml) was heated at reflux for 3.5 hours. The reaction mixture was then evaporated to dryness and the solid residue was dissolved in ethanol (50 ml). Saturated aqueous sodium bicarbonate solution was then added to give a pH of 7-8 and the solution was then evaporated to dryness. The solid residue was triturated with hexane (20 ml) to give an off-white powder which was crystallized from toluene (50 ml) to give 5-acetamido-4-cyano-1-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl)pyrazole (1.4 g), m.p. 153°-154° C., in the form of colourless crystals.
Reaction SMILES: C([Si](C)(C)[O:6][C@H:7]1[CH2:13][CH2:12][C@H:11]2[N:14]([CH2:15][CH:16]=[CH2:17])[C@:8]1([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][CH2:10]2)(C)(C)C.Cl>CO>[C:18]1([C@@:8]23[N:14]([CH2:15][CH:16]=[CH2:17])[C@@H:11]([CH2:10][CH2:9]2)[CH2:12][CH2:13][C@@H:7]3[OH:6])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C=CCN1[C@@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@]1(c1ccccc1)CC2
Agent: Cl
Solvent: CO
Product: C=CCN1[C@@H]2CC[C@H](O)[C@@]1(c1ccccc1)CC2
Reaction time: 120 h
Yield: 74.5 %

Procedure:
A mixture of (1S,2S,5S)-2-(tertbutyldimethylsilyloxy)-1-phenyl-8-(prop-2-enyl)-8-azabicyclo[3.2.1]octane (Description 56; 230 mg, 0.64 mmol), 2M hydrochloric acid (3 ml) and methanol (6 ml) was stirred at +55° C. over 5 days, then concentrated in vacuo and quenched with saturated aqueous NaHCO3. The mixture was extracted with dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (dichloromethane:methanol:ammonia) to give the title compound (116 mg, 74%).
Reaction SMILES: Cl[CH2:2][C:3]([CH3:21])([CH3:20])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])=[O:5].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:2][C:3]1([CH3:21])[CH2:20][N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=2[N+:17]([O-:19])=[O:18])[C:4]1=[O:5]
Reactant: CC(C)(CCl)C(=O)Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)CN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])C1=O
Temperature: 50 °C

Procedure:
To a mixture of 3-chloro-2,2-dimethyl-N-(2-nitro-4-(trifluoromethyl)phenyl)propanamide (3.24 g, 10.0 mmol, 1.0 equiv) in acetone (100 mL) was added K2CO3 (3.5 g, 25.0 mmol, 2.5 equiv). The mixture was heated to 50° C. for 48 h. After filtering, the solvent was removed in vacuo and the resulting residue purified by silica gel chromatography (1:10 hexanes:EtOAc to 1:5 hexanes:EtOAc) to afford lactam 3. MS (MH+) 289.1; Calculated 289.1 for C12H12F3N2O3.