Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:24][CH2:25][CH2:26][NH:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[OH:35])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\CC.[F:37][C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=1C1C=CC(O)=C(C(O)=O)C=1>>[F:37][C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=1[C:33]1[CH:32]=[CH:31][C:30]([OH:35])=[C:29]([C:28]([NH:27][CH2:26][CH2:25][NH:24][C:1](=[O:23])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20])=[O:36])[CH:34]=1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCNC(=O)c1ccccc1O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)NCCNC(=O)c1cc(-c2ccc(F)cc2F)ccc1O

Procedure:
2′,4′-Difluoro-4-hydroxy-N-(2-(5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamidoethyl)biphenyl-3-carboxamide was prepared in a similar fashion as N-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)-2-hydroxybenzamide, using the appropriate 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylic acid and EPA starting materials. for C35H42F2N2O3=576.72; found: [M+H]+=577.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20](O)[CH2:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[CH:34]=[CH:35][CH:36]=3)[CH2:27][CH2:26]2)=[CH:16][CH:15]=1.Cl>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([O:12][C:3]2[CH:4]=[C:5]([C:8]([F:10])([F:11])[F:9])[CH:6]=[CH:7][C:2]=2[F:1])[CH2:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:42])[CH:39]([CH3:40])[CH3:41])[CH:34]=[CH:35][CH:36]=3)[CH2:27][CH2:26]2)=[CH:18][CH:19]=1
Reactant: Oc1cc(C(F)(F)F)ccc1F
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccc(Cl)cc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(Oc3cc(C(F)(F)F)ccc3F)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 2-fluoro-5-(trifluoromethyl)phenol and N-(3-{1-[5-(4-chlorophenyl)-5-hydroxypentyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 7.61–6.92 (m, 11H), 5.24–5.16 (m, 1H), 3.70–3.58 (m, 2H), 3.02–2.91 (br, 2H), 2.80–2.64 (m, br, 3H), 2.64–2.50 (m, 3H), 2.18–1.94 (m, br, 6H), 1.62–1.44 (m, br, 2H) 1.25 (d, 6H, J=7.2 Hz); ESMS m/e: 605.3 (M+H)+.
Reaction SMILES: Br[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH:13]([CH3:15])[CH3:14])[CH:10]=2)[C:5]([CH3:17])([CH3:16])[O:4][CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:24][CH2:25][C@@H:26]([OH:45])[C@@H:27]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=1>CN(C)C=O.C(OCC)(=O)C>[F:35][C:33]1[CH:34]=[C:29]([CH:30]=[C:31]([F:36])[CH:32]=1)[CH2:28][C@H:27]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[C@H:26]([OH:45])[CH2:25][NH:24][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH:13]([CH3:15])[CH3:14])[CH:10]=2)[C:5]([CH3:17])([CH3:16])[O:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CN
Reactant: CC(C)Oc1ccc2c(c1)C(Br)COC2(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc2c(c1)C(NC[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C)COC2(C)C
Yield: 46.8 %

Procedure:
A solution of 4-bromo-6-isopropoxy-1,1-dimethyl-3,4-dihydro-1H-isochromene (0.61 g, 2.04 mmol), cesium carbonate (1.33 g, 4.08 mmol), and tert-butyl (1S,2R)-3-amino-1-(3,5-difluorobenzyl)-2-hydroxypropylcarbamate (0.64 g, 2.04 mmol) in N,N-dimethylformamide (10 mL) was stirred at 60° C., under nitrogen, for 24 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with 5% lithium chloride (3×40 mL), water (2×30 mL), saturated sodium chloride (30 mL), dried (sodium sulfate), and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica, 95:5 methylene chloride/methanol) to afford the desired product (0.51 g, 47%) as a pale-yellow foam: ESI MS m/z 535 [C29H40F2N2O5+H]+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:29]=[CH:30][C:31]=1[CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:13][O:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24](Br)=[CH:23][C:22]=2[CH3:28])[CH:18]=[CH:19][CH:20]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Li])CCC.[CH3:46][CH:47]([CH3:50])[CH:48]=[O:49]>>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:29]=[CH:30][C:31]=1[CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:13][O:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([CH:48]([OH:49])[CH:47]([CH3:50])[CH3:46])=[CH:23][C:22]=2[CH3:28])[CH:18]=[CH:19][CH:20]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)C=O
Reactant: Cc1cc(Br)ccc1-c1cccc(OCc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1
Agent: [Li]CCCC
Product: Cc1cc(C(O)C(C)C)ccc1-c1cccc(OCc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1

Procedure:
In a manner similar to that of Example 27(f), by reaction of 2 g (3.1 mmol) of 3′-[3,4-bis-(tert-butyldimethylsilanyloxymethyl)benzyloxy]-4-bromo-2-methylbiphenyl with 1.4 mL (3.5 mmol) of 2.5 M butyllithium and 400 μl (37 mmol) of 2-methylpropionaldehyde, the desired product is obtained in the form of a colourless oil (m=1.1 g; Y=56%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[CH:7]=1.C([Li])CCC.[O:17]=[C:18]1[CH2:24][CH:23]2[CH2:25][CH:19]1[CH2:20][N:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22]2>C(OCC)C.C1COCC1>[OH:17][C:18]1([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[CH:7]=2)[CH2:24][CH:23]2[CH2:25][CH:19]1[CH2:20][N:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22]2
Reactant: CC(C)Oc1cncc(Br)c1
Reactant: CCOC(=O)N1CC2CC(=O)C(C2)C1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)N1CC2CC(C1)C(O)(c1cncc(OC(C)C)c1)C2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
To a solution of 3-bromo-5-isopropoxypyridine (0.66 g, 3.1 mmol) in dry diethyl ether (15 mL) at −78° C. was added 2.5 M n-butyllithium (1.2 mL, 3.0 mmol). The reaction was stirred for 30 min under nitrogen at −78° C. and then slowly transferred by cannula into a solution of ethyl 6-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate (0.30 g, 1.5 mmol) in THF (15 mL) at −78° C. The reaction was stirred 4 h at −78° C. and then warmed to ambient temperature overnight, at which time it was quenched with saturated aqueous ammonium chloride (20 mL). The reaction was then extracted with chloroform (2×10 mL), and the combined extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation. Excess pyridine was removed by repeated azeotropic rotary evaporation with toluene, and the residue was chromatographed on a silica gel column (with 5% methanol in chloroform) to yield the desired product (0.34 g, 61%).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH2:17][C:18]4[CH:32]=[C:31]([F:33])[C:21]5[N:22](C6CCCCO6)[CH:23]=[N:24][C:20]=5[CH:19]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CO.O>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH2:17][C:18]4[CH:32]=[C:31]([F:33])[C:21]5[NH:22][CH:23]=[N:24][C:20]=5[CH:19]=4)[N:11]=3)[CH:5]=2)[CH2:2][CH2:3]1
Reactant: Fc1cc(CNc2nccc(Nc3cc(C4CC4)[nH]n3)n2)cc2ncn(C3CCCCO3)c12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: Fc1cc(CNc2nccc(Nc3cc(C4CC4)[nH]n3)n2)cc2nc[nH]c12

Procedure:
A mixture of 272 (140 mg, 0.31 mmol) and p-TsOH.H2O (59 mg, 0.31 mmol) in MeOH (5 mL) and H2O (1 mL) was heated at reflux for 2 h. The mixture was cooled and concentrated in vacuo. The crude product was purified by preparative HPLC to afford 50 mg (44%) of I-96 as white solid.
Reaction SMILES: C1C2C(=CC=CC=2)C=NN=1.[C:11]1(=O)[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[CH3:22][N:23]([CH3:25])[NH2:24]>>[CH3:22][N:23]([CH3:25])[N:24]1[C:14](=[O:15])[C:13]2[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]1=[O:16]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CN(C)N
Agent: c1ccc2cnncc2c1
Product: CN(C)N1C(=O)c2ccccc2C1=O

Procedure:
Phthalazine derivatives of formula IA were prepared as described in FIG. 8 and as further detailed in Example 4. The commercially available phthalic anhydride was reacted with N,N-dimethyl hydrazine to give 2-(dimethylamino)isoindoline-1,3-dione 16 in good yield [Hanefeld W et al. J Heterocyclic Chem. 1996;33:1443]. Then, 16 was reacted with phenylmagnesium bromide, to lead to the intermediate 17 in good yield [Deniau E et al. Tetrahedron: Asym. 2003;14:2253], which in turn was quantitatively converted by reaction with hydrazine to 4-phenylphthalazin-1(2H)-one 18 [Saito Y et al. Synthesis 2001;2:221]. Finally, the N-amidation product 19 (Compound I) was the major product obtained in good yield whatever the experimental conditions. Two different carbamoyl chlorides were used (R1=CH3—compound 19a; and i-Pr—compound 19b) for the preparation of phthalazine derivatives. (FIG. 8).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([NH2:13])[CH2:11][NH2:12])=[CH:4][CH:3]=1.[C:14](O)(=O)C.C(N)=N>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH:10]2[CH2:11][NH:12][CH:14]=[N:13]2)=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: NCC(N)CCc1ccc(Cl)cc1
Agent: N=CN
Solvent: CCO
Product: Clc1ccc(CCC2CNC=N2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
To a solution of 4-(4-chlorophenyl)-1,2-butanediamine (0.084 mg, 0.42 mmol) in ethanol (8 ml) was added formamidine acetate (0.15 g, 1.45 mmol) and the mixture was stirred overnight at room temperature. The solvent was evaporated, water (5 ml) was added and the mixture was extracted 3 times with dichloromethane (10 ml). The combined organic layers were dried over magnesium sulfate and evaporated. The residue was purified by chromatography (column: Isolute® Flash-NH2 from Separtis; eluent:ethyl acetate/methanol=90:10) to yield an off-white amorphous solid (0.041 g, 47%); MS (ISP): 209.3 ((M+H)+).
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.C(=O)([O-])[O-].[Na+].[Na+].[CH2:11]([N:13]1[C:17](=[O:18])[NH:16][N:15]=[N:14]1)[CH3:12]>CN(C)C=O.O>[Br:1][CH2:2][CH2:3][N:16]1[C:17](=[O:18])[N:13]([CH2:11][CH3:12])[N:14]=[N:15]1
Reactant: CCn1nn[nH]c1=O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nnn(CCBr)c1=O
Reaction time: 8 h
Yield: 22 %

Procedure:
To a stirred solution of 109 parts of 1,2-dibromoethane and 21.2 parts of sodium carbonate in 5 parts of water and 18 parts of N,N-dimethylformamide were added dropwise a solution of 22.5 parts of 1-ethyl-1,4-dihydro-5H-tetrazol-5-one in 5 parts of water and 27 parts of N,N-dimethylformamide at about 40° C. Upon completion, stirring was continued overnight at 40° C. The organic phase was separated, dried and distilled, yielding 9.8 parts (22%) of 1-(2-bromoethyl)-4-ethyl-1,4-dihydro-5H-tetrazol-5-one; bp. 110° C. at 0.1 mm pressure (interm. 47).
Reaction SMILES: [K].[CH:2]([CH:4]([CH2:7][C:8]#[N:9])[C:5]#[N:6])=O.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[NH2:18])=[CH:13][CH:12]=1.C(O)(=O)C>O>[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]([NH:18]/[CH:2]=[C:4](\[CH2:7][C:8]#[N:9])/[C:5]#[N:6])[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[CH:15][CH:16]=1
Reactant: N#CCC(C#N)C=O
Reactant: NC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [K]
Solvent: O
Solvent: CC(=O)O
Product: N#CC/C(C#N)=C\NC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of formyl succinonitrile potassium salt (6.67 g, 45.6 mmol) and 1,1-bis(4-fluorophenyl) methaneamine (11.0 g, 50.2 mmol) in water (19 ml) was added acetic acid (19 ml) at room temperature, and the mixture was stirred 100° C. for 30 minutes. The solvent was distilled off under reduced pressure. The residue was poured into iced water, made basic with potassium carbonate and then extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the objective product as oily matter. Yield (amount) 14.0 g, yield (rate) 99.3%
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].[O:5]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl-].[NH4+].Cl>O1CCCC1>[O:5]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]([OH:16])[CH:1]=[CH2:2])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C=C[Mg]Cl
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)c1cccc(Oc2ccccc2)c1

Procedure:
30 ml of a 1.6 molar solution of vinyl-magnesium chloride in tetrahydrofuran are introduced into 100 ml of absolute tetrahydrofuran at 0° C. 9.8 g (0.05 mole) of 3-phenoxybenzaldehyde in 100 ml of absolute tetrahydrofuran are added dropwise whilst stirring and excluding moisture. The reaction mixture is stirred for 3 hours at 25° C. and is then cautiously decomposed by adding a cold saturated ammonium chloride solution and a few milliliters of 10% strength hydrochloric acid until the precipitate dissolves. The mixture is then extracted three times by shaking with ether and the combined ether extracts are washed with sodium bisulfite solution, sodium bicarbonate solution and water, dried over sodium sulfate and concentrated under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([F:23])=[C:11]3[N:21]=[CH:20][N:19]([CH3:22])[C:12]3=[N:13][C:14]=2[C:15]([NH:17][NH2:18])=[O:16])=[C:4]([F:24])[CH:3]=1.Br[C:26]#[N:27].C([O-])(O)=O.[Na+]>O1CCOCC1.O>[NH2:27][C:26]1[O:16][C:15]([C:14]2[N:13]=[C:12]3[N:19]([CH3:22])[CH:20]=[N:21][C:11]3=[C:10]([F:23])[C:9]=2[NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:24])=[N:17][N:18]=1
Reactant: Cn1cnc2c(F)c(Nc3ccc(Br)cc3F)c(C(=O)NN)nc21
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cnc2c(F)c(Nc3ccc(Br)cc3F)c(-c3nnc(N)o3)nc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3 -methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid hydrazide (1.00 equivalent) in 1,4-dioxane at room temperature is added BrCN (2.0 equivalents) followed by a solution of NaHCO3 (1.0 equivalents) in H2O. After stirring for 3 hours at room temperature, the reaction mixture is diluted with water and extracted with EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that is purified by trituration or flash column chromatography to afford [5-(5-amino-[1,3,4]oxadiazol-2-yl)-7-fluoro-3-methyl-3H-imidazo[4,5-b]pyridin-6-yl]-(4-bromo-2-fluorophenyl)-amine.
Reaction SMILES: [CH2:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:16]=2)[C:11]([CH:25]=[O:26])=[CH:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[K].OO.[O-:30][Mn](=O)(=O)=O.[K+]>CC(C)=O.O>[CH2:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:16]=2)[C:11]([C:25]([OH:30])=[O:26])=[CH:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCCCCCCCn1cc(C=O)c2cc(-c3cccc(C)c3)ccc21
Agent: OO
Agent: [K+]
Agent: [K]
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCCn1cc(C(=O)O)c2cc(-c3cccc(C)c3)ccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 62 %

Procedure:
The method of Andreani, A.; Granaiola, M.; Leoni, A.; Locatelli, A.; Morigi, R.; Rambaldi, M.; Roda, A.; Guardigli, M.; Traniello, S.; Spisani, S. N-Benzyl-2-chloroindole-3-carboxylic acids as potential anti-inflammatory agents. Synthesis and screening for effects on human neutrophil functions and on COX1/COX2 activity. Eur J Med. Chem. 2004, 39, 785-91, was followed. Compound 9 (0.573 mmol, 1 equiv) was dissolved in 10 mL of acetone and treated with a solution of potassium permanaganate (KMnO4, 1.5 mmol) in water (5 mL). The reaction mixture was stirred at room temperature for 5 h, treated with 10% H2O2 until the pink color of KMnO4 was not observed and then filtered. The solvent was removed under reduced pressure and the resulting residue was filtered again (if necessary), acidified with 2M HCl and extracted with Et2O. The organic solvent was removed in vacuo and the residue was purified by column chromatography with hexane/EtOAc as eluting solvents. Yield: 62%; 1H NMR (300 MHz, CDCl3): δ 8.84 (s, 1 H), 7.92 (s, 1 H), 7.54-7.48 (m, 2 H), 7.41-7.29 (m, 3 H), 7.14 (d, J=6.6 Hz, 1 H), 4.12 (t, J=6.6 Hz, 2 H), 2.44 (s, 3 H), 1.87 (t, J=6.6 Hz, 3 H), 1.37-1.25 (m, 10 H), 0.86 (t, J=6.6 Hz, 3 H); 13C NMR (75 MHz, CDCl3): δ 170.3, 142.3, 141.9, 138.4, 138.2, 136.1, 136.0, 135.8, 128.5, 128.3, 127.4, 124.6, 120.3, 110.3, 106.3, 47.2, 31.7, 31.1, 29.8, 29.1, 22.6, 21.5, 21.5, 14.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[CH:18][CH:17]=1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44]>>[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[CH:18][CH:17]=2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(CCN(C)C)cc1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1ccc(CCN(C)C)cc1
Yield: 26.7 %

Procedure:
Following general procedure D, 1-(6-bromo-4-(4-(2-(dimethylamino)ethyl)phenyl amino)quinolin-3-yl)ethanone (76 mg, 0.18 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (76 mg, 0.28 mmol) to afford the desired product (23 mg, 27%) as a yellow-green solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.30 (s, 1H), 8.19 (dd, J=8.8, 2.0 Hz, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.76 (d, J=2.1 Hz, 1H), 7.60 (d, J=8.3 Hz, 2H), 7.50 (d, J=8.3 Hz, 2H), 6.99-6.92 (m, 2H), 3.46-3.39 (m, 2H), 3.27-3.19 (m, 2H), 3.00 (s, 6H), 2.82 (s, 3H); ESI MS m/z 478 [C27H25ClFN3O2+H]+; HPLC 98.4% (AUC), tR=10.91 min.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:12][C@@H:11]2[CH2:13][C@H:8]1[C:9](=[O:14])[S:10]2)=[O:6])[CH:2]=[CH2:3].[CH3:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.Cl>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:12][C@@H:11]([SH:10])[CH2:13][C@H:8]1[C:9]([N:19]1[CH2:20][CH2:21][CH:16]([CH3:15])[CH2:17][CH2:18]1)=[O:14])=[O:6])[CH:2]=[CH2:3]
Reactant: CC1CCNCC1
Reactant: C=CCOC(=O)N1C[C@@H]2C[C@H]1C(=O)S2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@@H](S)C[C@H]1C(=O)N1CCC(C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (1S,4S)-5-allyloxycarbonyl-2-thia-5-azabicyclo[2.2.1]heptan-3-one (38.5 mg) in tetrahydrofuran (1 ml) was added 4-methylpiperidine (19.7 mg). The mixture was stirred for 4 hours at room temperature. After the reaction was over, 1N-hydrochloric acid (0.036 ml) was added thereto, and the mixture was diluted with ethyl acetate (2 ml) and dried above magnesium sulfate. Distillation of the solvent, followed by purifying the residue by silica gel chromatography, gave oily 1-[(2S,4S) -1-allyloxycarbonyl-4-mercapto-2-pyrrolidinecarbonyl]-4-methylpiperidine.
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]C)=[N+:2]=[N-:3].N([CH2:25][CH2:26]N)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[C:8]1[CH:9]=[CH:10][C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:26][CH:25]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCN
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCc1ccc(C(=O)NCCN=[N+]=[N-])cc1
Yield: 61.1 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, (0.262 g, 1.19 mmol) the acid chloride was reacted with 2-azidoethanamine (0.103 g, 1.19 mmol) and triethylamine (0.242 g, 2.39 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)-4-octylbenzamide (0.220 g, 69% yield). 1H NMR (300 MHz, CDCl3) δ 7.73 (d, 2H), δ 7.37 (t, 1H), δ 7.17 (d, 2H), 63.56 (q, 2H), δ 3.44 (t, 2H), δ 2.59 (t, 2H), δ 1.58 (m, 2H), δ 1.27 (m, 10H), 60.86 (t, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 168.4, 147.3, 131.7, 128.8, 127.4, 50.9, 39.7, 36.1, 32.1, 31.5, 29.7, 29.5, 29.5, 22.9, 14.3 ppm; HRMS (ESI) calcd for C17H28N4O (M+) 302.2107. found 302.2104.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[C:17]([NH2:22])[N:16]=1.C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([O:13][C:19]2[CH:20]=[C:15]([Cl:14])[N:16]=[C:17]([NH2:22])[N:18]=2)[C:9]([F:11])([F:12])[F:10])=[CH:4][CH:3]=1
Reactant: O[C@H](c1ccc(Br)cc1)C(F)(F)F
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Nc1nc(Cl)cc(O[C@H](c2ccc(Br)cc2)C(F)(F)F)n1
Temperature: 80 °C

Procedure:
To a solution of (R)-1-(4-bromophenyl)-2,2,2-trifluoroethanol (150 mg, 0.60 mmol) in dioxane (10 mL) was added 4,6-dichloropyrimidin-2-amine (120 mg g, 0.71 mmol) and Cs2CO3 (290 mg, 0.88 mmol), and the reaction mixture was heated to 80° C. for 30 h. Then the reaction was cooled to RT. EtOAc was added and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided (R)-4-(1-(4-bromophenyl)-2,2,2-trifluoroethoxy)-6-chloropyrimidin-2-amine as a colorless oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.C(=O)([O-])[O-].[Na+].[Na+].Cl>CN(C)C=O.O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-n2ccnc2)cc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
In a 20 mL vial were combined 4-fluoronitrobenzene (1.1 mL, 10 mmol), imidazole (0.68 g, 10 mmol), and sodium carbonate (1.1 g, 11 mmol) in N,N-dimethylformamide (5 mL). The mixture is shaken at 100° C. for 24 hours and then allowed to cool to room temperature and then diluted with water. Concentrated hydrochloric acid is added to bring the pH to 1, and then the mixture is extracted thrice with chloroform (10 mL). The acidic aqueous phase is then treated with 2.5 M sodium hydroxide solution to give a pH of 10. A light yellow solid is collected and washed with water to give 1-(4-nitrophenyl)-1H-imidazole.