Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:5]=1[OH:21])([O-:3])=[O:2].C(N(C)C)C1C=CC=CC=1.[C:32](Cl)(=[O:36])/[CH:33]=[CH:34]/[CH3:35]>CCCCCCC>[C:32]([O:21][C:5]1[C:6]([CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:36])/[CH:33]=[CH:34]/[CH3:35]
Reactant: CCCCCCC(C)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1O
Reactant: C/C=C/C(=O)Cl
Agent: CN(C)Cc1ccccc1
Solvent: CCCCCCC
Product: C/C=C/C(=O)Oc1c(C(C)CCCCCC)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 91.2 %

Procedure:
2,4-Dinitro-6-(1-methylheptyl)phenol (98.5 percent pure) (252 gm) is dissolved in heptane (225 gm). Benzyldimethylamine (140.8 gm) is added dropwise over 40 minutes, keeping the temperature of the mixture below 40° C., and the mixture is stirred for 15 minutes. Crotonyl chloride (139 gm) is then added dropwise over 30 minutes, keeping the temperature below 60° C., and the mixture is stirred at 60° C. for 30 minutes and cooled to less than 50° C. The mixture is washed twice with water and then cooled to 20° C. The mixture is washed with a mixture of methanol and aqueous sodium hydroxide, with water and methanol, and finally with dilute hydrochloric acid. The organic layer is stripped at 70° C. under vacuum to remove heptane and leave 2,4-dinitro-6-(1-methylheptyl)phenyl crotonate (282.6 gm) as an orange/brown oil.
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.C1C(=O)N(Br)C(=[O:14])C1.C([O-])(O)=O.[Na+]>O>[CH3:8][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:14]
Reactant: CSc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CS(=O)c1ccccc1
Yield: 95.9 %

Procedure:
Methyl phenyl sulphide (20 g, 161.03 mmol) was added to a mixture of methanol (100 ml) and water (20 mL). NBS (34.39 g, 1.2 eq) was added in portions maintaining the temperature between 0° and 5° C. The mixture was stirred at the same temperature until the reaction was complete. Thereafter, the reaction mixture was quenched by the addition of Na2SO3 (10%, 60 ml). The pH of the resulting reaction mixture was adjusted to a value between 7 and 8 with saturated NaHCO3 solution. The mixture was concentrated under vacuum at a temperature between 20° C. and 25° C. The residue was extracted with dichloromethane (2×125 mL). The combined organic layer was washed with water (2×125 mL) and concentrated to 1/3 of the volume. Heptane (20 mL) was added and then removed by distillation to give 21.64 g (95.9%) of the desired product as colourless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[N:20]=[CH:19][C:18]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]([CH3:31])[NH:26][CH2:25][CH2:24]3)=[CH:17][CH:16]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[CH:29][CH:30]=[C:21]([C:18]5[CH:19]=[N:20][C:15]([F:14])=[CH:16][CH:17]=5)[CH:22]=4)[CH:27]3[CH3:31])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2cc(-c3ccc(F)nc3)ccc21
Product: CC1c2ccc(-c3ccc(F)nc3)cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-(6-Fluoro-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[C:23]3[C:18](=[C:19]([CH2:24][S:25][CH3:26])[CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:9][C:10](OCC)=[O:11])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:15]2[C:23]3[C:18](=[C:19]([CH2:24][S:25][CH3:26])[CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(c1ccc(Cl)cc1)c1c[nH]c2c(CSC)cccc12
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CSCc1cccc2c(C(CCO)c3ccc(Cl)cc3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 6.68 g (17.2 mmol) of the compound from Example 29A in 100 ml of tetrahydrofuran was added dropwise to 60 ml (60 mmol) of a 1N solution of lithium aluminum hydride in tetrahydrofuran under argon in 300 ml of tetrahydrofuran at RT. The mixture was stirred at RT for 15 min and then, while cooling in ice, 1N hydrochloric acid was added. The mixture was extracted with ethyl acetate, and the organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient). 5.93 g (99% of theory) of the target compound were obtained.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=[O:2].[F:24][C:25]([F:35])([F:34])[C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28]Br>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([O:3][CH2:28][C:27]4[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=4[C:25]([F:24])([F:34])[F:35])=[O:2])([CH2:9][CH2:8]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)OCc3ccccc3C(F)(F)F)(CC1)CC2
Yield: 89.3 %

Procedure:
In a similar manner to Example 8, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (30.0 mg) and 2-trifluoromethylbenzyl bromide (25.4 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-(2-trifluoromethylbenzyl)oxycarbonyl bicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (39.9 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][N:10]([CH3:12])[CH2:9][C:8](=[O:13])[NH:7][C:6]=2[CH:14]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])[C:19]([Cl:33])=[CH:18][N:17]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C.Cl.O1CCOCC1>[Cl:33][C:19]1[C:20]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])=[N:21][C:16]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][N:10]([CH3:12])[CH2:9][C:8](=[O:13])[NH:7][C:6]=3[CH:14]=2)=[N:17][CH:18]=1
Reactant: CN1CC(=O)Nc2cc(N)ccc2C1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)NC(=O)CN(C)C3)ncc1Cl
Temperature: 120 °C
Yield: 16 %

Procedure:
A mixture of 8-amino-4-methyl-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one and 2-(2,5-dichloropyrimidin-4-ylamino)-N-methylbenzamide (22 mg, 0.08 mmol), and camphorsulfonic acid (17.4 mg, 0.08 mmol) were heated in IPA (3 mL) at 120° C. for 16 hours. The mixture was heated for another 2.5 hours at 120° C. after the addition of 10 drops of 4 N HCl/dioxane. Concentration and chromatography on preparative TLC with methylene chloride and methanol (100:8) followed by semi-preparative HPLC gave 5 mg of 2-[5-chloro-2-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (16% yield): 1H NMR (300 MHz, CD3OD) δ 8.7 (d, 1H), 8.13 (s, 1H), 7.96 (s, 1H), 7.67 (m, 3H), 7.4 (m, 1H), 7.2 (m, 1H), 3.95 (s, 1H), 3.7 (s, 1H), 3.6 (s, 2H), 2.95 (s, 3H), 2.53 (s, 3H); MS (m/e): 452.2 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].S(OCC)(O[CH2:11][CH3:12])(=O)=O.C(#N)C.[O:19]1[C@@:36]2([CH3:37])[C@@H:20]1[CH2:21][C@@H:22]1[C:27]([C:28]([OH:30])=[O:29])=[CH:26][O:25][C@@H:24]([O:31][C:32](=[O:35])[NH:33][CH3:34])[C@H:23]12>CCCCCC.C(OCC)(=O)C>[CH2:11]([O:29][C:28]([C:27]1[C@H:22]2[CH2:21][C@@H:20]3[O:19][C@:36]3([CH3:37])[C@@H:23]2[C@H:24]([O:31][C:32](=[O:35])[NH:33][CH3:34])[O:25][CH:26]=1)=[O:30])[CH3:12]
Reactant: CCOS(=O)(=O)OCC
Reactant: CNC(=O)O[C@@H]1OC=C(C(=O)O)[C@H]2C[C@@H]3O[C@]3(C)[C@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=CO[C@@H](OC(=O)NC)[C@@H]2[C@@H]1C[C@@H]1O[C@]21C
Temperature: 70 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
130 mg of potassium carbonate and 121 μl of diethyl sulfate were added to an acetonitrile solution containing 210 mg of (1S,4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-7-methyl-1-(methylcarbamoyloxy) cyclopenta [c]-pyrane-4-carboxylic acid described in Example 1 followed by heating and stirring for 1 hour at 70° C. The reaction mixture was then extracted with ethyl acetate. After washing the organic phase with dilute hydrochloric acid, saturated aqueous sodium bicarbonate and brine, it was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain a colorless oil from the hexane-ethyl acetate eluate in the form of (1S,4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-7-methyl-1-(methylcarbamoyloxy) cyclopenta [c]-pyrane-4-carboxylic acid ethylester (204 mg, yield: 88%). The physicochemical properties of this compound are described in Table 1, Compound No. 4.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:30])[CH2:18][CH2:17][C:16]([CH2:28][NH2:29])([C:19]2[CH:20]=[N:21][C:22]([CH:25]3[CH2:27][CH2:26]3)=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:29][CH2:28][C:16]1([C:19]2[CH:20]=[N:21][C:22]([CH:25]3[CH2:26][CH2:27]3)=[CH:23][CH:24]=2)[CH2:17][CH2:18][C:13]([F:12])([F:30])[CH2:14][CH2:15]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC1(c2ccc(C3CC3)nc2)CCC(F)(F)CC1
Product: O=C(NCC1(c2ccc(C3CC3)nc2)CCC(F)(F)CC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and C-[4,4-difluoro-1-(6-cyclopropyl-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=439.0, tR (minutes, Method E)=0.55
Reaction SMILES: [CH2:1](F)[O:2][CH:3]([C:8]([F:11])([F:10])[F:9])[C:4]([F:7])([F:6])[F:5].[F-].[K+].[F:15][C:16]([F:24])([F:23])[CH:17]([OH:22])[C:18]([F:21])([F:20])[F:19].[Cl-].[Cl-].[Cl-].[Al+3].O1COCOC1>>[CH2:1]([O:22][CH:17]([C:18]([F:21])([F:20])[F:19])[C:16]([F:24])([F:23])[F:15])[O:2][CH:3]([C:8]([F:11])([F:10])[F:9])[C:4]([F:7])([F:6])[F:5]
Reactant: FCOC(C(F)(F)F)C(F)(F)F
Reactant: OC(C(F)(F)F)C(F)(F)F
Agent: C1OCOCO1
Agent: [Al+3]
Agent: [Cl-]
Product: FC(F)(F)C(OCOC(C(F)(F)F)C(F)(F)F)C(F)(F)F

Procedure:
U.S. Pat. No. 6,100,434 describes the synthesis of sevoflurane through the preparation of sevochlorane and subsequent fluorination of this intermediate with potassium fluoride in a high molecular weight solvent. Sevochlorane is prepared from hexafluoroisopropanol, aluminum trichloride and 1,3,5-trioxane. An excess of aluminum trichloride in the reaction medium results predominantly in the formation of 2,2′-[methylenebis(oxy)]bis-(1,1,1,3,3,3-hexafluoropropane)—hereinafter denominated P1. The reaction is interrupted by addition of a 6N HCl solution to decompose the gel of hydroxydichloroaluminate. The authors relate that the isolated product contained 95% sevochlorane, <5% of P1 and <1% of polyacetals of higher molecular weight. The crude yield described was 87%. Among the disadvantages of this process is the fact that large quantities of aluminum trichloride must be handled, which is a highly hygroscopic solid and whose reaction with atmospheric humidity or with residual water present tends to be violent. The fact that this reagent easily reacts with water, resulting in the formation of acidic gasses, causes a reduction in its content, compromising considerably the yield of the reaction and the purity of the isolated product. The addition of a 6N hydrochloric acid solution to interrupt the reaction is an additional disadvantage of the process, violently elevating the reaction temperature, resulting in partial product loss by decomposition, volatilization and polymerization. Finally, this reaction generates as a residue, an aqueous phase containing hydroxyaluminates that require incineration for disposal, incurring additional costs.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](I)=[CH:4][N:3]=1>COCCOC.[Cu]I>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2csc3c(I)cnc(N)c23)cc1
Agent: [Cu]I
Solvent: COCCOC
Product: CC(C)(C)OC(=O)Nc1ccc(-c2csc3c(-c4ccccn4)cnc(N)c23)cc1
Temperature: 90 °C
Yield: 66.3 %

Procedure:
A suspension of Example 77A (734 mg, 1.6 mmol) and pyridyl-2-trimethylstannane (418 mg, 1.72 mmol) in DME (12 mL) was degassed with nitrogen, and PdCl2(o-tol3P)2 (62 mg, 0.078 mmol) and CuI (15 mg, 0.078 mmol) were added. The reaction vessel was sealed and the reaction was heated to 90° C. for 16 h. After cooling, the mixture was partitioned between EtOAc and H2O. The extracts were dried (Na2SO4) and concentrated, and the residue was purified by flash chromatography on silica gel, eluting with 40-75% EtOAc/hexanes to give the desired product (222 mg). MS (ESI(+)) m/e 419.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]2[N:9]=[N:10][CH:11]=[C:4]2[CH:3]=1.[CH3:12][NH2:13]>O>[CH3:8][C:6]1[N:5]2[N:9]=[N:10][CH:11]=[C:4]2[CH:3]=[C:2]([NH:13][CH3:12])[N:7]=1
Reactant: Cc1nc(Cl)cc2cnnn12
Reactant: CN
Solvent: O
Product: CNc1cc2cnnn2c(C)n1

Procedure:
To a stirred solution of 3.4 g (20 mmole) of 5-chloro-7-methyltriazolo[1,5-c]pyrimidine in 50 ml of water was added 1.25 g (40 mmole) of methylamine as a 40% aqueous solution. The mixture was heated in an oil bath and thickened rapidly as a result. The solid was separated by filtration, and was then recrystallized from a benzene-hexane mixture with treatment with decolorizing charcoal. The product was white needles of 7-methyl-5-(N-methylamino)triazolo[1,5-c]pyrimidine, m.p. 162°-164° C. Analysis: Calculated for C7H9N5 : %C, 51.5; %H, 5.6; %N, 42.9; Found: %C, 51.6; %H, 5.4; %N, 43.1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:21]([F:22])=[CH:20][C:11]([C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13])=[C:10]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[F:31])[N:9]=1.C(Cl)(Cl)Cl.O>C(O)C.CCCCCC>[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[NH:23][C:10]1[N:9]=[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[C:21]([F:22])=[CH:20][C:11]=1[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13]
Reactant: C1CNCCN1
Reactant: CCOC(=O)CC(=O)c1cc(F)c(Cl)nc1Nc1ccc(F)cc1F
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCCCCC
Product: CCOC(=O)CC(=O)c1cc(F)c(N2CCNCC2)nc1Nc1ccc(F)cc1F
Yield: 41.2 %

Procedure:
In 1.5 ml of ethanol was dissolved 140 mg of anhydrous piperazine, and to the resulting solution was added 150 mg of ethyl 2-[6-chloro-2-(2,4-difluorophenylamino)-5-fluoronicotinoyl]acetate in portions, and the resulting mixture was subjected to reaction at room temperature for 30 minutes. Subsequently, the reaction mixture was added to a mixture of 5 ml of chloroform and 5 ml of water, and the organic layer was separated, washed successively with 3 ml of water and 3 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the crystalline material thus obtained was added 2 ml of n-hexane, after which crystals were collected by filtration to obtain 70 mg (yield 41.2%) of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-(1-piperazinyl)nicotinoyl]acetate.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH2:12][O:13][CH3:14])[N:5]=[C:4]([NH2:15])[CH:3]=1.NC1C(C#N)=C(OC(C)C)N=C(N[C:30](=[O:42])[CH2:31][C:32]2[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=2[O:40][CH3:41])C=1>N1C=CC=CC=1.C(Cl)Cl.O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH2:12][O:13][CH3:14])[N:5]=[C:4]([NH:15][C:30](=[O:42])[CH2:31][C:32]2[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=2[O:40][CH3:41])[CH:3]=1
Reactant: COCCOc1nc(N)cc(N)c1C#N
Reactant: COc1ccc(OC)c(CC(=O)Nc2cc(N)c(C#N)c(OC(C)C)n2)c1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCCOc1nc(NC(=O)Cc2cc(OC)ccc2OC)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 38.8 %

Procedure:
To a solution of 42 mg (0.20 mmol) of 4,6-diamino-2-(2-methoxy-ethoxy)-nicotinonitrile in 0.2 mL of pyridine and 1 mL of CH2Cl2 was added 75 mg (0.35 mmol) of 2,5-dimethoxyphenylacetyl chloride (Example 60B). The mixture was stirred at ambient temperature for 10 minutes then diluted with 1 mL of water and concentrated under reduced pressure. The residue was dissolved in 1 mL of ethyl acetate, then extracted with water (1×10 mL), 1M HCl(aq.) (2×5 mL), saturated NaHCO3(aq.) (2×5 mL), and brine (1×5 mL), dried over MgSO4, filtered, and concentrated to a yellow solid. The residue was recrystallized from 3 mL of ethyl acetate to provide 30 mg (38%) of a white solid. 1H NMR (300 MHz, d6-DMSO) δ 10.11 (s, 1H), 7.14 (s, 1H), 6.90 (m, 3H), 6.79 (m, 2H), 4.42 (m, 2H), 3.70 (s, 3H), 3.69 (s, 3H), 3.64 (m, 4H), 3.31 (s, 3H); MS (ESI) m/e=329 (M-CH2CH2OCH3+H)+, 387 (M+H)+, 385 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([S:29][CH3:30])=[C:9]([C:27]#[N:28])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][NH:20]C(=O)C(C)(C)C)=[CH:13][CH:12]=1)=[O:5])[CH3:2].[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>C(Cl)Cl>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([S:29][CH3:30])=[C:9]([C:27]#[N:28])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][NH2:20])=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(SC)c(C#N)c1-c1ccc(OCCNC(=O)C(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1sc(SC)c(C#N)c1-c1ccc(OCCN)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Combine 4-cyano-3-{4-[2-(2,2-dimethyl-propionylamino)-ethoxy]-phenyl}-5-methylsulfanyl-thiophene-2-carboxylic acid ethyl ester (211 mg, 0.45 mmol) and CH2Cl2 (1 ml), add trifluoroacetic acid 99% (1 ml) and stir at room temperature for 2 days. Remove the solvents in vacuo to give 222 mg (quantitative yield) of title compound: Rf (hexane:ethyl acetate, 4:1)=0.1. Mass spectrum (EI+): m/z 363 (M++1 free base).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[N:7]([CH3:18])[C:8]([CH2:12]OS(C)(=O)=O)=[N:9]2)=[CH:4][C:3]=1[CH2:20][N:21]([C:25]1[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=1)[CH2:22][C:23]#[CH:24].[CH2:38]([NH:40][CH2:41][CH3:42])[CH3:39]>ClCCl.C(OCC)(=O)C>[CH2:38]([N:40]([CH2:12][C:8]1[N:7]([CH3:18])[C:6](=[O:19])[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([CH2:20][N:21]([C:25]3[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])=[CH:27][CH:26]=3)[CH2:22][C:23]#[CH:24])[CH:4]=2)[N:9]=1)[CH2:41][CH3:42])[CH3:39]
Reactant: CCNCC
Reactant: C#CCN(Cc1cc2c(=O)n(C)c(COS(C)(=O)=O)nc2cc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C#CCN(Cc1cc2c(=O)n(C)c(CN(CC)CC)nc2cc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred under argon solution of tert-butyl 4-[N-[7-chloro-2-methanesulphonyloxymethyl-3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl]-N-(prop-2-ynyl)amino]benzoate (0.230 g, 0.42 mmol) in anhydrous dichloromethane (10 ml) was added diethyl amine (0.306 g, 4.2 mmol). The yellow solution was then stirred at room temperature for 18 hours. The solution was then diluted with ethyl acetate (250 ml) and washed with 5% aqueous sodium carbonate solution (2×100 ml), brine (100 ml), and concentrated in vacuo. Purification by column chromatography, on gradient elution with methanol in dichloromethane (0 to 2%) afforded a white crispy solid which was triturated diethyl ether/hexanes (v/v, 1:2). The white solid was collected by filtration, washed with hexanes and dried in vacuo over P2O5 (0.202 g, 92%), mp 112-113° C.; 1H-NMR (DMSO-d6) 0.95 (t, J=6.9 Hz, 6H, 2×CH2CH3), 1.49 (s, 9H, But), 2.56 (q obscured, J=6.85 Hz, 4H, 2×CH2CH3), 3.62 (s, 3H, N3-Me), 3.70 (s, 2H, 2-CH2), 4.40 (s, 2H, CH2C≡C), 4.79 (s, 2H, 6-CH2), 6.78 (d, J=8.9 Hz, 2H, 3′,5′-ArH), 7.72 (d, J=8.9 Hz, 2′,6′-ArH), 7.81, 7.86 (2×s, 2H, 5-H, 8-H); MS (FAB, m/z) 523, 525 [(M+H)+, 100%, 40% respectively; Cl isotopic pattern].
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([C:7]1[CH:16]=[CH:15][C:10]([CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:9][CH:8]=1)[CH3:6])=[O:4].P([O-])([O-])([O-])=[O:18].[K+].[K+].[K+]>C(O)C>[OH:18][C:12]([CH3:13])([CH3:14])[CH2:11][C:10]1[CH:9]=[CH:8][C:7]([CH:5]([CH3:6])[C:3]([O:2][CH3:1])=[O:4])=[CH:16][CH:15]=1
Reactant: COC(=O)C(C)c1ccc(CC(C)C)cc1
Reactant: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COC(=O)C(C)c1ccc(CC(C)(C)O)cc1
Reaction time: 0.03 h

Procedure:
Experimental description: 150 mg ibuprofen methyl ester were dissolved in 1.4 mL ethanol and added to 150 mL potassium phosphate buffer pH 8.0. Var3-4 was added to the mixture at a final concentration of 3 μM. The mixture was split in 4 mL-aliquots into 15 mL scintillation vials equipped with a stir bar. 500 μL 10 mM NADPH in KPi buffer were added to each vial and stirred for 2 minutes. 500 μL cofactor regeneration solution containing 500 mM glucose-6-phosphate and 10 units/mL glucose-6-phosphate dehydrogenase were then added to each vial. The resulting mixtures were stirred at room temperature. After 48 hours, the reaction mixtures were joined together and extracted with chloroform (3×50 mL). The organic phase was then dried over magnesium sulfate (MgSO4) and evaporated in vacuo. Purification of the resulting oil by silica gel chromatography (5-40% ethyl acetate/hexane) afforded the activated product (methyl 2-(4′-(2″-hydroxy-2″-methylpropyl)phenyl)propanoate, 81 mg). 15 mg (0.06 mmol) of activated product were dissolved in 2 mL dry dichloromethane (CH2Cl2) and a catalytic amount (4 drops) of ethanol was added to the solution. The solution was cooled to −78° C. (dry ice) and added with 11 μL DAST (0.72 mmol). The reaction was stirred in dry ice for 16 hours. The reaction mixture was then added with 5 mL saturated sodium bicarbonate (NaHCO3) and extracted with dichloromethane (3×15 mL). The organic phase was then dried over magnesium sulfate (MgSO4) and evaporated in vacuo. Purification of the resulting oil by silica gel chromatography (0-30% ethyl acetate/hexane) afforded the fluorinated product, methyl 2-(4′-(1″-fluoro-2″-methylpropyl)phenyl)propanoate (7 mg, 45% yield, colorless oil). 1H-NMR (300 MHz, CDCl3): δ 1.28 (s, 3H, CH3), δ 1.35 (s, 3H, CH3), δ 1.48 (d, J=6.9 Hz, 3H, CH3), δ 2.87 (d, J: 20.4 Hz, 2H), δ 3.65 (s, 3H, OCH3), δ 3.70 (q, J=7.15 Hz, 1H), δ 7.17 (m, 4H); 13C-NMR (75 MHz, CDCl3): δ 18.80, 26.83 (d, J: 24.2 Hz), 45.24, 47.37 (d, J: 22.8 Hz), 52.25, 129.12 (d, J: 258.8 Hz), ca. 130, ca. 132, ca. 139, ca. 173; 19F-NMR (282 MHz, CDCl3): δ −137.7 (m). HRMS (EI+): exact mass calculated for C14H19FO2 requires m/z 238.1369, found 238.1370.