Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].C1(C)C=CC(S([C:11]2[N:12]=[C:13]3[CH:19]=[N:18][N:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:14]3=[N:15][CH:16]=2)(=O)=O)=CC=1.[CH2:27]([OH:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[CH2:27]([O:33][C:11]1[N:12]=[C:13]2[CH:19]=[N:18][N:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:14]2=[N:15][CH:16]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCO
Reactant: Cc1ccc(S(=O)(=O)c2cnc3c(cnn3-c3ccccc3)n2)cc1
Agent: [Na]
Product: CCCCCCOc1cnc2c(cnn2-c2ccccc2)n1
Yield: 90 %

Procedure:
In 50 ml of hexanol was dissolved 2.1 g (0.091 mole) of metallic sodium, and then, 14.6 g (0.043 mole) of 5-(4-tolylsulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyrazine was added to the solution. The mixture was heated under reflux for 2 hours. After completion of the reaction, the exessive amount of hexanol was removed by distillation under a reduced pressure. The residue was washed with water, dried and then recrystallized from a benzene/methanol (1:2) mixed solvent to obtain 11.5 g (the yield was 90%) of 5-hexyloxy-1-phenyl-1H-pyrazolo[3,4-b]pyrazine in the form of a colorless needle crystal.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1([C:30]2[CH:40]=[CH:39][C:33]([O:34][CH2:35][C:36](O)=[O:37])=[CH:32][CH:31]=2)[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]3[N:21]([C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=3)[N:22]=2)[CH2:13][CH2:12]1.[CH3:41][O:42][CH2:43][CH2:44][NH:45][CH3:46].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[OH:10][C:11]1([C:30]2[CH:40]=[CH:39][C:33]([O:34][CH2:35][C:36]([N:45]([CH2:44][CH2:43][O:42][CH3:41])[CH3:46])=[O:37])=[CH:32][CH:31]=2)[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]3[N:21]([C:23]([C:26]([F:28])([F:27])[F:29])=[N:24][N:25]=3)[N:22]=2)[CH2:13][CH2:12]1
Reactant: O=C(O)COc1ccc(C2(O)CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reactant: CNCCOC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(C)C(=O)COc1ccc(C2(O)CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 48.7 %

Procedure:
DIPEA (0.321 mL, 1.94 mmol) was added to 2-[4-[4-hydroxy-1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]acetic acid (283 mg, 0.65 mmol), N-(2-methoxyethyl)methylamine (63 mg, 0.71 mmol) and HATU (270 mg, 0.71 mmol) in DMF (5 mL) at 20° C. under nitrogen. The resulting solution was stirred at 20° C. for 4 hours. Water (50 mL) was then added and the mixture was extracted with DCM (2×50 mL). The combined organics were dried (Na2SO4), filtered and evaporated to give a orange oil. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in isohexane then 0 to 10% MeOH in EtOAc. Pure fractions were evaporated to dryness then tritutated with isohexane, filtered and dried to afford 2-[4-[4-hydroxy-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]-N-(2-methoxyethyl)-N-methylacetamide (161 mg, 48.9%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14]>C(N(CC)CC)C.O1CCCC1.CN(C)C(=O)C.[Cu]I.C1(P([Pd-](Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N+:9]([C:5]1[CH:6]=[C:7]([C:17]#[C:16][Si:13]([CH3:15])([CH3:14])[CH3:12])[C:2]([NH2:1])=[N:3][CH:4]=1)([O-:11])=[O:10]
Reactant: Nc1ncc([N+](=O)[O-])cc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd-]([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: C[Si](C)(C)C#Cc1cc([N+](=O)[O-])cnc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.8 %

Procedure:
2-Amino-3-iodo-5-nitropyridine (10.0 g, 37.75 mmol) was dissolved in a mixture of triethylamine (250 mL), tetrahydrofuran (40 mL), N,N-dimethylacetamide (80 mL) and the solution was degassed and purged with nitrogen. Trimethylsilylacetylene (8.0 mL, 56.5 mmol), copper(I) iodide (0.145 g, 0.75 mmol) and bis(triphenylphosphino) palladium (II) chloride (0.53 g, 0.75 mmol) were added. The mixture was degassed and purged with nitrogen one more time, then stirred at ambient temperature for 16 h. The precipitate was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel from QingDao, 200-300 mesh, 15%-35% ethyl acetate/hexanes) to afford 5-nitro-3-trimethylsilanylethynyl-pyridin-2-ylamine (6.2 g, 70%) as a yellow solid: LC/MS m/e calcd for C10H13N3O2Si [M+H]+ 236.32, observed 236.0.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:23]=[CH:22][C:8]([NH:9][CH:10]=[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1.[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25].C1(C)C=CC=CC=1.P([O-])([O-])([O-])=O>C(OCC)(=O)C>[O:25]=[C:24]1[N:4]([C:5]2[CH:6]=[CH:7][C:8]([NH:9][CH:10]=[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:22][CH:23]=2)[CH2:3][CH2:2][O:1]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)C(=CNc1ccc(NCCO)cc1)C(=O)OCC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=CNc1ccc(N2CCOC2=O)cc1)C(=O)OCC
Yield: 88.7 %

Procedure:
To a flask containing diethyl 2-({4-[(2-hydroxyethyl)amino]anilino}methylene)-malonate (0.48 g) and 1,1'-carbonyldiimidazole (0.32 g) is added toluene (15 mL). The reaction mixture is heated to reflux under an argon atmosphere overnight. The reaction mixture is cooled to room temperatue and partioned between ethyl acetate and phosphate buffer (pH=7, 1M). The phases are separated and the aqueous layer is extracted with two additional portions of ethyl acetate. The combined organic layers are washed with buffer, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is chromatographed on silica eluting with ethyl acetate. The product-containing fractions are evaporated to give 0.46 g of diethyl 2-{[4-(2-oxo-1,3-oxazolidin-3-yl)anilino]methylene}malonate as a creme solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([F:12])=[CH:10][C:9]([C:13]3[O:14][C:15]4[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:8][C:7]=2[F:23])[CH2:3][CH2:2]1.O[CH2:25][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([F:12])=[CH:10][C:9]([C:13]3[O:14][C:15]4[CH:21]=[C:20]([O:22][CH2:27][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH3:25])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:8][C:7]=2[F:23])[CH2:2][CH2:3]1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: Oc1ccc2nc(-c3cc(F)c(OCC4CC4)c(F)c3)oc2c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C[C@@H](COc1ccc2nc(-c3cc(F)c(OCC4CC4)c(F)c3)oc2c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.6 %

Procedure:
To a solution of 2-(4-(cyclopropylmethoxy)-3,5-difluorophenyl)-1,3-benzoxazol-6-ol (1.92 g), tert-butyl ((2S)-1-hydroxypropan-2-yl)carbamate (1.59 g) and triphenylphosphine (2.38 g) in THF (15 mL) was added dropwise diisopropyl azodicarboxylate toluene solution (1.9 M, 4.78 mL), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (2.60 g). 1H NMR (300 MHz, CDCl3) δ 0.29-0.37 (2H, m), 0.56-0.67 (2H, m), 1.17-1.36 (4H, m), 1.46 (9H, s), 3.94-4.19 (5H, m), 4.67-4.82 (1H, m), 6.97 (1H, dd, J=8.7, 2.3 Hz), 7.10 (1H, d, J=2.3 Hz), 7.62 (1H, d, J=8.7 Hz), 7.68-7.81 (2H, m).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:23]([O-])=[O:24].[Na+]>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:23]=[O:24])[C:5]([N:7]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=N[O-]
Reactant: CC(C)CN(C(=O)NCCCl)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: [Na+]
Solvent: O=CO
Product: CC(C)CN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reaction time: 1 h
Yield: 26.3 %

Procedure:
7.0 g of 1-(2-chloroethyl)-3-isobutyl-3-D-galactopyranosylurea are dissolved in 15 ml of formic acid, and 5.0 g of sodium nitrite are added gradually thereto at 0° to 5° C. for one hour under stirring. The mixture is further stirred at the same temperature for one hour. After the reaction, the mixture is treated in the same manner as described in Example 5-(2). 2.0 g of 1-(2-chloroethyl)-1-nitroso-3-isobutyl-3-D-galactopyranosylurea are thereby obtained as a pale yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]([NH2:5])=[NH:4].C[O:7][C:8]([P:10](=[O:15])([O:13][CH3:14])[O:11][CH3:12])=O>O1CCCC1>[NH2:4][C:3](=[N:5][C:8]([P:10](=[O:15])([O:13][CH3:14])[O:11][CH3:12])=[O:7])[O:2][CH3:1]
Reactant: COC(=O)P(=O)(OC)OC
Reactant: COC(=N)N
Solvent: C1CCOC1
Product: COC(N)=NC(=O)P(=O)(OC)OC

Procedure:
a mixture of 23 parts of 0-methylisourea and 54 parts of dimethyl methoxycarbonylphosphonate in 1000 parts of anhydrous tetrahydrofuran was refluxed for one hour. The solvent was removed to give dimethyl 1-amino-1-methoxy-methyleneaminocarbonylphosphonate, nD27 = 1.4774.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[O:18][CH3:19])[C:7]([F:20])=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-:22].[K+].[K+].OO>CS(C)=O>[F:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[O:18][CH3:19])[C:7]([F:20])=[CH:6][C:3]=1[C:4]([NH2:5])=[O:22]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(F)cc1Oc1cc(F)c(C#N)cc1F
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(F)cc1Oc1cc(F)c(C(N)=O)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.6 %

Procedure:
To a solution of 2,5-difluoro-4-(2-methoxy-5-fluorophenoxy)benzonitrile (Preparation 52, 444 mg, 1.59 mmol) in dimethylsulfoxide (10 mL) was added potassium carbonate (440 mg, 3.18 mmol), and hydrogen peroxide (commercial 30% solution, 0.95 mL, 9.49 mmol) This suspension was stirred for 3 hours at room temperature. The reaction mixture was then quenched with saturated aqueous potassium bisulphate solution (20 mL), and the precipitated solid filtered off to afford the title compound (499 mg, 100%). This was used in the next step with no further purification.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][N:5]1[C:10](=[O:11])[C:9]2[C:12]([S:26][CH2:27][CH2:28][CH2:29][C:30]([O:32]C)=[O:31])=[C:13]([CH2:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)[S:14][C:8]=2[C:7]([CH2:34][CH:35]([CH3:37])[CH3:36])=[N:6]1.Cl>O.O1CCCC1>[CH3:4][N:5]1[C:10](=[O:11])[C:9]2[C:12]([S:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[C:13]([CH2:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)[S:14][C:8]=2[C:7]([CH2:34][CH:35]([CH3:37])[CH3:36])=[N:6]1
Reactant: COC(=O)CCCSc1c(Cc2cccc3ccccc23)sc2c(CC(C)C)nn(C)c(=O)c12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Cc1nn(C)c(=O)c2c(SCCCC(=O)O)c(Cc3cccc4ccccc34)sc12
Reaction time: 48 h
Yield: 25.7 %

Procedure:
A solution of lithium hydroxide hydrate (0.035 g) in water (1 ml) was added to a solution of methyl 4-{[4,5-dihydro-5-methyl-7-(2-methylpropyl)-2-(1-naphthalenylmethyl)-4-oxothieno[2,3-d]pyridazin-3-yl]thio}butanoate (0.20 g) in tetrahydrofuran (6 ml) at room temperature. After 2 days, 1M hydrochloric acid (20 ml) was added and the mixture was extracted with ethyl acetate (20 ml). The organic extracts were washed with brine, dried, filtered and evaporated. The residue was dissolved in ethyl acetate:isohexane (1:2) and the precipitated solid was collected. The solid was suspended in boiling ethyl acetate (20 ml), cooled and collected to give the title compound (0.05 g).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][O:7]S(C)(=O)=O.[CH3:12][O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN1C(=O)CCC1>O>[CH3:12][O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([O:7][CH2:6][C@@H:2]2[CH2:3][CH2:4][CH2:5][O:1]2)=[CH:17][CH:16]=1
Reactant: CS(=O)(=O)OC[C@@H]1CCCO1
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1ccc(OC[C@@H]2CCCO2)cc1
Temperature: 75 °C

Procedure:
A mixture of methanesulfonic acid (S)-1-(tetrahydrofuran-2-yl)methyl ester (7.6 g), 4-hydroxybenzoic acid methyl ester (6.4 g), cesium carbonate (20 g) and NMP (100 ml) was heated to 75° C. for 12 hours. The cooled reaction mixture was admixed with water and extracted with ethyl acetate. The organic phase was washed three times with water, dried over magnesium sulfate and concentrated. The product was thus obtained with the molecular weight of 236.27 (C13H16O4); MS (ESI): 237 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].C(N(CC)CC)C.[CH:18]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:24][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:6]
Reactant: NC1CCCCC1
Reactant: O=C(Cl)c1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CCCCC1)c1cccc(Br)c1
Reaction time: 2 h

Procedure:
A solution of 3-bromobenzoyl chloride (2.0 g, 9.1 mmol) in CH2Cl2 was added to a solution triethylamine (1.9 ml, 13.7 mmol) and cyclohexylamine (1.15 ml, 10.0 mmol) in CH2Cl2 at room temperature with stirring. After 2 h, the mixture was washed with HCl (4N), brine, dried over Na2SO4 and concentrated under reduced pressure to give 3-bromo-N-cyclohexylbenzamide as a white solid. Yield (2.43 g, 95%): 1H NMR (400 MHz, CD3OD) δ 8.29 (br s, 1H), 7.95 (t, J=2.0 Hz, 1H), 7.42-7.77 (m, 1H), 7.64-7.67 (m, 1H), 7.36 (t, J=8.0 Hz, 1H), 3.78-3.84 (m, 1H), 1.92-1.94 (m, 2H), 1.78-1.81 (m, 2H), 1.65-1.69 (m, 1H), 1.16-1.46 (m, 5H).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]([NH2:11])=[N:7][CH:8]=[CH:9][CH:10]=2)[CH2:3][CH2:2]1.[C:12](N1C=CN=C1)(N1C=CN=C1)=[O:13]>O1CCOCC1.CCOC(C)=O>[CH:1]1([N:4]2[C:5]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[NH:11][C:12]2=[O:13])[CH2:3][CH2:2]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ncccc1NC1CC1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=c1[nH]c2ncccc2n1C1CC1
Temperature: 60 °C

Procedure:
To a solution of N3-cyclopropylpyridine-2,3-diamine (1.0 g, 6.70 mmol) in dioxane (13.41 ml) was added 1,1′-carbonyldiimidazole (Acros Organics, 1.630 g, 10.05 mmol). The resulting mixture was heated to 60° C. for 2 h. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was loaded onto a Biotage samplet and purified (0-100% EtOAc/hexane, 25G biotage column) to afford product that solidified upon rotovap. Material was advanced to the next step. M+1: 176.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=2)=[CH:11][C:10]([C:20]([F:23])([F:22])[F:21])=[N:9]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:43]1[CH2:48][CH2:47][N:46]([CH2:49][CH2:50]O)[CH2:45][CH2:44]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=2)[O:19][CH2:50][CH2:49][N:46]2[CH2:47][CH2:48][O:43][CH2:44][CH2:45]2)=[CH:11][C:10]([C:20]([F:23])([F:21])[F:22])=[N:9]1
Reactant: OCCN1CCOCC1
Reactant: Oc1cccc(-c2cc(C(F)(F)F)nn2-c2ccccc2Cl)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: FC(F)(F)c1cc(-c2cccc(OCCN3CCOCC3)c2)n(-c2ccccc2Cl)n1
Temperature: 25 °C
Yield: 61.5 %

Procedure:
To a solution of 3-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenol (155 mg, 0.5 mmol) and triphenylphosphine (170 mg, 0.65 mmol) in THF (2 mL) was added 2-morpholinoethanol (72 μL, 0.59 mmol). The solution was cooled in an ice bath and treated with diisopropylazodicarboxylate (125 μL, 0.64 mmol). After a few minutes the ice bath was removed and the reaction was allowed to stir while warming to ambient temperature. After stirring for 16 hours LC/MS analysis showed desired product and triphenylphosphine oxide as the major peaks. The reaction solution was concentrated under reduced pressure and the resulting yellow oil was purified by flash column chromatography eluting with 30% followed by 40% EtOAc/hexane, and then a gradient of CH2Cl2 to 4% MeOH/CH2Cl2. The white solid that was obtained was found to be contaminated with triphenylphosphine oxide. This crude product was further purified by normal phase preparative HPLC eluting with a gradient from CH2Cl2 to 10% isopropanol/CH2Cl2 to afford 4-(2-(3-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenoxy)ethyl)morpholine (139 mg, 67% yield) as a thick syrup. MS(ES): 452 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10](=[O:33])[C@H:11]([CH2:18][C:19]1[C:20]([CH2:28][O:29]C(=O)C)=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][N:23]=[CH:22]2)[CH2:12][C:13]([O:15][CH2:16]C)=[O:14])C>CO>[CH3:7][O:9][C:10](=[O:33])[C@H:11]([CH2:18][C:19]1[C:20]([CH2:28][OH:29])=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][N:23]=[CH:22]2)[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: CCOC(=O)C[C@@H](Cc1ccc2[nH]ncc2c1COC(C)=O)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)C[C@@H](Cc1ccc2[nH]ncc2c1CO)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
Potassium carbonate (380 mg, 2.7 mmol) was added to a solution of 2-(R)-(4-acetoxymethyl-1H-indazol-5-ylmethyl)-succinic acid diethyl ester (420 mg, 1.1 mmol) in methanol (10 mL). Mixture was stirred at room temperature for 2 hours. Reaction was quenched with 1N hydrochloric acid. Methanol was removed from the mixture in vacuo. Remaining aqueous made basic with sodium bicarbonate. Mixture was extracted with ethyl acetate (2×20 mL). Combined organic layers were washed successively with water (20 mL) and brine (20 mL). Organic was dried (magnesium sulfate), filtered and concentrated in vacuo. Title compound was obtained as amber oil in 92% yield. MS m/e (M+H)+=307.1.
Reaction SMILES: C[O:2][C:3](=[O:24])/[CH:4]=[CH:5]/[CH:6]=[C:7](\[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])/[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.[OH-].[Na+]>CO>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1/[C:7](/[C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)=[CH:6]\[CH:5]=[CH:4]\[C:3]([OH:24])=[O:2]
Reactant: COC(=O)/C=C/C=C(/c1ccc(OC)cc1)c1ccccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(/C(=C/C=C/C(=O)O)c2ccccc2OC)cc1
Yield: 63.9 %

Procedure:
In the manner described in Example 99, (2E,4Z)-5-(2-methoxyphenyl)-5-(4-methoxyphenyl)-2,4-pentadienoic acid methyl ester (1.8 g) was saponified in a refluxing mixture of methanol (15 mL) and 1N NaOH (15 mL). After 1 hour the reaction was worked up in the usual fashion ant the crude acid was crystallized from 2-propanol to afford 1.1 g of (2E,4Z)-5-(2-methoxyphenyl)-5-(4-methoxyphenyl)-2,4-pentadienoic acid. A sample was recrystallized from 2-propanol-hexane to give the analytical specimen, mp 159°-161° C.
Reaction SMILES: I[CH2:2][CH2:3][C:4]([C:7]([O:10][C:11]([C:14]([S:17]([F:20])(=[O:19])=[O:18])([F:16])[F:15])([F:13])[F:12])([F:9])[F:8])([F:6])[F:5].C1CCN2C(=NCCC2)CC1>>[CH2:2]=[CH:3][C:4]([C:7]([O:10][C:11]([C:14]([S:17]([F:20])(=[O:19])=[O:18])([F:15])[F:16])([F:12])[F:13])([F:9])[F:8])([F:6])[F:5]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)CCI
Solvent: C1CCC2=NCCCN2CC1
Product: C=CC(F)(F)C(F)(F)OC(F)(F)C(F)(F)S(=O)(=O)F

Procedure:
The crude reaction solution from above containing ICH2CH2CF2CF2OCF2CF2SO2F was treated with an excess of DBU at room temperature for 4 hours. 19F NMR analysis showed no effect on the —SO2F group, and the triplet of CF2CH2— was changed into doublet×triplet at 121 ppm (Jd=7.8 Hz, Jt=3.6 Hz), indicating the desired reaction occurred to yield CH2═CHCF2CF2OCF2CF2SO2F. Addition of water to dissolve DBU/HI solid, and the bottom perfluorinated N-methyl morpholine solution was isolated. From F-NMR, no more I—CF2CF2OCF2CF2SO2F was observed in the isolated solution. The solution was dried over MgSO4. After filtration and rotary evaporation to remove the solvent, 22 g product was obtained (89% isolated yield; bp=115-116° C.). 19F NMR showed the chemical shifts at +43 ppm (—SO2F), −83.8 ppm (m, —CF2O—), −89.2 ppm (txt, —CF2O—), −114 ppm (dxt, —CF2SO2F) and 120 ppm (dxt, —CF2CH═). Also, H1 NMR confirmed the formation of CH2═CH— with chemical shift at 5.7˜6.3 ppm (m).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[C:13]2[C:12]([CH3:15])([CH3:14])[CH2:11][CH2:10][C:9]([CH3:17])([CH3:16])[C:8]=2[CH:7]=[C:6]([CH3:18])[CH:5]=1.S(OC)(O[CH3:23])(=O)=O>O.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C(Cl)Cl>[CH3:23][O:3][C:4]1[C:13]2[C:12]([CH3:14])([CH3:15])[CH2:11][CH2:10][C:9]([CH3:17])([CH3:16])[C:8]=2[CH:7]=[C:6]([CH3:18])[CH:5]=1
Reactant: COS(=O)(=O)OC
Reactant: Cc1cc(O)c2c(c1)C(C)(C)CCC2(C)C
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1cc(C)cc2c1C(C)(C)CCC2(C)C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
Methylation. A solution of sodium hydroxide (38 g, 0.95 mol) in water (1 L) was added to a mixture of 1-hydroxy-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene (109 g, 0.5 mol), dimethyl sulfate (126 g, 1 mol) and Adogen 464* (21.6 g) in methylene dichloride (2 L). The reaction mixture was stirred vigorously at 25°-28° C. for 1 h, after which the organic layer was separated, combined with ammonium hydroxide solution (500 mL, 10%), and stirred vigorously at 20°-25° C. for 0.5 h. The organic layer was then separated and the washing procedure repeated, after which the organic layer was separated, washed with water (2×100 mL), then with brine (50 mL), and dried (Na2SO4). The solvent was removed by distillation and the residue was crystallized from hexane yielding 1-methoxy-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene (95 g), mp 49°-50° C., GLC purity 99 %+. 1H-NMR (CDCl3) δ6.89 (1H, d, J=1.4 Hz), 6.63 (1H, d, J=1.4 Hz), 3.89 (3H, s), 2.41 (3H, s), 1.74 (4H, m), 1.48 (6H, s), 1.38 (6H, s). IR (KBr) 1273, 1257 cm-1, MS (m/e) 232 (M+, 16.9), 217 (100.0), 175.3 (19.6), 218.6 (16.0).
Reaction SMILES: CN1CCCC1.[NH2:7][C:8]1[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[N:9]=1.CN(C1C=CC=CN=1)C.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)([O-])[O-]>O>[Cl:14][C:12]1[N:11]=[C:10]([NH:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[N:9]=[C:8]([NH:7][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:13]=1
Reactant: N#Cc1ccc(Nc2nc(N)cc(Cl)n2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccccn1
Agent: CN1CCCC1
Agent: O=C([O-])[O-]
Solvent: O
Product: N#Cc1ccc(Nc2nc(Cl)cc(NC(=O)c3ccccc3)n2)cc1
Temperature: 82.5 °C
Reaction time: 0.5 h

Procedure:
1400 ml of N-methylpyrrolidine and 140 g of 4-(4-Amino-6-chloropyrimidin-2-ylamino)benzonitrile was charged into a reaction vessel. To this were added 85.49 g of dimethylamino pyridine and 87.21 g of diazabicyclo undecene and stirred for 30 mins. To the reaction mixture was added 27.36 g of benzoyl chloride and stirred at RT for 30 mins. and heated to 80-85° C. and maintained the same for 4 hrs. After completion of the reaction, the reaction mass was cooled to RT and 1400 ml of water was added, followed by 1400 ml of 50% carbonate solution. The reaction mass was extracted with 1400 ml of dichloromethane and the dichloromethane layer was washed with 700 ml of water. The organic layers were separated and dried over anhydrous sodium sulfate and filtered; distilled off dichloromethane and the solid was isolated.