Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH:7]1[O:11][CH2:10][CH2:9][O:8]1.C([Li])(C)(C)C.CN([CH:20]=[O:21])C.O.O.C(O)(=O)C(O)=O>CCOCC.O>[O:8]1[CH2:9][CH2:10][O:11][CH:7]1[C:3]1[O:4][CH:5]=[CH:6][C:2]=1[CH:20]=[O:21]
Reactant: Brc1ccoc1C1OCCO1
Reactant: CN(C)C=O
Agent: O=C(O)C(=O)O
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: O
Product: O=Cc1ccoc1C1OCCO1
Temperature: -78 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
2-(3-Bromo-2-furyl)-1,3-dioxolane (438 mg, 2.0 mmol) is dissolved in Et2O (5 mL) in an oven-dried flask, under nitrogen, cooled to −78° C., treated dropwise with tert-butyllithium (2.59 mL, 4.4 mmol) and stirred for 1 h. DMF (178 μL, 2.3 mmol) in Et2O (2 mL) is added dropwise, the mixture stirred for 4 h at −78° C., then treated with oxalic acid dihydrate (504 mg, 4.0 mmol) followed by water (2 mL). The cooling bath is removed and the mixture allowed to warm to rt over 1 h. The mixture is diluted with water (20 mL) and EtOAc (20 mL), the layers are separated and the aqueous layer extracted with EtOAc (1×20 mL). The organics are dried over Na2SO4 and concentrated to a yellow oil. The crude material is chromatographed over 12 g slurry-packed silica gel, eluting with 15% EtOAc/hexane. The appropriate fractions are combined and concentrated in vacuo to afford 228 mg (68%) of 2-(1,3-dioxolan-2-yl)-3-furaldehyde as a pale yellow oil. MS (EI) m/z: 168 (M+).
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7](O)=[O:8].C(Cl)(C([Cl:24])=O)=O.CN(C=O)C>C(Cl)Cl>[F:1][C:2]1[C:3]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([Cl:24])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1sc2ccc(-c3ccccc3)cc2c1F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1sc2ccc(-c3ccccc3)cc2c1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of compound 52d (136.2 mg, 0.5 mmol) in CH2Cl2 (5 mL) at room temperature was added (COCl)2 (0.064 mL, 0.75 mmol), followed by DMF (0.01 mL, 0.125 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was then concentrated to give compound 52e (light pink powder), which was used in the next reaction without further purification.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[C:13]([OH:18])(=[O:17])[C:14]([CH3:16])=O>Cl>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][N:10]=[C:14]([CH3:16])[C:13]([OH:18])=[O:17])=[CH:7][CH:8]=1
Reactant: CC(=O)C(=O)O
Reactant: NNc1ccc(C(F)(F)F)cc1
Agent: Cl
Product: CC(=NNc1ccc(C(F)(F)F)cc1)C(=O)O
Yield: 89.1 %

Procedure:
4-Trifluoromethylphenyl hydrazine (8.40 g, 47.7 mmol) was suspended in 1 N hydrochloric acid (130 ml) and fully stirred with a mechanical stirrer to obtain a suspension. A aqueous solution (50 ml) of pyruvic acid (4.20 g, 47.7 mmol) was added to the suspension and vigorously stirred to a mixture. 6 hours later, the mixture was extracted with ethyl acetate and washed with a saturated brine. The washed mixture was dried on sodium sulfate and then filtered. The residue obtained by concentrating the resulting filtrate was washed with a mixed solvent of hexane and chloroform (1:1) to obtain 2-(4-trifluoromethylphenyl hydrazono) propionic acid (10.47 g, 42.52 mmol, 89%). mp 190–191° C.; 1H NMR (400 MHz, CDCl3) δ 2.19 (3H, s), 7.23 (2H, d), 7.60 (2H, d), 7.87 (1H, brs).
Reaction SMILES: [C:1]([C:4]1[C:5]([C:21](=O)[CH3:22])=[C:6]([CH3:20])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][C:11]=2[CH3:19])[C:8]=1[CH3:9])(=O)[CH3:2].[NH2:24][NH2:25]>>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([N:7]2[C:8]([CH3:9])=[C:4]3[C:5]([C:21]([CH3:22])=[N:24][N:25]=[C:1]3[CH3:2])=[C:6]2[CH3:20])=[C:11]([CH3:19])[CH:12]=1)[CH3:18]
Reactant: NN
Reactant: CCOc1ccc(-n2c(C)c(C(C)=O)c(C(C)=O)c2C)c(C)c1
Product: CCOc1ccc(-n2c(C)c3c(C)nnc(C)c3c2C)c(C)c1

Procedure:
Utilizing the general procedure outlined in Example 48, 1-[4-acetyl-1-(4-ethoxy-2-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone and hydrazine reacted to give 6-(4-ethoxy-2-methyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as light yellow solid: 1H NMR (CDCl9, 500 MHz) δ 7.06 (d, 1H), 6.94 (s, 1H), 6.90 (m, 1H), 4.12 (q, 2H), 2.81 (s, 6H), 2.38 (s, 6H), 1.80 (s, 3H), 1.50 (t, 3H); MS (ESI) 310 (M+H)+.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]2[S:24][C:16]3=[N:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[N:15]3[CH2:14][CH2:13]2)(=O)=O)=CC=1.[CH2:26]([NH:29][CH2:30][CH2:31][CH3:32])[CH2:27][CH3:28].O1CCOCC1>O>[CH2:26]([N:29]([CH2:11][CH:12]1[S:24][C:16]2=[N:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:15]2[CH2:14][CH2:13]1)[CH2:30][CH2:31][CH3:32])[CH2:27][CH3:28]
Reactant: CCCNCCC
Reactant: Cc1ccc(S(=O)(=O)OCC2CCn3c(nc4ccccc43)S2)cc1
Solvent: O
Solvent: C1COCCO1
Product: CCCN(CCC)CC1CCn2c(nc3ccccc32)S1
Yield: 14.3 %

Procedure:
To 1.12 g of 3,4-dihydro-2-p-toluenesulfonyloxymethyl-2H-(1,3)-thiazino[3,2-a]benzimidazole were added 4 ml of di-n-propylamine and 20 ml of dioxane. The mixture was reacted in a sealed tube, at 120° C. and for 67 hours. After cooling down the temperature of the reaction mixture, it was condensed under reduced pressure. Water was added to the condensed reaction mixture, followed by an extraction with chloroform and dried over anhydrous magnesium sulfate. Chloroform was evaporated under reduced pressure and the residue was chromatographed on silica gel and eluted with chloroform to obtain 0.13 g (yield: 14.3%) of the intended product, m.p. 82°-84° C.;
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[CH:23]([CH3:25])[CH3:24].[CH:26]1([NH2:29])[CH2:28][CH2:27]1>>[CH:26]1([NH:29][C:6]2[C:5]3[C:10](=[CH:11][C:2]([F:1])=[C:3]([CH:23]([CH3:25])[CH3:24])[CH:4]=3)[N:9]=[C:8]([N:12]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]3)[N:7]=2)[CH2:28][CH2:27]1
Reactant: NC1CC1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(C(C)C)cc3c(=O)[nH]2)c1
Product: CC(C)c1cc2c(NC3CC3)nc(-n3cc(C(=O)O)cn3)nc2cc1F

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-fluoro-6-isopropyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and cyclopropyl amine in step E. MS (ESI): predicted mass calcd. for C18H18FN5O2, 355.1
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[O:22]1[CH:24]([CH:25]([CH3:27])[CH3:26])[CH2:23]1>>[OH:22][CH:24]([CH:25]([CH3:27])[CH3:26])[CH2:23][O:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C1CO1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Product: CC(C)C(O)COc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1

Procedure:
Alkylation reaction of phenol 58 with 1,2-epoxy-3-methylbutane gave 2-(3-(3-(2-hydroxy-3-methylbutoxy)phenyl)propyl)isoindoline-1,3-diorie as yellow oil. Yield (1.105 g, 76%): 1H NMR (400 MHz, CDCl3) δ 8.11-8.14 (m, 1H), 7.52-7.57 (m, 2H), 7.33-7.36 (m, 1H), 7.17-7.21 (m, 1H), 6.85 (s, 1H), 6.74 (dd, J=8.4, 2.0 Hz, 1H), 3.75 (d, J=5.6 Hz, 2H), 2.70 (t, J=7.2 Hz, 2H), 1.84-2.03 (m, 5H), 1.03 (d, J=6.8 Hz, 3H), 0.99 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2OS(C(F)(F)F)(=O)=O.Cl.C([NH2:25])CC>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[NH2:25]
Reactant: CCCN
Reactant: COc1ccc2nccc(OS(=O)(=O)C(F)(F)F)c2n1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc2nccc(N)c2n1
Yield: 91.4 %

Procedure:
A mixture of triflate (b) (25 g, 81.2 mmol) and propylamine hydrochloride (47 g, 487 mmol) in pyridine (300 ml) was heated to reflux overnight. The mixture was evaporated to dryness, dissolved in 0.5M aqueous hydrochloric acid (400 ml) and extracted three times with dichloromethane. The aqueous phase was then basified with 40% aqueous sodium hydroxide solution and extracted twice with dichloromethane. Drying and evaporation afforded a buff coloured solid (13.0 g, 90%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([C:9]2[C:10](=[O:16])[NH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:7][CH:6]=[C:5]([CH3:17])[N:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29].O>CN(C=O)C>[Cl:2][C:3]1[C:8]([C:9]2[C:10](=[O:16])[NH:11][C:12](=[O:15])[N:13]([CH2:25][CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29])[CH:14]=2)=[CH:7][CH:6]=[C:5]([CH3:17])[N:4]=1
Reactant: Cc1ccc(-c2c[nH]c(=O)[nH]c2=O)c(Cl)n1
Reactant: COC(CCBr)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(CCn1cc(-c2ccc(C)nc2Cl)c(=O)[nH]c1=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
A mixture of 5-(2-Chloro-6-methyl-pyridin-3-yl)-1H-pyrimidine-2,4-dione hydrochloride (Prep107, 345 mg, 1.27 mmol), K2CO3 (174 mg, 1.27 mmol) and 3-bromo-1,1dimethoxy-propane (86 μl, 0.63 mmol) in DMF (3 ml) was stirred at room temperature overnight. 3-Bromo-1,1dimethoxy-propane (86 μl, 0.63 mmol) was then added and the reaction mixture stirred for additional 2 days. Water was added and the aqueous layer washed with diethylether and then the product extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered and evaporated. The crude was purified by flash chromatography eluting with ethyl acetate-NH4OH (100-0.25) to give 90 mg of the title compound (21% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[S:27](Cl)(=[O:29])=[O:28].N12CCN(CC1)CC2>C(#N)C>[CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][N:6]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1)[S:27]([C:21]1[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=1[F:19])(=[O:29])=[O:28]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Reactant: COc1ccc(CNc2ccncn2)c(OC)c1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(F)cc2F)c(OC)c1
Yield: 58.8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 14b by using the N-(2,4-dimethoxybenzyl)pyrimidine-4-amine (0.40 g, 1.63 mmol) prepared in Example 14a, 2,4-difluorobenzenesulfonyl chloride (0.69 g, 3.26 mmol), 1,4-diazabicyclo[2.2.2]octane (0.37 g, 3.26 mmol) and acetonitrile (11 mL), to yield the title compound (403.8 mg, 59%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[F:19])=[CH:4][N:3]=1.C([Li])CCC.[C:25]([Si:29]([O:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([N:39]=[C:40]=[O:41])[CH2:35][CH2:34]1)([CH3:31])[CH3:30])([CH3:28])([CH3:27])[CH3:26]>O1CCCC1.C(OCC)(=O)C>[C:25]([Si:29]([CH3:31])([CH3:30])[O:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([N:39]2[C:6]3=[N:7][C:2]([Cl:1])=[N:3][CH:4]=[C:5]3[CH2:9][N:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=3[F:19])[C:40]2=[O:41])[CH2:35][CH2:34]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N=C=O)CC1
Reactant: COc1ccc(NCc2cnc(Cl)nc2Cl)c(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(N2Cc3cnc(Cl)nc3N([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)C2=O)c(F)c1
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a solution of (2,4-dichloro-pyrimidin-5-yl-methyl)-(2-fluoro-4-methoxy-phenyl)amine (1.1 g, 3.64 mmol) (from Example 17a supra) in tetrahydrofuran (50 mL) at −78° C. was added n-butyllithium (2.5 M in hexanes, 1.75 mL, 4.37 mmol) (Aldrich). After stirring at −78° C. for 40 minutes, tert-butyl-(trans-4-isocyanato-cyclohexyloxy)-dimethyl-silane (1.12 g, 4.37 mmol) (from Example 17b supra) was added. The mixture was stirred at −70° C. for 1 hour and then at room temperature for 3 hours. It was diluted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate-hexanes (3:7 then 2:3) to give 1-[trans-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-7-chloro-3-(2-fluoro-4-methoxy-phenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one. (Yield 0.60 g, 33%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[N:17]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[C:26]([O:25][C:23]([N:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=2)[C:5]([OH:7])=[O:6])[CH2:19][CH2:18]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: O=C(O)c1cc(Br)cc(S(F)(F)(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cc(C(=O)O)cc(S(F)(F)(F)(F)F)c2)CC1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
3.0 g (9.2 mmol) of the compound of Example 15A and 2.05 g (11.0 mmol) of tert-butyl piperazine-1-carboxylate were initially charged in 80 ml of toluene and the mixture was degassed with argon. 135 mg (0.18 mmol) of [2-(2-aminoethyl)phenyl](chloro)palladiumdicyclohexyl-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphane/tert-butyl methyl ether adduct, 87.5 mg (0.18 mmol) of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphane and 2.1 g (22.0 mmol) of sodium tert-butoxide were added successively to this solution. The mixture was stirred at 110° C. for 3 h. After this, another 67.8 mg (0.09 mmol) of [2-(2-aminoethyl)phenyl](chloro)palladiumdicyclohexyl-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphane/tert-butyl methyl ether adduct and 43.8 mg (0.09 mmol) of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphane were added and the mixture was stirred at 110° C. for a further 3 h. The hot mixture was then filtered through kieselguhr, and the mother liquor was concentrated on a rotary evaporator. The residue was suspended in 50 ml of pH 7 buffer solution and the precipitated solid was filtered off. The filter cake was washed with water and dried under reduced pressure. The residue was triturated with 20 ml of methylene chloride, the suspension was filtered again and the filter cake was once more dried under reduced pressure. This gave 2.98 g (72% of theory) of the title compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][CH2:7][O:6][C:4](=[O:5])[CH2:3]1.[BrH:9]>ClCCl>[Br:9][CH2:7][CH2:8][CH:2]([CH3:1])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: Br
Reactant: CC1CCOC(=O)C1
Solvent: ClCCl
Product: CC(CCBr)CC(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of β-methyl-δ-valerolactone (3.0 g) in anhydrous dichloromethane (30 ml), cooled to 0-5° C., was saturated with hydrogen bromide gas and the mixture was stirred for three days at room temperature. The mixture was diluted with dichloromethane (100 ml) and the resulting solution was washed with 10-% NaCl (3×30 ml). Next the solution was dried with anhydrous MgSO4 and the solvent was distilled under reduced pressure, Yield: 4.6 g. NMR ˜100% pure product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:15][CH2:14]S[CH2:12][CH2:11]2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[S:27](S([O-])=O)([O-:30])(=O)=[O:28].[Na+].[Na+]>C(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:11][CH2:12][S:27](=[O:30])(=[O:28])[CH2:14][CH2:15]2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: COc1cc(Br)cc(N2CCSCC2)c1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(Br)cc(N2CCS(=O)(=O)CC2)c1
Reaction time: 3 h

Procedure:
To a mixture of 4-(3-bromo-5-methoxy-phenyl)-thiomorpholine (239 mg, 0.83 mmol) in methylene chloride (10 ml) and methanol (5 drops) was added m-CPBA (409 mg, 1.83 mmol). After 1 hour methanol (10 drops) was added to enhance solubility. The mixture was stirred another 3 hours. Methylene chloride (25 ml) and a 10% solution of aqueous sodium metabisulfite (35 ml) were added and the material was shaken in a reparatory funnel. The organic phase was collected and washed consecutively with equal volumes of 5% aqueous sodium bicarbonate and then brine solution. The aqueous phases were back-extracted with methylene chloride (2×25 ml), the organic phases combined, dried (MgSO4), filtered and stripped to a crude residue. The material was loaded onto 2 preparative TLC plates, eluting with 40% ethyl acetate in hexanes. The product band was collected to afford 76 mg of 4-(3-bromo-5-methoxy-phenyl)-thiomorpholine 1,1-dioxide as a off-white solid.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Ca+2].[OH-].[Cl:12][CH2:13][CH2:14]CC(Cl)=O.CO.Cl>C1(C)C=CC=CC=1>[CH3:8][O:7][C:1](=[O:6])[CH2:2][C:3](=[O:4])[CH2:5][CH2:14][CH2:13][Cl:12]
Reactant: O=C(Cl)CCCCl
Reactant: COC(=O)CC(C)=O
Agent: Cl
Agent: [Ca+2]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)CC(=O)CCCCl
Temperature: 60 °C
Reaction time: 1 h

Procedure:
In an atmosphere of nitrogen, methyl acetoacetate (480 g, 4.14 mol), calcium hydroxide (80.0 g, 1.08 mol) and toluene (4822 ml) were added to a 10 liter capacity flask, and dehydration/draining was carried out under toluene reflux. After 1 hour, by cooling to 60° C., 4-chlorobutanoic acid chloride (254 g, 1.8 mol) was added dropwise thereto, followed by stirring at 60° C. Further 1 hour thereafter, methanol (1325 g, 41.4 mol) was added thereto, followed by stirring for 6 hours under methanol reflux. After completion of the reaction, the reaction was stopped with 432 ml (2.16 mol) of 5 N hydrochloric acid, and then the organic layer was separated and the organic layer was washed with 5% sodium carbonate aqueous solution and water. After evaporation of the solvent under a reduced pressure using an evaporator, the residue was distilled under a reduced pressure (75 to 85° C./0.1 ton) to obtain crude 6-chloro-3-oxo-hexanoic acid methyl ester (1); 214.9 g (GC purity; δ 0.3%).
Reaction SMILES: [F:1][C:2]1[C:30]([NH:31][S:32]([CH2:35][CH2:36][CH3:37])(=[O:34])=[O:33])=[CH:29][CH:28]=[C:27]([F:38])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:15]([CH:16]=[CH2:17])=[CH:14][N:13](S(C3C=CC=CC=3)(=O)=O)[C:10]2=[N:11][CH:12]=1)=[O:5].C([O-])([O-])=O.[K+].[K+]>CO.O>[F:1][C:2]1[C:30]([NH:31][S:32]([CH2:35][CH2:36][CH3:37])(=[O:33])=[O:34])=[CH:29][CH:28]=[C:27]([F:38])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:15]([CH:16]=[CH2:17])=[CH:14][NH:13][C:10]2=[N:11][CH:12]=1)=[O:5]
Reactant: C=Cc1cn(S(=O)(=O)c2ccccc2)c2ncc(NC(=O)c3c(F)ccc(NS(=O)(=O)CCC)c3F)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C=Cc1c[nH]c2ncc(NC(=O)c3c(F)ccc(NS(=O)(=O)CCC)c3F)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
2,6-Difluoro-N-(1-(phenylsulfonyl)-3-vinyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (0.0061 g, 0.0109 mmol) was dissolved in MeOH (1.0 mL) and water (0.3 mL). K2CO3 (0.0150 g, 0.109 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The solution was partitioned between water and EtOAc. The organic portion was washed with water (3×), brine, dried over Na2SO4 and concentrated. The resulting residue was purified by column chromatography (1:1 hexane/EtOAc/1% HCO2H) to give 2,6-difluoro-3-(propylsulfonamido)-N-(3-vinyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide (2.8 mg, 61.2%). 1H NMR (400 MHz, DMSO-d6) δ 11.81 (br s, 1H), 10.92 (s, 1H), 9.80 (br s, 1H), 8.61-8.62 (m, 1H), 8.44-8.45 (m, 1H), 7.65-7.67 (m, 1H), 7.52-7.58 (m, 1H), 7.24-7.29 (m, 1H), 6.81-6.88 (m, 1H), 5.56-5.61 (m, 1H), 5.11-5.14 (m, 1H), 3.10-3.14 (m, 2H), 1.74-1.80 (m, 2H), 0.98-1.02 (m, 3H); m/z (APCI-neg) M−1=419.3.
Reaction SMILES: [H-].[Na+].CN(C)[CH:5]=[O:6].[CH2:8]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CI>O>[CH2:8]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:6][CH3:5])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCCCCCOCc1ccccc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COCCCCCOCc1ccccc1
Temperature: 25 °C
Yield: 70 %

Procedure:
1.6 g (0.039 mol) of 55% sodium hydride in oil were added to 50 ml of dimethylformamide under stirring at room temperature. 5 ml (0.026 mol) of 5-benzyloxy-1-pentanol and 2.43 ml (0.039 mol) of methyl iodide were then added successively. After a night the excess of sodium hydride was decomposed with water and the solvent evaporated under vacuum. The residue was redissolved with methylene chloride and washed with water. The organic layer was finally dried over anhydrous sodium sulfate and evaporated to give 3.5 g (70% yield) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][N:16]([S:33]([CH2:36][CH2:37][CH3:38])(=[O:35])=[O:34])[C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH:20]=[CH:21][CH:22]=2)[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].[OH-].[Na+]>CO.C1COCC1>[CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][N:16]([S:33]([CH2:36][CH2:37][CH3:38])(=[O:34])=[O:35])[C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][CH:24]=3)[CH:20]=[CH:21][CH:22]=2)[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCCS(=O)(=O)N(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCS(=O)(=O)N(Cc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Reaction time: 0.17 h

Procedure:
To a solution of ethyl [2-methyl-4-({(propylsulfonyl)[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amino}methyl)phenoxy]acetate (20 mg, 0.036 mmol) in MeOH (1 mL) and THF (1 mL) at room temperature was added 2M NaOH (0.5 mL, 1 mmol). The resultant mixture was stirred for 2 h. The solvents were removed in vacuo and the residue was partitioned between CH2Cl2 (2×10 mL) and 2M HCl (10 mL). The organic solution was passed though a hydrophobic frit and the solvent was removed in vacuo. Purification by autoprep. HPLC conducted on a Supelco ABZ+ column (5 μm, 10 cm×21.2 mm ID), eluting at a flow rate of 8 mL/min with a gradient of 50–95% B over 20 mins and held at 95% B for 10 mins. Where solvent A=0.1% HCO2H in H2O and solvent B=0.05% HCO2H in MeCN. The title compound was afforded as a yellow oil (10.7 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:6][N:5]([C:7](=[S:9])[NH2:8])[N:4]=[CH:3]1.I[CH3:12]>CO>[CH3:12][S:9][C:7]([N:5]1[CH2:6][C:2]([CH3:10])([CH3:1])[CH:3]=[N:4]1)=[NH:8]
Reactant: CC1(C)C=NN(C(N)=S)C1
Reactant: CI
Solvent: CO
Product: CSC(=N)N1CC(C)(C)C=N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.9 %

Procedure:
1.50 g (1 mol equiv.) 4,4-Dimethyl-4,5-dihydro-pyrazole-1-carbothioic acid amide was dissolved in 30 ml methanol; 5.9 mL (10 mol equiv.) iodomethane was added and the reaction mixture was stirred at room temperature for 2 hours. Volatiles were removed under reduced pressure, and the residue was taken up in DCM and extracted with 5% aqueous NaHCO3. The organic layer was washed twice with water, dried over Na2SO4, filtered and evaporated to dryness, yielding 1.53 g (94%) 4,4-dimethyl-4,5-dihydro-pyrazole-1-carboximidothioic acid methyl ester. 1H NMR (400 MHz, CDCl3) δ 1.24 (s, 6H), 2.32 (s, 3H), 3.65 (s, 2H), 6.63 (s, 1H), 6.66-6.85 (br.s., 1H).