Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]=[C:2]1[C@@:7]([O:13][C:14]2[CH:19]=[C:18]([F:20])[C:17]([F:21])=[C:16]([F:22])[CH:15]=2)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][NH:3]1.[CH3:23]I>C(#N)C>[CH3:23][S:1][C:2]1[C@@:7]([O:13][C:14]2[CH:15]=[C:16]([F:22])[C:17]([F:21])=[C:18]([F:20])[CH:19]=2)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][N:3]=1
Reactant: CCOC(=O)[C@@]1(Oc2cc(F)c(F)c(F)c2)CCCNC1=S
Reactant: CI
Solvent: CC#N
Product: CCOC(=O)[C@@]1(Oc2cc(F)c(F)c(F)c2)CCCN=C1SC
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Lawesson's reagent (4.46 g) was added to a mixture of ethyl (3R)-2-oxo-3-(3,4,5-trifluorophenoxy)piperidine-3-carboxylate (5.00 g) in toluene (50 mL) at room temperature, and the mixture was stirred with heating at 100° C. for 1 hr. After cooling to room temperature, the reaction mixture was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give ethyl (3S)-2-thioxo-3-(3,4,5-trifluorophenoxy)piperidine-3-carboxylate (5.25 g). To a mixture of ethyl (3S)-2-thioxo-3-(3,4,5-trifluorophenoxy)piperidine-3-carboxylate (5.25 g) in acetonitrile (25 mL) was added methyl iodide (2.94 mL) at room temperature, and the mixture was stirred under a nitrogen atmosphere at 50° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, to the residue was added 10% aqueous potassium carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (NH, ethyl acetate) to give the title compound (5.65 g).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9]1[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=1>C(OCC)(=O)C>[CH3:11][C:12]([NH:13][C:9](=[O:10])[CH3:8])([CH3:15])[CH2:14][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1=NC(C)(C)CO1
Reactant: Oc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)NC(C)(C)COc1ccccc1
Temperature: 220 °C

Procedure:
A mixture of phenol (33.2 g) and 2,4,4-trimethyloxazoline (18.1 g) was heated in a stirred pressure vessel at 220° C. for 48 hours. The oil obtained on cooling was dissolved in ethyl acetate, washed with 5M sodium hydroxide solution, water, brine, then dried and evaporated to give an oil which was distilled under high vacuum to give N-(1,1-dimethyl-2-phenoxyethyl)acetamide, b.p. 115-122° C. at 0.67 mbar.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]3[N:26]([C:34]4[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=4)[N:27]=[C:28]([C:30]4([CH3:33])[CH2:32][CH2:31]4)[CH:29]=3)=[O:23])=[C:17]([CH3:41])[N:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.C(OCC)(=O)C>ClCCl>[CH3:33][C:30]1([C:28]2[CH:29]=[C:25]([NH:24][C:22]([NH:21][C:18]3[C:17]([CH3:41])=[N:16][C:15]([N:12]4[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]4)=[CH:20][CH:19]=3)=[O:23])[N:26]([C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)[N:27]=2)[CH2:31][CH2:32]1
Reactant: Cc1ccc(-n2nc(C3(C)CC3)cc2NC(=O)Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2C)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2nc(C3(C)CC3)cc2NC(=O)Nc2ccc(N3CCNCC3)nc2C)cc1
Reaction time: 0.5 h

Procedure:
Bubble gaseous hydrochloric acid through a solution of 4-(6-methyl-5-{3-[5-(1-methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-yl]-ureido}-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (assume 2.74 mmol) in 1:1 ethyl acetate:dichloromethane (200 mL) for 3 min to ensure saturation. Allow the mixture to stand for 30 min then concentrate under reduced pressure to a white solid. Dissolve the solid in MeOH and load onto a 20 g Varian SCX column, rinsing with additional MeOH. Elute the free base with 1:1 2 M ammonia in MeOH:dichloromethane. Concentrate the solution under reduced pressure to give a white solid (1.21 g, 99% over 2 steps). LCMS(ES+): m/z=446 [M+H].
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][C:21]=2[C:29]([F:32])([F:31])[F:30])(=[O:19])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[Cl-].[NH4+]>[Fe].O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=2[C:29]([F:32])([F:30])[F:31])(=[O:19])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(S(=O)(=O)N2CCN(C(=O)OCc3ccccc3)CC2)c(C(F)(F)F)c1
Temperature: 80 °C
Yield: 99.2 %

Procedure:
4-(4-Nitro-2-trifluoromethyl-benzenesulfonyl)-piperazine-1-carboxylic acid benzyl ester (0.5 g, 1.0 mmol) was suspended in a 5:1 mixture of ethanol and water (20 ml). To this solution was added iron powder (0.16 g, 2.6 mmol) followed by saturated ammonium chloride solution (1 ml) and the mixture was heated to 80° C. for three hours. After this time, the reaction mixture was cooled to room temperature and filtered through a pad of celite, the celite was washed with ethanol (10 ml) and ethyl acetate (50 ml) and the solution was concentrated under vacuum. The resulting residue was partitioned between DCM (50 ml) and water (20 ml), the organic layer was separated, dried with MgSO4, filtered and concentrated to afford the title compound (0.44 g, 94% yield) as a yellow solid. Tr=2.03 min, m/z (ES+) (M+H)+ 444.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][NH:13][C:14](C1C=CC(C(F)(F)F)=CN=1)=[O:15])=[CH:7][C:6]=2Br.C([Sn](CCCC)(CCCC)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)CCC.[Cl-].[Li+]>C1(C)C=CC=CC=1.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[C:6]1[CH:7]=[C:8]([CH2:12][NH:13][C:14]([C:37]2[CH:36]=[N:35][C:34]([C:2]([F:28])([F:27])[F:1])=[CH:39][CH:38]=2)=[O:15])[CH:9]=[C:10]2[C:5]=1[NH:4][C:3]([C:2]([F:28])([F:27])[F:1])=[CH:11]2
Reactant: O=C(NCc1cc(Br)c2[nH]c(C(F)(F)F)cc2c1)c1ccc(C(F)(F)F)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C(NCc1cc(-c2ccccn2)c2[nH]c(C(F)(F)F)cc2c1)c1ccc(C(F)(F)F)nc1
Temperature: 140 °C

Procedure:
In a 2 mL microwave reactor vial N-[(2-Trifluoromethyl-7-bromo-1H-indol-5-yl)methyl]-5-(trifluoromethyl)-2-pyridinecarboxamide (Intermediate 6, 50 mg), 2-tri-n-butylstannyl pyridine (Frontier Scientific Inc., 79 mg), lithium chloride (45.5 mg), copper(I) iodide (2.04 mg) and tetrakis(triphenylphosphine)palladium(0) (12.39 mg) were stirred in Toluene (2 mL) and de-gassed using argon gas. The reaction mixture was then heated in a microwave reactor at 140° C. for 3 h. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (40 mL). The organic extract was then washed with water (2×20 mL), dried (MgSO4), filtered and the solvent removed. The resulting residues were purified by MDAP and evaporated to dryness to give the title compound as an off white solid (25.7 mg);
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.C([C:10]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[CH:12][C:11]=1[S:20]([N:23]([CH2:40][CH2:41]Br)[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[CH2:31][C:32]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=1[F:39])(=[O:22])=[O:21])C>CN(C)C=O.C(OCC)(=O)C>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([N:23]([CH2:40][CH2:41][N:3]2[CH:7]=[CH:6][N:5]=[CH:4]2)[S:20]([C:11]2[CH:12]=[CH:13][C:14]([O:18][CH3:19])=[C:15]([O:16][CH3:17])[CH:10]=2)(=[O:22])=[O:21])=[C:25]([CH2:31][C:32]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=2[F:39])[CH:26]=1
Reactant: CCc1c(S(=O)(=O)N(CCBr)c2ccc(Cl)cc2Cc2c(F)cccc2F)ccc(OC)c1OC
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N(CCn2ccnc2)c2ccc(Cl)cc2Cc2c(F)cccc2F)cc1OC
Reaction time: 18 h
Yield: 22 %

Procedure:
To 2 ml of dimethylformamide are added, at room temperature, 51 mg of sodium hydride at 50% in oil, followed by 72 mg of imidazole. After 30 minutes at this temperature, 0.4 g of ethyl N-(2-bromoethyl)-N-[2-(2,6-difluorobenzyl)-4-chlorophenyl]-3,4-dimethoxybenzenesulfonamide dissolved in 5 ml of dimethylformamide is introduced. The reaction medium is left for 18 hours at room temperature and then taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a 97/3 (v/v) toluene/ethyl acetate mixture to give 0.082 g of the expected product.
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([CH3:11])=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:17](=[O:19])=[O:18]>O1CCCC1.C(OCC)C>[CH3:11][C:9]1[S:8][C:7]2[C:2]([C:17]([OH:19])=[O:18])=[CH:3][CH:4]=[CH:5][C:6]=2[CH:10]=1
Reactant: O=C=O
Reactant: Cc1cc2cccc(Br)c2s1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc2cccc(C(=O)O)c2s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 31.2 %

Procedure:
The solution of 7-bromo-2-methylbenzo[b]thiophene (508) (0.908 g, 4.0 mmol) in tetrahydrofuran (16 mL) was cooled to −78° C. under nitrogen. n-butyllithium (2.40 mL, 6.0 mmol, 1.0M in Hexanes) was added dropwise. After the addition was complete, the reaction mixture was stirred at −78° C. for 1 h, then poured on to the mixture of dry ice in ethyl ether (30 mL). The reaction was stirred to reach room temperature for 5 hours, followed by washing with 1N HCl, brine and dried over sodium sulfate, filtered, and concentrated in vacuo. The obtained white solid was washed with hexanes to provide 2-methylbenzo[b]thiophene-7-carboxylic acid (509) (0.240 g, 31.2%). LC-MS ESI m/z: found 191.0 [M−H]−.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:13][CH2:14][NH2:15])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[CH:16]([O:19][C:20]1[CH:21]=[C:22]([CH2:30][C:31](OCC)=[O:32])[CH:23]=[CH:24][C:25]=1[O:26][CH:27]([CH3:29])[CH3:28])([CH3:18])[CH3:17]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:13][CH2:14][NH:15][C:31](=[O:32])[CH2:30][C:22]2[CH:23]=[CH:24][C:25]([O:26][CH:27]([CH3:28])[CH3:29])=[C:20]([O:19][CH:16]([CH3:18])[CH3:17])[CH:21]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(CCN)cc1OCC
Reactant: CCOC(=O)Cc1ccc(OC(C)C)c(OC(C)C)c1
Solvent: ClC(Cl)Cl
Product: CCOc1ccc(CCNC(=O)Cc2ccc(OC(C)C)c(OC(C)C)c2)cc1OCC
Temperature: 160 °C
Reaction time: 20 h
Yield: 74.6 %

Procedure:
A mixture of 2-(3,4-diethoxyphenyl)-ethylamine (40.7 g, 0.195 mole) and ethyl 3,4-diisopropoxyphenylacetate (55.7 g, 0.195 mole) was heated with stirring at 160° C. for 20 hours, allowed to cool and the resulting oil taken up in 700 ml of chloroform. The organic solution was washed 3 times with 100 ml of N hydrochloric acid and then with water to pH 7. The chloroform solution was dried over magnesium sulphate, the solvent removed under reduced pressure and purification effected by chromatography over silica gel. 64.5 g (yield 72%) of product was obtained sufficiently pure to be used in step (b) below.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[O:3][Si:4]([CH3:7])([CH3:6])[CH3:5].F[C:11](F)(S(O)(=O)=O)[C:12](F)(F)[C:13](F)(F)C(F)(F)F.N>O>[CH3:1][Si:2]([CH3:9])([CH3:8])[O:3][Si:4]([CH3:7])([CH3:6])[CH2:5][CH2:11][CH2:12][CH3:13]
Reactant: C[Si](C)(C)O[Si](C)(C)C
Reactant: O=S(=O)(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: N
Solvent: O
Product: CCCC[Si](C)(C)O[Si](C)(C)C

Procedure:
984 g of adduct (8 mol of Mbutyl (=butyl-Me2SiO0.5) and 1312 (8 mol) of hexamethyldisiloxane are initially introduced into a flask equipped with stirrer, thermometer, water separator, reflux condenser and nitrogen blanketing, admixed with 0.1% sulphuric acids and 0.05% perfluorobutanesulphonic acid, neutralized for 4 h at a bottom temperature of 70° C. with 20 g of calcined soda, 3 g of water and 0.5 g of 25% strength NH3 solution, distilled to 110° C., cooled and filtered. This gives 1950 g of a crude product consisting of 36% hexamethyldisiloxane, 47% 1,1,1,3,3-pentamethyl-3-butyldisiloxane and 17% 1,1,3,3-tetramethyl-1,3-dibutyldisiloxane, which, as result of fractional distillation, produces 810 g of 97%-pure 1,1,1,3,3-pentamethyl-3-butyldisiloxane with a boiling temperature of 166-169° C. Bottoms and separated-off hexamethyldisiloxane can be passed to further equilibrations.
Reaction SMILES: S(=O)(=O)(O)O.Cl.[S:7]([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)([OH:10])(=[O:9])=[O:8].[CH2:18]([N:25]1[CH2:30][CH2:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[CH:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH2:38]=[O:39].[OH-].[Na+]>O.C1(C)C=CC=CC=1>[S:7]([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)([OH:10])(=[O:9])=[O:8].[CH2:18]([N:25]1[CH2:26][CH:27]=[C:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH:38]([OH:39])[CH:30]1[CH3:29])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Fc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Reactant: C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC1C(O)C(c2ccc(F)cc2)=CCN1Cc1ccccc1
Yield: 59.6 %

Procedure:
After adding portionwise 140 ml of concentrated sulfuric acid to 160 ml of water under stirring and cooling, 40 ml of concentrated hydrochloric acid, 88 g (0,2 mol) of 1-benzyl-4-(4-fluorophenyl)-1,2,5,6-tetrahyropyridine tosylate and 8 g (0.267 mol) of paraformaldehyde are added at room temperature. The mixture is stirred at 80° C. for one hour, 300 ml of toluene and then 300 ml of water are added. Finally, the mixture is alkalinized by adding a solution of 240 g of sodium hydroxide in 500 ml of water at a temperature not higher than 40° C. under cooling. After separating the mixture at 30° C., the aqueous layer is extracted with 50 ml of toluene. The combined toluene solution is extracted successively with 3.2 ml of concentrated hydrochloric acid diluted with 200 ml of water, and then with the solution of 1 ml of concentrated hydrochloric acid in 100 ml of water. After drying, the organic phase over anhydrous magnesium sulfate and filtering, the filtrate is evaporated to dryness under reduced pressure. The evaporation residue is a light yellow thick oil, which is dissolved in 100 ml of acetone and 30 g of p-toluenesulfonic acid monohydrate are added. The crystalline precipitate is stirred at 10° C. for one hour, then filtered, twice washed with 10 ml of acetone each, and dried to yield 56 g (59.7%) of the title compound, m.p.: 170-172° C.
Reaction SMILES: C1(C)C=CC(S([Cl:10])(=O)=O)=CC=1.[NH2:12][C:13]1[C:14]([NH:18][C:19]([NH:21][C:22]2[C:26]([CH3:27])=[CH:25][S:24][C:23]=2[Cl:28])=S)=[CH:15][S:16][CH:17]=1.[OH-].[Na+].Cl>C1COCC1.O.C(OCC)(=O)C>[ClH:10].[Cl:28][C:23]1[S:24][CH:25]=[C:26]([CH3:27])[C:22]=1[NH:21][C:19]1[NH:18][C:14]2=[CH:15][S:16][CH:17]=[C:13]2[N:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1csc(Cl)c1NC(=S)Nc1cscc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1csc(Cl)c1Nc1nc2cscc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 108.4 mg of p-toluenesulfonyl chloride in 5 ml of anhydrous THF was added dropwise to a mixture prepared from a solution of 157 mg of N-(4-amino-3-thienyl)-N′-(2-chloro-4-methylthienyl)thiourea in 15 ml of THF and a solution of 51.08 mg of NaOH in 2 ml of water. The resulting dark solution was stirred at room temperature for 2 hours, the solvent was distilled off and the residue was admixed with water. After extraction with ethyl acetate, the organic phase was washed with water and dried over sodium sulfate. After the solvent had been distilled off, the residue was purified by column chromatography on silica gel using a mixture of 20 parts by volume of ethyl acetate, 10 parts by volume of n-heptane, 3 parts by volume of glacial acetic acid as the eluent, which was then distilled off under reduced pressure. A viscous amorphous product was obtained and was dissolved in ethyl acetate and made strongly acidic using hydrogen chloride gas-saturated diethyl ether. The crystallization of the amorphous hydrochloric acid salt which separated out was brought about by scratching. M.p.: >300° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:6]=1[CH2:19]Br)=[O:4].[CH3:21][O:22][C:23](=[O:36])[CH2:24][NH:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)(=[O:28])=[O:27].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:6]=1[CH2:19][N:25]([CH2:24][C:23]([O:22][CH3:21])=[O:36])[S:26]([C:29]1[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=1)(=[O:28])=[O:27])=[O:4]
Reactant: COC(=O)CNS(=O)(=O)c1ccc(C)cc1
Reactant: CCC(CC)Cn1c(CBr)c(C(=O)OC)cc(Br)c1=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)Cn1c(CN(CC(=O)OC)S(=O)(=O)c2ccc(C)cc2)c(C(=O)OC)cc(Br)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.2 %

Procedure:
A mixture of 5-bromo-2-bromomethyl-1-(2-ethyl-butyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (4.9 g, 12.0 mmol), (toluene-4-sulfonylamino)-acetic acid methyl ester (2.62 g, 10.8 mmol), sodium iodide (3.6 g, 24.0 mmol) and potassium carbonate (3.3 g, 24.0 mmol) in DMF (75 mL) was stirred at r.t. for 16 h. Brine was added, and the resulting mixture was extracted with EtOAc. The organic layer was washed with water and dried over MgSO4. After the solvent was evaporated in vacuo, the crude product was purified by silica gel chromatography (5-60% EtOAc/hexanes) to give 4.89 g of the title compound. MS: (+) m/z 571.22, 573.11 (M+H, 79/81Br).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:17]([C:18]3[N:26]=[C:25]([CH3:27])[N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][N:22]4C3CCCCO3)=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[BH4-].[Na+].C(Cl)Cl.Cl>CO>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[CH:12][C:13]([CH2:14][OH:15])=[CH:16][C:17]=2[C:18]2[N:26]=[C:25]([CH3:27])[N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][NH:22]3)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2ncc(C=O)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(Nc2ncc(CO)cc2-c2nc(C)nc3[nH]cnc23)cn1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 71.2 %

Procedure:
6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)nicotinaldehyde (157 mg, 0.352 mmol) was dissolved in methanol (5.0 mL) and sodium borohydride (21.6 mg, 0.571 mmol) was added. The reaction was stirred at room temperature for 75 minutes, and then more NaBH4 (26 mg, 0.69 mmol) was added, along with DCM (3 mL). After 40 more minutes, 5 N aqueous HCl (0.50 mL, 2.5 mmol) was added, along with a MeOH rinse (about 1 mL), and stirring was continued at room temperature overnight. Then, the reaction was diluted with water (20 mL), and the suspension was filtered. The filtration was sluggish, so the filtrate was discarded, and the solid was collected, and the unfiltered material was extracted with 10:1 DCM/MeOH. These organic extracts were combined with the solid that was collected, while the aqueous suspension was again filtered. The solid from this filtration was combined with the solid and organic extracts collected earlier. The resultant solution was concentrated, treated with EtOAc, and filtered. The solid was washed with EtOAc and MeOH, but the solid was not 95% pure by HPLC, so the filtrate and solid were collected, concentrated, treated with DCM, and filtered again. The solid was washed with DCM. The product was still not 95% pure by HPLC, so the filtrate and solid were again collected, concentrated, and this time purified on HPLC (10% to 100% MeCN/water with 0.1% TFA over 30 minutes with a total flow rate of 100 mL/min) to give (6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9H-purin-6-yl)pyridin-3-yl)methanol (91.1 mg, 71% yield). MS (ESI pos. ion) m/z 364 (M+H)+. 1H NMR (d6-DMSO, 400 MHz) δ 12.62 (s, 1H), 9.79 (s, 1H), 8.62 (s, 1H), 8.54 (s, 1H), 8.24 (s, 1H), 8.17 (d, J=8.41 Hz, 1H), 6.86 (d, J=8.61 Hz, 1H), 4.52 (s, 2H), 3.85 (s, 3H), 2.86 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH2:23]([OH:26])[CH2:24][OH:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:3]([O:25][CH2:24][CH2:23][OH:26])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: OCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(OCCO)c(Br)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 44.2, 400 mg, 1.011 mmol), ethane-1,2-diol (1 mL, 17.88 mmol), K2CO3 (210 mg, 1.517 mmol) and DMF (2 mL) was stirred at 50° C. overnight. The solvent was evaporated off under reduced pressure and the residue was treated with water and extracted with DCM. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to afford the title compound which was used directly. UPLC-MS (Condition 2) tR=1.04 min, m/z=421.3/423.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]Br)=[CH:5][CH:4]=1.[CH:11]1[C:16]([C:17]2[CH:18]=[CH:19][C:20]([F:24])=[CH:21][C:22]=2[F:23])=[CH:15][C:14]([C:25]([OH:27])=[O:26])=[C:13]([OH:28])[CH:12]=1.O>CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[F:23][C:22]1[CH:21]=[C:20]([F:24])[CH:19]=[CH:18][C:17]=1[C:16]1[CH:11]=[CH:12][C:13]([OH:28])=[C:14]([C:25]([O:27][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:26])[CH:15]=1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Reactant: COc1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: COc1ccc(COC(=O)c2cc(-c3ccc(F)cc3F)ccc2O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.3 %

Procedure:
PMBBr (1.20 mL, 8.325 mmol) was added to a solution of diflunisal (1.50 g, 5.995 mmol) in TBAF (7 mL, 1 M solution in THF) and the mixture was stirred at r.t. overnight (16 h). The reaction mixture was poured into H2O (100 mL) and extracted with EtOAc (70 mL). It was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (5→10% EtOAc/hexanes) to furnish 1.85 g of 4-methoxybenzyl 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylate (white solid, yield: 83%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[F:12].[F:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]([NH2:22])[CH3:21])=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C>CCCCO>[Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:22][C@H:20]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)[CH3:21])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(F)c(Br)cc1F
Reactant: C[C@H](N)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1cc(Br)c(F)cc1[N+](=O)[O-])c1ccc(F)cc1
Yield: 90.5 %

Procedure:
A solution of 1-bromo-2,5-difluoro-4-nitrobenzene (0.464 g, 1.95 mmol), (S)-1-(4-fluoro-phenyl)-ethylamine (0.298 g, 2.14 mmol), and DIEA (0.41 ml, 2.34 mmol) in n-BuOH (5 ml) was heated at 80° C. for 17 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane:EtOAc=5:1) to give the title compound as a yellow solid (0.63 g, 96%). NMR (400 MHz, CDCl3) 8.23 (br, 1H), 7.95 (d, J=8.8 Hz, 1H), 7.29 (m, 2H), 7.08 (m, 2H), 6.84 (d, J=5.6 Hz, 1H), 4.62 (m, 1H), 1.63 (d, J=6.8 Hz, 3H).