Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K+].C1(O)C=CC=CC=1.[C:16](=[O:18])=[O:17]>O>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([C:16]([OH:18])=[O:17])=[CH:3][CH:2]=1
Reactant: [O-]c1ccccc1
Reactant: O=C=O
Agent: [K+]
Solvent: Oc1ccccc1
Solvent: O
Product: O=C(O)c1ccc(O)cc1

Procedure:
In a pressure reaction vessel were charged 100 g of potassium phenolate, 35 g of phenol and 500 g of a mixture of hydrogenated triphenyls, and a reaction was allowed to proceed at 250° C. and at a carbon dioxide pressure of 7 kg/cm2 (G) for 20 minutes, with stirring. The reaction mixture was cooled and charged into 200 ml of water, followed by separation into the reaction medium layer and the water layer at 60° C. The water layer was made acid with dilute sulfuric acid to give 81.6 g of p-hydroxybenzoic acid (having a purity of 99%). The yield based on potassium phenolate was 77.3%, and the recovered potassium phenolate was 21.0 g, with the selectivity being 99.7%.
Reaction SMILES: C(N(CC)CC)C.CN(C1C=CC=CN=1)C.C(O[C:21](=[O:23])[CH3:22])(=O)C.[NH2:24][C:25]1[CH:45]=[CH:44][C:28]([CH2:29][C:30]2[NH:31][C:32](=[O:43])[C:33]3[N:38]([CH3:39])[N:37]=[C:36]([CH2:40][CH2:41][CH3:42])[C:34]=3[N:35]=2)=[CH:27][CH:26]=1>ClCCl>[CH3:39][N:38]1[C:33]2[C:32](=[O:43])[NH:31][C:30]([CH2:29][C:28]3[CH:44]=[CH:45][C:25]([NH:24][C:21](=[O:23])[CH3:22])=[CH:26][CH:27]=3)=[N:35][C:34]=2[C:36]([CH2:40][CH2:41][CH3:42])=[N:37]1
Reactant: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(N)cc3)nc12
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(NC(C)=O)cc3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (160 μl, 0.0011 mol), dimethylaminopyridine (10 mg), and acetic anhydride (50 μl, 0.0005 mol) were added to a solution of 5-(4-aminobenzyl)-1-methyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-one (110 mg, 0.00037 mol) in dichloromethane (9 ml). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The mixture was then partitioned between 2M aqueous hydrochloric acid solution (15 ml) and dichloromethane (15 ml) and the aqueous phase extracted with dichloromethane/methanol (30 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure to give, after crystallisation from ethyl acetate/methanol, the title compound as an off white solid (105 mg), m.p.272-275° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([OH:17])[C:11](C(O)=O)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:19][O:20][C:21](=[O:24])[CH2:22][NH2:23].C(N(C(C)C)CC)(C)C.Cl>O.CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([OH:17])[C:11]([NH:23][CH2:22][C:21]([O:20][CH3:19])=[O:24])=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CN
Reactant: O=C(O)c1ncc(-c2cccc(Cl)c2)cc1O
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNc1ncc(-c2cccc(Cl)c2)cc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 50 mL round bottom flask adapted for magnetic stirring and fitted with a nitrogen inlet tube was charged 5-(3-chlorophenyl)-3-hydroxypyridine-2-carboxylic acid, 3, (1 gm, 4 mmol), N,N′-carbonyldiimidazole (CDI) (0.97 g, 6 mmol) and dimethyl sulfoxide (5 mL). The reaction mixture was stirred at 45° C. for about 1 hour then cooled to room temperature. Glycine methyl ester hydrochloride (1.15 g, 12 mmol) is added followed by the dropwise addition of diisopropylethylamine (3.2 mL, 19 mmol). The mixture was then stirred for 2.5 hours at room temperature after which water (70 mL) was added. The contents of the reaction flask was cooled to 0° C. to 5° C. and 1N HCl was added until the solution pH is approximately 2. The solution was extracted with dichloromethane (100 mL) and the organic layer was dried over MgSO4 for 16 hours. Silica gel (3 g) is added and the solution slurried for 2 hours after which the solids are removed by filtration. The filtrate is concentrated to dryness under reduced pressure and the resulting residue was slurried in methanol (10 mL) for two hours. The resulting solid was collected by filtration and washed with cold methanol (20 mL) then hexane and the resulting cake is dried to afford 0.85 g of the desired product as an off-white solid. The filtrate was treated to afford 0.026 g of the desired product as a second crop. The combined crops afford 0.88 g (68% yield) of the desired product. 1H NMR (DMSO-d6) δ 12.3 (s, 1H), 9.52 (t, 1H), 8.56 (d, 1H), 7.93 (s, 1H), 7.80 (q, 2H), 7.55 (t, 2H), 4.12 (d, 2H), and 3.69 (s, 3H).
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].C(NCC)C.[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[O:17])[CH:11]=1>C(O)C>[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]([OH:17])[CH2:4][N+:1]([O-:3])=[O:2])[CH:11]=1
Reactant: O=Cc1cccnc1
Reactant: C[N+](=O)[O-]
Solvent: CCO
Solvent: CCNCC
Product: O=[N+]([O-])CC(O)c1cccnc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a cooled stirring solution of 15 grams (0.25 mol) nitromethane and 0.35 gram (0.005 mol) diethylamine in 26 milliliters of ethanol was added dropwise 10 grams (0.093 mol) 3-pyridine carboxaldehyde. The reaction was stirred for 3 hours at 0° C. then warmed to ambient temperature. Concentration yielded crude 1-(3-pyridyl)-2-nitroethanol.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][C@H:29]2[CH2:34][CH2:33][CH2:32][C@@H:31]([NH2:35])[CH2:30]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:9]=2)=[N:6][CH:7]=1.[N:36]1([C:42](Cl)=[O:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:1][C:2]1[C:3]([NH:28][C@H:29]2[CH2:34][CH2:33][CH2:32][C@@H:31]([NH:35][C:42]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[O:43])[CH2:30]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)(=[O:19])=[O:20])[CH:9]=2)=[N:6][CH:7]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](N)C4)n3)c3cc(F)cnc32)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](NC(=O)N5CCOCC5)C4)n3)c3cc(F)cnc32)cc1
Reaction time: 1 h

Procedure:
(1S,3R)—N1-[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]cyclohexane-1,3-diamine, 44e, (2.3 g, 4.6 mmol) was dissolved in DMF (50 mL) and treated with morpholine-4-carbonyl chloride (2.1 g, 13.8 mmol) and DIPEA (4.2 g, 5.6 mL, 32.3 mmol). After one hour, the resulting solution was diluted with water (400 mL) and stirred for an additional two hours. The resulting precipitate was collected by filtration, washed with water (3×50 mL) and dried to provide the crude product. This material was purified by flash chromatography on a 40 g column using EtOAc/DCM 20-100%, to provide 2.0 g of N-[(1R,3S)-3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyl]morpholine-4-carboxamide as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[C:11]([OH:23])[C:10]([C:24](=[N:26][NH:27][C:28]([C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36]C)=[O:35])=[CH:32][CH:31]=2)=[O:29])[CH3:25])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Na+].Cl>O>[CH2:1]([N:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]([C:19]([CH3:22])([CH3:20])[CH3:21])=[CH:17][CH:18]=2)=[C:11]([OH:23])[C:10]([C:24](=[N:26][NH:27][C:28]([C:30]2[CH:39]=[CH:38][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=2)=[O:29])[CH3:25])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(Cc3ccccc3)c(-c3ccc(C(C)(C)C)cc3)c2O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=NNC(=O)c1ccc(C(=O)O)cc1)c1nn(Cc2ccccc2)c(-c2ccc(C(C)(C)C)cc2)c1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68.8 %

Procedure:
To methyl 4-[(2-{1-[1-benzyl-5-(4-t-butylphenyl)-4-hydroxy-1H-pyrazol-3-yl]ethylidene}hydrazino)carbonyl]benzoate (0.045 mmol, 23.5 mg), methanol was added, and 1 M aqueous sodium hydroxide (0.224 mmol, 0.224 mL) was added at room temperature. After 30 minutes of stirring at room temperature and 1.5 hours of stirring at 60° C., the reactor was cooled to 0° C., and 1 M hydrochloric acid (0.224 mmol, 0.224 mL) and water were added. The precipitated solid was recovered by filtration, washed with water, dried by means of a vacuum pump and purified by silica gel thin layer chromatography (chloroform/methanol=10/1) to give the desired product as a yellow solid (15.8 mg, yield 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.[CH3:26][NH:27][C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][N:29]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>>[CH3:26][N:27]([C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][N:29]=1)[C:8]([C:5]1[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:23])[F:24])[CH:16]=2)(=[O:13])=[O:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:9]
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNc1cc(C)ccn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccnc(N(C)C(=O)c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1

Procedure:
5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid (100 mg, 0.24 mmol), methyl-(4-methyl-pyridin-2-yl)-amine (88 mg, 0.72 mmol), BOP (137 mg, 0.31 mmol) and DIEA (265 μL, 1.44 mmol) were reacted according to the procedure D to provide the title compound. HPLC purification (20→90% gradient of MeCN-water) provided 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid methyl-(4-methyl-pyridin-2-yl)-amide: MS m/z: 519.0(M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH3:11])[CH:6]=[CH:5][C:4]=1[OH:12].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH3:11])[CH:6]=[CH:5][C:4]=1[O:12][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCCc1ccc(O)c(OC)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1ccc(Oc2ccc(OC)cc2)c(OC)c1

Procedure:
A mixture containing 2-methoxy-4-propylphenol (0.625 mmol; 100 μl), copper(II) acetate (0.625 mmol; 114 mg), 4-methoxyphenylboronic acid (1.25 mmol; 190 mg), triethylamine (3.12 mmol; 0.43 ml), some crushed molecular sieves 4 Å in dichloromethane (3 ml) was stirred at rt under air for 24 h. The residue is filtered with chloroform on Celite. The organic phase is washed with saturated NH4Cl, saturated NaHCO3 and brine. After drying (MgSO4), concentration and purification by preparative TLC on silica gel (ethyl acetate/cyclohexane—20/80), the title compound is collected as a colorless oil (70 mg; 0.26 mmol; 41%).
Reaction SMILES: [CH2:1]([C:3]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[N:34](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:6]2[CH:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8][CH2:9][CH2:10][C:5]=2[N:4]=1)[CH3:2].[C:54]([O:60][CH2:61][CH3:62])(=[O:59])[CH2:55][C:56]([O-])=[O:57].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>ClCCl>[CH2:1]([C:3]1[N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:31][N:32]=[N:33][N:34]=3)=[CH:22][CH:23]=2)[C:6]2[CH:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]([C:56](=[O:57])[CH2:55][C:54]([O:60][CH2:61][CH3:62])=[O:59])[CH2:9][CH2:10][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCOC(=O)C1NCCc2nc(CC)n(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)c21
Reactant: CCOC(=O)CC(=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)N1CCc2nc(CC)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c2C1C(=O)OCC
Yield: 67.5 %

Procedure:
A solution of ethyl 2-ethyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (1.94 g), monoethyl malonate (0.74 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.80 g), triethylamine (1.40 g) in dichloromethane (20 ml) is stirred overnight at room temperature. The reaction mixture is washed with water and dried over sodium sulfate, and then evaporated. The residue is dissolved in ethanol (30 ml), fumaric acid (2.00 g) is added, and the solution is refluxed for three hours. The solvent is evaporated and the residue is treated with a saturated sodium hydrogen carbonate solution and then extracted with chloroform. The organic layer is dried and evaporated. Purification by silica gel column chromatography (solvent; chloroform/methanol) gives ethyl 2-ethyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-5-ethoxycarbonylacetyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4carboxylate (1.07 g) as a foam.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:24]([O-:26])=[O:25])=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10](N)[CH:9](C(=O)C1C=CC=CC=1CCC)[CH2:8][CH2:7]2.C(N([CH:35]1[CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)O[CH2:36]1)CCC)(=O)CC.NC1C=C2C(CCCC2[N:56](CCC)[C:57](=[O:60])CC)=CC=1>>[Cl:1][C:2]1[C:3]([N+:24]([O-:26])=[O:25])=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([NH:56][C:57](=[O:60])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:43]=1[CH2:44][CH2:35][CH3:36])[CH2:8][CH2:7]2
Reactant: CCCN(C(=O)CC)C1COc2ccccc2C1
Reactant: CCCN(C(=O)CC)C1CCCc2ccc(N)cc21
Reactant: CCCc1ccccc1C(=O)C1CCc2ccc([N+](=O)[O-])c(Cl)c2C1N
Product: CCCc1ccccc1C(=O)NC1CCc2ccc([N+](=O)[O-])c(Cl)c2C1

Procedure:
Fuming nitric acid (100 ml), 33% in concentrated sulphuric acid was added dropwise to a solution of 72 g (0.22 mol) 8-chloro-2-(n-propylbenzoyl)amino-1,2,3,4-tetrahydronaphthalene in 300 ml nitromethane at 0° C. The mixture was allowed to reach ambient temperature and was stirred over night. After pouring on ice water/diethyl ether the mixture was basified (sodium carbonate solution) and the phases separated. The organic phase was dried (magnesium sulphate), filtered and evaporated to a residue of 65.5 g of an isomeric mixture. Elution of the mixture on a silica column (isooctane/diethyl ether, 1:1) gave 19 g of 8-chloro-5-nitro-2-(n-propylbenzoyl)amino-1,2,3,4-tetrahydronaphthalene and 12 g of the desired isomer; 8-chloro-7-nitro-2-(n-propylbenzoyl)-amino-1,2,3,4-tetrahydronaphthalene. MS m/e 372 (M+, 3), 374 (M+ +2, isotope, 1), 105 (100), 164 (72), 77 (35), 134 (16), 165 (9).
Reaction SMILES: [NH:1]([C:3](=[O:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[NH2:2].[Si:10]([O:27][CH2:28][C:29](O)=[O:30])([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(#N)C.C(OCC)(=O)C.C(N(CC)CC)C>[Si:10]([O:27][CH2:28][C:29]([NH:2][NH:1][C:3](=[O:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:30])([C:23]([CH3:25])([CH3:26])[CH3:24])([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)[Si](OCC(=O)O)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)NNC(=O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.3 %

Procedure:
To a solution of ethyl hydrazino(oxo)acetate (3.58 g) in acetonitrile (100 mL) were successively added triethylamine (6.86 mL), {[tert-butyl(diphenyl)silyl]oxy}acetic acid (7.74 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (5.20 g) and 1-hydroxybenzotriazole (415 mg) under ice-cooling. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (3.20 g, yield 30%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [H-].[Na+].[Cl-].[CH3:4][O:5][C:6]1[CH:31]=[CH:30][C:9]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:8][C:7]=1[CH3:32].[O:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]1[O:39][CH2:40][C:41]1[N:42]=[C:43]([C:48]2[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=2)[S:44][C:45]=1[CH:46]=O>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[CH3:4][O:5][C:6]1[CH:31]=[CH:30][C:9](/[CH:10]=[CH:46]/[C:45]2[S:44][C:43]([C:48]3[CH:53]=[CH:52][C:51]([C:54]([F:56])([F:57])[F:55])=[CH:50][CH:49]=3)=[N:42][C:41]=2[CH2:40][O:39][CH:34]2[CH2:35][CH2:36][CH2:37][CH2:38][O:33]2)=[CH:8][C:7]=1[CH3:32]
Reactant: O=Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1COC1CCCCO1
Reactant: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1C
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(/C=C/c2sc(-c3ccc(C(F)(F)F)cc3)nc2COC2CCCCO2)cc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a suspension of NaH (60% dispersion in mineral oil, 242 mg, 6.32 mmoles, 1.4 eq) in dry CH2Cl2 (15 ml) was added (4-Methoxy-3-methylbenzyl)(triphenyl)phosphonium chloride (2.62 g, 6.32 mmoles, 1.4 eq). This was allowed to stir at room temperature for 1.5 hours followed by the dropwise addition of 4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carbaldehyde (1.68 g, 4.51 mmoles, 1 eq) in anhydrous carbon tetrachloride (25 ml). The resulting reaction mixture was refluxed overnight at which point (after cooling to room temperature) the reaction was washed with 1N NaOH, H2O, brine, dried over Na2SO4 and concentrated in vacuo to yield a >100% yield of a light green oil. The crude material was used without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]([F:21])[C:14]=3[Cl:22])[CH3:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:23][C:24]1[C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]([C@H:38]2[CH2:43][CH2:42][C@H:41]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:40][CH2:39]2)[N:25]=1.[F-].[K+].O>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.O1CCOCC1>[Cl:22][C:14]1[C:15]([F:21])=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[C:13]=1[C@H:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:28]3[C:24]([CH3:23])=[N:25][N:26]([C@H:38]4[CH2:39][CH2:40][C@H:41]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:42][CH2:43]4)[CH:27]=3)[CH:3]=2)[NH:8][CH:9]=1)[CH3:12]
Reactant: CCOC(=O)[C@H]1CC[C@H](n2cc(B3OC(C)(C)C(C)(C)O3)c(C)n2)CC1
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)[C@H]1CC[C@H](n2cc(-c3cnc4[nH]cc([C@H](C)c5c(OC)ccc(F)c5Cl)c4c3)c(C)n2)CC1

Procedure:
A mixture of 5-bromo-3-[(S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (57.8 mg, 0.150 mmol), ethyl trans-4-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]cyclohexanecarboxylate (60.0 mg, 0.166 mmol), Pd(PPh3)4 (8.70 mg, 0.00753 mmol), potassium fluoride (26.2 mg, 0.452 mmol) and 4:1 dioxane:H2O (3 mL, 30 mmol) was heated to 90° C. for 2 h. The organic solvent was removed in vacuo, and the material was extracted with DCM and water. The organic layer was purified via column chromatography, eluting with 1-3% MeOH/DCM. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. MS (ES+): m/z=539.18/541.20 (100/50) [MH+]. HPLC: tR=1.70 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[C:4]([Cl:13])[N:3]=1.ClC1C=CC=C(C(OO)=[O:22])C=1.O>C(O)C>[NH2:1][C:2]1[N+:7]([O-:22])=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[C:4]([Cl:13])[N:3]=1
Reactant: CCCCNc1cc(Cl)nc(N)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCO
Solvent: O
Product: CCCCNc1cc(Cl)nc(N)[n+]1[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.6 %

Procedure:
8.5 g of 2-amino-4-butylamino-6-chloropyrimidine are dissolved in 150 ml of ethanol. 19.95 g of meta-chloroperbenzoic acid are added dropwise as solution in 150 ml of ethanol. The reaction mixture is stirred at room temperature for 2 hours. 250 ml of water are added and ethanol is then evaporated off. The pH is adjusted to 1 with concentrated hydrochloric acid. After 1 hour's stirring, the precipitate is filtered off on sintered glass, rinsed with 50 ml of water and discarded. The pH of the solution is adjusted to 8 by adding sodium hydroxide. The mixture is extracted with 3×100 ml of dichloromethane. The organic phase is dried over sodium sulfate and then evaporated to dryness. The precipitate obtained is recrystallized from 50 ml of acetonitrile. 2.35 g of 2-amino-4-butylamino-6-chloropyrimidine 3-oxide are obtained.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[C:5]1([C:11]2[CH:19]=[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:13]3[N:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O.C(O)(=O)C>[N:1]([C:19]1[C:11]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[N:12][N:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=12)=[O:3]
Reactant: O=N[O-]
Reactant: c1ccc(-c2cc3ccccn3n2)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=Nc1c(-c2ccccc2)nn2ccccc12
Reaction time: 0.33 h
Yield: 71.3 %

Procedure:
A solution of sodium nitrite (533 mg) in water (2.5 ml) was added dropwise to a solution of 2-phenylpyrazolo[1,5-a]pyridine (1.0 g) in acetic acid (5 ml) at 13° to 15° C. After being stirred at the same temperature for 20 minutes, the reaction mixture was poured onto ice-water. Resultant precipitates were collected by filtration, washed with water and recrystallized from acetone to give crystals of 3-nitroso-2-phenylpyrazolo[1,5-a]pyridine (0.82 g).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:22]=[C:21]4[C:15]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20]4)=[N:14]3)=[CH:9][CH:8]=2)[O:4][N:3]=1.[CH3:23][CH:24]([CH3:27])[CH:25]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.CO>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:22]=[C:21]4[C:15]([CH2:16][CH2:17][N:18]([CH2:23][CH:24]([CH3:27])[CH3:25])[CH2:19][CH2:20]4)=[N:14]3)=[CH:9][CH:8]=2)[O:4][N:3]=1
Reactant: CC(C)C=O
Reactant: Cc1noc(-c2ccc(-n3cc4c(n3)CCNCC4)cc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: Cc1noc(-c2ccc(-n3cc4c(n3)CCN(CC(C)C)CC4)cc2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-[4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine (may be prepared as described in Description 35) (31 mg, 0.10 mmol) in dichloromethane (4 ml) was added 2-methylpropanal (30 mg, 0.42 mmol) and acetic acid (3 drops). The resulting mixture was stirred at room temperature, under argon, for 20 minutes. Sodium triacetoxyborohydride (89 mg, 0.42 mmol) was added and stirring continued overnight. The resulting crude mixture was diluted with methanol and then purified by SCX, eluting with methanol and then with 2M ammonia/methanol. The basic fractions were combined and solvent evaporated in vacuo. Crude product was purified further by column chromatography on silica gel, eluting with a mixture of 2M ammonia in methanol in dichloromethane (0-1%) to afford the title compound (E21). MS (ES+) m/e 352 [M+H]+.