Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][CH:3](OC)[CH:4]([CH3:26])[C@@H:5]1[C@:22]2([CH3:23])[C@H:8]([C:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12]([CH2:13][C@@H:14]([OH:25])[CH2:15][C@@H:16]2[OH:24])=[CH:11][CH:10]=3)[CH2:7][CH2:6]1.CC1(C)COC(C([C@@H]2[C@]3(C)[C@H](C4[C@H](CC3)[C@]3(C)C(C[C@@H](O)C[C@@H]3O)=CC=4)CC2)C)OC1>>[OH:24][C@@H:16]1[C@@:17]2([CH3:18])[C:12](=[CH:11][CH:10]=[C:9]3[C@@H:19]2[CH2:20][CH2:21][C@@:22]2([CH3:23])[C@H:8]3[CH2:7][CH2:6][C@@H:5]2[CH:4]([CH:3]=[O:2])[CH3:26])[CH2:13][C@@H:14]([OH:25])[CH2:15]1
Reactant: COC(OC)C(C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Product: CC(C=O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 78.3 %

Procedure:
The procedure of Example 25 was repeated except that 2.6 mg (0.00667 mmole) of 21,21-dimethoxy-20-methylpregna-5,7-diene-1α,3β-diol was used in lieu of 4.3 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)pregna-5,7-diene-1α,3β-diol to give 1.8 mg of 1α,3β-dihydroxypregna-5,7-diene-20-carbaldehyde (yield: 78%).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[CH:5]=[CH:4]1.[CH3:12][Si:13]([CH3:20])([CH3:19])[CH2:14][CH2:15][O:16][CH2:17]Cl>CN(C=O)C>[CH3:12][Si:13]([CH3:20])([CH3:19])[CH2:14][CH2:15][O:16][CH2:17][N:3]1[C:11]2=[N:10][CH:9]=[CH:8][CH:7]=[C:6]2[CH:5]=[CH:4]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: c1cnc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2cccnc21
Reaction time: 1 h

Procedure:
Sodium hydride (60% dispersion in mineral oil; 16.2 g, 0.404 mol) was added in portions over 25 min to a solution of 7-azaindole (39.8 g, 0.337 mol) in DMF (200 mL) at 0° C. and the mixture was stirred for 1 h. 2-(Trimethylsilyl)ethoxymethyl chloride (71.8 mL, 0.404 mol) was then added slowly over 15 min, keeping the temperature of the reaction mixture below 10° C. After 1 h, the reaction was quenched with water (500 mL) and the mixture was extracted with CH2Cl2 (5×300 mL). The combined organic layers were washed with saturated brine, dried over MgSO4, filtered, concentrated and dried under high vacuum to give the title compound. MS: m/z=249 (M+1).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=O)C.C([Sn](CCCC)(CCCC)[C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([O:49][CH3:50])[N:44]=1)CCC.BrC1C=CC(=O)N(CC2C=CC(CC)=CC=2)C=1>>[C@@H:6]1([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]3[S:33][C:34]([C:43]4[CH:48]=[CH:47][CH:46]=[C:45]([O:49][CH3:50])[N:44]=4)=[CH:35][CH:36]=3)[CH:25]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(OC)n1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCc1ccc(Cn2cc(Br)ccc2=O)cc1
Product: COc1cccc(-c2ccc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)s2)n1

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene 71 obtained in Example 128-(4) and tri-n-butyl(6-methoxy-2-pyridyl)tin (see Gros, Philippe; Fort, Yves. Synthesis (1999), 754-756) were treated in a manner similar to Example 128-(5) and (6) to give the target compound. APCI-Mass m/Z 478/480 (M+H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([C:31]([F:34])([F:33])[F:32])[C:12]([O:15][CH2:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)=[N:13][CH:14]=2)O1.[NH2:36][C:37]1[C:38]([C:46]#[N:47])=[N:39][C:40](Cl)=[CH:41][C:42]=1[NH:43][CH3:44].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:36][C:37]1[C:42]([NH:43][CH3:44])=[CH:41][C:40]([C:9]2[CH:14]=[N:13][C:12]([O:15][CH2:16][CH2:17][CH:18]3[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[CH2:22][CH2:23]3)=[C:11]([C:31]([F:32])([F:33])[F:34])[CH:10]=2)=[N:39][C:38]=1[C:46]#[N:47]
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2ncc(B3OC(C)(C)C(C)(C)O3)cc2C(F)(F)F)CC1
Reactant: CNc1cc(Cl)nc(C#N)c1N
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CNc1cc(-c2cnc(OCCC3CCN(C(=O)OC(C)(C)C)CC3)c(C(F)(F)F)c2)nc(C#N)c1N
Temperature: 100 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
A suspension of tert-butyl 4-(2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yloxy)ethyl)piperidine-1-carboxylate (8.95 g), 3-amino-6-chloro-4-(methylamino)picolinonitrile (2.29 g), tris(dibenzylideneacetone)dipalladium (0) (0.59 g), tricyclohexylphosphine (0.43 g) and potassium phosphate (5.48 g) in 1,4-dioxane (80 ml) and water (40 ml) was stirred at 100° C. under nitrogen for 2 h. The reaction mixture was cooled and partitioned between water and ethyl acetate, washed with water, brine, dried over sodium sulphate, filtered and concentrated. Purified by Biotage SNAP cartridge KP-Sil column (340 g, heptane:ethyl acetate=1:0, 2:1, 1:1 to 1:2) to give 6.43 g light brown solid as tert-butyl 4-(2-(5-amino-6-cyano-4-(methylamino)-5′-(trifluoromethyl)-2,3′-bipyridin-6′-yloxy)ethyl)piperidine-1-carboxylate (99%, 90% purity).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([O:12][CH2:13][CH:14](OCC)OCC)[CH:5]=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]2[O:12][CH:13]=[CH:14][C:5]=12)=[O:21]
Reactant: CCOC(COc1cc(OC)cc(C(=O)OC)c1)OCC
Solvent: c1ccccc1
Product: COC(=O)c1cc(OC)cc2occc12
Yield: 62.4 %

Procedure:
3-(2,2-Diethoxy-ethoxy)-5-methoxy-benzoic acid methyl ester (6b) (1.95 g, 6.53 mmol) was added to a solution of polyphosphoric acid (1.47 g) in benzene (10 mL). The reaction mixture was heated to reflux for 2 hr, filtered and concentrated. The residue was purified by flash column chromatography (5% EtOAc in hexanes) to give a pale yellow solid (840 mg, 62% yield). 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J=2.27 Hz, 1H) 7.61 (d, J=2.27 Hz, 1 H) 7.26 (d, J=2.02 Hz, 1 H) 7.25 (d, J=2.27 Hz, 1 H) 3.99 (s, 3 H) 3.90 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH:10]=[C:11]([C:13]([NH:15][CH:16]2[CH2:21][CH2:20][N:19](C(OCC)=O)[CH2:18][CH2:17]2)=[O:14])[N:12]=1.[Si](I)(C)(C)C.CO.C[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)[CH:10]=[C:11]([C:13]([NH:15][CH:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]2)=[O:14])[N:12]=1
Reactant: CCOC(=O)N1CCC(NC(=O)c2cn(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)n2)CC1
Agent: C[O-]
Agent: C[Si](C)(C)I
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C(NC1CCNCC1)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Yield: 35.5 %

Procedure:
To a solution of ethyl 4-({[2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazol-4-yl]carbonyl}amino)-1-piperidinecarboxylate (Table entry 221) (0.595 g, 1.221 mmol) in CH2Cl2 (10 mL) was added TMSI (0.176 mL, 2.7 mmol). The mixture was heated at reflux for 3 h, diluted by methanol, and concentrated. The residue was dissolved in methanol and NaOMe (0.62 mmol) was added. The mixture was concentrated and purified by flash chromatography (2M NH3 in methanol:EtOAc=15:85) to afford the product 2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-(4-piperidinyl)-1H-imidazole-4-carboxamide (180 mg, 36% yield): LC-MS m/z 415.3 (MH+), retention time 2.22 min (method 1); Rf=0.25 (1:1 EtOAc/2M NH3 in MeOH). 1H NMR (300 MHz, CDCl3) δ 1.35-1.51 (2H, m), 1.91-2.15 (3H, br), 2.63-2.78 (2H, m), 3.03-3.09 (2H, m), 3.97-4.15 (1H, m), 6.96-7.52 (8H, m), 7.81 (1H, s).
Reaction SMILES: C(OC(N1[CH2:11][CH:10]([C:12](=[O:43])[NH:13][C:14]2[S:15][C:16]3[CH:22]=[C:21]([O:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([NH:33][CH2:34][CH2:35][N:36]([CH:40]([CH3:42])[CH3:41])[CH:37]([CH3:39])[CH3:38])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[CH:20]=[CH:19][C:17]=3[N:18]=2)C1)=O)(C)(C)C>O1CCOCC1>[NH2:18][CH2:17][CH2:16][CH2:22][CH2:21][CH2:20][CH2:11][CH2:10][C:12]([NH:13][C:14]1[S:15][C:16]2[CH:22]=[C:21]([O:23][S:24]([C:27]3[CH:28]=[CH:29][C:30]([NH:33][CH2:34][CH2:35][N:36]([CH:37]([CH3:38])[CH3:39])[CH:40]([CH3:42])[CH3:41])=[CH:31][CH:32]=3)(=[O:26])=[O:25])[CH:20]=[CH:19][C:17]=2[N:18]=1)=[O:43]
Reactant: CC(C)N(CCNc1ccc(S(=O)(=O)Oc2ccc3nc(NC(=O)C4CN(C(=O)OC(C)(C)C)C4)sc3c2)cc1)C(C)C
Solvent: C1COCCO1
Product: CC(C)N(CCNc1ccc(S(=O)(=O)Oc2ccc3nc(NC(=O)CCCCCCCN)sc3c2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 212.8 %

Procedure:
3 ml of hydrochloric dioxane are added to a solution of 153 mg of 3-{6-[4-(2-diisopropylaminoethylamino)benzenesulfonyloxy]benzothiazol-2-yl-carbamoyl}azetidine-1-carboxylic acid tert-butyl ester (intermediate 36) in 3 ml of dioxane. The resulting solution is stirred for 5 hours at room temperature and then evaporated under reduced pressure to give 152 mg of 4-(2-diisopropylaminoethylamino)benzenesulfonic acid 2-(8-aminooctanoylamino)-benzothiazol-6-yl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:27]=[CH:26][NH:25][C:24]2=[O:28])=[CH:19][CH:18]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:25]1[CH:26]=[CH:27][N:23]([C:20]2[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=2)[C:24]1=[O:28])[CH3:13]
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: COc1ccc(-n2cc[nH]c2=O)cc1
Product: COc1ccc(-n2ccn([C@H](C)[C@@]3(c4ccc(F)cc4F)CO3)c2=O)cc1
Yield: 25 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.66 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.26 g of 1-(4-methoxyphenyl)-2(1H,3H)-imidazolone, 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-(4-methoxyphenyl)-2(1H,3H)-imidazolone (617 mg) was obtained as colorless prisms.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[O:5]=[C:6]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][CH:8]=[C:7]1/[CH:16]=[CH:17]/[C:18]#[N:19].[N-:20]=[N+:21]=[N-:22].[Na+].Cl>O1CCCC1>[O:5]=[C:6]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][CH:8]=[C:7]1/[CH:16]=[CH:17]/[C:18]1[NH:22][N:21]=[N:20][N:19]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#C/C=C/c1coc2ccccc2c1=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: O=c1c(/C=C/c2nnn[nH]2)coc2ccccc12

Procedure:
Under stirring, 4.6 parts of anhydrous aluminum chloride are added to 100 volume parts of dry tetrahydrofuran, followed by the addition of 3.11 parts of trans-3-(4-oxo-4H-1-benzopyran-3-yl)-acrylonitrile and 4.5 parts of sodium azide. The whole mixture is refluxed for 28 hours and, then, 35 volume parts of 15 weight% hydrochloric acid are added to the resulting mixture, followed by distilling off tetrahydrofuran under reduced pressure. The resulting residue is recovered by filtration and recrystallized from methanol, dimethylformamide-water and, then, from methanol. This procedure yields trans-1-(4-oxo-4H-1-benzopyran-3-yl)-2-(1H-tetrazol-5-yl) ethylene as light-yellow needles. Melting point: 254.5°-255° C.(decomp. with foaming).
Reaction SMILES: [Na+].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@@H:10]([O:14][CH3:15])[C:11]([O-:13])=[O:12])=[CH:5][CH:4]=1.[CH3:16]S(O)(=O)=O>CO>[CH3:16][O:12][C:11](=[O:13])[C@H:10]([O:14][CH3:15])[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=1
Reactant: CS(=O)(=O)O
Reactant: CO[C@H](Cc1ccc(O)cc1)C(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H](Cc1ccc(O)cc1)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
Compound (a), (R)-3-(4-hydroxy-phenyl)-2-methoxy-propionic acid sodium salt, (Example 2, Step 5) (5.00 g, 22.9 mmol) is dissolved in methanol (125 mL) and treated with methanesulfonic acid (7.44 mL, 114.6 mmol). The reaction is stirred at room temperature for 1 h. The reaction is concentrated in vacuo and the resulting residue taken up in diethyl ether. The organic portion is washed with water (2×) and saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated in vacuo to yield 4.00 g (83%) of an off-white solid. The material is used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.06 (dd, J=2.2, 6.4 Hz, 2H), 6.72 (dd, J=2.2, 6.4 Hz, 2H), 5.38 (bd s, 1H), 3.95 (dd, J=5.3, 7.1 Hz, 1H), 3.71 (s, 3H), 3.35 (s, 3H), 2.95 (m, 2H); MS (electrospray), 209.2 (ES−).
Reaction SMILES: [OH-].[K+:2].[CH3:3][CH2:4][CH2:5][CH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]3[N:29]=[N:28][NH:27][N:26]=3)=[CH:17][CH:18]=2)[C:10]([CH2:30][OH:31])=[C:9]([Cl:32])[N:8]=1>C(O)(C)C>[CH3:3][CH2:4][CH2:5][CH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]3[N:29]=[N:28][N-:27][N:26]=3)=[CH:15][CH:14]=2)[C:10]([CH2:30][OH:31])=[C:9]([Cl:32])[N:8]=1.[K+:2]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nn[n-]n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
A solution of potassium hydroxide (9.4 g) and isopropyl alcohol (200 mL) was slowly added to a suspension of losartan (60 g) in isopropyl alcohol (280mL). The reaction mixture was stirred for about 2 hours at room temperature. The mixture was filtered, heated to reflux, concentrated to about a 180 mL volume and stirred for about 12 hours at room temperature. The precipitate was filtered, washed with isopropyl alcohol, and dried under reduced pressure for about 2 hours at about 50° C. to give losartan potassium (52.2 g, 85% yield) as a white powder. Purity was determined to be 99.74% by HPLC. Losartan potassium (1.0 g) was triturated with ethyl acetate (10 mL) and recovered from the triturate in a purity of 99.775% by HPLC.
Reaction SMILES: [C:1]([NH:22][CH2:23][CH2:24][O:25][P:26](=[O:28])=[O:27])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH:8]=[CH:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[C:29](O)(=O)[CH2:30]C/C=C\CC=CCC=CCC=CCC=CCC=CCC>>[C:1]([NH:22][CH2:23][CH2:24][O:25][P:26](=[O:28])=[O:27])(=[O:21])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH:7]=[CH:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:29][CH3:30]
Reactant: CCCCCC=CCC=CCC=CC/C=C\CCCC(=O)NCCOP(=O)=O
Reactant: CCC=CCC=CCC=CCC=CCC=CC/C=C\CCC(=O)O
Product: CCC=CCC=CCC=CCC=CCC=CC/C=C\CCC(=O)NCCOP(=O)=O

Procedure:
This compound was prepared as described above for (5), using 0.5 mmol (164 mg) of cis-4,7,10,13,16,19-docosahexaenoic acid; yield 99 mg (44%); Rf 0.10-0.15 (system B); 1H NMR (CD3SOCD3, 200 MHz) δ0.9-1.0 (t, 3H, ω-CH3); 2.0-2.1 (t, 2H, CH2CO); 2.2-2.4 (m, 4H, 2CH2CH═CH); 2.7-2.9 (br s, 10H, 5HC═CHCH2CH═CH); 3.4-3.5 (br s, 2H, CH2NH); 3.9-4.0 (br s, 2H, CH2OP); 5.2-5.4 (br s, 12H, 6HC═CH); 8.2-8.4 (m, 3H, NH and 2POH).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[S:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.[Br:10][C:11]1[CH:12]=[CH:13][C:14]([Cl:19])=[C:15]([CH:18]=1)[CH:16]=O>>[S:9]1[C:8]([CH2:16][C:15]2[CH:18]=[C:11]([Br:10])[CH:12]=[CH:13][C:14]=2[Cl:19])=[CH:7][C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]1=2
Reactant: c1ccc2sccc2c1
Reactant: O=Cc1cc(Br)ccc1Cl
Product: Clc1ccc(Br)cc1Cc1cc2ccccc2s1

Procedure:
Thianaphthene and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 7 to give the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][N:3]=1.[F:10][C:11]([F:22])([F:21])[C:12]([N:14]=[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][NH:16]1)=[O:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][N:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]2=[N:14][C:12](=[O:13])[C:11]([F:21])([F:22])[F:10])=[CH:6][CH:7]=1
Reactant: BrCc1ccc(Br)nc1
Reactant: O=C(N=c1cccc[nH]1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(N=c1ccccn1Cc1ccc(Br)nc1)C(F)(F)F

Procedure:
70 mg (0.28 mmol) of the 2-bromo-5-bromomethylpyridine obtained by the aforementioned method was dissolved in 10 ml of anhydrous acetonitrile, 54 mg (0.28 mmol) of 2,2,2-trifluoro-N-(pyridin-2(1H)-ylidene)acetoamide synthesized by the method described in (1) of Synthetic Example P1 and 46 mg (0.34 mmol) of potassium carbonate were added thereto in sequence, and the resulting mixture was heated and refluxed for 6 hours. After the reaction was completed, the reaction solution was returned to room temperature to filter insoluble materials, and the filtrate was concentrated under reduced pressure. Diethyl ether was added thereto to precipitate a solid, and thus the solid was collected, washed with diethyl ether, and then dried under reduced pressure in a desiccator to obtain the subject material. Amount obtained 81 mg (yield 82%).
Reaction SMILES: [B-](F)(F)(F)F.C1C=CN=CC=1.C1C=CN=CC=1.[IH2+:18].[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[I:18][C:30]1[CH:31]=[C:26]([CH2:25][C:20]2[N:21]=[CH:22][CH:23]=[CH:24][N:19]=2)[CH:27]=[CH:28][C:29]=1[OH:32]
Reactant: Oc1ccc(Cc2ncccn2)cc1
Reactant: [IH2+]
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: Oc1ccc(Cc2ncccn2)cc1I
Reaction time: 1 h

Procedure:
Bis(pyridine)iodonium tetrafluoroborate (379 mg, 1.02 mmol) was added to a solution of 4-(pyrimidin-2-ylmethyl)phenol (200 mg, 1.07 mmol) in 9:1 DCM:TFA (6 mL) at 0° C. The mixture was stirred for 1 h, partitioned between EtOAc and water, the layers were separated, and the organic layer was washed with satd. sodium thiosulfate. The organic layer was dried over MgSO4, concentrated in vacuo, and purified by column chromatography to give 2-iodo-4-(pyrimidin-2-ylmethyl)phenol. MS (ESI) m/z: Calculated: 312.0; Observed: 313.0 (M++1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C1(S([N:16]2[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[C:18]([C:25]3[C:29]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)=[N:28][N:27]4[CH2:36][CH2:37][CH2:38][C:26]=34)=[CH:17]2)(=O)=O)C=CC=CC=1>CO.O>[N:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:29]1[C:25]([C:18]2[C:19]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[NH:16][CH:17]=2)=[C:26]2[CH2:38][CH2:37][CH2:36][N:27]2[N:28]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2c(-c3ccccn3)nn3c2CCC3)c2cccnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: c1ccc(-c2nn3c(c2-c2c[nH]c4ncccc24)CCC3)nc1
Yield: 6.9 %

Procedure:
Add potassium carbonate (21 mg, 0.15 mmol) to a solution of 1-benzenesulfonyl-3-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-pyrrolo[2,3-b]pyridine (Example 3, Part A; 34 mg, 0.77 mmol) in methanol/water (0.9 mL/0.3 mL). Reflux the reaction overnight (16 h). Concentrate in vacuo, add aqueous sodium chloride (10 mL), and extract with chloroform (3×25 mL). Dry the combined organic extracts with sodium sulfate, filter, and concentrate in vacuo. Purify by flash column chromatography, using the appropriate mixture of methylene chloride, chloroform, methanol, and concentrated aqueous ammonium hydroxide, to provide 16 mg (68%) of the title compound as an off-white solid. MS (ES) m/z=302 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15]Cl)[CH:10]=2)=[N:6][CH:7]=1.[P:17]([O:24]CC)([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20].C(OCC)(=O)C>CCCCCCC>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=2)[CH2:15][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])=[N:6][CH:7]=1
Reactant: CCOP(OCC)OCC
Reactant: ClCc1cccc(Oc2ncc(Br)cn2)c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCOP(=O)(Cc1cccc(Oc2ncc(Br)cn2)c1)OCC
Temperature: 150 °C
Reaction time: 16 h
Yield: 83.5 %

Procedure:
5-Bromo-2-(3-(chloromethyl)phenoxy)pyrimidine (810 mg, 2.70 mmol) was treated with triethyl phosphite (1 mL, 2.2 mmol), and heated to 150° C. After 16 h, the reaction mixture was removed from the heat and ethyl acetate (about 3 mL) followed by heptane were added. As the reaction mixture cooled an oily precipitate formed. The mixture was made homogenous by addition of ethyl acetate. Heptane was added dropwise until a white solid precipitated. Additional heptane was added and the solid was filtered, washed with heptane and dried in vacuo to afford the title compound (0.737 g, 68% yield) as a white solid. MS (APCI) M+1=401; 1H NMR (400 MHz, CDCl3) δ ppm 1.26 (t, J=6.92 Hz, 6H) 3.18 (d, J=21.64 Hz, 2H) 3.98-4.10 (m, 4H) 7.06-7.11 (m, 1H) 7.15 (q, J=2.01 Hz, 1H) 7.20-7.26 (m, 1H) 7.35-7.42 (m, 1H) 8.56 (s, 2H).
Reaction SMILES: [CH2:1]([N:9]1[CH:17]=[N:16][C:15]2[C:14](=[O:18])[NH:13][CH:12]=[N:11][C:10]1=2)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1C(=O)N([Br:26])C(=O)C1>O1CCOCC1>[Br:26][C:17]1[N:9]([CH2:1][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:10]2[N:11]=[CH:12][NH:13][C:14](=[O:18])[C:15]=2[N:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1[nH]cnc2c1ncn2CCc1ccccc1
Solvent: C1COCCO1
Product: O=c1[nH]cnc2c1nc(Br)n2CCc1ccccc1
Temperature: 105 °C
Yield: 57 %

Procedure:
To a solution of purinone from step 2 (0.29 g, 1.21 mmol) from above reaction in dioxane (0.1M) is added NBS (0.32 g, 1.81 mmol). The resulting reaction mixture was heated to 105° C. until HPLC shows consumption of starting material (ca. 2 h). The reaction was cooled to rt and purified by MPLC using a solvent gradient of 0-20% MeOH/CH2Cl2. The product containing fractions were collected and concentrated to provide the desired product (0.22 g, 57% yield). 1H NMR (DMSO-d6) δ 12.49 (s, 1H), 8.08 (s, 1H), 7.30-7.21 (m, 3H), 7.10-7.04 (m, 2H), 4.36 (t, J=7.0 Hz, 2H), 3.17 (t, J=7.3 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>CN(C=O)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:26][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1c(Cl)ccnc1Cl
Reactant: COc1ccc(CN)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(CNc2ccnc(Cl)c2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 50.9 %

Procedure:
To a solution of 2,4-dichloro-3-nitropyridine (12.0 g, 62.2 mmol) in DMF (78 mL) was added NEt3 (10.4 mL, 74.6 mmol) and p-methoxybenzylamine (8.12 ml, 62.18 mmol) at 0° C. After stirring for 10 h at rt, DMF was removed at reduced pressure. The residue was triturated with EtOAc, filtered, washed with EtOAc and hexane, and dried to afford 2-chloro-N-(4-methoxybenzyl)-3-nitropyridin-4-amine (9.29 g, 51%). Additional product (8.0 g, 44%) was obtained by column chromatography (SiO2, eluent) from the filtrates.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][C:7]2([C:13]1[NH:14][CH2:15][CH2:16][N:17]=1)C.C(=O)([O-])[O-].[Na+].[Na+].[CH:24]1(B(O)O)[CH2:26][CH2:25]1.O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[CH:24]1([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][O:6][CH:7]3[C:13]2[NH:14][CH2:15][CH2:16][N:17]=2)[CH2:26][CH2:25]1
Reactant: OB(O)C1CC1
Reactant: CC1(C2=NCCN2)OCCc2c(Br)cccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: c1cc(C2CC2)c2c(c1)C(C1=NCCN1)OCC2
Temperature: 120 °C

Procedure:
The mixture of 2-(5-bromo-1-methylisochroman-1-yl)-4,5-dihydro-1H-imidazole (Example 11, 0.15 g), sodium carbonate (0.27 g), bis(triphenylphosphine)palladium(II) chloride (0.02 g), cyclopropylboronic acid (0.09 g), water (1 ml), and acetonitrile (2 ml) was heated in a microwave oven at 120° C. for 15 min. The title compound was purified with separation methods A and G. (Yield 8 mg).