Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:21])[CH:4]([C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[C:18]([OH:20])=[O:19])C(OC)=O.[OH-].[Na+]>CO.O>[C:3]([CH2:4][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[C:18]([OH:20])=[O:19])([OH:21])=[O:2]
Reactant: COC(=O)C(C(=O)OC)c1cc([N+](=O)[O-])ccc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cc1cc([N+](=O)[O-])ccc1C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 102 %

Procedure:
To a solution of 2-(carboxy-5-nitro-phenyl)malonic acid dimethyl ester, (25.0 g, 84 mmol) in methanol (200 mL), sodium hydroxide (5 g, 125 mmol) in water (200 mL) was added. After 3 hrs the reaction was complete, the methanol removed under vacuum, contents cooled to 0° C. and acidified with concentrated HCl (37 mL). The aqueous layer was extracted twice with ethyl acetate (200 mL then 100 mL), the combined organic layers dried with magnesium sulfate, most of the solvent removed under vacuum, and methylene chloride (30 mL) was then added. The white solid was filtered off and dried to give 19.3 g of product as a white solid, mp=180-82° C. IR(KBr) 3080, 3055, 2983, 1707, 1611, 1585, 1516, 1491, 1424, 1358; 1298, 1237 cm-1.
Reaction SMILES: [Cl:1][CH:2]1[CH:12]=[CH:11][CH:5]2[C:6]([O:8][C:9](=[O:10])[CH:4]2[CH2:3]1)=[O:7]>ClC1C=CC(Cl)=CC=1Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1
Reactant: O=C1OC(=O)C2CC(Cl)C=CC12
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: O=C1OC(=O)c2cc(Cl)ccc21
Temperature: 230 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
Into a 3 necked round bottom flask is placed 49.47 grams of 4-chlorotetrahydrophthalic anhydride, 20.26 g activated carbon (NORIT CA-1) and 200 ml of 1,2,4-trichlorobenzene. The flask is fitted with an air inlet tube, a stirrer, and an addition funnel-condenser to collect water and allow the reflux to return to the flask. The flask was heated and raised to 230° C. with a constant flow of air. The reaction was conducted for eight hours. The carbon was removed by filtration and washed. The contents was concentrated under vacuum and analysis confirmed a yield of 67% 4-chlorophthalic anhydride and 4% of unreacted starting material.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.Cl.[Br:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.[C:21](=[O:23])=[O:22]>C1COCC1>[Br:14][C:15]1[C:20]([C:21]([OH:23])=[O:22])=[CH:19][N:18]=[CH:17][CH:16]=1
Reactant: O=C=O
Reactant: Brc1ccncc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1cnccc1Br
Temperature: -55 °C
Reaction time: 1 h

Procedure:
Butyllithium (82.0 mL, 205.6 mmol, 2.0 eq.) was added dropwise to a solution of diisopropylamine (20.8 g, 205.6 mmol, 2.0 eq.) in THF (100 mL) at −78° C., under nitrogen. The resulting solution was stirred for 1 hour at approximately −60 to −50° C. The resulting solution was added dropwise to a solution of 4-bromopyridine hydrochloride (20.0 g, 102.9 mmol, 1.0 eq.) in THF (100 mL) at −78° C. The resulting solution was stirred for 2 hours. Carbon dioxide gas was introduced into the reaction vessel for 30 minutes. The resulting solution was stirred overnight at room temperature. The reaction was then quenched with water (100 mL). The resulting solution was extracted with EtOAc (3×200 mL) and the aqueous layers were combined. The pH of the solution was adjusted to 3-4 with 1N HCl to yield 4-bromonicotinic acid (16.8 g) as a white solid. ES m/z: [M+H]+ 202.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C[O-].[Na+]>CO>[O:20]([C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Reactant: Oc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1ccc([N+](=O)[O-])cc1Oc1ccccc1
Temperature: 180 °C
Yield: 120.4 %

Procedure:
To a stirred solution of 2-chloro-4-nitrobenzoic acid (3 g, 14.9 mmole) and phenol (3 g, 31.9 mmole) in MeOH (20 mL) was added a solution of NaOMe in MeOH (25 wt %, 9 mL, 39.4 mmole). After 15 minutes the solution was concentrated to dryness and the residue was taken up in dimethylacetamide (50 mL). Copper powder (100 mg) was added and the mixture was heated at reflux with stirring (180° C. oil bath). After 1 hr the reaction was cooled to RT, acidified with 1.0 N HCl (40 mL), and extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), and concentrated under vacuum. The remaining residue was triturated with 1:1 Et2O/petroleum ether and dried under vacuum to afford the title compound (4.65 g). This was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11](=[O:20])[C:12]([CH3:19])=[N:13][NH:14]2.Br[CH:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25].[H-].[Na+]>CN1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11](=[O:20])[C:12]([CH3:19])=[N:13][N:14]2[CH:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25]
Reactant: Cc1ccc(-c2cccc3[nH]nc(C)c(=O)c23)c(C)c1
Reactant: CCCC(Br)CCC
Agent: CN1CCCC1
Agent: [H-]
Agent: [Na+]
Product: CCCC(CCC)n1nc(C)c(=O)c2c(-c3ccc(C)cc3C)cccc21
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 75 %

Procedure:
To 0.041 g (0.16 mmol) of 5-(2,4-dimethylphenyl)-3-methylcinnolin-4(1H)-one in 0.5 mL of N-methylpyrrolidine was added 0.069 mL of 4-bromoheptane and 0.012 g (0.31 mmol) of sodium hydride (60% dispersion in mineral oil). The mixture was stirred for 75 min. at room temperature and quenched with water. The mixture was extracted with ethyl acetate and the combined organics were washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography eluting with a 8% ethyl acetate/hexanes mixture to give 0.042 g (75%) of the title compound as a light green-yellow semisolid.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[CH2:25][C:26]#[N:27]>>[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1/[C:25](=[CH:12]/[C:11]1[C:2]([Cl:1])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([O:14][CH3:15])=[CH:6][CH:5]=2)/[C:26]#[N:27]
Reactant: N#CCc1nc2ccccc2s1
Reactant: COc1ccc2nc(Cl)c(C=O)cc2c1
Product: COc1ccc2nc(Cl)c(/C=C(\C#N)c3nc4ccccc4s3)cc2c1
Yield: 78.4 %

Procedure:
2-Chloro-6-methoxy-3-quinolinecarboxaldehyde (111 mg) was condensed with 2-benzothiazoleacetonitrile (87 mg) through Method B (production step 3), to thereby yield the target product (yield: 148 mg, 78%).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].O1C=C[CH2:12][C:11]1=O>>[C:3]([CH:2]1[CH2:9][CH:8]([CH2:11][CH3:12])[O:7][C:1]1=[O:6])(=[O:4])[CH3:5]
Reactant: O=C1CC=CO1
Reactant: CCOC(=O)CC(C)=O
Product: CCC1CC(C(C)=O)C(=O)O1

Procedure:
Sodium hydroxide (65 g, 1.625 moles) in 65 g H2O was added over a period of one hour to a stirring solution of ethyl acetoacetate (192 g, 1.47 moles), 1,2-butylene oxide (120 g, 1.66 moles) and H2O (470 g) in a two liter, four-neck flask equipped with a mechanical stirrer, thermometer, addition funnel, and condenser. The reaction was run at about 25° C. for three hours. The mixture was transferred to a separatory funnel and acidified with 155 g 20° Baume hydrochloric acid. The organic fraction (182.6 g) was placed on a Rotovap and stripped at 60° C. and 15 torr to yield 151.8 g residue and 29.5 g distillate. The main fraction (151.8 g) and a methylene chloride extract (32 g) of the aqueous phase were distilled using a Raschig ring packed column and a Perkins Triangle Head as in Example I. Three fractions were obtained upon distillation. Fraction 1 contained mostly unreacted ethyl acetoacetate. Fraction 2 (7.6 g) had a boiling point of 90-100° C. at 2 torr and contained 86.6% of the desired furanone product. Fraction 3 (88.3 g) boiled in the range 100-160° C. at 2 torr and contained 93.4% lactone. Total yield of lactone was 90.4 g or 39.3%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:30]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31]1.C(N(CC)CC)C.NCCN(CCN)CCN>C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:22][CH:23]=2)[C:35]([N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:36])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Reactant: O=C(Cl)N1CCCC1
Agent: NCCN(CCN)CCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-n3cccn3)cc2)C(=O)N2CCCC2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of {3-[(4-pyrazol-1-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester (15 mg, 0.038 mmol), prepared in Step A of Example 13a, pyrrolidine-1-carbonyl chloride (5 eq), and triethylamine (5 eq) in CH2Cl2 (1-2 mL) was stirred at room temperature for 72 h. Additional pyrrolidine-1-carbonyl chloride (5 eq) and triethylamine (5 eq) were added and the reaction was stirred for 24 h followed by addition of tris(2-aminoethyl)amine on polymer support. The reaction was stirred for 24 h and the resin was removed by filtration with the aid of CH2Cl2. The organic solution was washed sequentially with 5.5% aqueous HCl and saturated NaHCO3 solution. The organic solution was concentrated and was used in Step B without further purification.
Reaction SMILES: [CH2:1]([O:3][CH:4]1[CH2:8][C:7]2=[C:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([OH:13])=[CH:11][CH:12]=[C:6]2[O:5]1)[CH3:2].[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22](S(C)(=O)=O)[N:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([O:13][C:10]2[C:9]([C:14]([O:16][CH3:17])=[O:15])=[C:7]3[CH2:8][CH:4]([O:3][CH2:1][CH3:2])[O:5][C:6]3=[CH:12][CH:11]=2)[N:21]=1
Reactant: CCOC1Cc2c(ccc(O)c2C(=O)OC)O1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC1Cc2c(ccc(Oc3nc(OC)cc(OC)n3)c2C(=O)OC)O1
Temperature: 100 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A mixture comprising 1.0 g of methyl 2-ethoxy-5-hydroxy-2,3-dihydrobenzofuran-4-carboxylate, 1.0 g of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 0.78 g of potassium carbonate in 30 ml of N,N-dimethylformamide, was heated and stirred at 100° C. for two hours. The mixture was returned to room temperature, then poured into water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. It was concentrated under reduced pressure, and the oily substance thereby obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to obtain 1.5 g (yield: 95%) of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:13][CH3:14])([CH3:12])[C:7](=O)[NH:8]2)=[CH:4][CH:3]=1.CO>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:13][CH3:14])([CH3:12])[CH2:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CCC1(C)C(=O)Nc2cc(Cl)ccc21
Solvent: C1CCOC1
Solvent: CO
Product: CCC1(C)CNc2cc(Cl)ccc21
Temperature: 70 °C
Reaction time: 3 h
Yield: 68.3 %

Procedure:
BH3-Me2S (2 M in THF, 5.7 mL, 11.5 mmol) was added to a solution of 6-chloro-3-ethyl-3-methyl-1,3-dihydro-indol-2-one (240 mg, 1.1 mmol) in THF (10 mL). The reaction mixture was stirred at 70° C. for 3 h. The reaction was cooled to room temperature and MeOH (ca. 20 mL) was carefully added. The resulting solution was heated at reflux for 2 h. The solvents were then removed in vacuo and the residue was purified by flash chromatography to give the title compound (147 mg) as a colourless oil. MS: [M+H]+=196.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Cl:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)C.O.O1CCOCC1>[Cl:11][C:12]1[CH:17]=[C:16]([C:2]2[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=2[O:9][CH3:10])[CH:15]=[CH:14][CH:13]=1
Reactant: COc1cccc(F)c1Br
Reactant: OB(O)c1cccc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCO
Product: COc1cccc(F)c1-c1cccc(Cl)c1
Temperature: 180 °C
Yield: 115.2 %

Procedure:
To 2-bromo-3-fluoroanisole (1.0 g, 4.88 mmol), 3-chlorophenylboronic acid (0.91 g, 5.88 mmol), PPh3 (0.64 g, 2.44 mmol), K2CO3 (0.27 g, 1.95 mmol) and Pd(OAc)2 (0.13 g, 0.58 mmol) was added dioxane (8 mL), and EtOH—H2O (1:1, 4 mL). Ar gas was bubbled through the stirred reaction for 5 min. The reaction was heated at 180° C. using microwave oven (Biotage Intiator II) for 20 min. The reaction was cooled to room temperature, combined with another 0.5 g scale run, concentrated. The residue was purified by silica gel column chromatography using 1:1 dichloromethane-hexanes to afford 1.33 g (77%) 3′-chloro-6-fluoro-2-methoxy-biphenyl (I-16, R1═CH3, R2═Cl, Y═F) as a viscous liquid.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:6][CH3:7])[C:3](Cl)=[O:4].Cl.[CH:10]1([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][C:24]([NH2:26])=[CH:25][C:20]=3[N:19]=[C:18]2[C:27]([CH3:31])([CH3:30])[CH2:28][CH3:29])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>CN(C1C=CN=CC=1)C.C(#N)C.CCOC(C)=O>[CH:10]1([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][C:24]([NH:26][C:3](=[O:4])[C:2]([CH3:8])([CH3:1])[CH2:6][CH3:7])=[CH:25][C:20]=3[N:19]=[C:18]2[C:27]([CH3:30])([CH3:31])[CH2:28][CH3:29])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: CCC(C)(C)c1nc2cc(N)ccc2n1CC1CCCCC1
Reactant: CCC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCC(C)(C)C(=O)Nc1ccc2c(c1)nc(C(C)(C)CC)n2CC1CCCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.5 %

Procedure:
2,2-Dimethylbutyryl chloride (24.6 mg, 0.18 mmol) was added to a mixture of 1-(cyclohexylmethyl)-2-(1,1-dimethylpropyl)-1H-benzimidazol-5-amine hydrochloride (65.0 mg, 0.15 mmol) (for preparation see in Example 7, step B) and DMAP (73.3 mg, 0.60 mmol) in acetonitrile (5 mL) at 0° C. The mixture was stirred for 6 h at room temperature, diluted with EtOAc (50 mL), washed with saturated NaHCO3 aqueous solution (10 mL), saturated NaCl aqueous solution (10 mL) and dried over Na2SO4. After filtration and evaporation, the residue was purified by MPLC (EtOAc as eluent on silica gel) to give the desired title compound as a syrup (51.6 mg, 87%). 1H NMR (400 MHz, CD3OD): δ 0.84 (t, J=7.52 Hz, 3H), 0.91 (t, J=7.52 Hz, 3H), 1.25 (m, 5H), 1.28 (s, 6H), 1.64 (m, 3H), 1.67 (s, 6H), 1.72 (q, J=7.49 Hz, 2H), 1.78 (m, 2H), 2.02 (q, J=7.49 Hz, 2H), 2.13 (m, 1H), 4.45 (d, J=7.62 Hz, 2H), 7.64 (dd, J=8.98, 1.76 Hz, 1H), 7.85 (d, J=9.18 Hz, 1H), 8.34 (s, 1H). MS (ESI) (M+H)+: 398.3. Anal. Calcd for C25H39N3O+1.50 TFA+0.70H2O (581.25): C, 57.86; H, 7.27; N, 7.23. Found: C, 57.90; H, 7.19; N, 7.34.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH2:28][CH3:29])[NH:11]1.[CH3:30][S:31](Cl)(=[O:33])=[O:32].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:23][CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH2:28][CH3:29])[NH:11]1
Reactant: CS(=O)(=O)Cl
Reactant: CCc1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc(N)cc3)nc(=O)c1-2
Agent: Cl
Solvent: c1ccncc1
Product: CCc1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc(NS(C)(=O)=O)cc3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 39 h
Yield: 98.7 %

Procedure:
To a stirred solution of 45 mg (0.1 mmol) of 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one in 2 mL of ether-CH2Cl2 was added 0.5 mL of pyridine followed by 0.020 mL (0.26 mmol) of methanesulfonyl chloride. The solution was stirred 39 h at ambient temperature and poured into 1 N aq. HCl. The mixture was extracted with EtOAc, then hexanes. The combined organic extracts were washed with water then brine, dried (MgSO4), and concentrated under reduced pressure to afford 52 mg of 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-methanesulfonylaminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one as an amorphous solid. Mass ESI+): 526(M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH:9]=2)[N:4]([CH3:30])[C:3]=1[CH:31]=[O:32].Cl.[CH2:34]([NH:36][C:37](=[O:46])[C@H:38]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[NH2:39])[CH3:35].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(O)(=O)C.C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:34]([NH:36][C:37](=[O:46])[CH:38]([NH:39][C:31]([C:3]1[N:4]([CH3:30])[C:5]2[C:10]([C:2]=1[Cl:1])=[CH:9][C:8]([NH:11][C:12]([C:14]1[C:15]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:27])[F:29])=[CH:22][CH:21]=3)=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:13])=[CH:7][CH:6]=2)=[O:32])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH3:35]
Reactant: CCNC(=O)[C@@H](N)c1ccccc1
Reactant: Cn1c(C=O)c(Cl)c2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCNC(=O)C(NC(=O)c1c(Cl)c2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2n1C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.2 %

Procedure:
The product from step (b) (407.5 mg, 0.892 mmol), (S)-N-ethyl-2-phenylglycinamide hydrochloride salt (316.3 mg, 1.47 mmol) and acetic acid (10 drops) were suspended in CH2Cl2 (25 mL), and the reaction mixture was stirred at room temperature for 20 min. NaB(OAc)3H (2.1 eq) was then added, and the reaction mixture was stirred at 50° C. for 5.5 h. Saturated NaHCO3 (8 mL) and CHCl3 (12 mL) were then added, and the organic layer was washed with water (6 mL), and then concentrated in vacuo. The product was purified by flash chromatography using 30:70 of hexane:EtOAc to afford 441.4 mg of the title compound.
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[CH2:22]([NH2:25])[C:23]#[CH:24]>>[CH2:22]([NH:25][C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19])[C:23]#[CH:24]
Reactant: C#CCN
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c2[nH]c(C(F)(F)F)nc12
Product: C#CCNc1c(C(F)(F)F)cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c12

Procedure:
4-Chloro-7-nitro-2,5-bis(trifluoromethyl)benzimidazole is reacted with 2-propynylamine to obtain 4-(2-propynylamino)-7-nitro-2,5-bis(trifluoromethyl)benzimidazole, m.w., 352.2.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([N+:24]([O-:26])=[O:25])=[CH:13][C:14]2[NH:19][C:18](=[O:20])[O:17][C:16]([CH3:22])([CH3:21])[C:15]=2[CH:23]=1)(=O)=O.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([SH:37])[CH:32]=[CH:33][C:34]=1[O:35][CH3:36]>>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([S:37][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[C:12]([N+:24]([O-:26])=[O:25])=[CH:13][C:14]3[NH:19][C:18](=[O:20])[O:17][C:16]([CH3:21])([CH3:22])[C:15]=3[CH:23]=2)[CH:32]=[CH:33][C:34]=1[O:35][CH3:36]
Reactant: COc1ccc(S)cc1OC
Reactant: CC1(C)OC(=O)Nc2cc([N+](=O)[O-])c(OCCCCOS(C)(=O)=O)cc21
Product: COc1ccc(SCCCCOc2cc3c(cc2[N+](=O)[O-])NC(=O)OC3(C)C)cc1OC

Procedure:
Prepared analogously to Example 210 from 6-(4-methanesulfonyloxy-butoxy)-7-nitro-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 3,4-dimethoxy-thiophenol.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[CH:9][C:10]([C:18]([OH:20])=[O:19])=[N:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:17][CH2:16]1.[O:21]1[CH2:24][C:23](=[O:25])[CH2:22]1>C1COCC1>[CH:15]1([CH2:14][O:13][C:12]2[N:11]=[C:10]([C:18]([OH:20])=[O:19])[CH:9]=[CH:8][C:7]=2[C:23]2([OH:25])[CH2:24][O:21][CH2:22]2)[CH2:17][CH2:16]1
Reactant: O=C1COC1
Reactant: O=C(O)c1ccc(Br)c(OCC2CC2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C2(O)COC2)c(OCC2CC2)n1
Reaction time: 1 h
Yield: 12.3 %

Procedure:
Under a nitrogen atmosphere, n-BuLi (3.23 mL, 5.6 mmol) was added dropwise to a solution of 5-bromo-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 9 d, 1.1 g, 4.0 mmol) in THF (50 mL) at −78° C. and stirred for 1 h at this temperature. Then a solution of oxetan-3-one (CAN 6704-31-0, 0.73 g, 10 mmol) in THF (5 mL) was added at −78° C. The reaction mixture was stirred for 1 h at room temperature and quenched with aq. NH4Cl solution. The pH was adjusted to 2 with conc. HCl. The mixture was extracted with ethyl acetate (3×50 mL), the organic layers were combined, washed with brine (2×50 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by chromatography over silica gel using petroleum ether/ethyl acetate=1/1 to give the title compound (0.13 g, 30.8%) as a yellow solid; MS (EI): m/e=266.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]=[N+:9]=[N-:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]1([C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([OH:20])[C:18]#[CH:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C[C-]1C(C)=C(C)C(C)=C1C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ru+].C1C=CC=CC=1>[CH2:1]([N:8]1[C:18]([C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:20])=[CH:19][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: C#CC(O)(c1ccccc1)c1ccccc1
Agent: Cl[Ru+]
Agent: Cc1c(C)c(C)[c-](C)c1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: OC(c1ccccc1)(c1ccccc1)c1cnnn1Cc1ccccc1

Procedure:
Benzyl azide (0.200 g, 1.50 mmol), 1,1-diphenyl-2-propyn-1-ol (0.344 g, 1.65 mmol), Cp*RuCl(PPh3)2 (12 mg, 0.015 mmol). Solvent, benzene; reaction temperature, 80° C.; reaction time, 4 hours; yield, 0.39 g (75%). The reaction was performed under air. EI-MS: m/z 342 [M+1].
Reaction SMILES: [CH3:1][N:2](C=O)C.C1(S([N:15]2[C:19]3[CH:20]=[N:21][C:22]([C:33]#[N:34])=[C:23]([O:24][CH:25]4[CH2:30][CH2:29][N:28]([CH2:31][CH3:32])[CH2:27][CH2:26]4)[C:18]=3[C:17]3[CH:35]=[C:36](Br)[CH:37]=[N:38][C:16]2=3)(=O)=O)C=CC=CC=1.C(N(CC)CC)C>C(=O)(O)[O-].[Na+].[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:31]([N:28]1[CH2:27][CH2:26][CH:25]([O:24][C:23]2[C:18]3[C:17]4[CH:35]=[C:36]([C:1]#[N:2])[CH:37]=[N:38][C:16]=4[NH:15][C:19]=3[CH:20]=[N:21][C:22]=2[C:33]#[N:34])[CH2:30][CH2:29]1)[CH3:32]
Reactant: CN(C)C=O
Reactant: CCN1CCC(Oc2c(C#N)ncc3c2c2cc(Br)cnc2n3S(=O)(=O)c2ccccc2)CC1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [C-]#N
Solvent: CCN(CC)CC
Product: CCN1CCC(Oc2c(C#N)ncc3[nH]c4ncc(C#N)cc4c23)CC1
Temperature: 150 °C
Yield: 5 %

Procedure:
DMF (8 mL) was added to a mixture of 9-benzenesulfonyl-3-bromo-5-(1-ethyl-piperidin-4-yloxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (200 mg, 0.37 mmol), zinc cyanide (217 mg, 1.85 mmol) and tetrakis(triphenylphosphine) palladium(0) (43 mg, 0.04 mmol) and the reaction mixture heated under microwave irradiation at 150° C. for 30 min. Triethylamine (2 mL) was then added and the reaction mixture heated at 50° C. for 24 h. The mixture was diluted with saturated aqueous sodium bicarbonate solution (100 mL) and extracted into 10% MeOH in DCM (2×25 mL). The combined organic phase was adsorbed onto HM-N then purified by flash chromatography (silica, 12 g column, ISCO, 0-10% MeOH in DCM) to afford the title compound as a cream solid (6 mg, 5%). 1H NMR (DMSO-D6, 400 MHz): 9.07 (d, J=2.0 Hz, 1H), 8.99 (d, J=1.9 Hz, 1H), 8.84 (s, 1H), 4.86-4.76 (m, 1H), 2.97-2.87 (m, 2H), 2.42 (q, J=7.2 Hz, 2H), 2.23-2.13 (m, 2H), 2.12-1.94 (m, 4H), 1.03 (t, J=7.2 Hz, 3H). LCMS (Method H): RT=5.27 min, M+H+=347.