Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27](OCC)=[O:28])=[CH:21][CH:20]=1.[Li+].CC([N-]C(C)C)C>>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:26]([CH2:25][C:22]3[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=3)[C:27]2=[O:28])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)CCc1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: O=c1c(Cc2ccncc2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), ethyl 3-(pyridin-4-yl)propionate (1.1 eq.) and LDA (1.5 eq.) to obtain a product which was subjected to recrystallization from ethyl acetate-methanol to give 1-(3-nitrophenyl)-3-(pyridin-4-ylmethyl)-1,8-naphthyridin-2(1H)-one as a pale brown powder, mp 230° C./EtOAc-MeOH (decomp.).
Reaction SMILES: [C:1]([O:11]CC(N)CC)(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]>O>[C:1]([OH:11])(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: CCC(N)COC(=O)[C@H](O)c1ccccc1
Solvent: O
Product: O=C(O)[C@H](O)c1ccccc1
Temperature: -5 °C
Yield: 72.6 %

Procedure:
A portion of the (-)-2-amino-1-butanol D-(-)-mandelate wet cake (155 grams "as is" -90.3% pure; 0.58 mole) from resolution A is dissolved in water (125 mls) at 50°-55° C. and the resulting solution is distilled under vacuum to remove 48.5 mls of methanol and water. The concentrated solution is treated with 37% hydrochloric acid (60 mls) and the acidified solution is cooled to -5° C. over about 5 hours to crystallize D-(-)-mandelic acid from the solution. The crystals are isolated by filtration, washed twice with ice cold (0°-5° C.) water (20 mls), twice with hexane (20 mls), and dried at 60° C. to obtain 64.1 grams of D-(-)-mandelic acid (72.6% of theoretical; m.p. 131°-133° C.; [α]D25 =-154.1° (C=2, H2O)).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[CH2:10]([NH2:14])[CH2:11][CH2:12][CH3:13]>>[CH2:10]([NH:14][C:3](=[O:5])[C:2]([F:1])([F:8])[F:9])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCN
Reactant: CCOC(=O)C(F)(F)F
Product: CCCCNC(=O)C(F)(F)F
Yield: 54.4 %

Procedure:
Ethyl trifluoroacetate (298 g, 2.1 m) was reacted in a manner similar to Example 5 with n-butylamine (169 g, 2.3 m), except that the amine was added as a liquid within 1 hour. After the exotherm (peak 56° C.) had subsided, the reaction mixture was heated under reflux for 31/2 hours (pot temperature 96° to 98° C.). The mixture was then distilled to yield 193 g of a liquid which boiled at 83° C./7 mm Hg.
Reaction SMILES: S(=O)(=O)(O)O.[N:6]1[C:15]2[C:10](=[CH:11][C:12]([CH2:16][C:17]([OH:19])=[O:18])=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.[OH-].[Na+].[C:22](=O)(O)[O-].[Na+]>CO>[N:6]1[C:15]2[C:10](=[CH:11][C:12]([CH2:16][C:17]([O:19][CH3:22])=[O:18])=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: O=C([O-])O
Reactant: O=C(O)Cc1ccc2ncccc2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)Cc1ccc2ncccc2c1
Yield: 98 %

Procedure:
As shown in step i of Scheme 1, concentrated sulfuric acid (206 mL, 3.868 mol) was added dropwise to a solution of 2-(quinolin-6-yl)acetic acid (compound 1001, 658.2 g, 3.516 mol, Okeanos Tech Co., Cat. No. OK-J-05024) in 6.5 liters of methanol. During the addition, a slight exotherm was observed. After the addition was complete, the reaction was stirred at reflux for 4 hours. After cooling, the volatiles were removed under reduced pressure, the resulting residue was diluted with 4 liters of ethyl acetate, cooled in an ice bath, treated with 2N NaOH (2.1 liters, 1.2 equiv.) until a pH of 4 was achieved, and then treated with saturated sodium bicarbonate until a pH of 8 was achieved. The layers were separated and the aqueous layer extracted twice with ethyl acetate. The combined organics were washed with saturated sodium bicarbonate, washed with water, washed with brine, dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure to afford methyl 2-(quinolin-6-yl)acetate as a clear brown oil (compound 1002, 696.8 g, 98% yield): ESMS (M+1), 202.14; 1H NMR (300.0 MHz, DMSO-d6) δ 8.90 (1H, dd, J=1.7, 4.2 Hz), 8.14-8.10 (1H, m), 8.08 (1H, d, J=8.7 Hz), 7.72 (1H, d, J=1.4 Hz), 7.65 (1H, dd, J=2.0, 8.7 Hz), 7.40 (1H, dd, J=4.2, 8.3 Hz), 3.83 (2H, s), 3.73 (3H, s).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[N:10]=[C:9]2[CH:11]=[CH:12][NH:13][C:8]2=[CH:7][CH:6]=1.[Br:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17]Br>CN(C)C=O>[Br:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][N:13]1[C:8]2[C:9](=[N:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[CH:11]=[CH:12]1
Reactant: COc1ccc2[nH]ccc2n1
Reactant: BrCc1ccccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2Cc2ccccc2Br)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon and in an anhydrous medium, 590 mg (14.75 mmol) of sodium hydride (60% in oil) are added slowly to a solution of 1.81 g (12.23 mmol) of the compound obtained in Step B in 50 ml of N,N-dimethylformamide at 0° C. After 30 minutes' stirring at room temperature, 2.27 ml (14.75 mmol) of 2-bromobenzyl bromide in 15 ml of N,N-dimethylformamide are added dropwise to the reaction mixture. Stirring is maintained at room temperature under argon for two hours. After hydrolysis and then extraction with ethyl acetate, the organic phase is washed several times with water, dried over magnesium sulphate, concentrated and purified by flash chromatography over silica gel (eluant: petroleum ether/ethyl acetate, 8:2) to yield the title compound in the form of a brown solid.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][C:12]=1[N+:19]([O-])=O)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[H][H]>CO.[Pd]>[CH2:7]([O:6][P:4]([CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][C:12]=1[NH2:19])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: [H][H]
Reactant: CCOP(=O)(COc1ccc(C=O)cc1[N+](=O)[O-])OCC
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(COc1ccc(CO)cc1N)OCC

Procedure:
A solution of 2-diethylphosphonomethyloxy-5-formylnitrobenzene (1 mmole) in methanol (5 mL) was treated with 10% palladium on carbon (0.05 mmole) under 1 atmosphere of hydrogen at room temperature for 12 h. Filtration followed by evaporation gave 2-diethylphosphonomethyloxy-5-hydroxymethylaniline which was subjected to Step B of Example 36 followed by Step D of Example 34 to give 2-amino-7-hydroxymethyl-6-thiocyanato-4-phosphonomethoxybenzothiazole (39.1). mp 181–184° C. Anal. Calcd. for C10H10N3O5PS2+0.35H2O: C, 33.97; H, 3.05; N, 11.88. Found: C, 33.76; H, 2.66; N, 11.61.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([OH:3])=[O:2].OS(O)(=O)=O.[CH2:18](O)[CH3:19]>>[CH2:18]([O:2][C:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)=[O:3])[CH3:19]
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc2cc[nH]c2c1
Reaction time: 4 h

Procedure:
Combine 6-carboxy-1H-indole and ethanol (110 ml) and cool to 5° C. Add dropwise concentrated H2SO4 (96%, 11.08 ml) while keeping the temperature below 10° C. Heat to reflux. After 4 hours, cool and pour onto ice/water, adjust the pH to about pH 9 and extract with ethyl acetate. Combine the organic extracts, wash with brine, dry Na2SO4), then concentrate to residue. Chromatograph the residue on silica gel eluting with chloroform to give, after evaporation, the title compound: mp 72-75° C. MS (ACPI): m/e 189.9 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[NH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20]>>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([N:15]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:10](=[O:11])[C:5]=12)=[O:9])([O-:3])=[O:2]
Reactant: NCCCC(=O)O
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Product: O=C(O)CCCN1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Yield: 78.8 %

Procedure:
3-nitrophthalic anhydride (0.5 g, 0.0026 mol) and 4-aminobutyric acid (0.268 g, 0.0026 mol) were refluxed as above overnight. The clear solution was purified as per 120 to yield 0.57 g (79%) 122 as a very pale orange powder: mp=144–146° C.; Rf 0.62 (A): Rf 0.87 (C): Rf 0.78(D): IR (cm−1): 3000–3250 (OH), 3219 (C═CH), 2953 (C—H), 1778 (C═O), 1716 (C═O), 1667 (C═O), 1615 (C═C), 1548 (N═O), 1442 (C═C), 1395 (C—O), 1355 (N═O), 1189 (C—O), 723 (C═CH); MS m/z (rel intensity) 313 (100), 278 (65), 277 (42), 191 (71).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][C:8]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:13][OH:14])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.Cl.[OH2:22]>>[CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][C:8]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([OH:22])=[O:14])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: CCCCCC(CO)c1ccc2c(c1)OCCC2(C)C
Reactant: O
Agent: Cl
Product: CCCCCC(C(=O)O)c1ccc2c(c1)OCCC2(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 50 %

Procedure:
A solution of 2-(4,4-dimethyl-chroman-7-yl)-heptan-1-ol (0.2 g, 0.72 mmol, from Example 5.1, Step 6) in 1.5 mL of CCL4 and 2.2 mL of water containing 4 mg RuCl3 was treated with 628 mg, 2.94 mmol of NaIO4. The mixture was stirred at room temperature for 2.5 h, diluted with 10 mL of water and the pH adjusted to 2 with 10% aqueous HCl. The mixture was extracted with dichloromethane, concentrated to dryness, and purified via flash chromatography (0-20% ethyl acetate/hexane gradient elution) to give 105 mg (50%) of 2-(4,4-dimethyl-chroman-7-yl)-heptanoic acid.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1Cl)=[CH:8][C:7]([Cl:14])=[CH:6][CH:5]=2.Cl>CN(C)C=O>[CH2:10]([O:13][C:2]1[C:3](=[O:15])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1[O:15][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:8][C:7]([Cl:14])=[CH:6][CH:5]=2)[CH2:9][CH2:8][CH3:7]
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2cc(Cl)ccc21
Agent: Cl
Solvent: CN(C)C=O
Product: CCCCOC1=C(OCCCC)C(=O)c2cc(Cl)ccc2C1=O
Yield: 68.2 %

Procedure:
To a solution of sodium-n-butoxide (25.8 g) in dry dimethylformamide (125 ml) was added 2,3,6-trichloro-1,4-naphthoquinone (28 g) in one amount. The mixture was refluxed for 2 hours, then cooled, acidified with 6 M hydrochloric acid and evaporated. The residue was chromatographed over silica gel using dichloromethane as eluant to yield 2,3-di-n-butoxy-6-chloro-1,4-naphthoquinone (12.3 g) as a red oily solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH2:5][N:4]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17].[C:29]([O:33][C:34]([NH:36][CH2:37][C:38](O)=[O:39])=[O:35])([CH3:32])([CH3:31])[CH3:30].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[Si:9]([O:8][C@H:6]1[CH2:5][N:4]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[O:17])[C@H:3]([CH2:2][NH:1][C:38]([CH2:37][NH:36][C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])=[O:39])[CH2:7]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CN)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)NC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 77.8 %

Procedure:
To a solution of (2S, 4R)-2-aminomethyl-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (8.43 g) in dichloromethane (80 ml) were added t-butoxycarbonylglycine (3.61 g), 1-hydroxybenzotriazole (2.78 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.95 g) under ice-cooling. The mixture was stirred under ice-cooling for 1 hour and at ambient temperature for 15 hours. The solution was washed with water (80 ml), saturated aqueous sodium hydrogen carbonate (80 ml), and brine (80 ml) successively, dried over magnesium sulfate, and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (80 g) and eluted with a mixture of methanol and chloroform (2:98 v/v) to give (2S, 4R)-4-t-butyldimethylsilyloxy-2-[(t-butoxycarbonylamino)methylcarbonyl]aminomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (9.07 g).
Reaction SMILES: C1(C)C=CC(S([O:10][CH2:11][CH:12]2[CH2:16][O:15][C:14](=[O:17])[NH:13]2)(=O)=O)=CC=1.[C:19]([O-])(=[S:21])[CH3:20].C([N+](CCCC)(CCCC)CCCC)CCC>CC(C)=O>[C:19]([O:10][CH2:11][CH:12]1[CH2:16][O:15][C:14](=[O:17])[NH:13]1)(=[S:21])[CH3:20]
Reactant: Cc1ccc(S(=O)(=O)OCC2COC(=O)N2)cc1
Reactant: CC([O-])=S
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC(C)=O
Product: CC(=S)OCC1COC(=O)N1
Yield: 75 %

Procedure:
A solution of 2-oxo-1,3-oxazolidin-4-ylmethyl p-toluenesulfonate (1.22 g., 0.0045 mole) and tetrabutylammonium thioacetate (1.71 g, 0.0054 mole) in 75 ml. acetone was refluxed under nitrogen for 90 min. The reaction mixture was concentrated to dryness and the residue was chromatographed on silica gel (250 g). Elution with 4:1 ethyl acetate-hexane yielded 580 mg. of the title compound (75% yield). NMR (CDCl3): 2.38 (s, 3H); 3.06 (d, 2H); 3.84-4.67 (c, 3H); and 6.3 (b, 1H)ppm.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH3:10][O:11][CH2:12][CH2:13][CH2:14]OS(C)(=O)=O>CN(C=O)C>[CH3:10][O:11][CH2:12][CH2:13][CH2:14][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: COCCCOS(C)(=O)=O
Reactant: O=Cc1cccc(O)c1
Solvent: CN(C)C=O
Product: COCCCOc1cccc(C=O)c1

Procedure:
Alkylation of 3-hydroxybenzaldehyde (11) with methanesulfonic acid 3-methoxypropyl ester following the method used in Example 34 except that the reaction solvent was DMF gave 3-(3-methoxypropoxy)benzaldehyde as a clear oil. Yield (1.32 g, 55%): 1H NMR (400 MHz, CDCl3) δ 9.97 (s, 1H), 7.40-7.47 (m, 3H), 7.15-7.20 (m, 1H), 4.12 (t, J=6.4 Hz, 2H), 3.56 (t, J=6.2 Hz, 2H), 3.35 (s, 3H), 2.05-2.11 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][O:18][CH3:19]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][CH2:17][O:18][CH3:19])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
To a solution of 4-bromophenol (646, 5.0 g, 28.9 mmol) in dimethylformamide (15 mL) were added potassium carbonate (4.40 g, 31.8 mmol) and 1-bromo-2-methoxyethane (5.00 g, 36.0 mmol) under an atmosphere of nitrogen. The reaction mixture was stirred at ambient temperature overnight and concentrated under reduced pressure. The residue was slurried in ethyl acetate (50 mL) and filtered. The filtrate was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and filtered. Silica gel column chromatography (0-10% ethyl acetate in hexanes) gave the desired compound as a colorless oil (647, 3.2 g, 48%).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:10]2[C:5](=[CH:6][C:7]([N+:22]([O-:24])=[O:23])=[C:8]([NH:11][C:12](=[O:21])[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:9]=2)[NH:4][C:3]1=[O:25].Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)=[O:29].CCN(CC)CC>C1(C)C=CC=CC=1>[N+:37]([C:34]1[CH:33]=[CH:32][C:31]([O:30][C:28]([N:4]2[C:5]3[C:10](=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]4[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=4)=[C:7]([N+:22]([O-:24])=[O:23])[CH:6]=3)[C:2]([CH3:26])([CH3:1])[C:3]2=[O:25])=[O:29])=[CH:36][CH:35]=1)([O-:39])=[O:38]
Reactant: COc1ccc(C(=O)Nc2cc3c(cc2[N+](=O)[O-])NC(=O)C3(C)C)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)Nc2cc3c(cc2[N+](=O)[O-])N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)C3(C)C)cc1

Procedure:
A solution of N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)4-methoxy-benzamide (200 mg), 4-nitrophenyl chloroformate (166 mg; 0.83 mmol) and NEt3 (0.2 ml) in dry toluene (3 ml) is stirred in a microwave apparatus at 150° C. for 800 s. The resulting precipitate is collected by filtration and washed with cold toluene. After drying under reduced pressure the compound (240 mg) is obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.[F:15][CH:16]([F:26])[C:17]1[NH:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Cl:8][C:6]1[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=[C:2]([N:18]2[C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=[C:17]2[CH:16]([F:15])[F:26])[N:7]=1
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Reactant: FC(F)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.6 %

Procedure:
11.8 g (50 mmol) of 2,4-dichloro-6-morpholino-1,3,5-triazine, 8.41 g (50 mmol) of 2-difluoromethyl-benzimidazole and 55.3 g (400 mmol) of anhydrous potassium carbonate added to DMF (250 ml) were stirred at room temperature for 16 hours. The reaction solution was poured into water and the resulting precipitates were washed with DMF and ethanol to obtain 15.7 g (yield: 86%) of 4-chloro-2-(2-difluoromethylbenzimidazol-1-yl)-6-morpholino-1,3,5-triazine. (2) 0.36 g (0.98 mmol) of the obtained 4-chloro-2-(2-difluoromethylbenzimidazol-1-yl)-6-morpholino-1,3,5-triazine, 0.16 g (1.0 mmol) of cis-2,3-dimethylmorpholine hydrochloride and 0.3 g (2.2 mmol) of anhydrous potassium carbonate added to DMF (10 ml) were stirred at room temperature for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate. The separated organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to obtain 0.38 g (yield: 87%) of the titled compound as colorless crystals.
Reaction SMILES: ClC1C=CC=CC=1[C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH3:16])=[CH:12][C:13]=2[CH3:15])[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[C:7]1[C:24]([O:26][CH3:27])=[O:25])=O.[OH-].[Na+].Cl>CO>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:8]1[C:9]2[C:14](=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[CH:10]=2)[N:6]([CH3:4])[C:7]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1c(-c2ccccc2Cl)c2cc(C)cc(C)c2n1C(=O)c1ccccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2Cl)c2cc(C)cc(C)c2n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.9 %

Procedure:
Methyl 1-(2-chlorobenzoyl)-3-(2-chlorophenyl)-5,7-dimethylindole-2-carboxylate (compound K) was obtained in the same manner as for compounds I and J in Reference Example 4. In 20 cc of methanol was dissolved 0.96 g of compound K, followed by adding thereto 4.2 cc of 2N sodium hydroxide, and the resulting mixture was heated under reflux for 2 hours. After cooling, the mixture was acidified with 2N HCl, followed by extraction with ethyl acetate. The extract was dried over magnesium sulfate and distilled to remove the solvent. The resulting crude product was dissolved in 2 cc of dimethylformamide, and 0.26 g of 63% sodium hydride in 1.5 cc of dimethylformamide was added at room temperature. The resulting mixture was stirred at room temperature for 30 minutes, and then 0.4 cc of methyl iodide was added dropwise and stirred for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was dried over magnesium sulfate and distilled to remove the solvent. The crude product thus obtained was washed with hexane to obtain 0.41 g of methyl 3-(2-chlorophenyl)-1,5,7-trimethylindole-2-carboxylate (compound L).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]([CH3:22])[S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)(=[O:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.[NH2:23][CH2:24][C:25]1[C:30]([CH2:31][CH3:32])=[N:29][C:28]2[N:33]([CH2:36][CH3:37])[N:34]=[CH:35][C:27]=2[C:26]=1[NH:38][CH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]([CH3:22])[S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([NH:23][CH2:24][C:25]2[C:26]([NH:38][CH:39]3[CH2:40][CH2:41][O:42][CH2:43][CH2:44]3)=[C:27]3[CH:35]=[N:34][N:33]([CH2:36][CH3:37])[C:28]3=[N:29][C:30]=2[CH2:31][CH3:32])=[O:18])(=[O:11])=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1cccc(Br)c1)S(=O)(=O)c1cccc(C(=O)O)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(S(=O)(=O)N(C)Cc2cccc(Br)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
To 3-{[[(3-bromophenyl)methyl](methyl)amino]sulfonyl}benzoic acid (150 mg, 0.390 mmol) in DCM 7.8 mL) was added 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (133 mg, 0.390 mmol), HBTU (163 mg, 0.429 mmol), and TEA (0.163 mL, 1.171 mmol). This mixture was stirred at room temperature for 2 h. The reaction mixture was washed with H2O (2×3 mL), dried over Na2SO4, filtered, and concentrated. The crude product was further purified by CombiFlash flash chromatograph to afford the title compound (0.2453 mg, 94%). LC-MS m/z 669 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[CH3:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][C:18](=[O:24])[NH:19]2>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=[C:17]1[C:16]2[C:20](=[CH:21][CH:22]=[CH:23][C:15]=2[CH3:14])[NH:19][C:18]1=[O:24])([CH3:3])[CH3:2]
Reactant: Cc1cccc2c1CC(=O)N2
Reactant: COc1ccc(C=O)cc1C(C)C
Product: COc1ccc(C=C2C(=O)Nc3cccc(C)c32)cc1C(C)C

Procedure:
3-Isopropyl-4-methoxybenzaldehyde was condensed with 4-methyl-2-oxindole to give 0.25 g of 3-(3-isopropyl-4-methoxybenzylidene)-4-methyl-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[O:19][CH3:18])[CH:9]=2)=[O:4]
Reactant: COc1ccccc1B(O)O
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Product: COC(=O)c1c(O)c2ccc(-c3ccccc3OC)cc2sc1=O

Procedure:
4-Hydroxy-7-(2-methoxy-phenyl)-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5 e) and 2-methoxyphenylboronic acid under conditions analogous to Example 7(a). MS ESI(−) m/e: 341.07 (M−1).