Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NCCCC[C@H](NC(=O)N[C@H:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])C(OC(C)(C)C)=O.CC(O)=O.C(C1N(CC(OC(C)(C)C)=O)C=CN=1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[C:26]([O:25][C:23](=[O:24])[CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)[C@H](CCCCN)NC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)OC(=O)Cn1ccnc1C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)CCCC(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 227.7 %

Procedure:
A solution of (S)-4-(3-((S)-6-amino-1-tert-butoxy-1-oxohexan-2-yl)ureido)-5-tert-butoxy-5-oxopentanoic acid (432 mg, 70% pure, 0.70 mmol), AcOH (0.10 mL) and tert-butyl 2-(2-formyl-1H-imidazol-1-yl)acetate (470 mg, 2.0 mmol) in DCE (20 mL) was stirred at 75° C. for 30 min under nitrogen. The reaction mixture was cooled to 0° C., and treated with NaBH(OAc)3 (0.633 g, 3.0 mmol). The reaction was allowed to proceed overnight with stirring at room temperature. The reaction mixture was quenched with water and concentrated under reduced pressure to afford a residue which was purified by on a Biotage SP4 utilizing a gradient of 5-50% MeOH in DCM to afford (S)-4-(34(S)-6-(bis((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)-1-tert-butoxy-1-oxohexan-2-yl)ureido)-5-tert-butoxy-5-oxopentanoic acid (300 mg, 52%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 6.99 (s, 2H), 6.84 (s, 2H), 4.57 (s, 4H), 4.29-4.19 (m, 2H), 3.66-3.56 (m, 4H), 2.98-2.90 (m, 2H), 2.49-2.37 (m, 4H), 1.95-1.41 (m, 42H); ESMS m/z: 410.8 (M/2+H)+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=2)[CH2:2]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:46][CH2:47][C:48]1[C:49]([OH:56])=[N:50][C:51]([CH3:55])=[CH:52][C:53]=1[CH3:54]>ClCCl>[OH:56][C:49]1[C:48]([CH2:47][NH:46][C:10](=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([CH:3]3[CH2:4][CH2:5][O:1][CH2:2]3)=[CH:14][CH:13]=2)=[C:53]([CH3:54])[CH:52]=[C:51]([CH3:55])[N:50]=1
Reactant: O=C(O)c1ccc(C2CCOC2)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C3CCOC3)cc2)c(O)n1
Reaction time: 0.5 h
Yield: 26.8 %

Procedure:
To a solution of 4-(tetrahydrofuran-3-yl)benzoic acid (100 mg, 0.52 mmol) in dichloromethane (20 mL) was added 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (35 mg, 0.5 mmol), triethylamine (32 mg, 0.7 mmol). The mixture was stirred for 0.5 hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (27 mg, 0.4 mmol) was added and the mixture was stirred at room temperature for 12 hours. The mixture was washed with water (50 mL), the organic layer was concentrated. The residue was purified by preparative-HPLC to give Compound I-83 as a white solid (35 mg, 21%). LRMS (M+H+) m/z: calcd 326.16. found 326. 1H NMR (300 MHz, CD3OD): δ 7.75 (d, J=6 Hz, 2H), 7.36 (d, J=6 Hz, 2H), 6.10 (s, 1H), 4.48 (s, 2H), 4.06 (m, 2H), 4.03 (m, 1H), 3.88 (m, 1H), 3.70 (m, 1H), 2.37 (s, 3H), 2.35 (s, 3H), 2.00 (m, 2H).
Reaction SMILES: O.[OH:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7](O)[C:8]([O-])=O)=[CH:5][CH:4]=1.[Na+].[Cl-].[Na+].[C-]#[N:18].[Na+].O>CN(C)C=O.C(O)=O>[OH:2][C:3]1[CH:13]=[CH:12][C:6]([CH2:7][C:8]#[N:18])=[CH:5][CH:4]=1
Reactant: O=C([O-])C(O)c1ccc(O)cc1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: O=CO
Solvent: CN(C)C=O
Product: N#CCc1ccc(O)cc1
Temperature: 135 °C

Procedure:
A stirred suspension of sodium p-hydroxymandelate monohydrate (50 g. of 77% w/w material, the impurity being sodium chloride) and sodium cyanide (12.5 g.) in N,N-dimethylformamide (67.5 ml.) is heated at 135° C. for 2 hours and then cooled. Water (200 ml.) and formic acid (20 ml.) are added and the mixture is extracted twice with methyl isobutyl ketone (200 ml. and 100 ml.). The combined extracts are washed twice with water (50 ml. each time) and are then concentrated by evaporation. There is thus obtained a solution of p-hydroxybenzyl cyanide in methyl isobutyl ketone which is suitable for conversion to p-hydroxyphenylacetamide without further purification.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:14]([CH:16]1[O:18][CH2:17]1)Br>CN(C)C=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:14][CH:16]2[CH2:17][O:18]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCC1CO1
Reactant: OCCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(CCCCOCC2CO2)cc1

Procedure:
A procedure similar to that described in Preparation 46 was repeated, except that 5.00 g of 4-phenyl-1-butanol, 1.58 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 3.9 ml of epibromohydrin and 110 ml of anhydrous dimethylformamide were used. The resulting crude product was purified by silica gel column chromatography, using an 8:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 3.83 g of the title compound as a colorless oil having an Rf value of 0.77 (on silica gel thin layer chromatography, using a 2:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:15][O:16][C:17](Cl)=[O:18].O>C(Cl)Cl>[CH3:15][O:16][C:17]([N:5]1[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]1)=[O:18]
Reactant: CC1CCNCC1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)N1CCC(C)CC1
Reaction time: 8 h

Procedure:
To a three neck round bottom flask was added 360 g of 4-methylpiperdine, 470 mL of triethylamine, and 390 mL of methylene chloride and the mixture was cooled in an ice bath. To this mixture was added methylchloroformate (260 mL) in methylene chloride (215 mL) slowly to maintain a reaction temperature of 20 C or below. The reaction was stirred overnight, then 200 mL of water was added and the layers were separated. The organic layer was washed with dilute HCl, satd. NaHCO3, and brine, and then the organic layer was dried over sodium sulfate and the solvent was removed in vacuo. The product was distilled at 90-93 C at ˜10 mm pressure to provide 338 g of product.
Reaction SMILES: [CH:1]([N:4]1[C:9]2[N:10]=[C:11]([S:15][CH3:16])[N:12]=[C:13]([CH3:14])[C:8]=2[CH:7]=[CH:6][C:5]1=[O:17])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:26])C=1.[OH2:29]>C(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>[CH:1]([N:4]1[C:9]2[N:10]=[C:11]([S:15]([CH3:16])(=[O:26])=[O:29])[N:12]=[C:13]([CH3:14])[C:8]=2[CH:7]=[CH:6][C:5]1=[O:17])([CH3:3])[CH3:2]
Reactant: CSc1nc(C)c2ccc(=O)n(C(C)C)c2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1nc(S(C)(=O)=O)nc2c1ccc(=O)n2C(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99 %

Procedure:
8-Isopropyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (5.38 g, 21.59 mmol) was dissolved in 100 mL DCM. To the stirring solution, m-CPBA (13.97 g, 64.78 mmol) was added. The reaction was allowed to stir for 2.5 h at room temperature. LCMS indicated reaction had gone to completion. Sample was diluted with 300 mL of DCM and 300 mL K2CO3, upon addition of base a white precipitate formed that dissolved in excess H2O. Organic layer was extracted further with H2O and brine, and then dried over Na2CO3. The solvent was evaporated to afford 8-isopropyl-4-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (6.0 g, 99% yield) as a light yellow oil that was used immediately in the next reaction.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:14])[CH:3]=1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:23]1([SH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1CCCCC1>C(O)(=O)C.C(O)C>[OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:5][C:4](=[O:14])[C:3]=1[CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[S:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Sc1ccccc1
Reactant: O=c1cc(O)cc(-c2ccccc2)o1
Reactant: O=Cc1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Solvent: C1CCNCC1
Product: O=c1oc(-c2ccccc2)cc(O)c1C(Sc1ccccc1)c1ccccc1

Procedure:
The title compound was prepared by Method E using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL), benzaldehyde (0.593 mL, 5.84 mmol), thiophenol (1.40 mL, 13.8 mmol), piperdine (0.5 mL), acetic acid (0.5 mL). m.p. dec. >220° C.; 1H NMR (400 MHz, DMSO-d6) δ5.80 (s, 1 H), 6.70 (s, 1 H), 7.23 (m, 8H), 7.54 (m, 4 H), 7.74 (m, 2 H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[CH2:12]=[C:13]1[O:17][C:15](=O)[CH2:14]1.C(OC(=O)C)(=O)C>C(Cl)(Cl)(Cl)Cl>[CH2:14]([C:15]1[O:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=2[N:11]=1)[C:13]([CH3:12])=[O:17]
Reactant: Cc1ccc(C(=O)O)c(N)c1
Reactant: C=C1CC(=O)O1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Cc1nc2cc(C)ccc2c(=O)o1
Yield: 47.1 %

Procedure:
A mixture of 4-methylanthranilic acid (25.0 g., 0.17 mole) and diketene (13.95 g., 0.17 mole) in CCl4 (250 ml.) was heated at reflux for 2.5 hours. Acetic anhydride (18.3 g., 0.18 mole) was added and the mixture was stirred under reflux for 16 hours. The mixture then was cooled and the product isolated by filtration; upon recrystallization there was obtained 2-acetonyl-7-methyl-4H-3,1-benzoxazin-4-one (17.4 g., 48 percent), mp 142°-144° C.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.Br[CH2:12][CH2:13][CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:12]([O:10][C:3]1[CH:4]=[CH:5][C:6]([N+:7]([O-:9])=[O:8])=[CH:1][CH:2]=1)=[CH:13][CH2:14][CH3:15]
Reactant: C=CCCBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC=COc1ccc([N+](=O)[O-])cc1
Reaction time: 48 h

Procedure:
A 500 ml flask equipped with a mechanical stirrer, condenser, thermometer, and heating mantle was charged with p-nitrophenol (30.0 g, 216 mmol), 4-bromo-1-butene (29.1 g, 216 mmol), potassium carbonate (32.8 g, 237 mmol) and DMF (300 ml). The reaction mixture was heated to reflux and stirred for 48 hours. It was then cooled and solvent removed under reduced pressure. The residue was dissolved in 250 ml of methylene chloride and washed repeatedly with water to remove traces of DMF. The methylene chloride layer was dried (MgSO4), filtered, and solvent removed under reduced pressure. The product was used without further purification for the next step. Yield=7.0 g (17%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[CH2:12][C:13](=[O:26])[N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:16][CH2:15]1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[C:39]([O:47][C:48]([F:51])([F:50])[F:49])[CH:38]=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:43]([C:40]1[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[CH:38][C:39]=1[O:47][C:48]([F:49])([F:50])[F:51])(=[O:45])=[O:44])[C:6](=[O:11])[C:5]2([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[CH2:12][C:13](=[O:26])[N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15]1
Reactant: COc1ccccc1C1(CC(=O)N2CCN(c3ccncc3)CC2)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(CC(=O)N3CCN(c4ccncc4)CC3)(c3ccccc3OC)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Product: Cl

Procedure:
With 300 mg of 5-chloro-3-(2-methoxyphenyl)-3-[2-oxo-2-(4-pyridin-4-yl piperazin-1-yl)ethyl]-1,3-dihydro-2H-indol-2-one, which is the compound described in Example 1A of the brochure Publication No. WO03/008407, and 201 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 382 mg of a free form of the title compound (pale yellow amorphous) was obtained by a similar method to Example 2. To a solution of 360 mg of the obtained free form in CHCl3 (10 ml) was added a solution of 4 mol/L hydrochloric acid/EtOAc (0.62 ml), and the reaction mixture was stirred at room temperature for 3 hours. Thereafter, the solvent was evaporated under reduced pressure, IPA (5 ml) was added to the obtained residue, then the mixture stirred for 30 minutes while heating at 90° C. external temperature, then, the mixture was stirred at room temperature for 62 hours. The precipitated solid was collected by filtration to obtain 375 mg of the title compound (colorless solid).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH:6]([C@H:19]1[CH2:24][C@H:23]([OH:25])[CH2:22][CH2:21][O:20]1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:6]([C@H:19]1[CH2:24][C@H:23]([O:25][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:22][CH2:21][O:20]1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: O[C@@H]1CCO[C@@H](C(c2ccccc2)c2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O[C@@H]1CCO[C@@H](C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
Methanesulfonyl chloride (0.62 g, 5.41 mmol) in dry methylene chloride (10 ml) was added dropwise to a mixture of trans-2-diphenylmethyl-4-hydroxypyran 3a (0.73 g, 2.70 mmol), triethylamine (0.41 g, 4.06 mmol) in methylene chloride (10 ml) and was cooled to 0° C. After one hour, the reaction was gradually allowed to reach room temperature over a period of four hours. Additional methylene chloride (20 ml) was added to the reaction mixture, and the mixture was washed in turn with saturated aqueous sodium bicarbonate, brine and water, then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and purification by flash chromatography gave compound 4a (0.93 g, 99.9% yield) as an oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:21])[C:13]([NH:15][N:16]=[CH:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH3:2].[CH3:22]N(C=O)C.[C:27](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>C1(C)C=CC=CC=1.O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:21])[C:13]([N:15]([CH3:22])[N:16]=[CH:17][CH:18]([CH3:19])[CH3:20])=[O:14])[CH3:2].[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:21])[C:13](=[N:15][N:16]=[CH:17][CH:18]([CH3:19])[CH3:20])[O:14][CH3:27])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)NN=CC(C)C
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COS(=O)(=O)OC
Solvent: Cc1ccccc1
Product: CCc1cc(C)cc(CC)c1C(=O)C(=NN=CC(C)C)OC
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=CC(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a 50 mL volume three-necked flask, 5.0 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-2-(2-methyl-1-propylidene)hydrazine ((40-a)-(14)-4), 16 ml of DMF, 7.19 g of potassium carbonate and 2.13 ml of dimethyl sulfate were added and the mixture was stirred at room temperature for 2.5 hours. Water and toluene were added to the reaction mixture and the resultant was extracted. Further, aqueous layer was extracted with toluene two times. The organic layers were combined and washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resultant was subjected to column chromatography (hexane:ethyl acetate=6:1 to 2:1) to give 3.04 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(2-methyl-1-propylidene)hydrazine ((40-b)-(15)-4) and 0.74 g of methyl 2-(2,6-diethyl-4-methylphenyl)-N-(2-methyl-1-propylidene)-2-oxoethanehydrazonate (x-2).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([CH3:17])[C:8]([C:12](=O)[CH2:13][C:14]#[N:15])=[N:9]2)=[CH:4][CH:3]=1.O.[NH2:19][NH2:20]>C(O)C.C(O)(=O)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([CH3:17])[C:8]([C:12]3[CH:13]=[C:14]([NH2:15])[NH:20][N:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: Cc1nc2ccc(F)cc2nc1C(=O)CC#N
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1nc2ccc(F)cc2nc1-c1cc(N)[nH]n1

Procedure:
To a suspension of 3-(7-fluoro-3-methylquinoxalin-2-yl)-3-oxopropanenitrile (48.6 g, 212 mmol) in ethanol (530 mL) and acetic acid (53 mL) was added hydrazine hydrate (79%, 19.6 mL, 318 mmol). The reaction mixture was reflux for 5 h, and then concentrated in vacuo. The residue was triturated with water and diisopropyl ether subsequently to give 3-(7-fluoro-3-methylquinoxalin-2-yl)-1H-pyrazol-5-amine. MS (APCI): m/z 244 (M+H).
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[CH:13][C:14]([CH3:27])=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][C:22]([CH2:25]Cl)=[CH:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].[C:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:30])[CH3:29].[C:37](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:28]([N:31]1[CH2:36][CH2:35][N:34]([CH2:25][C:22]2[S:21][C:20]([C:17]3[NH:18][C:19]4[C:15]([CH:16]=3)=[C:14]([CH3:27])[CH:13]=[CH:12][C:11]=4[N:2]([CH2:1][CH3:37])[S:3]([C:6]3[S:7][CH:8]=[CH:9][CH:10]=3)(=[O:5])=[O:4])=[N:24][CH:23]=2)[CH2:33][CH2:32]1)(=[O:30])[CH3:29]
Reactant: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(-c3ncc(CCl)s3)cc12
Reactant: CC(=O)N1CCNCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(c1ccc(C)c2cc(-c3ncc(CN4CCN(C(C)=O)CC4)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.1 %

Procedure:
To a solution of N-methyl-N-{2-[5-(chloromethyl)-1,3-thiazol-2-yl]-4-methyl-1H-indol-7-yl}thiophene-2-sulfonamide (0.20 g) and N-acetylpiperazine (0.11 g) in N,N-dimethylformamide (10 ml) was added potassium carbonate (0.14 g) under ice-cooling, and the mixture was stirred at room temperature for 18 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to basic silica gel column chromatography (ethyl acetate:hexane=3:7-6:4), and the obtained colorless crystals was recrystallized from ethyl acetate-hexane to give the title compound (112 mg, yield 47%) as colorless crystals. melting point 157-158° C.
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].C1C2NC3C(=CC=CC=3)SC=2C=CC=1.[C:20]1([CH3:27])[C:25]([OH:26])=[CH:24][CH:23]=[CH:22][CH:21]=1.P(=O)(O)(O)O>C1(C)C(C)=CC=CC=1.O>[CH3:4][C:3]1([CH3:5])[C:23]2[C:22](=[CH:21][C:20]([CH3:27])=[C:25]([OH:26])[CH:24]=2)[CH2:1][CH2:2]1.[CH3:4][C:3]1([CH3:5])[C:21]2[C:22](=[CH:23][CH:24]=[C:25]([OH:26])[C:20]=2[CH3:27])[CH2:1][CH2:2]1
Reactant: Cc1ccccc1O
Reactant: C=CC(=C)C
Agent: O=P(O)(O)O
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: Cc1ccccc1C
Solvent: O
Product: Cc1c(O)ccc2c1C(C)(C)CC2
Product: Cc1cc2c(cc1O)C(C)(C)CC2
Reaction time: 8 h

Procedure:
370 g of isoprene, stabilized with 1 g of phenothiazine, were added dropwise over the course of 6 hours to a solution of 535 g of o-cresol, 63 g of 85% strength phosphoric acid and 5 ml of water in 1.2 liters of xylene at 110° C. To complete the reaction, stirring was continued overnight at 110° C. The acid phase was separated off and extracted with toluene. The combined organic phases were washed until neutral. Fractional distillation gave 270 g of 3,3,6-trimethyl-5-hydroxy-indane (boiling point: 142°-143° C/12 mm Hg; melting point: 70° - 71° C) and 179 g of 3,3,4-trimethyl-5-hydroxy-indane (boiling point: 146° C/12 mm Hg; melting point 92° - 93° C). ##STR33##
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=2)[C:10]([C:22]([OH:24])=O)=[C:9]1[CH:25]([CH3:27])[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.[F:32][C:33]1[CH:34]=[C:35]([CH2:39][NH2:40])[CH:36]=[N:37][CH:38]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=2)[C:10]([C:22](=[O:24])[NH:40][CH2:39][C:35]2[CH:36]=[N:37][CH:38]=[C:33]([F:32])[CH:34]=2)=[C:9]1[CH:25]([CH3:27])[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc2c(C(=O)O)c(C(C)C)n(Cc3ccccc3)c2c1
Reactant: NCc1cncc(F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(C(=O)NCc3cncc(F)c3)c(C(C)C)n(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Following General Procedure E, 1-benzyl-6-(ethoxylcarbonyl)-2-isopropyl-1H-indole-3-carboxylic acid (Compound 39, 93 mg, 0.254 mmol) in CH2Cl2 (6 ml) was added EDC (97 mg, 0.508 mmol) and DMAP (46 mg, 0.381mmol), followed by (5-fluoropyridin-3-yl)methanamine (81 mg, 0.63 mmol). The reaction was stirred at room temperature for 12 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→80% EtOAc-hexanes) to yield the title compound as a yellow solid.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].[CH2:15](N(CC)CC)C>ClCCl.CN(C)C=O>[CH:8]([O:5][CH:1]([CH3:2])[CH3:15])([CH3:13])[CH3:9].[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH-:14]
Reactant: Nc1ccccc1N
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)OC(C)C
Product: [NH-]c1ccccc1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a 50 ml three-necked flask, place 1.615 g of 7-nitro-9-oxo-9H-fluorene-4-carboxylic acid, which can be obtained according to WO2003057145, in suspension in 30 ml of dichloromethane, and then add successively 567 μl of oxalyl chloride and 1 drop of dimethylformamide. After stirring for 4 hours at room temperature, add 0.779 g of 1,2-diaminobenzene and 1.686 ml of triethylamine. After stirring for 20 hours at room temperature, the precipitate that formed is filtered off, and washed with water, then with a 10% saturated aqueous solution of sodium hydrogen carbonate and, finally, with water. After formation of a paste with diisopropyl ether, in this way we obtain 1.6 g of (2-aminophenyl)amide of 7-nitro-9-oxo-9H-fluoren -4-carboxylic acid, in the form of an orange powder, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[C:12]3[N:13]([N:18]=[C:19]([NH:21][CH:22]4[CH2:27][CH2:26][N:25]([C:28]5[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30][N:29]=5)[CH2:24][CH2:23]4)[N:20]=3)[CH:14]=[C:15]([CH3:17])[CH:16]=2)[CH:8]=[CH:9][CH:10]=1.C(N(CC)C(C)C)(C)C.Cl[C:45]([O:47][CH2:48][CH3:49])=[O:46]>ClCCl>[CH3:17][C:15]1[CH:16]=[C:11]([C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[CH2:4][NH:3][C:45](=[O:46])[O:47][CH2:48][CH3:49])[C:12]2[N:13]([N:18]=[C:19]([NH:21][CH:22]3[CH2:23][CH2:24][N:25]([C:28]4[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30][N:29]=4)[CH2:26][CH2:27]3)[N:20]=2)[CH:14]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1cc(-c2cccc(CN)c2)c2nc(NC3CCN(c4cc(C)ncn4)CC3)nn2c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)NCc1cccc(-c2cc(C)cn3nc(NC4CCN(c5cc(C)ncn5)CC4)nc23)c1
Temperature: 25 °C

Procedure:
To a suspension of 8-(3-(aminomethyl)phenyl)-6-methyl-N-(1-(6-methylpyrimidin-4-yl)piperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine dihydrochloride (37 mg, 73.8 μmol) in dichloromethane (0.75 mL) was added N,N-diisopropylethylamine (38.1 mg, 51.5 μL, 295 mmol). To the resulting yellow solution was added ethyl chloroformate (8.99 mg, 7.89 μL, 81.2 mmol) and the reaction was stirred at room temperature over night. The title compound was obtained as a light yellow solid (35 mg, 95%) after column chromatography on silica gel using a gradient from methylene chloride to a mixture of methylene chloride/methanol 19:1 (v/v) as eluent. MS ISP (m/e): 501.2 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): (ppm)=8.51 (s, 1H), 8.13 (s, 1H), 7.83 (br s, 2H), 7.44 (t, 1H), 7.36 (s, 1H), 7.33 (d, 1H), 6.41 (s, 1H), 5.08 (br m, 1H), 4.53 (br d, 1H), 4.44 (d, 2H), 4.32 (br d, 2H), 4.15 (q, 2H), 3.96 (m, 1H), 3.69 (m, 1H), 3.20 (t, 2H), 3.10 (m, 1H), 2.40 (s, 3H), 2.38 (s, 3H), 2.22 (br d, 2H), 1.25 (t, 3H).