Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2.O1CCCC1.[C:24]([C@H:28]1[CH2:33][CH2:32][C@H:31](O)[CH2:30][CH2:29]1)([CH3:27])([CH3:26])[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[C:24]([C@@H:28]1[CH2:33][CH2:32][C@H:31]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([C@:12]2([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]2)[CH:6]=[CH:5]3)[CH2:30][CH2:29]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[C@H]1CC[C@H](O)CC1
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[C@H]1CC[C@@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1

Procedure:
(R)-4-(6-Hydroxy-naphthalen-2-yl)-4-methyl-oxazolidin-2-one (0.0575 g, 0.000236 mol;) was dissolved in tetrahydrofuran (3.00 mL, 0.0370 mol) in a capped 40 mL reaction vial equipped with a magnetic stir bar. trans 4-tert-Butyl-cyclohexanol (0.0443 g, 0.000284 mol) was added, followed by triphenylphosphine (0.0992 g, 0.000378 mol;) and the mixture was heated to reflux. diisopropyl azodicarboxylate (0.0745 mL, 0.000378 mol) was then added and the reaction mixture was heated at reflux overnight. TLC analysis showed that the reaction was complete. The stir bar was removed and the mixture was concentrated via Genevac. The resulting product was purified by flash chromatography (20-30% EtOAc in methylene chloride) to give 0.0446 g of the title compound (49% yield).
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([OH:13])=[C:7]([C:14](=[O:16])[CH3:15])[C:6]=1[CH2:17][CH3:18])(=[O:3])[CH3:2].[C:19]1(=O)[CH2:22][CH2:21][CH2:20]1.N1CCCC1>C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[C:6]([CH2:17][CH3:18])=[C:7]2[C:8](=[C:9]([CH3:12])[C:10]=1[CH3:11])[O:13][C:19]1([CH2:22][CH2:21][CH2:20]1)[CH2:15][C:14]2=[O:16])(=[O:3])[CH3:2]
Reactant: CCc1c(OC(C)=O)c(C)c(C)c(O)c1C(C)=O
Reactant: O=C1CCC1
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: CCc1c(OC(C)=O)c(C)c(C)c2c1C(=O)CC1(CCC1)O2

Procedure:
To a solution of 3-acetyl-2-ethyl-4-hydroxy-5,6-dimethylphenyl acetate (3.5 g) in 20 mL of toluene was added cyclobutanone (1.16 mL) and pyrrolidine (1.4 mL). The reaction was allowed to reflux for 2 hours and Dean-Stark apparatus was used to remove water from the reaction. After the reaction was complete, the mixture was extracted with ethyl acetate and then was washed with 1N HCl and water. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give 5-ethyl-7,8-dimethyl-4-oxo-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-yl acetate, which was hydrolyzed in 1N NaOH in MeOH/water. After the reaction was complete as indicated by TLC, the mixture was acidified with 1N HCl and extracted with ethyl acetate and dried over anhydrous Na2SO4. Evaporation of the solvents gave 0.8 g of 5-ethyl-6-hydroxy-7,8-dimethylspiro[chromene-2,1′-cyclobutan]-4(3H)-one as a yellow paste.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5][N:4]=1.[OH-].[NH4+].[CH:18](O)=[O:19]>>[CH:18]([NH:1][CH2:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5][N:4]=1)=[O:19]
Reactant: O=CO
Reactant: COC(=O)CCCc1ccnc(CN)c1
Agent: [NH4+]
Agent: [OH-]
Product: COC(=O)CCCc1ccnc(CNC=O)c1
Temperature: 25 °C

Procedure:
2-Aminomethyl-4-(3-methoxycarbonylpropyl)pyridine (0.11 g) is heated at 90° in 0.5 ml of 97% formic acid for 18 hours. The reaction is cooled to room temperature, made basic with ammonium hydroxide solution and extracted with methylene chloride (4×20 ml). The organic extracts are dried over sodium sulfate and evaporated to yield 2-(N-formylaminomethyl)-4-(3-methoxycarbonylpropyl)pyridine; IR (CH2Cl2) 1735, 1685 cm-1.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.CC1(C)C(C)(C)OB([C:23]2[O:27][C:26]([Si](C(C)C)(C(C)C)C(C)C)=[N:25][CH:24]=2)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.[Cl-].[NH4+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:12][C:11]([F:14])([F:13])[C:9]1[CH:8]=[C:7]2[C:3]([CH:4]=[CH:5][NH:6]2)=[C:2]([C:23]2[O:27][CH:26]=[N:25][CH:24]=2)[CH:10]=1
Reactant: FC(F)(F)c1cc(Br)c2cc[nH]c2c1
Reactant: CC(C)[Si](c1ncc(B2OC(C)(C)C(C)(C)O2)o1)(C(C)C)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: COCCOC
Product: FC(F)(F)c1cc(-c2cnco2)c2cc[nH]c2c1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
A mixture of 4-bromo-6-(trifluoromethyl)-1H-indole (300 mg), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triisopropylsilyl)oxazole (422 mg), tetrakis(triphenylphosphine)palladium(0) (131 mg) and potassium carbonate (314 mg) in DME/water (3/0.5 mL) was stirred with microwave irradiation at 120° C. for 30 min. The reaction mixture was diluted with saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in THF (5 mL), 1N hydrochloric acid (2 mL) was added thereto, and the mixture was stirred overnight at room temperature. To the reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (174 mg).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH2:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([Br:14])=[CH:9][CH:8]=2.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(OCC)C>[Br:14][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH2:6][C:5]([CH2:4][CH2:3][OH:2])=[CH:13]2
Reactant: COC(=O)CC1=Cc2cc(Br)ccc2C1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: OCCC1=Cc2cc(Br)ccc2C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The product from Example 52C (1.1 g, 4.1 mmol) in diethyl ether (5 mL) was added dropwise to a suspension of lithium aluminum hydride (0.125 g, 3.3 mmol) in diethyl ether (10 mL) maintaining the internal temperature below 10° C. After stirring for 30 minutes, the reaction mixture was diluted with diethyl ether (10 mL), cooled to 0° C., and treated with saturated aqueous sodium sulfate dropwise. The ethereal solution was decanted, dried with sodium sulfate, filtered, and the filtrate was concentrated to provide the title compound which was used without further purification in the next step. 1H NMR (CDCl3) δ 2.77 (m, 2H); 3.32 (s, 2H); 3.88 (t, J=6.5 Hz, 2H); 6.56 (m, 1H), 7.23 (m, 2H); 7.40 (m, 1H).
Reaction SMILES: [C:1]1([C:11]([OH:13])=O)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:14]([O:16][C:17]([C:19]1([NH2:29])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([F:28])[CH:25]=2)[CH2:20]1)=[O:18])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:14]([O:16][C:17]([C:19]1([NH:29][C:11]([C:1]2[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[CH:4]=[CH:3][CH:2]=2)=[O:13])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([F:28])[CH:25]=2)[CH2:20]1)=[O:18])[CH3:15]
Reactant: O=C(O)c1cccc2c1CCCC2
Reactant: CCOC(=O)C1(N)Cc2ccc(F)cc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc3c2CCCC3)Cc2ccc(F)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.8 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-naphthalene-1-carboxylic acid (400 mg, 2.27 mmol), 2-amino-5-fluoro-indan-2-carboxylic acid ethyl ester (610 mg, 2.72 mmol), HATU (1.30 g, 3.41 mmol) in anhydrous DMF (15 mL) is added DIPEA (563 μL, 3.41 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (70 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5%-40% EtOAc in heptane) to give a pure product (86) as white solid (345 mg, 40%).
Reaction SMILES: [F:1][C:2]1[C:3]([CH:9]=[O:10])=[N:4][CH:5]=[CH:6][C:7]=1[F:8].[BH4-].[Na+]>C(O)C>[F:1][C:2]1[C:3]([CH2:9][OH:10])=[N:4][CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=Cc1nccc(F)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1nccc(F)c1F
Reaction time: 1 h
Yield: 97.3 %

Procedure:
Intermediate 5 (142 mg, 0.992 mmol) was dissolved in ethanol (5 mL) under N2(g) atmosphere. Sodium borohydride (ALDRICH, 113 mg, 2.98 mmol) was added and mixture of reaction was stirred for 1 hour. Crude of reaction was partitioned between DCM (15 mL) and distilled water (15 mL). Aqueous layer was extracted with DCM (2×15 mL). Organic layers were dried over MgSO4(anh), filtered and concentrated to yield title compound (3,4-difluoro-2-pyridinyl)methanol (140 mg, 0.965 mmol, 97% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.37-8.40 (m, 1H), 7.50-7.55 (m, 1H), 5.45 (t, 1H), 4.61-4.63 (m, 2H). [ES+MS] m/z 146 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].Cl[CH2:11][C:12]1[N:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][CH2:11][C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[C:2]([CH:7]=1)[NH2:1]
Reactant: ClCc1ncccn1
Reactant: Nc1cc(Cl)ccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(Cl)ccc1SCc1ncccn1
Yield: 50.8 %

Procedure:
Following General Procedure A, the title compound (284 mg, 39%) was prepared from 2-amino-4-chlorobenzenethiol (529 mg, 3.33 mmol), 2-(chloromethyl)pyrimidine (366 mg, 2.22 mmol) and K2CO3 (1.53 g, 11.09 mmol) in DMF (10 ml).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[N:18][S:19]([CH:22]=[CH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:21])=[O:20])=[C:9]1[CH3:30])([CH3:4])([CH3:3])[CH3:2].C[Al](C)C.[CH:36]([Mg]Br)=[CH2:37]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:31])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]([NH:18][S:19]([CH:22]=[CH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:21])=[O:20])[CH:36]=[CH2:37])=[C:9]1[CH3:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[Mg]Br
Reactant: Cc1c(C=NS(=O)(=O)C=Cc2ccccc2)c2ccccc2n1CC(=O)OC(C)(C)C
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: C=CC(NS(=O)(=O)C=Cc1ccccc1)c1c(C)n(CC(=O)OC(C)(C)C)c2ccccc12
Temperature: 0 °C

Procedure:
The product of step b) (2.2 g, 5 mmol) was treated with 100 mL toluene. The slurry was stirred at 0° C. and treated with Me3Al (3.8 mL of 2 M in toluene) followed by vinyl magnesium bromide (10 mL of 1 M). The reaction was warmed to rt and stirred for 10 minutes. The reaction was cooled to 0° C., quenched with aqueous acetic acid, and partitioned between water and EtOAc (200 mL each). The organic layer was washed with 1 M NaOH, dried over MgSO4 and purified over silica gel (30% EtOAc/Hex) to give 1.25 g of the sub-title compound as an oil.
Reaction SMILES: C1(C)C(S([C:10]2[CH:11]=[C:12]([NH2:19])[C:13](=[CH:17][CH:18]=2)[C:14]([OH:16])=O)(=O)=O)=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1C=CC=CC=1>[NH2:19][C:12]1[CH:11]=[CH:10][CH:18]=[CH:17][C:13]=1[C:14]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:17][CH:18]=1)=[O:16]
Reactant: Cc1ccccc1S(=O)(=O)c1ccc(C(=O)O)c(N)c1
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Al+3]
Solvent: c1ccccc1
Product: Nc1ccccc1C(=O)c1ccccc1
Temperature: 50 °C
Yield: 134.5 %

Procedure:
The mixture of 14.6 g (0.050 mol) of p-toluenesulfonylanthranilic acid prepared in Example 8 and 11.9 g (0.057 mol) of phosphorus pentachloride in 150 ml of dry benzene were heated at about 50° C. for 0.5 h. Cooled to 20-25° C. and 29.0 g (0.218 mol) of anhydrous aluminum chloride was added in portions. When addition was complete, the mixture was heated at 80-90° C. for 4 h and then cooled, poured onto a mixture of ice and 60 ml of 1N hydrochloride acid. The benzene was removed by vacuo distillation, the crude product was separated by filtration and washed with sodium carbonate and water. The filter cake is sucked reasonably dry, dissolved in 160 ml of conc. sulfuric acid and heated to 120° C. for 15 minutes. The reaction mixture was cooled and poured onto the mixture of ice and 1 g of norit, and the solution is filtered. The filtrate was neutralized with 12N ammonium hydroxide. The solid filtered off, washed with water and dried, recrystallized from 95% ethanol to give the title compound (6.63 g) as yellow crystal, yield 65.0%, m.p. 105-106° C.
Reaction SMILES: [CH2:1]([N:8]([C@@H:16]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:22][CH:21]=1)[CH:17]=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]>>[CH2:27]([O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C@H:16]([N:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@H:17]([OH:18])[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH3:35])=[CH:25][CH:24]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C[C@H](Cc1ccc(OCc2ccccc2)cc1)N(Cc1ccccc1)Cc1ccccc1
Reactant: CCCCCCCCCCCCCCCBr
Product: CCCCCCCCCCCCCCC[C@@H](O)[C@H](Cc1ccc(OCc2ccccc2)cc1)N(Cc1ccccc1)Cc1ccccc1

Procedure:
According to the method of Example 26, from aldehyde 20 (597 mg, 1.37 mmol) and 1-bromopentadecane (999 mg, 3.43 mmol), alcohol 74 was obtained as a colorless oil (496 mg, 56% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[N:9]=2)=[CH:4][CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>C(Cl)Cl>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([C@H:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:32]([NH:31][C:27]4[CH:28]=[CH:29][CH:30]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=4)=[O:33])=[CH:3][CH:4]=3)[C:16]=12
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Nc1ccc(-c2nn([C@H]3CCOC3)c3ncnc(N)c23)cc1
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc1)nn2[C@H]1CCOC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 3-(4-aminophenyl)-1-((S)-tetrahydrofuran-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.1 g, 0.34 mmol) in CH2Cl2 (10 mL) was cooled in an ice-water bath. To this, 3-(trifluoromethyl)phenyl isocyanate (0.047 mL, 0.34 mmol) diluted in CH2Cl2 (5 mL) was added dropwise. The reaction was allowed to warm to room temperature and left stirring for 12 hours. Reaction completion was judged by TLC and LC-MS. The reaction mixture was filtered, dried onto silica, and purified using silica gel column chromatography (50% EtOAc:Hexanes to 100% EtOAc gradient) to afford final compound AD66. ESI-MS m/z [M+H]+ found 484.4, calculated 484.2.
Reaction SMILES: C(O)(=[O:3])C.[O:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH2:6]1.[OH-].[Na+].Cl>C(O)C>[O:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:3])=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH2:6]1
Reactant: CC(=O)O
Reactant: C1=Cc2ccccc2OC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Oc1ccc2c(c1)C=CCO2
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 291.5 %

Procedure:
A solution of the chromene acetate (1.0 g, 2.13 mmol) in ethanol (20 mL) was treated with 2 N NaOH (20 mL) and stirred at 60° C. for 90 min. The reaction mixture was cooled, acidified with 5 N HCl, and the ethanol was removed in vacuo. The resulting aqueous solution was extracted with ether and concentrated to a light yellow oil that was purified by silica gel chromatography eluting with ethyl acetate (15%, v/v) in hexanes. This yielded the desired chromene-6-ol intermediate as a colorless oil (0.92 g, 98%). 1H-NMR (CDCl3/TMS, ppm): 0.87 (m, 12H, 4a′-, 8a′-, 12a′-, 13′-CH3), 1.0-1.6 (m, 24H, 4′-, 8′-, 12′-CH, 2′-, 3′-, 5′-, 6′-, 7′-, 9′-, 10′-, 11′-CH2, 2a-CH3), 2.14, 2.18, 2.19 (3×s, 9H, 5a-, 7a-, 8a-CH3), 5.63, 6.55 (2×d, J=10.0 Hz, 2H, CH); 13C-NMR (CDCl3, ppm): 10.8, 11.6, 12.4 (5a-, 7a-, 8a-CH3), 19.6, 19.7 (CH3), 21.3 (CH2), 22.6, 22.7 (CH3), 24.4, 24.8 (CH2), 25.2 (2a-CH3), 27.9 (CH), 30.9 (3-CH2), 32.7, 32.8 (CH), 37.2, 37.4, 37.5, 39.3, 40.5 (CH2), 50.8 (2-C), 116.2, 117.8, 120.1, 122.3, 123.0, 130.0 (aryl and vinyl C), 144.6, 145.3 (aryl C—O), 169.4 (CO); HRMS (CI, m/z): 428.365275 M+H+, Calc. for C29H48O2 428.365431.
Reaction SMILES: [CH:1]1([CH2:4][C:5](=[O:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.C1C(=O)N([Br:19])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH:4]([CH:1]1[CH2:3][CH2:2]1)[C:5](=[O:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C(=O)CC1CC1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(=O)C(Br)C1CC1

Procedure:
To a solution of ethyl 3-cyclopropyl-2-oxopropanoate (4.75 g, 30.44 mmol) in CCl4 (60 mL) at rt was added NBS (5.96 g 33.49 mmol). The resulting mixture was heated at reflux overnight, then cooled, filtered, and evaporated to provide ethyl 3-bromo-3-cyclopropyl-2-oxopropanoate; 1H NMR (CDCl3): δ 4.46-4.32 (3H, m), 1.41 (3H, t, J=8 Hz), 0.96-0.86 (1H, m), 0.55-0.50 (2H, m), 0.07-0.03 (2H, m). This compound was used without purification for the preparation of compounds of the invention such as 1-(4-chlorophenyl)-2-(2-chlorophenyl)-N-(1-piperidinyl)-5-cyclopropyl-1H-imidazole-4-carboxamide hydrochloride (Table entry 22). In a similar manner, ethyl 3-bromo-3-cyclobutyl-2-oxopropanoate and ethyl 3-bromo-3-isobutyl-2-oxopropanoate were prepared.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:25])[CH:9]2[C:13]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:4][N:3]=1.Cl.[CH3:27][N:28]1[CH:32]=[C:31]([NH2:33])[CH:30]=[N:29]1.CCN(C(C)C)C(C)C>CCCCO>[CH3:25][N:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:33][C:31]2[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=2)[N:7]=1)[CH:9]1[C:13]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]1
Reactant: Cn1cc(N)cn1
Reactant: CN(c1ccnc(Cl)n1)C1CN(C(=O)OC(C)(C)C)CC12CCCC2
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ccnc(Nc2cnn(C)c2)n1)C1CN(C(=O)OC(C)(C)C)CC12CCCC2
Temperature: 150 °C
Yield: 55.3 %

Procedure:
To a suspension of tert-butyl 4-((2-chloropyrimidin-4-yl)(methyl)amino)-2-azaspiro[4.4]nonane-2-carboxylate (0.34 g, 0.93 mmol) in n-BuOH (5.0 mL) was added 1-methyl-1H-pyrazol-4-amine hydrochloride (0.25 g, 1.85 mmol) and DIPEA (0.48 g, 3.71 mmol). The mixture was stirred in a sealed tube and heated to 150° C. overnight, then concentrated in vacuo. The residue was purified by silica gel column chromatography (EA) to give the product as a yellow solid (0.22 g, 55%).
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:25])[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:16][N:15]=2)=[CH:10][CH:9]=1)(=[O:3])[CH3:2]>[Pd].O1CCCC1>[C:1]([O:4][CH:5]([CH3:25])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][Si:21]([CH3:24])([CH3:22])[CH3:23])=[CH:16][N:15]=2)=[CH:10][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)C=Cc1ccc(-c2ccc(O[Si](C)(C)C)cn2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(=O)OC(C)CCc1ccc(-c2ccc(O[Si](C)(C)C)cn2)cc1
Yield: 85.2 %

Procedure:
14 g of 2-[4-(3-acetoxy-1-butenyl)phenyl]-5-trimethylsilyloxy-pyridine, 2 g of palladium on active charcaol (10 wt. %) and 200 ml of tetrahydrofuran are hydrogenated in an analogous manner to Example 1(a) to give 12 g of 2-[4-(3-acetoxy-1-butyl)phenyl]-5-trimethylsilyloxy-pyridine.
Reaction SMILES: II.Br[CH2:4][CH2:5][CH:6]=[CH2:7].[CH2:8]([O:10][P:11]([C:16]([C:24]#[N:25])=[CH:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)(=[O:15])[O:12][CH2:13][CH3:14])[CH3:9].[NH4+].[Cl-]>C1COCC1.[Cu]I.C(OCC)(=O)C>[CH2:8]([O:10][P:11]([CH:16]([C:24]#[N:25])[CH:17]([CH:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1)[CH2:7][CH2:6][CH:5]=[CH2:4])(=[O:15])[O:12][CH2:13][CH3:14])[CH3:9]
Reactant: C=CCCBr
Reactant: CCOP(=O)(OCC)C(C#N)=CC1CCOCC1
Agent: [Cu]I
Agent: II
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCCC(C1CCOCC1)C(C#N)P(=O)(OCC)OCC

Procedure:
In a flask, Mg (5.7 g) was placed in THF (50 mL) with an iodine chip. The reaction mixture was vigorously stirred and heated slightly, as 4-bromobutene (25 mL) was added. After consumption of Mg metal, the resulting solution was cannulated into a flask containing a mixture of [1-cyano-2-(tetrahydro-pyran-4-yl)-vinyl]-phosphonic acid diethyl ester (21.78 g, 79.7 mmol), prepared as described in Example 1 Step D above, and CuI (0.3 g) with THF (30 mL). The resulting mixture was stirred for three hours. Saturated aqueous NH4Cl solution and ethyl acetate were then added. The organic layer was separated and dried with MgSO4, filtered, and evaporated in vacuo to yield an oil.
Reaction SMILES: C([NH:4][C:5]1[N:9]([CH3:10])[N:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=1)(=O)C.[N+:15]([O-])([OH:17])=[O:16]>S(=O)(=O)(O)O>[NH2:4][C:5]1[N:9]([CH3:10])[N:8]=[C:7]([C:11]([CH3:12])([CH3:13])[CH3:14])[C:6]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1cc(C(C)(C)C)nn1C
Agent: O=S(=O)(O)O
Product: Cn1nc(C(C)(C)C)c([N+](=O)[O-])c1N
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
To 30 cm3 of concentrated sulphuric acid were added 8.5 g (0.044 mol) of 5-acetamido-1-methyl-3-tert-butylpyrazole, at 5° C. with vigorous stirring, followed by 2.5 cm3 (0.066 mol) of fuming nitric acid. After stirring for 2 hours, the reaction mixture was poured onto 100 g of ice and stirred for 30 minutes. The solid obtained was filtered off on a sinter funnel, washed with 20 cm3 of water and then dried under vacuum at 40° C. 8.5 g of the expected product were obtained in the form of a yellow solid, the melting point of which was 124° C.
Reaction SMILES: [O:1]=[C:2]1[C:13]2[C:14]3[C:6](=[C:7]([C:15]([OH:17])=O)[NH:8][C:9]=3[CH:10]=[CH:11][CH:12]=2)[CH2:5][CH2:4][NH:3]1.[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:15]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:2](=[O:1])[NH:3][CH2:4][CH2:5][C:6]=2[C:14]=34)=[O:17])=[CH:21][CH:20]=1
Reactant: O=C(O)c1[nH]c2cccc3c2c1CCNC3=O
Reactant: Nc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)cc1)c1[nH]c2cccc3c2c1CCNC3=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
6-Oxo-3,4,5 ,6-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic acid (100 mg, 0.43 mmol), 4-fluoroaniline (48 mg, 0.43 mmol), and diisoprophylethylamine (168 mg, 1.30 mmol) were dissolved in 5 mL dry DMF. HATU (173 mg, 0.46 mmol) was added and the resulting mixture stirred at room temperature under argon for 3 d. The reaction mixture was partitioned between water and 25% iPrOH/CHCl3. The layers were separated, and the aqueous layer extracted thrice with 25% iPrOH/CHCl3. The combined organic layers were dried (MgSO4) and concentrated in vacuo leaving an off-white solid which was recrystallized from chloroform/methanol to yield 6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic acid (4-fluoro-phenyl)-amide, 70 mg (50%) as a pale yellow solid: m.p. 330-332° C. (dec); 1H NMR (300 MHz, d6-DMSO) δ3.28 (m, 2H), 3.42 (m, 2H), 7.22 (m, 2H), 7.35 (app t, J=7.8 Hz, 1H), 7.65 (dd, J=7.8, 0.6 Hz, 1H), 7.77 (m, 3H), 8.16 (br t, 1H), 10.08 (br s, 1H), 11.81 (br s, 1H). MS (electrospray, MH+) 324. Anal. (C18H14FN3O2.0.4 H2O) C, H, N.