Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:9][CH2:10][CH:11]([CH2:35][CH:36]([O:38][C:39](=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH3:37])[CH2:12][O:13][C:14](=[O:34])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=O)C1C=CC=CC=1.[OH-].[Na+].C(OCC)(=O)C>CO.O1CCCC1>[C:39]([O:38][CH:36]([CH3:37])[CH2:35][CH:11]([CH2:12][O:13][C:14](=[O:34])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:10][OH:9])(=[O:46])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(COC(=O)c1ccccc1)CC(C)OC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CO)CC(C)OC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
To an ice cooled solution of 2.879 g (4.51 mM) of 2-(2-benzoyloxypropan-1-yl)-3-octadecylcarbamoyloxypropyl benzoate m6 in 25 ml of methanol and 25 ml of tetrahydrofuran, is added 4.51 ml (9.02 mM) of 2N aqueous sodium hydroxide and the mixture is stirred at 0° C. for 2 hours. The mixture is poured into ice-water and the product is isolated by ethyl acetate extraction. The ethyl acetate layer is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated. Purification of the product by column silica gel chromatography using n-hexane-ethyl acetate (2:1) as an eluent gives 1.72 g (71.4% yield) of the titled compound m7.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[F:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][C:24]2[N:29]=[CH:28][C:27]([CH:30]([NH2:32])[CH3:31])=[CH:26][C:25]=2[CH3:33])=[CH:19][CH:18]=1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:32]([CH:30]([C:27]3[CH:28]=[N:29][C:24]([S:23][C:20]4[CH:19]=[CH:18][C:17]([F:16])=[CH:22][CH:21]=4)=[C:25]([CH3:33])[CH:26]=3)[CH3:31])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(C(C)N)cnc1Sc1ccc(F)cc1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1Sc1ccc(F)cc1
Yield: 48 %

Procedure:
The title compound is prepared in 48% yield (290 mg, off white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (400 mg, 1.4 mmol, Step-1 of Intermediate-1) and 1-(6-((4-fluorophenyl)thio)-5-methylpyridin-3-yl)ethanamine hydrochloride (410 mg, 1.6 mmol, Amine-42, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([C:11]#[N:12])=[CH:6][C:5]=1[Cl:13].[N:15]([Sn](CCCC)(CCCC)CCCC)=[N+:16]=[N-:17]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:14])[C:4]1[C:5]([Cl:13])=[CH:6][C:7]([C:11]2[NH:17][N:16]=[N:15][N:12]=2)=[CH:8][C:9]=1[Cl:10]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: COC(=O)c1c(Cl)cc(C#N)cc1Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1c(Cl)cc(-c2nnn[nH]2)cc1Cl
Temperature: 100 °C
Reaction time: 72 h

Procedure:
The mixture of 185 mg of 2,6-dichloro-4-cyanobenzoic acid methylester, 266 mg of azidotributyltin and 5 ml of toluene was stirred at 100° C. for 3 days. The reaction mixture was concentrated and diluted with ethyl acetate. After Celite filtration, the filtrate was concentrated and the residue was purified by reverse phase HPLC to obtain the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH:24]=O)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH2:27]([NH2:29])[CH3:28].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][C:15]=2[CH2:24][NH:29][CH2:27][CH3:28])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCN
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Temperature: 25 °C

Procedure:
To (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (1.0 g, 2.73 mmol) in MeOH (8 mL) was added ethylamine (2M in THF; 5 mL, 10 mmol), followed by acetic acid (0.23 mL, 4.09 mmol). Sodium cyanoborohydride (0.260 g, 4.14 mmol) was then added, and the reaction was stirred at room temperature and monitored by analytical LCMS. The reaction never reached completion, so the mixture was concentrated and partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0-6% MeOH in CH2Cl2) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][CH:22]=2)=[CH:5][CH:4]=1.[H-].[Na+].C(S)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20](=[O:29])[C:21]2[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)c2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Solvent: CN(C)C=O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Yield: 55.9 %

Procedure:
2-(4-Methoxyphenyl)-3-(4-Methoxybenzoyl)-6-Methoxybenzo[b]thiophene (19.8 g, 49 mmol) was dissolved in dimethylformamide and sodium hydride (10 g of a 50% oil dispersion) was added. The reaction was cooled and ethylmercaptan (12.4 g) was added slowly. The reaction was warmed to 65° C.-70° C. until the reaction was complete. The volatiles were removed by evaporation, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The ethyl acetate extracts were washed with water and evaporated to dryness. The residue was chromatographed on a silica gel column eluting with 1500 mL of benzene-ethyl acetate (99:1), then benzene-ethyl acetate (97:3). The fractions containing the title compound were evaporated to dryness and the residue was crystallized from benzene to give 10.7 g of the title compound. mp 114° C.-116° C. EA calculated for C23H18O4S: C, 70.75; H, 4.64; O, 16.39. Found: C, 70.88; H, 4.50; O, 16.11.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1[N:8]=[CH:7][C:6]([C:9]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:26][CH3:27])=[C:20]([O:23][CH3:24])[CH:21]=3)[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][C@@H:14]([OH:28])[CH2:15]3)[N:10]=2)=[CH:5][N:4]=1.[O:30]=[C:31]([CH2:35][CH2:36][C:37]([OH:39])=[O:38])[C:32](O)=[O:33]>ClCCl>[O:30]=[C:31]([CH2:35][CH2:36][C:37]([OH:39])=[O:38])[C:32]([O:28][C@@H:14]1[CH2:13][CH2:12][C@@H:11]2[C@@H:16]([C:17]3[C:22]([C:9]([C:6]4[CH:7]=[N:8][C:3]([N:2]([CH3:1])[CH3:29])=[N:4][CH:5]=4)=[N:10]2)=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH3:27])[CH:18]=3)[CH2:15]1)=[O:33]
Reactant: O=C(O)CCC(=O)C(=O)O
Reactant: CCOc1cc2c(cc1OC)C(c1cnc(N(C)C)nc1)=N[C@@H]1CC[C@@H](O)C[C@H]21
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1cnc(N(C)C)nc1)=N[C@@H]1CC[C@@H](OC(=O)C(=O)CCC(=O)O)C[C@H]21
Yield: 58.9 %

Procedure:
(2R,4aR,10bR)-6-(2-Dimethylamino-pyrimidin-5-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol (39.4 mg, 0.1 mmol) are dissolved in 1.0 ml of dichloromethane. 16.1 mg (0.11 mmol) of 2-oxo-pentanedioic acid (dissolved in 0.5 ml of acetone) are added. The crystals are filtered off and dried to obtain 30.9 mg (57%) of the title compound (m.p.: 112° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:19]([O:21]C)=[O:20])=[N:11][CH:12]=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH2:1]([O:8][C:9]1[C:10]([C:19]([OH:21])=[O:20])=[N:11][CH:12]=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ncc(OC)c(OC)c1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cnc(C(=O)O)c(OCc2ccccc2)c1OC
Reaction time: 3 h

Procedure:
Methyl 3-benzyloxy-4,5-dimethoxypicolinate (20 mg) was dissolved in 1 ml of methanol. A 1 N aqueous sodium hydroxide solution (0.33 ml) was added to the solution, and a reaction was allowed to proceed at room temperature for 3 hr. The reaction solution was neutralized with 1 N hydrochloric acid, and was then concentrated under the reduced pressure to give the title compound.
Reaction SMILES: C(OC)(=O)[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Na+].Cl.C([O-])(=O)C.[NH4+].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][CH:26]([CH3:30])[CH2:27][CH:28]=[O:29])=[CH:21][CH:20]=1>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[OH:29][CH:28]([CH2:27][CH:26]([S:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=1)[CH3:30])[CH2:2][C:3](=[O:4])[CH3:5]
Reactant: COc1ccc(SC(C)CC=O)cc1
Reactant: COC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(SC(C)CC(O)CC(C)=O)cc1
Reaction time: 3 h
Yield: 53.6 %

Procedure:
9.86 Grams of methyl acetoacetate were dissolved in 15 ml of water, and 12.67 g of a 30% aqueous sodium hydroxide solution were added thereto by drops while cooling the mixture to 25° C. or less. After having been stirred at 30°-35° C. for 3 hours, the mixture was adjusted to pH 7.0 with a concentrated aqueous hydrochloric acid solution. Thereafter, 0.76 g of ammonium acetate and 2.42 g of tetrabutylammonium bromide were added, and then an additional concentrated aqueous hydrochloric acid solution was added thereto so that the mixture was controlled to have a pH of 6.8. Further, 28.00 g of a toluene solution containing 33.6% of 3-(4-methoxyphenylthio)butanal were added thereto and the resulting mixture was stirred at 45°-50° C. for 9 hours. The organic layer separated from the mixture was washed with a 5% aqueous acetic acid solution and then with a saturated aqueous sodium chloride solution. Then it was dried over anhydrous magnesium sulfate. Removing the solvent from the layer under reduced pressure gave 12.04 g of crude 4-hydroxy-6-(4-methoxyphenylthio)-2-heptanone (purity: 53.3%, yield: 53.6%). A purified product was obtained by column chromatography. The purified product had an nD21 of 1.5428.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]2[N:7]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:6]=[CH:5][C:4]=2[C:3]=1[CH:22]=O.[C:24](Br)(Br)([Br:26])[Br:25].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:25][C:24]([Br:26])=[CH:22][C:3]1[C:2]([CH3:1])=[CH:10][C:9]([CH3:11])=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[S:12]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13]
Reactant: BrC(Br)(Br)Br
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C=O)c(C)cc(C)c32)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C=C(Br)Br)c(C)cc(C)c32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5,7-dimethyl-1-tosyl-1H-indole-4-carbaldehyde (Example 46-D) (1.5 g, 4.58 mmol) and CBr4 (3.04 g, 9.16 mmol) in CH2Cl2 (50 mL) was added PPh3 (3.61 g, 13.74 mmol) at 0° C., and then the mixture was stirred at room temperature for 1 hr. The reaction mixture was directly purified by silica gel flash chromatography (heptanes/EtOAc=1/0 to 1/1) to give the title compound. MS (ESI+) m/z 483.9, 485.9, 481.9, 487.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][C@@H:5]([OH:29])[C@@H:6]2[N:12]1[C:20]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]=2[C:14]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]#[N:25])=[N:13]1.C(N(CC)CC)C.[C:37](Cl)(=[O:40])[CH2:38][CH3:39].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][C@@H:5]([OH:29])[C@@H:6]2[N:12]1[C:20]2[CH2:19][CH2:18][N:17]([C:37](=[O:40])[CH2:38][CH3:39])[CH2:16][C:15]=2[C:14]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]#[N:25])=[N:13]1
Reactant: N#Cc1cccc(-c2nn([C@@H]3c4cc(F)cc(F)c4C[C@H]3O)c3c2CNCC3)c1
Reactant: CCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2[C@@H]2c3cc(F)cc(F)c3C[C@H]2O)C1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 26.3 %

Procedure:
According to Scheme 9: To a solution of 3-[1-((1R,2R)-4,6-difluoro-2-hydroxy-indan-1-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (13c) (0.05 g, 0.127 mmol) in CH2Cl2 (2 ml) at 0° C. triethylamine (19 mg, 0.191 mmol) and propionyl chloride (13 mg, 0.140 mmol) was added and the mixture was stirred for 30 min at 0-5° C. After addition of aqueous saturated NaHCO3 (2 ml), the mixture was extracted with CH2Cl2 (10 ml), the organic layer was dried over Na2SO4, solvents were evaporated in vacuo and the crude product was purified by reverse phase HPLC (CH3CN/water gradient with 0.1% trifluoroacetic acid) to give 15 mg of 3-[1-((1R,2R)-4,6-difluoro-2-hydroxy-indan-1-yl)-5-propionyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (14a).
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:2].[Na+].[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1)([O-:17])=[O:16].C(=O)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([N:27]1[CH2:26][CH2:25][CH:24]([C:21]2[CH:22]=[CH:23][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=2)[CH2:29][CH2:28]1)[CH3:2]
Reactant: O=[N+]([O-])c1ccc(C2CCNCC2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCN1CCC(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
Sodium triacetoxyborohydride (3.1 g, 14.6 mmol, 3 equiv) is added to a cold (5° C.) solution of 4-(4-nitro-phenyl)-piperidine (1 g, 4.9 mmol) and acetaldehyde (0.82 mL, 14.6 mmol, 3 equiv) in DCM (20 mL). The reaction mixture is stirred for 1 h at 5° C. and then diluted with DCM and a saturated aqueous solution of NaHCO3. The layers are separated and the aqueous layer is extracted with DCM. The organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (DCM/MeOH+1% NH3aq, 98:2) to provide the title compound as a yellow oil. ESI-MS: 235.1 [MH]+; tR=2.64 min (purity: 85%, system 1); TLC: Rf=0.14 (DCM/MeOH+1% NH3aq, 98:2).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1/[CH:10]=[N:11]/[C:12]1[C:17]([Cl:18])=[CH:16][C:15]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:14][C:13]=1[Cl:23])=[N+]=[N-]>C1(C)C=CC=CC=1>[Cl:23][C:13]1[CH:14]=[C:15]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[C:17]([Cl:18])[C:12]=1[N:11]1[CH:10]=[C:5]2[CH:6]=[N:7][CH:8]=[CH:9][C:4]2=[N:1]1
Reactant: CS(=O)(=O)c1cc(Cl)c(/N=C/c2cnccc2N=[N+]=[N-])c(Cl)c1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1cc(Cl)c(-n2cc3cnccc3n2)c(Cl)c1
Temperature: 105 °C
Yield: 52.1 %

Procedure:
A mixture of [1-(4-azidopyridin-3-yl)meth-(E)-ylidene]-(2.6-dichloro-4-methanesulfonylphenyl)amine (4.21 mmol) in toluene (15 mL) was heated to 105° C. for 18 hours. The reaction mixture was allowed to cool and then concentrated under reduced pressure. The residue was recrystallised from ethyl acetate and the solid was collected by filtration to afford the title compound as a beige solid (0.75 g, 52% yield). 1H NMR (300 MHz, DMSO-d6): δ 9.38 (d, J=1.4 Hz, 1H) 9.15 (d, J=1.0 Hz, 1H), 8.34 (s, 2H) 8.31 (d, J=6.4 Hz, 1H) 7.68 (dt, J=6.4, 1.2 Hz, 1H) 3.49 (s, 3H). LCMS (Method D): RT=1.72 min, m/z: 342 [M+H+].
Reaction SMILES: [NH:1]1[C:9](=O)[C:8]2[NH:7][CH:6]=[N:5][C:4]=2[N:3]=[CH:2]1.[NH3:11]>P(Cl)(Cl)(Cl)=O.C1COCC1>[N:1]1[C:9]([NH2:11])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1
Reactant: N
Reactant: O=c1[nH]cnc2nc[nH]c12
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1ncnc2nc[nH]c12
Temperature: 60 °C
Yield: 90.5 %

Procedure:
1.27 g (2.8 mM) of the above hypoxanthine (C.) was heated in 13 ml of phosphorus oxychloride to 70° C. for 30 min. Evaporation in vacuo and twice repetition with toluene gave the crude 6-chloro intermediate, which was dissolved in 40 ml of THF and added at 0-5° C. to 12 ml of 32% aqueous ammonia. After the addition of 50 g of liquid ammonia the solution was heated to 60° C. in a 450 ml pressure reactor (340 psi). After 3.5 hr the solid was filtered off and the solution evaporated in vacuo to dryness. The residue was dissolved in dichloromethane, extracted with 1 n NaOH and evaporated again to dryness. The residue was dissolved in 20 ml of methanol, treated with 2.9 ml of 1 m methanolic HCl and evaporated to dryness. Crystallization from ethyl acetate gave 1.24 g (90.5%) of title adenine with mp 172-175° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>O1CCOCC1>[CH2:30]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22])[CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCBr
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCCCCN1C(=O)[C@@]2(COc3cc4c(cc32)OCCO4)c2ccccc21
Temperature: 25 °C
Yield: 71.6 %

Procedure:
A suspension of (S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (1.0 g, 3.4 mmol), cesium carbonate (3.3 g, 10.2 mmol) and 1-bromopentane (1.02 g, 6.77 mmol) in anhydrous 1,4-dioxane (25 mL) was heated at reflux under nitrogen for 2 h. The reaction mixture was allowed to cool to ambient temperature, filtered and concentrated in vacuo. Purification of the residue by column chromatography and eluted with a 15% to 50% gradient of ethyl acetate in hexanes, followed by recrystallization from methanol afforded (S)-1′-pentyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one as an off-white solid (0.89 g, 72%): mp 111-113° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ7.23-7.30 (m, 1H), 7.13 (dd, J=7.4, 0.9 Hz, 1H), 7.00-7.03 (m, 1H), 6.89 (d, J=7.8 Hz, 1H), 6.46 (s, 1H), 6.19 (s, 1H), 4.73 (ABq, 2H), 4.19-4.05 (m, 4H), 3.86-3.59 (m, 2H), 1.82-1.62 (m, 2H), 1.43-1.28 (m, 4H), 0.89 (t, J=6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ177.2, 155.2, 144.5, 142.4, 138.2, 132.5, 128.7, 123.9, 123.0, 121.1, 111.4, 108.5, 99.3, 80.1, 64.5, 63.9, 58.0, 40.3, 29.0, 27.1, 22.3, 14.0; MS (ES+) m/z 366.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[N+:16]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH:28]=O)([O-:18])=[O:17].N1CCCCC1>CN(C)C=O>[N+:16]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2/[CH:28]=[CH:14]/[C:13]([C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:15])([O-:18])=[O:17]
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: O=Cc1c[nH]c2ccc([N+](=O)[O-])cc12
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: COc1cc(C(=O)/C=C/c2c[nH]c3ccc([N+](=O)[O-])cc23)cc(OC)c1OC
Temperature: 100 °C
Reaction time: 72 h
Yield: 5.3 %

Procedure:
3',4',5'-Trimethoxyacetophenone (1.31 g) and 5-nitroindole-3-carboxaldehyde (1.18 g) were dissolved in N,N-dimethylformamide (20 ml), and piperidine (528.7 mg) was added thereto, followed by stirring at 100° C. for 72 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. The obtained crude crystals were recrystallized from methanol to give Compound 21 (125 mg).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([C:14]3([C:17]([F:20])([F:19])[F:18])[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23]1>CCCCO>[Br:1][C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:23]2)=[C:4]2[C:10]([NH:11][C:12]([C:14]3([C:17]([F:20])([F:19])[F:18])[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)C1(C(F)(F)F)CC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4(C(F)(F)F)CC4)c23)C1
Temperature: 160 °C
Reaction time: 48 h
Yield: 19 %

Procedure:
A solution of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-(trifluoromethyl)cyclopropanecarboxamide (229 mg, 0.627 mmol) in n-BuOH (5 mL) was treated with (R)-tert-butyl piperidin-3-ylcarbamate (505 mg, 2.507 mmol) and stirred at 160° C. for 48 hours in a sealed tube. The mixture was concentrated in vacuo, and the residue diluted with water (25 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 5-85% CH3CN/water gradient; 25 CV) to provide (R)-tert-butyl 1-(5-bromo-3-(1-(trifluoromethyl)cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (65 mg, 19% yield) as a solid. LCMS (APCI+) m/z 429.1, 446.1, 492.1, 548.1 (M+H)+, Retention time=3.79 minutes (Method 3).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([OH:39])[CH2:20][CH2:19][N:18]([CH:21]3[CH:25]([OH:26])[CH2:24][N:23]([C:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]([F:38])([F:37])[F:36])=[O:28])[CH2:22]3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.[C:40](OC(=O)C)(=[O:42])[CH3:41]>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([OH:39])[CH2:20][CH2:19][N:18]([CH:21]3[CH2:22][N:23]([C:27](=[O:28])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]([F:37])([F:36])[F:38])[CH2:24][CH:25]3[O:26][C:40](=[O:42])[CH3:41])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(c1ccccc1C(F)(F)F)N1CC(O)C(N2CCC(O)(c3ccc(Cl)cc3)CC2)C1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OC1CN(C(=O)c2ccccc2C(F)(F)F)CC1N1CCC(O)(c2ccc(Cl)cc2)CC1
Reaction time: 2 h

Procedure:
A mixture of (3R,4R; 3S,4S)-{3-[4-(4-Chloro-phenyl)-4-hydroxy-piperidin-1-yl]4-hydroxy-pyrrolidin-1-yl}-(2-trifluoromethyl-phenyl)-methanone trifluoroacetate (2.2 mg, 0.005 mmol, see Example 43 for preparation) was dissolved in DMF (0.4 mL) and acetic anhydride was added. The reaction mixture was shaken for 2 h and directly used for LC-MS purification, to yield 1.1 mg of the title compound as the trifluoroacetate salt. ESIMS ([M+H]+): 511.2 (100).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]([OH:17])=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[C:18]([O:23][CH2:24][CH:25]1[O:27][CH2:26]1)(=[O:22])[C:19]([CH3:21])=[CH2:20].C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C>[Cl-].C[N+](C)(C)C>[CH:11]1[C:12]2[C:7](=[CH:6][C:5]3[C:14]([C:13]=2[C:15]([O:17][CH2:26][CH:25]([OH:27])[CH2:24][O:23][C:18](=[O:22])[C:19]([CH3:21])=[CH2:20])=[O:16])=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: C=C(C)C(=O)OCC1CO1
Reactant: O=C(O)c1c2ccccc2cc2ccccc12
Agent: C[N+](C)(C)C
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Cl-]
Product: C=C(C)C(=O)OCC(O)COC(=O)c1c2ccccc2cc2ccccc12
Temperature: 100 °C
Reaction time: 4 h

Procedure:
Anthracene-9-carboxylic acid (50 g) was added over 30 minutes with stirring to glycidyl methacrylate (33.9 g, epoxide content 6.6 equiv./kg) containing 0.13 g of 2,6-di-tert.butyl-p-cresol and 0.25 g of tetramethylammonium chloride and heated to 100° C. Heating at 100° C. was continued for a further 4 hours, by which time the epoxide content of the mixture had fallen to a negligibly low value. The resultant product was a brown, glassy solid.