Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:23][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([C:19]([O:21]C)=[O:20])=[CH:11][C:12]=3[C:13]3([O:18][CH2:17][CH2:16][CH2:15][O:14]3)[C:5]2=[N:4][CH2:3]1.CCO.[OH-].[Na+].O>C1COCC1>[CH3:1][C:2]1([CH3:24])[CH2:23][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([C:19]([OH:21])=[O:20])=[CH:11][C:12]=3[C:13]3([O:14][CH2:15][CH2:16][CH2:17][O:18]3)[C:5]2=[N:4][CH2:3]1
Reactant: COC(=O)c1ccc2c(c1)C1(OCCCO1)C1=NCC(C)(C)CN12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CN=C2N(C1)c1ccc(C(=O)O)cc1C21OCCCO1
Yield: 50.3 %

Procedure:
To a solution of methyl 3′,3′-dimethyl-3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2-a]indole]-8′-carboxylate (0.200 g, 0.610 mmol) in THF (4 mL)/EtOH (4 mL) was added 1N NaOH (2 mL) and H2O (2 mL) and the reaction was refluxed for 1 hr. The reaction was quenched with 1 N HCl and extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated to give the title compound as white solid (0.097 g, 50%). NMR (400 Mz, DMSO-d6): consistent. MS (ES+) m/z 317.3 [M+H]. m.p.: 151.1-153.3° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([O:23][C@H:24]2[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][C:25]32[CH2:27][CH2:26]3)[CH:20]=[N:19][CH:18]=1.[Br-].[F:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:42]=1[Zn+].C1COCC1.O.C(CN(CCO)CCN(CC([O-])=O)CC([O-])=O)([O-])=O.[Na+].[Na+].[Na+].O>C(Cl)Cl.[Pd](Cl)Cl.C(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)(C)C.C(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)(C)C>[F:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:42]=1[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([O:23][C@H:24]2[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:29][CH2:28][C:25]32[CH2:27][CH2:26]3)[CH:20]=[N:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)n2)C1
Reactant: Fc1cccc(F)c1[Zn+]
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])CN(CCO)CCN(CC(=O)[O-])CC(=O)[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(-c5c(F)cccc5F)cc34)n2)C1
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
A 75 mL threaded pressure vessel was flushed with argon and was charged with a stir bar, bis(4-(di-tert-butylphosphino)-N,N-dimethyl-benzenamine) palladium dichloride (0.061 g, 0.086 mmol) and (4R)-tert-butyl 4-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (1.00 g, 1.711 mmol). (2,6-Difluorophenyl)zinc(II) bromide 0.5 M in THF (Rieke metals) (5.13 mL, 2.57 mmol) was added, the reaction was sealed, and the slurry was heated to 70° C. After ˜10 min, a clear solution resulted. After 3 h the reaction was cooled and judged complete by LCMS. The reaction was treated with sodium 2,2′-(2-((carboxylatomethyl)(2-hydroxyethyl)amino)ethylazanediyl)diacetate hydrate 10 wt % in water (10.23 mL, 2.82 mmol) (10% aqueous EDTA-H) and DCM. An additional 2-3 mL of 10% EDTA-H solution was added to break up emulsion. The layers were separated, and the aqueous layer was extracted 3×DCM. The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (80 g column) eluting with 0-40% EtOAc/hexane. The product-containing fractions were concentrated to afford (4R)-tert-butyl 4-(6-(5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (1.10 g, 1.781 mmol, quant.) as a light-yellow foam: MS (ESI, pos. ion) m/z: 618 (M+1)
Reaction SMILES: C([O:5][C:6](=[O:14])[C@H:7]([CH3:13])[CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])(C)(C)C>O1CCOCC1>[CH3:13][C@H:7]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:6]([OH:14])=[O:5]
Reactant: C[C@H](CS(C)(=O)=O)C(=O)OC(C)(C)C
Solvent: C1COCCO1
Product: C[C@H](CS(C)(=O)=O)C(=O)O
Reaction time: 19 h

Procedure:
To 2.68 g of 2(S)-methyl-3-(methylsulfonyl)propionicacid t-butyl ester was added 20 mL of 4Nhydrochloric acid/dioxane and the mixture stirred at roomtemperature for 19 hours. The solvent was removed underreduced pressure to afford 2.18 g of crude product, whichwas recrystallized from ethyl acetate/hexane to yield 1.44 gof 2(S)-methyl-3-(methylsulfonyl)propionic acid as whitecrystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[Cl:16][C:17]1[S:21][C:20]([S:22](Cl)(=[O:24])=[O:23])=[CH:19][CH:18]=1>N1C=CC=CC=1>[Cl:16][C:17]1[S:21][C:20]([S:22]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]3)(=[O:24])=[O:23])=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: CCOC(=O)c1cc2cccc(N)c2[nH]1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2cccc(NS(=O)(=O)c3ccc(Cl)s3)c2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
To a mixture of ethyl 7-amino-1H-indole-2-carboxylate (0.70 g) and pyridine (10 mL) was added 5-chlorothiophene-2-sulfonyl chloride (0.89 g) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, 10% aqueous citric acid solution was added, and the resulting crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography, and eluted with ethyl acetate. The eluate was treated with activated carbon and concentrated to give the title compound (1.09 g, yield 83%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point 180-181° C.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].[C:5]12([CH2:14][CH:13]([N:15]3[C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:17]=[CH:16]3)[C:12]3[CH:24]=[CH:25][CH:26]=[CH:27][C:11]=3[O:10]1)[CH2:9][CH2:8][CH2:7][CH2:6]2.CO.[Br:30]Br>O>[N+:1]([O-:4])([OH:3])=[O:2].[Br:30][C:25]1[CH:26]=[CH:27][C:11]2[O:10][C:5]3([CH2:9][CH2:8][CH2:7][CH2:6]3)[CH2:14][CH:13]([N:15]3[C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:17]=[CH:16]3)[C:12]=2[CH:24]=1
Reactant: BrBr
Reactant: COC(=O)c1cncn1C1CC2(CCCC2)Oc2ccccc21
Solvent: CO
Solvent: O
Solvent: O=[N+]([O-])O
Product: COC(=O)c1cncn1C1CC2(CCCC2)Oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.4 %

Procedure:
To a stirred solution of 6.0 parts of methyl 1-[3,4-dihydrospiro-[2H-1-benzopyran-2,1'-cyclopentan]-4-yl]-1H-imidazole-5-carboxylate mononitrate in 135 parts of methanol were added 3.2 parts of bromine. The mixture was stirred for 1 hour at room temperature. The reaction mixture was poured into water and the whole was made alkaline. The product was extracted with 1,1'-oxybisethane. The extract was dried, filtered and evaporated. The residue was converted into the nitrate salt in a mixture of 16 parts of 2-propanone and 40 parts of 2,2'-oxybispropane. The salt was filtered off and dried in vacuo, yielding 4.4 parts (48.4%) of methyl 1-(6-bromo-3,4-dihydrospiro-[2H-1-benzopyran-2,1'-cyclopentan]-4-yl)-1H-imidazole-5-carboxylate mononitrate; mp. 162.3° C. (compound 1.63).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:23][CH2:24][O:25][CH2:26][CH3:27])[C:15](=[O:28])[C:14]=2[C:29]#[N:30])[CH2:9]1)=O)(C)(C)C.[ClH:31]>O1CCOCC1>[ClH:31].[NH:8]1[CH2:11][CH:10]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:23][CH2:24][O:25][CH2:26][CH3:27])[C:15](=[O:28])[C:14]=2[C:29]#[N:30])[CH2:9]1
Reactant: CCOCCn1c(=O)c(C#N)c(NC2CN(C(=O)OC(C)(C)C)C2)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: CCOCCn1c(=O)c(C#N)c(NC2CNC2)c2ccccc21
Reaction time: 24 h

Procedure:
To a solution of 3-[3-Cyano-1-(2-ethoxy-ethyl)-2-oxo-1,2-dihydro-quinolin-4-ylamino]-azetidine-1-carboxylic acid tert-butyl ester (0.120 g, 0.29 mmole) in 1,4-dioxane (2 mL) was treated with 4N HCl in dioxane (5.0 ml). Reaction stirred for 24 h before concentrating to residue and triturating with diethyl ether to afford 4-(Azetidin-3-ylamino)-1-(2-ethoxy-ethyl)-2-oxo-1,2-dihydro-quinoline-3-carbonitrile hydrochloride salt as a yellow solid (0.100 g, quantitative yield, calc M+H 313, obs M+H 313).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([N:12]([CH2:35][CH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1)[CH2:13][CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24](O)=[O:25])[CH:22]=2)[NH:17][C:16]=1[C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)[N:63]2[CH2:67][CH2:66][CH2:65][CH2:64]2)C2C=CC=CC=2N=N1.C(N(CC)CC)C.C(NCC)C>C(Cl)Cl>[CH2:2]([O:9][C:10](=[O:11])[N:12]([CH2:13][CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24](=[O:25])[N:63]([CH2:67][CH3:66])[CH2:64][CH3:65])[CH:22]=2)[NH:17][C:16]=1[C:27]1[CH:28]=[C:29]([CH3:34])[CH:30]=[C:31]([CH3:33])[CH:32]=1)[CH2:35][CH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)O)cc3c2CCN(CCCCc2ccncc2)C(=O)OCc2ccccc2)c1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCNCC
Product: CCN(CC)C(=O)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN(CCCCc3ccncc3)C(=O)OCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 846 mg (1.38 mmol) of 3-[2-[benzyloxycarbonyl-[4-(pyridin-4-yl)butyl]amino]ethyl]-2-(3,5-dirnethylphenyl)-1H-indole-5-carboxylic acid hydrochloride, 862 mg (1.66 mmol) of benzotriazol-1-yloxy-tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP), and 8.5 mL of dry methylene chloride was treated with 1.16 mL (839 mg; 8.29 mmol) of triethylamine, followed after a few minutes by 0.715 mL (505 mg, 6.91 mmol) of diethylamine. The resulting solution was stirred under nitrogen at room temperature overnight and then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient elution with 1-5% methanol in methylene chloride) afforded a quantitative yield of the desired product; homogeneous by TLC in 95:5 CH2Cl2 -MeOH. 500 MHz 1H NMR (CDCl3) was complex, owing to rotamers, but was consistent with the assigned structure. Mass spectrum (ESI): m/e=631.5 (M+H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:15]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:26][CH2:27][CH3:28])[N:18]=2)[OH:16])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].C(O)C>[OH:8][C:9]1[CH:10]=[C:11]([C:15]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:26][CH2:27][CH3:28])[N:18]=2)=[O:16])[CH:12]=[CH:13][CH:14]=1
Reactant: CCCn1nc(C(O)c2cccc(OCc3ccccc3)c2)c2ccccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCCn1nc(C(=O)c2cccc(O)c2)c2ccccc21
Yield: 43.6 %

Procedure:
A mixture of [3-(benzyloxy)phenyl]-(1-propyl-1H-indazol-3-yl)methanol (0.067 g, 0.18 mmol.), ammonium formate (0.09 g, 1.17 mmol) and 10% palladium on carbon (0.09 g) in 10 mL ethanol was heated at reflux for 18 hours. The reaction was filtered (celite) and the cake washed with excess ethanol. The filtrate was concentrated in vacuo. The crude product was purified by HPLC [column: silica gel 150×12 mm (Biotage) at 10 mL/min with methyl-t-butyl ether/hexane, gradient elution, 1:9 to 1:1 over 15 min) to give the title compound (0.022 g) as a white solid.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[CH3:5][Si:6]([C:9]#[C:10][C:11]([CH2:13][CH2:14][CH2:15][CH3:16])=[O:12])([CH3:8])[CH3:7]>CCOCC>[CH3:8][Si:6]([C:9]#[C:10][C:11]([OH:12])([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3][C:2]#[CH:1])([CH3:7])[CH3:5]
Reactant: C#CCBr
Reactant: CCCCC(=O)C#C[Si](C)(C)C
Solvent: CCOCC
Product: C#CCC(O)(C#C[Si](C)(C)C)CCCC
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred suspension of 1.29 g of magensium and 10 mg of mercuric chloride in 12 ml of ether is added 0.4 ml of propargyl bromide. The reaction is initiated after stirring at room temperature for a few minutes. The stirred mixture is cooled in an ice-water bath and a solution of 9.64 g of n-butyl trimethylsilylethynyl ketone and 3.51 ml of propargyl bromide in 13 ml of ether is added dropwise so that the mixture is very gently boiling during 40 minutes. After addition, the cooling bath is removed and the mixture is stirred at room temperature for 1.5 hours. The mixture is recooled in an ice bath and 10 ml of saturated ammonium chloride solution is added. The resulting white mixture is filtered through diatomaceous earth. The clear mother liquid is washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is evaporated to dryness giving 10.5 g of a red liquid. This liquid is Kugelrohr-distilled at 60° C./0.25-0.3 mm. The pale yellow liquid distillate which is the desired product weighs 8.5 g.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N+:3]=1[O-:12].CC(C)([O-])C.[K+].[F:19][C:20]([F:24])([F:23])[CH2:21][OH:22]>[Pd](Cl)Cl>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:22][CH2:21][C:20]([F:24])([F:23])[F:19])[CH:5]=[CH:4][N+:3]=1[O-:12]
Reactant: Cc1c([N+](=O)[O-])cc[n+]([O-])c1C
Reactant: OCC(F)(F)F
Agent: Cl[Pd]Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: Cc1c(OCC(F)(F)F)cc[n+]([O-])c1C
Temperature: 85.5 °C
Yield: 95 %

Procedure:
13.5 ml of 2,2,2-trifluoroethanol were added to the solution of 2,3-dimethyl-4-nitropyridine N-oxide (60 ml, 0.080 mole) obtained in the previous step. Then methylene chloride was distilled off. The resulting concentrated solution was added to a solution of 14.85 g (0.133 mole) potassium tert-butoxide in 54 ml of 2,2,2-trifluoroethanol and 0.034 g of palladium(II) chloride. The reaction mixture was heated to 83-88° C. for 6-8 hours. After cooling to 30° C., potassium nitrite was filtered off, following by distillation of 2,2,2-trifluoroethanol. To this residue 17 ml of a saturated solution of sodium chloride were added and the pH was adjusted by the addition of conc. hydrochloric acid to 6.6. The product was extracted with methylene chloride and 100 ml of a saturated solution of sodium chloride. The organic phases were dried with sodium sulphate and concentrated to a volume of 40 ml. The yield was 95-97%, determined by HPLC.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:11]([CH3:13])[CH3:12])=[C:6]([CH:9]=1)[CH:7]=[O:8].[Cu][C:15]#[N:16].CN(C=O)C.O>C(OCC)(=O)C>[C:15]([C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:11]([CH3:13])[CH3:12])=[C:6]([CH:9]=1)[CH:7]=[O:8])#[N:16]
Reactant: CC(C)Oc1ccc(Br)cc1C=O
Reactant: N#C[Cu]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(C#N)cc1C=O

Procedure:
The title compound was prepared by the treatment of 5-bromo-2-isopropoxy-benzaldehyde (3.5 gm, 0.014 mol) with copper(I) cyanide (2.5 gm, 0.028 mol) in refluxing DMF for 28 hours. The cooled mixture was poured into a mixture of water (100 mL) and ethyl acetate (100 mL). The mixture was filtered through a pad of Celite, the organic layer separated, washed with saturated brine solution, dried (Na2SO4), and evaporated. The title compound was purified by flash chromatography eluting with 15% ethyl acetate in hexane; yield 1.9 gm of a white solid.
Reaction SMILES: [CH2:1]([Sn:5](Cl)([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[CH:15]1([Mg]Br)[CH2:17][CH2:16]1>C1COCC1>[CH2:1]([Sn:5]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:6][CH2:7][CH2:8][CH3:9])[CH:15]1[CH2:17][CH2:16]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)C1CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tri-n-butyltin chloride (4 g, 11.8 mmol) in THF (20 mL) at 0° C. is added 0.5 M cyclopropylmagnesium bromide in THF (28.3 mL, 14.2 mmol). The reaction mixture is stirred under N2 at ambient temperature for 4 h and poured into pH 7 aqueous buffer. The resulting mixture is extracted with diethyl ether, washed with brine, dried over magnesium sulfate and filtered through sintered funnel. The filtrate is concentrated and the residue is distilled under vacuum to give tributylcyclopropyltin as a colorless oil which is used in the next step without further purification.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH3:22])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([N:32]([CH3:40])[CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[O:31])=[CH:26][CH:25]=1>>[CH:1]1([CH:7]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([N:32]([CH3:40])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:31])=[CH:28][CH:29]=2)[C:9]2[C:10]([CH3:22])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(-n2cc(C(O)C3CCCCC3)c(C)n2)cc1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Product: COc1ccc(-n2cc(C(Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)C3CCCCC3)c(C)n2)cc1
Yield: 33.1 %

Procedure:
Using cyclohexyl[1-(4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]methanol (0.68 g) synthesized in Example 23(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.42 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.28 g, 24%) was obtained as a white solid.
Reaction SMILES: [N:1]1([C:6]2[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][NH2:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:16][CH2:17][C:18](=O)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C([BH3-])#N.[Na+]>CO>[N:1]1([C:6]2[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][NH:13][CH:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:17][CH3:16])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NCCOc1ccc(-n2ccnc2)cc1
Reactant: CCCCCC(=O)CC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCCCC(CC)NCCOc1ccc(-n2ccnc2)cc1

Procedure:
In a manner similar to Preparation 8, react 2-[4-(1H-imidazol-1-yl)phenoxy]ethanamine with 3-octanone and sodium cyanoborohydride in methanol to obtain the title compound.
Reaction SMILES: Br[C:2]([F:6])=[C:3]([F:5])[F:4].Br[CH:8]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[CH:9]([CH3:11])[CH3:10]>CN(C)C=O.CC1CC[C@@H](C(C)=C)CC=1.[Cl-].[NH4+].N.[Zn].[Cu]Br>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([CH:9]([CH3:11])[CH3:10])[C:2]([F:6])=[C:3]([F:5])[F:4])=[CH:13][CH:14]=1
Reactant: FC(F)=C(F)Br
Reactant: CC(C)C(Br)c1ccc(Cl)cc1
Agent: [Cu]Br
Agent: C=C(C)[C@H]1CC=C(C)CC1
Agent: N
Solvent: CN(C)C=O
Product: CC(C)C(C(F)=C(F)F)c1ccc(Cl)cc1
Temperature: 38 °C
Reaction time: 0.5 h
Yield: 29.7 %

Procedure:
A mixture of zinc dust (15.72 g) and bromotrifluoroethylene (48.34 g, 0.30 mol) in N,N-dimethylformamide is heated to 38° C. After stirring at 38° C. for several minutes, the reaction mixture temperature rises to 65° C. over 30 minutes. The reaction mixture is then stirred for 90 minutes and cooled to −5° C. Copper(I) bromide (34.5 g, 0.24 mol) is then added to the cooled mixture. The reaction mixture is stirred at room temperature for 1 hour, treated sequentially with 1-(1-bromo-2-methylpropyl)-4-chlorobenzene (18.56 g, 0.075 mol) and limonene (5 drops), stirred at 49° C. overnight, cooled, and diluted with saturated ammonium chloride solution (400 mL) and concentrated ammonia solution (100 mL). The resultant aqueous mixture is extracted with hexanes. The combined organic extracts are washed sequentially with water, 10% hydrochloric acid, water, saturated sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain an oil. Column chromatography of the oil using silica gel and hexanes gives the title product as an oil (5.54 g) which is identified by NMR spectral analyses.
Reaction SMILES: [N:1]1(C(OCC2C3C(=CC=CC=3)C3C2=CC=CC=3)=O)[CH2:48][CH2:47][CH2:46][C@H:2]1[C:3]([N:5]1[CH2:45][CH2:44][CH2:43][C@H:6]1[C:7]([NH:9][C@H:10]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:35])[NH:16][S:17]([C:20]1[C:33]([CH3:34])=[C:31]([CH3:32])[C:30]2[O:29][C:26]([CH3:28])([CH3:27])[CH2:25][CH2:24][C:23]=2[C:21]=1[CH3:22])(=[O:19])=[O:18])=[O:8])=[O:4].N1CCCCC1>C(#N)C>[NH:1]1[CH2:48][CH2:47][CH2:46][C@H:2]1[C:3]([N:5]1[CH2:45][CH2:44][CH2:43][C@H:6]1[C:7]([NH:9][C@H:10]([C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:35])[NH:16][S:17]([C:20]1[C:33]([CH3:34])=[C:31]([CH3:32])[C:30]2[O:29][C:26]([CH3:28])([CH3:27])[CH2:25][CH2:24][C:23]=2[C:21]=1[CH3:22])(=[O:19])=[O:18])=[O:8])=[O:4]
Reactant: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)OCC2c3ccccc3-c3ccccc32)C(=O)OC(C)(C)C)c(C)c2c1OC(C)(C)CC2
Solvent: CC#N
Solvent: C1CCNCC1
Product: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2)C(=O)OC(C)(C)C)c(C)c2c1OC(C)(C)CC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Fmoc-Pro-Pro-Arg(Pmc)-OtBu 1.7 g (1.86 mmol) was dissolved in acetonitrile (50 mL) and treated with piperidine (2 mL) and the mixture was stirred at RT for 4 h. The solvents were removed and the residue was purified by chromatography using methylene chloride-methanol (8:2).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[CH3:20][O:21][CH2:22][CH2:23][NH2:24]>>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:24][CH2:23][CH2:22][O:21][CH3:20])=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: COCCN
Product: CCCCN1C(=O)C(NCCOC)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 2-methoxyethanamine in a similar manner as described for e.g. Example 6 and 7. 1H NMR (400 MHz, CD3CN): δ 7.55-7.49 (m, 5H), 5.83 (bs, 1H), 3.67 (t, 2H), 3.27 (t, 2H), 3.21 (s, 3H), 3.05-3.00 (m, 2H), 1.80-1.72 (m, 2H), 1.48-1.38 (m, 2H), 0.97 (t, 3H); Mass Spectrum: M+H+ 339.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]2[N:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[C@H:24]1[CH2:28][CH2:27][CH2:26][NH:25]1.C(N(C(C)C)CC)(C)C.C(O)CCC>CCOC(C)=O.O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[C@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]2[N:3]=1
Reactant: CCOC(=O)c1cnn2ccc(Cl)nc12
Reactant: Fc1ccc(F)c([C@H]2CCCN2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Temperature: 100 °C
Yield: 64.6 %

Procedure:
A mixture of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (Preparation B, 2.00 g, 8.86 mmol), (R)-2-(2,5-difluorophenyl)pyrrolidine (Preparation A, 1.62 g, 8.86 mmol), diisopropylethylamine (3.09 mL, 17.7 mmol) and butan-1-ol (2.95 ml, 8.86 mmol) was heated at 100° C. for 15 hours. The reaction mixture was cooled to ambient temperature and was diluted with EtOAc (30 mL) and water (10 mL). Undissolved solid was filtered and washed with Et2O to afford the title compound as a light orange solid (2.13 g). The organic layer was separated from the filtrate, washed with brine (10 mL) and dried over MgSO4. The solution was filtered and concentrated to provide additional solid that was purified by silica chromatography using gradient elution with 50-100% EtOAc/hexanes. This afforded the title compound (0.50 g) as a light yellow solid. The combined yield was 2.63 g, 79.7%. MS (apci) m/z=373.1 (M+H).