Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].C([O-])(O)=O.[Na+].[OH-].[Na+].[C:16](Cl)(=[O:20])[C:17]([CH3:19])=[CH2:18]>C(OCC)C.O>[C:16]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])(=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: C=C(C)C(=O)Cl
Reactant: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: C=C(C)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mechanically stirred mixture of L-proline (42.0 grams, g), NaHCO3 (148 g), H2O (680 milliliters, ml) and diethyl ether (280 ml) was maintained in an ambient temperature bath at pH 10.5-10.7 (adjusted by the addition of concentrated aqueous NaOH), then treated portionwise over 20 minutes with a solution of redistilled methacryloyl chloride (40 ml) in diethyl ether (20 ml). Additional concentrated aqueous NaOH was added as needed to keep the pH at 10.5-10.7. Upon addition of all of the methacryloyl chloride (and pH stabilization), the mixture was stirred for 20 minutes at ambient temperature. The resulting immiscible phases were separated and the aqueous phase was extracted with two 250 ml portions of diethyl ether. The combined organic extracts were washed with H2O (50 ml), and the aqueous extract was added to the aqueous phase which phase was then acidified to pH 1 with concentrated aqueous HCl and then extracted with four 250 ml portions of ethyl acetate. The combined ethyl acetate extracts were washed with about 100 ml of brine (saturated aqueous sodium chloride solution) and then dried over Na2SO4. The resulting solution was filtered and concentrated in vacuo to about 230 ml and then heated to boiling, diluted with hexane (80 ml) and allowed to cool. Upon cooling, the desired N-methacryloyl-L-proline spontaneously crystallized as chunky white prisms (51.3 g). The concentrated mother liquor yielded a second crop of crystals (4.26 g) when crystallized as described above. A portion of the first crop was recrystallized twice from ethyl acetate to give an analytical sample, m.p. 102°-104.5° C., having the following spectral characteristics:
Reaction SMILES: [O-]CC.[Na+].[C:5]([CH:9]([C:15]([O:17]CC)=O)[C:10]([O:12]CC)=O)([CH3:8])([CH3:7])[CH3:6].[NH2:20][C:21]([NH2:23])=[O:22]>C(O)C>[C:5]([C:9]1[C:10](=[O:12])[NH:20][C:21](=[O:22])[NH:23][C:15]=1[OH:17])([CH3:6])([CH3:7])[CH3:8]
Reactant: NC(N)=O
Reactant: CCOC(=O)C(C(=O)OCC)C(C)(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1c(O)[nH]c(=O)[nH]c1=O
Yield: 48.5 %

Procedure:
To a stirred solution of sodium ethoxide (prepared from 2.55 g of sodium, 10 mmol) in ethanol (60 ml), was added diethyl tert-butylmalonate (20 g, 92 mmol). The mixture was heated up to reflux. Urea (5.83 g, 97 mmol) in hot ethanol (50 ml) was added and the mixture was refluxed for 6 hr. The mixture was then evaporated in vacuo and the residue was dissolved in water (80 ml). The solution was washed with ether and the water layer was cooled in an ice bath and acidified by the addition of conc. hydrochloric acid. The precipitate was filtered, washed with cold water and n-hexane, and dried in vacuo to give 8.22 g (48%) of a white solid. m.p. 247-248° C.; 1H NMR (200 MHz, DMSO-d6) δ 1.00 (9H, s), 2.83 (1H, s), 11.11 (2H, s).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>CC(N(C)C)=O>[CH3:8][C:7]1[C:2]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:3][CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: C1CNCCN1
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Solvent: CC(=O)N(C)C
Product: Cc1cc([N+](=O)[O-])cnc1N1CCNCC1

Procedure:
1-(3-Methyl-5-nitro-pyridin-2-yl)-piperazine is prepared by heating a solution of 1 g of 2-chloro-3-methyl-5-nitro-pyridine (Maybridge Chemical Company Ltd.) and piperazine (5 g) in DMA at 110° C. for 16 h. Partition between EtOAc and water and wash the organic layer with water (2×). Dry the organic layer with Na2SO4 and concentrate to give crude product. Purify via flash chromatography eluting with MeOH:DCM:NH4OH (9:90:1) to give the title compound.
Reaction SMILES: [O:1]=[C:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[BH4-].[Na+]>CO>[OH:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:3][C:4]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5]
Reactant: CCCCCCCCCCCCCCCC(=O)CC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCCCCCCC(O)CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
To a solution of tert-butyl 3-oxooctadecanoate (130 g) in methanol (700 ml) was added sodium borohydride (15 g) at 0° C. in a portionwise. The mixture was stirred for 1 hour at 0° C. To the reaction mixture was added ice water and from this whole the object compound was extracted with ethyl acetate. The ethyl acetate solution was washed with water, dried over magnesium sulfate and then evaporated to give a residue which was dried up by using high vacuum pump to afford crude tert-butyl 3-hydroxyoctadecanoate (126.6 g) as an oil.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:13]([C:24]([NH2:26])=[O:25])[CH2:12]2)[CH:8]=[CH:9][CH:10]=1)(=O)C.Cl.[OH-].[Na+]>CO>[NH2:4][C:5]1[CH:6]=[C:7]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:13]([C:24]([NH2:26])=[O:25])[CH2:12]2)[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1cccc(N2CCN(Cc3ccccc3)C(C(N)=O)C2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)C1CN(c2cccc(N)c2)CCN1Cc1ccccc1

Procedure:
To 4-[3-(acetylamino)phenyl]-1-(phenylmethyl)-2-piperazinecarboxamide (14.0 g, 39.9 mmol) in methanol (115 mL) add 6N aqueous hydrochloric acid (28 mL). Stir the reaction at reflux. Monitor the progress of the reaction by thin-layer chromatography. Upon completion of the reaction adjust the pH to 12 with 4N aqueous NaOH to obtain a white precipitate. Filter the precipitate to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:40]([C:42]1[CH:47]=[CH:46][C:45](O)=[CH:44][CH:43]=1)#[N:41].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:20])[C@@H:4]1[CH2:8][C@H:7]([O:9][C:45]2[CH:46]=[CH:47][C:42]([C:40]#[N:41])=[CH:43][CH:44]=2)[CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: N#Cc1ccc(O)cc1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H](Oc2ccc(C#N)cc2)CN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 88.9 %

Procedure:
To a solution of N-carbobenzyloxy-trans-4-hydroxy-L-proline methyl ester (10.0 g, 35.8 mmol) in 200 mL of anhydrous THF under N2 was added triphenylphosphine (10.6 g, 39.4 mmol) and 4-cyanophenol (4.7 g, 39.4 mmol). This solution was cooled to 0° C. and then treated with diethylazodicarboxylate (6.3 mL, 39.4 mmol), added dropwise over 30 minutes. The reaction was warmed to room temperature and stirred for 2 days. The solvent was removed in vacuo, and the residue chromatographed (SiO2, 30% ethyl acetate/hexanes) to provide 12.1 g (89%) of N-carbobenzyloxy-4-(cis)-(4-cyanophenoxy)-L-proline methyl ester as a colorless oil. (MS).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Si:9]([O:16][CH:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Si:9]([O:16][CH:17]1[CH2:18][CH2:19][CH:20]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[I:1])[CH2:21][CH2:22]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: Nc1ccccc1I
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCC(Nc2ccccc2I)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a solution of 2-iodoaniline (2.5 g, 10.9 mmol) in dichloromethane (160 mL) was added 4-(tert-butyldimethylsilanyloxy)cyclohexanone (2.39 g, 10.9 mmol) and acetic acid (8 mL). After the reaction was stirred for 1 hour at room temperature, sodium triacetoxyborohydride (3.47 g, 16.4 mmol) was added and the reaction was stirred at room temperature overnight. The reaction was quenched with saturated sodium bicarbonate and extracted with dichloromethane. The organic solution was dried (MgSO4) and concentrated to give 4.47 g of the desired amine, which was used without further purification. LC-MS (C18H30INOSi calc'd 431) m/z 432 (M+H).
Reaction SMILES: C(N[C:6](=[O:38])[C:7]([NH:34]C(=O)C)([CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=2)[CH2:23][CH2:22]1)[CH2:8][CH2:9][CH2:10][CH2:11][B:12]1[O:16]C(C)(C)C(C)(C)[O:13]1)(C)(C)C.[OH2:39]>Cl>[NH2:34][C:7]([CH:21]1[CH2:22][CH2:23][N:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=2)[CH2:25][CH2:26]1)([CH2:8][CH2:9][CH2:10][CH2:11][B:12]([OH:13])[OH:16])[C:6]([OH:38])=[O:39]
Reactant: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)C1CCN(c2ccc(Cl)cn2)CC1
Reactant: O
Agent: Cl
Product: NC(CCCCB(O)O)(C(=O)O)C1CCN(c2ccc(Cl)cn2)CC1
Temperature: 25 °C
Yield: 82 %

Procedure:
A solution of 2-acetylamino-2-(5′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)hexanoic acid, tert-butylamide (1.07 g) in 6 N HCl (20 mL) was stirred at 90° C. for 1 day. After cooling to room temperature, the reaction mixture was transferred to a separatory funnel, diluted with deionized water (10 mL) and washed with dichloromethane (3×). The aqueous layer was frozen in liquid nitrogen and lyophilized to give title compound as a white solid (590 mg, 82%); 1H NMR (D2O, 300 MHz) δ 8.00 (d, J=2.5 Hz, 1H), 7.47 (dd, J1=9.0 Hz, J2=2.5 Hz, 1H), 6.79 (d, J=9 Hz, 1H), 4.42 (d, J=13.5 Hz, 1H), 4.32 (d, J=13 Hz, 1H), 2.79 (t, J=12 Hz, 2H), 2.06 (m, 1H), 1.78-1.94 (m, 3H), 1.55-1.70 (m, 2H), 1.43 (m, 4H), 1.30 (m, 1H) and 0.82 (t, J=7 Hz, 2H); MS (+CI): m/z for C16H25BClN3O4: expected 369.2. found 370.2 (M+H)+, 352.23 (M+H−H2O)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([C:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:26])[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH2:13][CH2:12]1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[CH:27]1([C:25]([N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH2:15][CH2:16]2)=[O:26])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: COc1ccccc1N1CCN(CCN(C(=O)C2CCCCC2)c2ccccc2N)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCN(C(=O)C2CCCCC2)c2ccccc2NS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 39 %

Procedure:
To a solution of 0.22 g of the compound of example 27 and 0.08 mL of triethylamine (TEA) in 5 mL of CH2Cl2, stirred at r.t. under anhydrous nitrogen atmosphere, was added dropwise a solution of 0.04 mL of methanesulphonyl chloride in 0.5 mL of CH2Cl2. The solution was stirred for 6 h at room temperature, afterwards, it was evaporated to dryness in vacuo and the residue was purified by flash chromatography (CH2Cl2-MeCN 9:1) affording 0.10 g (39%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23]4[C:28]([C:29](=[O:37])[C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17]C)[CH:12]=3)[C:3]=12>ClCCl.B(Br)(Br)Br>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23]4[C:28]([C:29](=[O:37])[C:30]=3[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=3)[C:3]=12
Reactant: COc1cccc(-c2nn(C(C)c3oc4ccccc4c(=O)c3-c3ccccc3)c3ncnc(N)c23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(c1oc2ccccc2c(=O)c1-c1ccccc1)n1nc(-c2cccc(O)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 55.6 %

Procedure:
To a solution of example 41 (0.130 g, 0.265 mmoles) in dichloromethane (26 ml), BBr3 (1M in dichloromethane, 2.6 ml) was added at 0° C. and the reaction mixture was warmed to RT and then stirred for 12 h. The reaction mixture was quenched with 1.5N HCl solution and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as light yellow solid (0.070 g, 56% yield). MP: 212-216° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 9.78 (s, 1H), 8.24 (d, J=7.5 Hz, 1H), 8.05 (d, J=7.9 Hz, 1H), 7.85 (t, J=8.4 Hz, 1H), 7.65 (d, J=8.6 Hz, 1H), 7.53 (t, J=7.7 Hz, 1H), 7.36-7.02 (m, 9H), 6.90 (d, J=8.2 Hz, 1H), 6.03 (q, J=6.9 Hz, 1H), 1.91 (d, J=7.3 Hz, 3H). Mass: 476.17 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]2[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]3[C:21]([CH:22]4[CH2:32][CH:23]4[CH2:24][O:25]3)=[CH:20][CH:19]=2)(=[O:16])=[O:15])=[C:10]([CH2:33][N:34](C)[C:35](=O)C(F)(F)F)[CH:9]=1>O.CO>[F:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]2[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]3[C:21]([CH:22]4[CH2:32][CH:23]4[CH2:24][O:25]3)=[CH:20][CH:19]=2)(=[O:15])=[O:16])=[C:10]([CH2:33][NH:34][CH3:35])[CH:9]=1
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2CN(C)C(=O)C(F)(F)F)ccc2c1OCC1CC21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CNCc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21
Temperature: 45 °C
Yield: 74.6 %

Procedure:
A solution of potassium carbonate (0.345 g) in water (2 mL) was added to a solution of methyl (1aRS,7bSR)-5-(4-fluoro-2-[N-methyl-N-(2,2,2-trifluoroacetyl)-aminomethyl]-benzenesulfonyl-amino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 157, 0.257 g) in methanol (12 mL) and the mixture was heated at 45° C. for 3 hours. After cooling, the volatiles were removed in vacuo and the residue was treated with water (30 mL) and saturated with sodium chloride and extracted with ethyl acetate (50 mL). The organic layer was dried (Na2SO4) and filtered and the filtrate was evaporated to dryness to give methyl (1aRS,7bSR)-5-(4-fluoro-2-methylaminomethylbenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.156 g) as a solid.
Reaction SMILES: CN(C)C=O.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([O:14][CH2:15][O:16][CH3:17])=[C:11]([OH:13])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH:24]1(Br)[CH2:27][CH2:26][CH2:25]1>O>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([O:14][CH2:15][O:16][CH3:17])=[C:11]([O:13][CH:24]2[CH2:27][CH2:26][CH2:25]2)[CH:12]=1
Reactant: COCOc1ccc(Br)cc1O
Reactant: BrC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(Br)cc1OC1CCC1
Temperature: 100 °C
Reaction time: 5 h
Yield: 65.9 %

Procedure:
To 10 ml of N,N-dimethylformamide solution containing 1.73 g (7.4 mmol) of 5-bromo-2-methoxymethoxyphenol obtained in Reference Example 5-(b) were added 1.0 g (7.2 mmol) of potassium carbonate and 1.0 g (7.4 mmol) of cyclobutyl bromide, and the mixture was stirred at 100° C. for 5 hours. After completion of the reaction, 10 ml of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 1.4 g of the title compound as a colorless oil. (Yield: 66%)
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]1([CH3:19])[C@@H:11]([CH:12]=[C:13]([CH3:15])[CH3:14])[C@@H:10]1[C:16](Cl)=[O:17].[CH3:20][C:21]1([CH3:31])[C@@H:23]([CH:24]=[C:25]([CH3:27])[CH3:26])[C@@H:22]1[C:28]([OH:30])=[O:29]>N1C=CC=CC=1>[CH3:8][C:9]1([CH3:19])[C@@H:11]([CH:12]=[C:13]([CH3:15])[CH3:14])[C@@H:10]1[C:16]([O:30][C:28]([C@H:22]1[C@H:23]([CH:24]=[C:25]([CH3:27])[CH3:26])[C:21]1([CH3:31])[CH3:20])=[O:29])=[O:17]
Reactant: CC(C)=C[C@H]1[C@H](C(=O)Cl)C1(C)C
Reactant: CC(C)=C[C@H]1[C@H](C(=O)O)C1(C)C
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)=C[C@H]1[C@H](C(=O)OC(=O)[C@H]2[C@H](C=C(C)C)C2(C)C)C1(C)C
Reaction time: 5 h
Yield: 97.4 %

Procedure:
In a 500 ml flask were placed 200 g of toluene, 27.8 g of (-)-trans-2,2-dimethyl-3-isobutenylcyclopropane-1-carboxylic acid chloride and 25.0 g of (-)-trans-2,2-dimethyl-3-isobutenylcyclopropane-1-carboxylic acid. Into the mixture was added drop-wise 11.9 g pyridine, while stirring under nitrogen at a temperature of 20° to 25° C. After 5 hours, the reaction mixture was washed sequentially with an aqueous 10% hydrogen chloride solution, an aqueous 5% sodium hydroxide solution, and water, and then concentrated in vacuo. The residue was distilled in vacuo at boiling point 130° to 135° C./0.2 mmHg, to obtain 46.1 g of (-)-trans-2,2-dimethyl-3-isobutenylcyclopropane-1-carboxylic acid anhydride, with [α]D -17.3° (C=1, CH2Cl2).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].Cl[C:22]1[C:27]([I:28])=[CH:26][N:25]=[CH:24][N:23]=1.[F-].[Cs+].C(N(CC)C(C)C)(C)C>>[I:28][C:27]1[C:22]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])=[N:23][CH:24]=[N:25][CH:26]=1
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Reactant: Clc1ncncc1I
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccn2nc([C@H](C)Nc3ncncc3I)n(-c3ccccc3)c(=O)c12
Yield: 32.7 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (400 mg, 1.49 mmol) was treated 4-chloro-5-iodopyrimidine (538 mg, 2.24 mmol), cesium fluoride (453 mg, 2.98 mmol) and N,N-diisopropylethylamine (1.3 mL, 7.46 mol) according to Preparation 13. The residue was purified by reverse phase using SP1® Purification System to give 230 mg (33% yield) of the title compound as a solid. Purity 100%.
Reaction SMILES: Cl.Cl.Cl.N1C=C(C[N:10]2[C:16]3[CH:17]=CC(C4C=NC=CC=4)=[CH:20][C:15]=3[CH2:14][N:13]([C:27](=[O:32])[C:28](F)(F)F)[CH:12]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:11]2)N=C1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:11]([C:12]1[CH:33]=[CH:17][C:16]2[NH:10][CH2:11][C@@H:12]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:13]([C:27](=[O:32])[CH2:28][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:14][C:15]=2[CH:20]=1)#[N:10]
Reactant: O=C(N1Cc2cc(-c3cccnc3)ccc2N(Cc2c[nH]cn2)CC1Cc1ccccc1)C(F)(F)F
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)CN(C(=O)Cc1ccccc1)[C@H](Cc1ccccc1)CN2
Yield: 131.1 %

Procedure:
A solution of Compound B (1.1g, 2.8 mmol) in TFA (8 mL) and methylene chloride (8 mL) was stirred for 3 h and concentrated. Trituration with ethyl ether and drying under vacuum afforded 700 mg (74%) of Compound C as a white solid. MS (M+H)+ 337.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6].[C:14]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[NH2:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc([N+](=O)[O-])c(N)c1O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1c(C#N)ccc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.2 %

Procedure:
To a stirring suspension of 11A (0.34 g, 1.86 mmol) and K2CO3 (0.283 g, 2.05 mmol) in DMF (3 mL) was added iodomethane (0.127 mL, 2.05 mmol). After the addition, the reaction mixture was stirred at rt for 16 h, then partitioned between H2O and CH2Cl2. The separated CH2Cl2 layer was washed with water, brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was chromatographed (silica gel) eluting with 5% to 40% EtOAc/hexane to yield the title compound (0.22 g) as a solid.
Reaction SMILES: [F:1][C:2]([CH2:9][CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].CC(C)=[O:25].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[F:1][C:2]([CH2:9][CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:3][CH2:4][CH2:5][CH2:6][C:7]([OH:25])=[O:8]
Reactant: CCCCCC=CCCCCC=CCC(F)=CCCCCO
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CCCCCC=CCCCCC=CCC(F)=CCCCC(=O)O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of the alcohol prepared in 2K (21 mg, 0.067 mmoles) in acetone (2 ml) cooled to 0° C. was added dropwise 2.67M Jones reagent until the organe color was stable. The mixture was stirred 15 min at 0° C. The excess of Jones reagent was reacted with isopropanol. The acetone was evaporated under reduced pressure without heating. The residue was taken with water and extracted three times with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to leave an oil (20 mg). Flash chromatography on silicagel and elution with a 25:75 mixture of ethyl acetate and hexane gave pure title acid (14 mg, 64%). NMR (H1, CDCl3, 360 MHz): 0.89 (t, JHH ~7 Hz, 3), 1.21 to 1.45 (m, 10), 1.51 (quint, JHH ~7 Hz, 2), 1.98 to 2.12 (m, 8), 2.37 (t, JHH ~7 Hz, 2), 2.96 (dd, JHF =23 Hz, JHH =6.8 Hz, 2), 4.98 (dt, JHH =21.2Hz, JHH =7.9 Hz, ]), 5.3 to 5.5 (m, 4).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:42])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36](N(OC)C)=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[CH:43]1([Mg]Br)[CH2:45][CH2:44]1.Cl>O1CCCC1>[CH:43]1([C:36](=[O:37])[CH2:35][O:34][C@H:31]2[CH2:32][CH2:33][C@H:28]([N:18]3[C:17](=[O:42])[C:16]([CH2:15][C:12]4[CH:11]=[CH:10][C:9]([C:4]5[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=5)=[CH:14][CH:13]=4)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]4[N:25]=[CH:26][N:27]=[C:19]34)[CH2:29][CH2:30]2)[CH2:45][CH2:44]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)N(C)OC)CC2)c2ncnn12
Reactant: Br[Mg]C1CC1
Agent: Cl
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)C3CC3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-[(trans-4-{6-[(2′-Cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide (0.32 g) was dissolved in tetrahydrofuran (4 mL), cyclopropylmagnesium bromide (3.3 mL, 0.5M tetrahydrofuran solution) was added dropwise, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.23 g, 75%).