Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[CH2:2][OH:3].[C:5]1([CH:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:12][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:19]1([CH:11]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:12][N:13]2[CH2:14][CH2:15][N:16]([CH2:1][CH2:2][OH:3])[CH2:17][CH2:18]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(C(CN2CCNCC2)c2ccccc2)cc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCN1CCN(CC(c2ccccc2)c2ccccc2)CC1

Procedure:
Ethylene bromohydrin (4.03 g) was added dropwise to a mixture of 1-(2,2-diphenylethyl)piperazine (4.30 g), potassium carbonate (6.7 g) and N,N-dimethylformamide (20 ml) with stirring. The mixture was stirred at room temperature overnight, diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over Na2SO4. The solvent was then distilled off and the residue was subjected to silica gel chromatography. Elution with ethyl ether-ethyl acetate-methanol (10:2:1, v/v) gave 4-(2,2-diphenylethyl)-1-piperazineethanol as an oil. Yield 4.24 g.
Reaction SMILES: [C@H:1]12[NH:8][CH2:7][C@H:6]1[CH2:5][CH2:4][N:3]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2]2.C([O-])([O-])=O.[Na+].[Na+].[C:22](Cl)([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C1COCC1.O>[C@H:1]12[N:8]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:7][C@H:6]1[CH2:5][CH2:4][N:3]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2]2
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2CN[C@@H]2C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H]2CN(C(=O)OCc3ccccc3)[C@@H]2C1
Reaction time: 18 h
Yield: 101.9 %

Procedure:
To (1S,6R)-tert-butyl 3,8-diazabicyclo[4.2.0]octane-3-carboxylate (1.4 g, 6.8 mmol) in THF (35 mL) and H2O (35 mL) was added Na2CO3 (1.4 g. 13.6 mmol) and CbzCl (1.1 mL, 7.5 mmol). After 18 h, the reaction mix was diluted with H2O and extracted with CH2Cl2 (2×). The combined organics were dried (Na2SO4) to give 2.4 g of the title compound as a clear oil that was used without further purification.
Reaction SMILES: [CH2:1]([OH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:15](Cl)(=[O:18])[CH:16]=[CH2:17]>C1COCC1.ClCCl>[C:15]([O:7][CH2:1][C:2]1[O:6][CH:5]=[CH:4][CH:3]=1)(=[O:18])[CH:16]=[CH2:17]
Reactant: C=CC(=O)Cl
Reactant: OCc1ccco1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)OCc1ccco1
Temperature: 0 °C
Reaction time: 3 h
Yield: 84.5 %

Procedure:
Furfuryl alcohol (5.3 mL, 1 eq.) was dissolved in THF (100 mL) in a dry, round bottomed flask and stirred with triethylamine (10.7 mL, 1.25 eq.). The solution was cooled to 0° C. and acryloyl chloride (5 mL, 1 eq.) was added dropwise. The mixture was stirred for 3 h at 20° C. The reaction was worked up by diluting with dichloromethane (50 mL) and filtered through a celite plug to remove the triethylammonium chloride, and the solvent was removed under vacuum. The residue was purified by silica column chromatography using tert-butylmethyl ether-hexane (1:7) (furfuryl acrylate Rf 0.51) to give an oil (7.9 g 84.5% yield). IR (cm−1): 1728 (C═O st), 3147, 3124 (═C—H st), 810, 748 (C—H δ, furan ring). 1H NMR (CDCl3, 300 MHz): δ 6.39 (dd, 1H, H-1A, J1A,1B=17.3 Hz, J1A,2=1.47 Hz), 6.10 (dd, 1H, H-1B J1B,2=10.41 Hz), 5.79 (dd, 1H, H-2), 5.10 (s, 2H, CH2) ppm. Furan ring: 6.40 (bd, 1H, H-3′, J3′,4′=3.2 Hz), 6.33 (dd, 1H, H-4′, J4′,5′=1.9 Hz), 7.39 (m, 1H, H-5′) ppm. 13C NMR (CDCl3, 75 MHz): δ 131.1, 128.0 (C-1/C-2), 165.6 (C-3), 58.0 (CH2) ppm. Furan ring: 149.4 (C-2′), 110.6, 110.5 (C-3′, C-4′), 143.2 (C-5′) ppm. CI-Mass Spectrometry. m/z: 152 (M+), 97 [(OCH2-fur)+], 81 (main peak) [(CH2-fur)+], 55 [(CH2CHCO)+]. HRMS: Theoretical molecular weight for C8H8O3 (M+) 152.047344, experimental molecular weight: 152.046924.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[Cl:7][CH2:8][CH:9]([OH:12])[CH2:10][OH:11]>CO>[Cl-:7].[OH:12][CH:9]([CH2:10][OH:11])[CH2:8][N+:4]1[CH:5]=[CH:6][N:2]([CH3:1])[CH:3]=1
Reactant: Cn1ccnc1
Reactant: OCC(O)CCl
Solvent: CO
Product: Cn1cc[n+](CC(O)CO)c1
Product: [Cl-]
Reaction time: 48 h
Yield: 100.2 %

Procedure:
1-Methylimidazole (8.21 g, 100 mmol) and 3-chloro-1,2-propanediol (11.05 g, 100.0 mmol) were stirred in a 130° C. oil bath for 48 h, after which the flask was placed under vacuum and stirring continued at 130° C. for another 48 h. The residue was then dissolved in CH3OH, transferred to a tared flask and concentrated to afford the product as a viscous brown oil (19.3 g, 100%). 1H NMR: δH ppm (400 MHz; DMSO-d6) 3.19-3.29 (m, 1H) 3.36-3.48 (m, 1H) 3.77 (dd, J=6.78, 4.21 Hz, 1H) 3.87 (s, 3H) 4.10 (dd, J=13.74, 7.69 Hz, 1H) 4.32 (dd, J=13.74, 3.11 Hz, 1H) 5.13 (br. s., 1H) 5.53 (d, J=5.13 Hz, 1H) 7.72 (t, J=1.74 Hz, 1H) 7.74 (t, J=1.74 Hz, 1H) 9.18 (s, 1H).
Reaction SMILES: [PH4+].[C:2]1([P:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21][CH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[Cl-:21].[C:27]([C:26]1[CH:29]=[CH:30][C:23]([CH2:22][P+:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:24][CH:25]=1)#[N:28]
Reactant: N#Cc1ccc(CCl)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [PH4+]
Solvent: Cc1ccccc1
Product: N#Cc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: [Cl-]
Yield: 57.1 %

Procedure:
The phosphonium salt used for this preparation was made as follows:- a solution of triphenylphosphine (39.3g) and 4-chloromethylbenzonitrile (22.7g) in toluene (400 ml) was heated under reflux for 53 hr. After cooling, the solid was collected, washed with toluene and dried to give 4-cyanobenzyltriphenylphosphonium chloride (35.4g), νmax (nujol) 2230 (CN) and 1436 cm.-1 (PPH3), τ (d6 -DMSO; 60 MHz) values include 2.0-2.5 (aromatic protons), 4.47 (CH2).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][C:11]2[CH:12]=[N:13][CH:14]=[C:15]([CH:18]=2)[C:16]#[N:17])[CH:5]=[CH:6][C:7]=1[F:8].[C:19](OCC)(=O)C.[O:25]1[CH2:29][CH2:28][CH2:27]C1>>[C:16]([C:15]1[CH:18]=[C:11]([C:10]#[C:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([NH:1][C:29](=[O:25])[CH:28]([CH3:19])[CH3:27])[CH:3]=2)[CH:12]=[N:13][CH:14]=1)#[N:17]
Reactant: N#Cc1cncc(C#Cc2ccc(F)c(N)c2)c1
Reactant: CCOC(C)=O
Reactant: C1CCOC1
Product: CC(C)C(=O)Nc1cc(C#Cc2cncc(C#N)c2)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
Add a solution of isobutynyl chloride (0.09 g, 1.08 mmol) dissolved in tetrahydrofuran to a solution of 5-(3-amino-4-fluorophenylethynyl) -nicotinonitrile, (prepared as described in EXAMPLE 160), (0.2 g, 0.8 mmol) in anhydrous tetrahydrofuran and stir overnight at room temperature. Pour into ethyl acetate, wash with water and an aqueous saturated solution of sodium chloride, dry (potassium carbonate), filter and concentrate. Purify the residue by silica gel chromatography, eluting with 100:0 to 95:5 dichloromethane:ethyl acetate, to give the title compound as a white solid (210 mg, 84%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][Cl:37]>CN(C=O)C>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][Cl:37])=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: ClCCCCCBr
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCCl)c2n1
Temperature: 50 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
2-(Butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate (2 g, 5.69 mmol) and potassium carbonate (1.967 g, 14.23 mmol) were suspended in DMF (20 ml) and heated to 50° C., under nitrogen for 1 hour. The mixture was cooled to room temperature, 1-bromo-5-chloropentane (0.75 ml, 5.69 mmol) was added and stirring was continued at room temperature for 18 hours. The reaction mixture was partitioned between DCM (40 ml) and water (40 ml) and the layers were separated using a hydrophobic frit. The aqueous layer was extracted again with DCM (10 ml) and the combined organics were washed with saturated lithium chloride solution, separated (hydrophobic frit) and concentrated in vacuo to give the title compound as a yellow oil (1.946 g).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]#[CH:30])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:32][CH2:33][CH2:34][CH2:35][O:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][O:38]1>>[C:14]([Si:1]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]#[C:30][CH2:32][CH2:33][CH2:34][CH2:35][O:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][O:38]1)([CH3:15])([CH3:16])[CH3:17]
Reactant: C#CCCCCCCCCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: BrCCCCOC1CCCCO1
Product: CC(C)(C)[Si](OCCCCCCCCCCC#CCCCCOC1CCCCO1)(c1ccccc1)c1ccccc1
Yield: 66 %

Procedure:
Alkylation of 12-(tert-butyldiphenylsilyloxy)dodec-1-yne with 2-(4-bromobutoxy)tetrahydropyran as described above gave tert-butyldiphenyl-[16-(tetrahydropyran-2-yloxy)hexadec-11-ynyloxy]silane (66%) as a colorless oil which was used in the next reaction without further purification. TLC: 10% EtOAc/hexane, Rf≈0.5.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[N:23]=3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>>[ClH:28].[Cl:28][C:24]1[N:23]=[C:22]([CH2:21][O:20][C:16]2[N:15]=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:19]=[CH:18][N:17]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccnc(OCc3cccc(Cl)n3)n2)CC1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: Clc1cccc(COc2nccc(N3CCNCC3)n2)n1

Procedure:
The title compound (5-A) was prepared from 4-[2-(6-chloro-pyridin-2-ylmethoxy)-pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (I-5b) and TFA according to a procedure analogous to that described in Example 3.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][C:4]([NH:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:3]1.CN(C(O[N:32]1N=N[C:34]2C=CC=[CH:38][C:33]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.C(N)(C)C>CN(C=O)C>[CH:33]([NH:32][C:7]([C:6]1[N:2]([CH3:1])[N:3]=[C:4]([NH:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:5]=1)=[O:9])([CH3:38])[CH3:34]
Reactant: Cc1onc(-c2ccccn2)c1CNc1cc(C(=O)O)n(C)n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)N
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccn2)c1CNc1cc(C(=O)NC(C)C)n(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of 1-methyl-3-((5-methyl-3-(pyridin-2-yl)isoxazol-4-yl)methylamino)-1H-pyrazole-5-carboxylic acid (80 mg, 255 μmol) in DMF (3 mL) were added TBTU (91 mg, 281 μmol) and N,N-diisopropyl ethyl amine (217 μL, 1.28 mmol) followed by isopropylamine (24 μL, 281 μmol). The mixture was stirred at RT for 1 h, then evaporated. The residue was purified by flash-chromatography over NH2 silica gel using gradient EtOAc/heptane 10-70% to afford the title compound (75 mg, 83%) as a white solid. MS: m/e=355.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].N1C=CC=[CH:14][CH:13]=1.C(Cl)(=O)C>C1COCC1>[CH3:13][C:14]1[NH:6][C:4](=[O:5])[C:3]2[C:2](=[C:10]([CH3:11])[CH:9]=[CH:8][CH:7]=2)[N:1]=1
Reactant: c1ccncc1
Reactant: Cc1cccc(C(N)=O)c1N
Solvent: CC(=O)Cl
Solvent: C1CCOC1
Product: Cc1nc2c(C)cccc2c(=O)[nH]1
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To a solution of 2-amino-3-methylbenzamide (0.5 g, 3.3 mmol) (prepared by conventional methods) and pyridine (0.35 ml, 4.3 mmol) in dry THF (15 ml), was added a solution of acetyl chloride (0.36 ml, 5.0 mmol) in THF (2 ml) dropwise, and the mixture was stirred overnight under nitrogen. The solvent was removed under vacuum and the remaining white slurry was resuspended in 2% aqueous sodium hydroxide solution and neutralised with aqueous hydrochloric acid, whereupon a white precipitate formed. The solid was collected and recrystallised from methanol-water to furnish the required quinazolinone (0.47 g, 81%) m.p. 217°-220° C.;
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[OH:22])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:27](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[C:23]([C:20]1[CH:19]=[C:7]([CH:6]=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[C:21]=1[OH:22])[N:8]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:13][CH:14]=1)[CH3:27])([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1cc(Nc2ccc(CC(=O)O)cc2)cc(C(C)(C)C)c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(c1ccc(CC(=O)O)cc1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of a solution of 6.3 g (0.018 mole) of 4-[3,5-di-(tertiary-butyl)-4-hydroxyanilino]phenylacetic acid in 10 ml of N,N-dimethylformamide and 5 g (0.036 mole) of potassium carbonate was heated on a steam bath until gas evolution ceased. The mixture was allowed to cool to ambient temperature, and 5 milliliters of methyl iodide were then added. The mixture was heated at its boiling temperature and 5 ml aliquots of methyl iodide were added at 20, 45 and 60 minutes. After the mixture had evaporated, the residue was taken up in water and 2N sodium hydroxide solution was added. The mixture was warmed, and the insoluble residue of methyl 4-[3,5-di(tertiary-butyl)-4-hydroxy-N-methyl-anilino] phenylacetate was separated by filtration. The residue was suspended and partially dissolved in 50 ml of methanol, and 10 ml of 2.5N sodium hydroxide solution was added. The mixture was stirred for about 16 hours, diluted with 300 ml of water and 300 ml of diethyl ether, and was then further diluted with about 100 ml of hexane. The mixture was acidified with dilute hydrochloric acid and the aqueous phase was discarded. The organic phase was washed first with 10% sodium bicarbonate solution and then with 5% sodium carbonate solution. The product remained in the organic phase as the sodium salt. The organic phase was acidified with 10% aqueous hydrochloric acid and washed with sodium chloride solution, followed by drying. Evaporation provided a residue which was extracted with 20 ml of boiling benzene. Hexane (6 ml) was added, and the light yellow solid was recrystallized first from 80% aqueous ethanol, and then from benzene to provide fine yellow needles of 4-[3,5-di(tertiary-butyl)-4-hydroxy-N-methylanilino]phenylacetic acid, m.p. 81°-182.5° C. Analysis: Calculated for C23H31NO3 ; % C, 74.8; % H, 8.5; % N, 3.8; Found: % C, 74.8; % H, 8.6; % N, 3.6.
Reaction SMILES: [CH3:1][NH2:2].[O:3]([CH2:10][CH2:11][CH2:12]Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1>[CH3:1][NH:2][CH2:12][CH2:11][CH2:10][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCCCOc1ccccc1
Reactant: CN
Solvent: C1CCOC1
Product: CNCCCOc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.57 g of methylamine is condensed in a solution of 1.6 ml of 3-phenoxy-propylbromide in 15 ml of anhydrous tetrahydrofuran at −78° C., and it is stirred overnight at room temperature in a pressurized reactor. After the pressurized reactor was opened at −20° C., it is allowed to come to room temperature to allow excess methylamine to evaporate off. Then, the reaction solution is added to saturated sodium chloride solution, extracted with ether, dried on magnesium sulfate and concentrated by evaporation in a vacuum. 2.01 g of methyl-(3-phenoxy-propyl)-amine is obtained as a crude product, which is used without further purification in the next stage.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:15]2[C:28]([F:29])=[CH:27][C:18]([C:19]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])=[C:17]([F:30])[C:16]=2[F:31])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:34](OC)[N:35]([CH3:37])C.Cl.N[S:42][CH2:43]CO.C(N(CC)CC)C>C1C=CC=CC=1.C(O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1([C:15]2[C:28]([F:29])=[CH:27][C:18]([C:19]([C:21](=[CH:37][NH:35][CH2:34][CH2:43][SH:42])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])=[C:17]([F:30])[C:16]=2[F:31])[CH2:13][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)c1cc(F)c(C2(NC(=O)OCc3ccccc3)CC2)c(F)c1F
Reactant: COC(OC)N(C)C
Reactant: NSCCO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: c1ccccc1
Product: CCOC(=O)C(=CNCCS)C(=O)c1cc(F)c(C2(NC(=O)OCc3ccccc3)CC2)c(F)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.7 %

Procedure:
In 5 ml of benzene was dissolved 500 mg of ethyl 4-(1-benzyloxycarbonylaminocyclopropyl)-2,3,5-trifluorobenzoylacetate. To the resulting solution was added 411 mg of N,N-dimethylformamide-dimethylacetal, and the resulting mixture was refluxed for 40 minutes. The reaction mixture was concentrated under reduced pressure, and the residue obtained was dissolved in 5 ml of ethanol. To the resulting solution were added 157 mg of 2-aminothioethanol hydrochloride and 139 mg of triethylamine, and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by a column chromatography (eluant: toluene/ethyl acetate=5/1) to obtain 250 mg (yield: 41.7%) of ethyl 2-[4-(1-benzyloxycarbonylaminocyclopropyl)-2,3,5-trifluorobenzoyl]-3-(2-mercaptoethylamino)acrylate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH:13]([S:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12](=[O:24])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:25](O)[CH2:26][OH:27].B(F)(F)F.C(OCC)(=O)C.C1CCCCC1>ClCCl>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:10][CH2:11][C:12]2([O:27][CH2:26][CH2:25][O:24]2)[C@H:13]([S:15][C:16](=[O:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)C(SC(=O)c2ccccc2)C1
Reactant: OCCO
Agent: FB(F)F
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCC2(OCCO2)[C@H](SC(=O)c2ccccc2)C1
Reaction time: 48 h
Yield: 28.1 %

Procedure:
A mixture of the compound of Example 35 Step A (2.00 g, 5.72 mmol), 1,2-ethandiol (2.0 ml, 35.8 mmol), 25 ml of dichloromethane and BF3 (48% purity, 0.60 ml, 4.25 mmol) was stirred for 2 days. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate and brine, dried and stripped of the solvent. After chromatography (silica, ethyl acetate/cyclohexane=1/9->15/85) the title compound (toluene/ethyl acetate=9/1, Rf=0.28, 632 mg, 28% yield) was obtained as foam.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].[CH2:15]([O:19][C:20](Cl)=[O:21])[CH:16]([CH3:18])[CH3:17].Cl>O>[CH2:15]([O:19][C:20]([NH:1][CH:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]([OH:12])=[O:11])=[O:21])[CH:16]([CH3:18])[CH3:17]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)COC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)COC(=O)NC(Cc1ccccc1)C(=O)O
Temperature: 12.5 °C
Reaction time: 3.5 h

Procedure:
L-phenylalanine (50 gm) in water (50 mL) was stirred for about 30 minutes and reaction mass was cooled to 10-15° C. To the resulting solution, aq. NaOH was added followed by addition of isobutylchloroformate (45.5 gm). The reaction mass was stirred at about 25° C. for about 3-4 h and pH was adjusted to 2-3 by addition of conc. HCl at 10-15° C. Reaction mass was stirred at 10-15° C. for 1 h, filtered, washed with water and dried to obtain the title compound.
Reaction SMILES: [CH:1]1([C:6]([O:8][CH2:9][O:10][C:11]2[N:16]=[C:15]([NH:17]C=O)[C:14]([F:20])=[CH:13][N:12]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.O.NN>CCOCC>[CH:1]1([C:6]([O:8][CH2:9][O:10][C:11]2[N:16]=[C:15]([NH2:17])[C:14]([F:20])=[CH:13][N:12]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CNc1nc(OCOC(=O)C2CCCC2)ncc1F
Agent: NN
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: Nc1nc(OCOC(=O)C2CCCC2)ncc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 36.6 %

Procedure:
A 25 mL vial was charged with (5-fluoro-4-formamidopyrimidin-2-yloxy)methyl cyclopentanecarboxylate (34.0 mg, 0.120 mmol), ethanol (1 mL), and hydrazine monohydrate (23.3 μL, 0.479 mmol). The resulting clear, colorless solution was then agitated on an orbital shaker at room temperature for 45 min. The crude reaction mixture was diluted with Et2O (50 mL) and was washed with saturated aqueous NaCl solution (50 mL×2). The organic was dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (11.2 mg, 36%) as a white solid: mp 101-104° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.97 (d, J=3.4 Hz, 1H), 7.44 (bs, 1H), 5.86 (s, 2H), 2.69-2.83 (m, 1H), 1.42-1.91 (m, 8H); MS (ESI) m/z 256 (M+H)+, 254 (M−H)−.
Reaction SMILES: CCN=C=NCCCN(C)C.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[C:21]([C:28]([OH:30])=O)[CH:20]=2)=[CH:15][CH:14]=1.C1C=[CH:33][C:34]2[N:39](O)N=N[C:35]=2C=1.CN1[C:46](=[O:47])CCC1>C(Cl)Cl.CN(C=O)C>[CH3:46][O:47][CH2:33][CH:34]([NH:39][C:28]([C:21]1[CH:20]=[C:19]([C:16]2[CH:15]=[CH:14][C:13]([CH3:12])=[CH:18][CH:17]=2)[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=1)=[O:30])[CH3:35]
Reactant: CN1CCCC1=O
Reactant: On1nnc2ccccc21
Reactant: Cc1ccc(-c2cc(C(=O)O)cc([N+](=O)[O-])c2)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCC(C)NC(=O)c1cc(-c2ccc(C)cc2)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 83.4 %

Procedure:
EDCI (16.17 g, 84.38 mmol) was added portion wise to a stirred solution of 4′-methyl-5-nitro-biphenyl-3-carboxylic acid (15.49 g, 60.27 mmol), HOBt (11.44 g, 84.38 mmol) and 2-amino-1-methoxy-1-propane (7 ml, 66.31 mmol) in NMP (9.29 ml, 84.38 mmol), CH2Cl2 (180 ml) and DMF (20 ml) at 0° C. The mixture was allowed to warm to room temperature and was stirred at the same temperature for 14 hours. The reaction mixture was washed with 2N HCl, 2N NaOH, saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered, and concentrated under vaccum to give 4′-methyl-5-nitro-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide as a yellow oil (16.5 g, 83.5%). MS (M+H)=329.