Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH:2]([CH3:28])[CH:3]([NH:15][C:16]([CH:18]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:20][NH:19]1)=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1.Br[CH2:30][C:31]1[O:32][C:33](=[O:37])[O:34][C:35]=1[CH3:36]>CN(C=O)C>[Cl:1][CH:2]([CH3:28])[CH:3]([NH:15][C:16]([CH:18]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:20][N:19]1[CH2:30][C:31]1[O:32][C:33](=[O:37])[O:34][C:35]=1[CH3:36])=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1
Reactant: CCCC1CCNC(C(=O)NC(C(C)Cl)C2OC(SC)C(O)C(O)C2O)CC1
Reactant: Cc1oc(=O)oc1CBr
Solvent: CN(C)C=O
Product: CCCC1CCC(C(=O)NC(C(C)Cl)C2OC(SC)C(O)C(O)C2O)N(Cc2oc(=O)oc2C)CC1
Reaction time: 16 h
Yield: 65.6 %

Procedure:
The title compound from example 47 (55 mg, 0.13 mmol) was dissolved in dry DMF (5 mL), then solid KHCO3 (26 mg, 0.25 mmol) and 4-Bromomethyl-5-methyl-[1,3]dioxol-2-one (48 mg, 0.25 mmol, prepared as described in J. Alexander, et. al. J. Med. Chem, 1996, 39, 480-486) were added. The resulting mixture was stirred for 16 h, and the solvents were removed under reduced pressure, then the residue was purified by chromatography on silica with 5% MeOH/DCM followed by preparative HPLC to provide the title compound (47 mg, 68%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.C([N-]C(C)C)(C)C.[Li+].[C:17](=[O:19])=[O:18]>C1CCCCC1.C1COCC1.O>[F:8][C:4]1[N:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[C:17]([OH:19])=[O:18]
Reactant: O=C=O
Reactant: Fc1cccc(F)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: C1CCCCC1
Product: O=C(O)c1ccc(F)nc1F
Reaction time: 2 h
Yield: 97 %

Procedure:
2,6-Difluoropyridine (7.89 mL, 0.087 mmol) is added dropwise under N2 at 78° C. to a stirred solution of lithium diisopropylamide (59.0 mL of a 1.5 N solution in cyclohexane, 0.089 mmol) in THF (250 mL). After 2 h at 78° C., a stream of dry CO2 is passed through the solution and the mixture is diluted with water and washed with EtOAc. The aqueous portion is neutralized with 3 N HCl, extracted with EtOAc and worked up to give 2,6-difluoronicotinic acid (13.4 g, 97%) . 1H NMR (DMSO) δ 8.59 (1H, dd, J=9.2, 8.2 Hz), 7.30 (1H, dd, J=8.2, 2.1 Hz), 4.03 (1H, brs).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=O)=[CH:5][CH:4]=1.[C:14]([CH2:16]C(O)=O)#[N:15].C(O)(=O)CCCCCC.C(N)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]=[C:10]2[CH2:16][C:14]#[N:15])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)CCC2
Reactant: N#CCC(=O)O
Agent: CCCCCCC(=O)O
Solvent: Cc1ccccc1
Solvent: NCc1ccccc1
Product: COc1ccc2c(c1)C(CC#N)=CCC2
Yield: 90 %

Procedure:
There are introduced into a 670 litre reactor 85.0 kg of 7-methoxy-1-tetralone, 60.3 kg of cyanoacetic acid and 15.6 kg of heptanoic acid in toluene in the presence of 12.7 kg of benzylamine. The mixture is heated at reflux. When all the starting substrate has disappeared, the solution is cooled and filtered. The precipitate obtained is washed with toluene and then the filtrate obtained is washed with a 2N sodium hydroxide solution and subsequently with water until neutral. After removal of the solvent by evaporation, the resulting solid is recrystallised from an ethanol/water (80/20) mixture to give the title product in a yield of 90% and with a chemical purity exceeding 99%.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9]2)=[CH:4][CH:3]=1.C(Cl)Cl.C1C=CC=CC=1.[Br-].[CH2:28]([O:30][C:31](=[O:36])[CH2:32][CH2:33][CH2:34][Zn+])[CH3:29]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:14][C:13]([F:16])([F:15])[C:12]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:2]([CH2:34][CH2:33][CH2:32][C:31]([O:30][CH2:28][CH3:29])=[O:36])=[CH:3][CH:4]=2)[CH2:9]1)=[O:17]
Reactant: O=C(N1CCc2ccc(Br)cc2C1)C(F)(F)F
Reactant: CCOC(=O)CCC[Zn+]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CCOC(=O)CCCc1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C

Procedure:
A mixture of 1-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone (5.34 g, 17.3 mmol) and Pd(dppf)Cl2.CH2Cl2 (708 mg, 0.867 mmol) was azeotroped with benzene and suspended in 50 mL of dry THF. At room temperature, 4-ethoxy-4-oxobutylzinc bromide (0.5M in THF, 52 mL, 26 mmol) was added dropwise with syringe. The orange suspension became a clear brown solution. The reaction mixture was then refluxed for 2 h. After cooling to room temperature, it was quenched with brine, extracted with EtOAc, washed with 10% HCl and brine, dried over Na2SO4, and evaporated to dryness. Flash chomatography (SiO2, EtOAc/hexane=15:100 to 20:100) gave ethyl 4-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)butanoate as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([NH:15]C(=O)C)=[C:10]([CH3:19])[CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[OH-].[Na+]>C(O)C>[CH3:19][C:10]1[CH:9]=[C:8]([N:3]2[C:4]([CH3:7])=[CH:5][CH:6]=[C:2]2[CH3:1])[C:13]([CH3:14])=[CH:12][C:11]=1[NH2:15]
Reactant: CC(=O)Nc1cc(C)c(-n2c(C)ccc2C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(-n2c(C)ccc2C)c(C)cc1N

Procedure:
A mixture of the product from stage b) (0.6 g), aqueous sodium hydroxide solution (10 ml, 10%) and ethanol (30 ml) was heated under reflux for 24 hours. On cooling, the mixture was extracted with diethyl ether (x2). The combined diethyl ether extracts were water washed, dried (MgSO4) and concentrated to give a crude product. Filtration through silica gave the title product.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15].[CH2:17]([O:19][C:20](=[O:24])[CH:21](Cl)[CH3:22])[CH3:18]>CN(C=O)C>[F:7][C:8]1[CH:13]=[C:12]([CH:21]([CH3:22])[C:20]([O:19][CH2:17][CH3:18])=[O:24])[CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15]
Reactant: CCOC(=O)C(C)Cl
Reactant: O=[N+]([O-])c1ccccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
To a stirred solution of potassium t-butoxide (20 mmol) in DMF (20 mL) was added a mixture of 2-fluoro-nitrobenzene (10 mmol) and ethyl-2-chloropropionate (10 mmol) at 0° C. dropwise. After being stirred for 10 min at 0° C., the mixture was quenched by 1 N HCl solution, diluted with water and extracted with diethyl ether several times. The combined organic layers were washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:10) as eluant to afford ethyl 2-(3-fluoro-4-nitrophenyl)propionate (1-1, SU-654).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].I.[NH2:24][C:25]1[C:26]([C:33]([NH:35][C:36](=[NH:39])SC)=[O:34])=[N:27][C:28]([Cl:32])=[C:29]([NH2:31])[N:30]=1.C(N(CC)CC)C>C1COCC1>[C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:36]([NH2:39])=[N:35][C:33]([C:26]2[C:25]([NH2:24])=[N:30][C:29]([NH2:31])=[C:28]([Cl:32])[N:27]=2)=[O:34])=[CH:13][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(CCCCN)cc1
Agent: I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)cc1
Yield: 92.5 %

Procedure:
{2-[4-(4-Aminobutyl)phenoxy]ethyl}carbamic acid tert-butyl ester 2 (1.7 g, 5.5 mmol), 1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (2.6 g, 6.6 mmol), and triethylamine (3.1 mL) were combined in THF (18 mL). The reaction was stirred at reflux under argon for 1.5 h. The product mixture was allowed to cool, and the solvent was evaporated. Chromatography (silica gel, methylene chloride/methanol/concentrated ammonium hydroxide, 100:10:1) afforded 2.65 g (92%) of the pure product as a yellow foamy solid. 1H NMR (300 MHz, CDCl3) δ 1.44 (s, 9H), 1.62 (m, 2H), 1.61 (m, 2H), 1.75 (br s, 2H), 2.56 (t, 2H), 2.71 (t, 2H), 3.51 (m, 2H), 3.99 (t, 2H), 5.07 (br s, 1H), 6.80 (d, 2H), 7.08 (d, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:18])[CH:16]=[CH2:17])[CH:11]=[CH:12][CH:13]=2)[C:5]([Cl:19])=[CH:4][N:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:19][C:5]1[C:6]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:18])[CH:16]=[CH2:17])[CH:11]=[CH:12][CH:13]=2)=[N:7][C:2]([NH:31][C:30]2[CH:29]=[CH:28][C:27]([N:24]3[CH2:23][CH2:22][N:21]([CH3:20])[CH2:26][CH2:25]3)=[CH:33][CH:32]=2)=[N:3][CH:4]=1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: C=CC(=O)Nc1cccc(-c2nc(Cl)ncc2Cl)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C=CC(=O)Nc1cccc(-c2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2Cl)c1
Temperature: 200 °C

Procedure:
N-(3-(2,5-dichloropyrimidin-4-yl)phenyl)acrylamide (30 mg, 0.102 mmol), 4-(4-methylpiperazin-1-yl)aniline (21 mg, 0.110 mmol)) and potassium carbonate (14 mg, 0.101 mmol) were dissolved in toluene (4 mL) in a sealable microwave compatible reaction tube, then Pd2(dba)3 (2 mg, 0.002 mmol) and Xantphos (2.7 mg, 0.005 mmol) were added. The reaction tube was sealed and the reaction was heated under microwave irradiation (40 min, 200° C., 3 atm). The reaction was monitored by TLC. The product was purified by column chromatography (5% CH3OH/CH2Cl2) to give the title compound. 1H NMR (400 MHz, CD3OD): δ 8.40 (s, 1H), 8.20 (s, 1H), 7.77 (d, 1H, J=7.2 Hz), 7.59 (m, 3H), 7.46 (t, 1H, J=7.6 Hz), 6.96 (m, 2H), 6.46-6.36 (m, 2H), 5.79 (dd, 1H, J=2.4 & 9.6 Hz), 3.14 (m, 4H), 2.61 (m, 4H), 2.34 (s, 3H). ESI-MS: m/z 449.10 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:14]=[CH:13][C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=1.[I-].[K+].C[N:18](C)C=O>>[NH2:18][CH2:2][CH2:3][C:4]1[CH:14]=[CH:13][C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=1
Reactant: O=C1COc2cc(CCBr)ccc2N1
Reactant: CN(C)C=O
Agent: [I-]
Agent: [K+]
Product: NCCc1ccc2c(c1)OCC(=O)N2

Procedure:
In a 250-cm3 ground-necked flask, 0.01 mol of 7-(2-bromoethyl)-3-oxo-2,3-dihydro-1,4-benzoxazine and 0.3 g of potassium iodide are dissolved in 30 cm3 of dimethylformamide.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:14][CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:19]1[O:20][C:21]2[C:22](=[C:24]([C:28]([O:30][CH3:31])=[O:29])[CH:25]=[CH:26][CH:27]=2)[N:23]=1>COCCOC>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:19]2[O:20][C:21]3[C:22](=[C:24]([C:28]([O:30][CH3:31])=[O:29])[CH:25]=[CH:26][CH:27]=3)[N:23]=2)[C@@H:10]([CH2:14][CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@H]1CN(Cc2ccccc2)CCN1
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC[C@H]1CN(Cc2ccccc2)CCN1c1nc2c(C(=O)OC)cccc2o1
Reaction time: 0.75 h
Yield: 94.7 %

Procedure:
To a solution of (S)-1-benzyl-3-ethylpiperazine (650 mg, 3.22 mmol) in DME (10 mL) at room temperature, was added NaH (60% suspension in mineral oil, 144 mg, 3.50 mmol) and the mixture was stirred for 45 min. Methyl 2-chlorobenzoxazole-4-carboxylate (510 mg, 2.42 mmol) was added to the reaction mixture and the reaction was stirred at room temperature for 17 h. The reaction mixture was quenched with CH3OH (10 mL), silica gel (15 mL) was added, and solvent removed under reduced pressure. The mixture was purified by column chromatography (silica gel, 0 to 80% EtOAc in hexanes) to afford (S)-methyl 2-(4-benzyl-2-ethylpiperazine-1-yl)benzoxazole-4-carboxylate (0.87 g, 71%) as an oily solid. 1H NMR and MS consistent.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[N:3]=1.[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.C(OCC)(=O)C.O>[Br:19][C:8]1[N:7]2[C:2]([Cl:1])=[N:3][C:4]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])=[CH:5][C:6]2=[N:10][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1ccc(-c2cc3nccn3c(Cl)n2)c(Cl)c1
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Clc1ccc(-c2cc3ncc(Br)n3c(Cl)n2)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
200 mg (0.67 mmol) of 5-chloro-7-(2,4-dichlorophenyl)imidazo[1,2-c]pyrimidine (Example 6A) are suspended in chloroform (30 ml), 238 mg (1.34 mmol) of N-bromosuccinimide are added, and the reaction mixture is stirred at RT for 12 h. The reaction mixture is diluted with ethyl acetate (100 ml) and water (75 ml), and the organic phase is separated off, dried over magnesium sulphate and concentrated in a rotary evaporator. The residue is stirred with acetonitrile (20 ml) and then diethyl ether (20 ml), and the solid is filtered off with suction and dried. 103 mg (41% of theory) of the product are isolated.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:27]=1.[Cl:28][C:29]1[N:34]=[C:33](Cl)[CH:32]=[CH:31][N:30]=1.CN(C)C(=O)C>C(=O)([O-])O.[Na+]>[Cl:28][C:29]1[N:34]=[C:33]([NH:1][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:12]=[C:13]([NH:17][C:18]([C:20]5[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=5)=[O:19])[CH:14]=[CH:15][CH:16]=4)=[CH:6][N:5]3[CH:27]=2)[CH:32]=[CH:31][N:30]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc3nc(N)cn3c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc3nc(Nc4ccnc(Cl)n4)cn3c2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 19.7 %

Procedure:
A mixture of N-{3-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]phenyl}-3-methylpyridine-2-carboxamide (150 mg, 0.417 mmol), 2,4-dichloropyrimidine (63.8 mg, 0.428 mmol) and N,N-dimethylacetamide (5 mL) was stirred at room temperature for 20 hr. The reaction mixture was diluted with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, 0%→100% ethyl acetate-hexane→2% methanol-ethyl acetate) to give the title compound (38.8 mg, 20%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[C:12]([CH:14]=[CH2:15])[CH:11]=[C:10]([CH3:16])[N:9]=2)[N:3]=1.[N+](=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N-]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[C:12]([C@@H:14]3[CH2:15][C@H:19]3[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:11]=[C:10]([CH3:16])[N:9]=2)[N:3]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=Cc1cc(C)nc(-n2nc(C)nc2C)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1C[C@H]1c1cc(C)nc(-n2nc(C)nc2C)c1
Temperature: 25 °C

Procedure:
To a solution of 2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-6-methyl-4-vinylpyridine (25-1) (200 mg, 0.933 mmol) in toluene (8 mL) was added at reflux ethyl diazoacetate (852 mg, 7.47 mmol) in three portions over 4 hours. The mixture was refluxed for another 2 hours, cooled to room temperature, and concentrated. The residue was purified by silica gel column chromatography (0-70% ethyl acetate in hexanes) to give ethyl trans-2-(2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-6-methylpyridin-4-yl)cyclopropanecarboxylate (25-2) as a yellow oil. 1H NMR (300 MHz, CDCl3) 57.32 (br s, 1H), 6.83 (br s, 1H), 4.18 (q, 2H, J=7.2 Hz), 2.80 (s, 3H), 2.55-2.46 (m, 1H), 2.51 (s, 3H), 2.41 (s, 3H), 2.09-1.99 (m, 1H), 1.73-1.63 (m, 1H), 1.46-1.36 (m, 1H), 1.28 (t, 1H, J=7.2 Hz). LRMS m/z (M+H) 301 found, 301 required.
Reaction SMILES: [ClH:1].C(OCC)(=O)C.[CH2:8]([O:15][C:16]([NH:18][CH2:19][CH:20]1[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCOCC1.CO>[ClH:1].[CH2:8]([O:15][C:16]([NH:18][CH2:19][CH:20]1[CH2:23][NH:22][CH2:21]1)=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CC(CNC(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(NCC1CNC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 99.7 %

Procedure:
A 4 N hydrochloric acid/ethyl acetate solution (3.90 mL, 15.6 mmol) was added to a solution of tert-butyl 3-({[(benzyloxy)carbonyl]amino}methyl)azetidine-1-carboxylate obtained in Example (233a) (560 mg, 1.75 mmol) in 1,4-dioxane/methanol (8 mL/8 mL), and the mixture was stirred at room temperature for 4.5 hours. The reaction solution was concentrated to obtain 448 mg of 3-({[(benzyloxy)carbonyl]amino}methyl)azetidine hydrochloride (100%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][CH2:8]OS(C)(=O)=O)=[C:5]([CH3:14])[N:4]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[N:3]=1.[CH3:25][O:26][C:27](=[O:41])/[CH:28]=[CH:29]/[C:30]1[CH:35]=[CH:34][C:33]([C@@H:36]2[CH2:40][CH2:39][CH2:38][NH:37]2)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CN(C)C(=O)C>[CH3:25][O:26][C:27](=[O:41])/[CH:28]=[CH:29]/[C:30]1[CH:35]=[CH:34][C:33]([C@@H:36]2[CH2:40][CH2:39][CH2:38][N:37]2[CH2:8][CH2:7][C:6]2[C:2]([CH3:1])=[N:3][N:4]([S:15]([C:18]3[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=3)(=[O:17])=[O:16])[C:5]=2[CH3:14])=[CH:32][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)n2nc(C)c(CCOS(C)(=O)=O)c2C)cc1
Reactant: COC(=O)/C=C/c1ccc([C@@H]2CCCN2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CC#N
Product: COC(=O)/C=C/c1ccc([C@@H]2CCCN2CCc2c(C)nn(S(=O)(=O)c3ccc(C)cc3)c2C)cc1
Yield: 60.8 %

Procedure:
To a mixture of methanesulfonic acid 2-[3,5-dimethyl-1-(toluene-4-sulfonyl)-1H-pyrazol-4-yl]-ethyl ester (600 mg, 1.61 mmol) and (E)-3-((S)-4-pyrrolidin-2-yl-phenyl)-acrylic acid methyl ester (317 mg, 1.37 mmol) in 10 mL acetonitrile-N,N-dimethylacetamide (3:1 v/v) was added potassium carbonate (334 mg, 2.42 mmol). The mixture was subjected to microwave irradiation for 15 minutes and the crude mixture was filtered through a plug of Celite, which was washed with dichloromethane. The combined filtrates were partially concentrated and partitioned between ethyl acetate and aqueous ammonium chloride solution. The organic layer was washed three times with the same salt solution, which was back extracted once. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give a yellow oil, which was purified via silica gel column chromatography (0-50% ethyl acetate in heptane) to give ((E)-3-[4-((S)-1-{2-[3,5-dimethyl-1-(toluene-4-sulfonyl)-1H-pyrazol-4-yl]-ethyl}-pyrrolidin-2-yl)-phenyl]-acrylic acid methyl ester (423 mg, 0.833 mmol, 52% yield) as a colorless solid.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:25]([OH:27])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][C:36]=2[S:38](Cl)(=[O:40])=[O:39])[CH:31]=[CH:30][CH:29]=1>>[N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][C:36]=2[S:38]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]([C:25]([OH:27])=[O:26])[NH:18][C:16]([O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[O:17])(=[O:40])=[O:39])[CH:31]=[CH:30][CH:29]=1
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Product: O=C(N[C@@H](CCCCNS(=O)(=O)c1cccc2cccnc12)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 81 %

Procedure:
Nα-(9-fluorenylmethoxycarbonyl)-L-lysine was reacted with 8-quinolinesulfonyl chloride under the conditions used in example 2 giving 81% of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]N)#[N:2].C1N2CN3CN(C2)CN1C3.O.S(=O)(=O)(O)[OH:23]>C(O)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:23])#[N:2]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cccc(CN)c1
Agent: C1N2CN3CN1CN(C2)C3
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1cccc(C=O)c1
Temperature: 25 °C
Yield: 75.3 %

Procedure:
7.9 g of m-cyanobenzylamine, 8.4 g of hexamethylenetetramine, 40 ml of water and 40 ml of acetic acid were mixed and reacted at 104° C. for 2 hours while stirring. The reaction solution was cooled to room temperature and thereto 12 g of concentrated sulfuric acid was added. The solvent was concentrated to dry in an evaporator with a water bath at 70° C. The concentration residue was separated by toluene/water and washed with water. The toluene layer obtained was concentrated until crystals were precipitated. The concentrated toluene solvent was placed in water and after removing toluene by azeotropic distillation, the residue was cooled to room temperature. The crystals precipitated were collected by filtration, washed with water and dried to obtain 5.9 g (yield: 74%) of m-cyanobenzaldehyde. The purity was 99% or more.
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11](O)=[O:12].B>C1COCC1>[F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][OH:12]
Reactant: Cc1cccc(CCC(=O)O)c1F
Agent: B
Solvent: C1CCOC1
Product: Cc1cccc(CCCO)c1F
Yield: 82.5 %

Procedure:
According to procedures described above, 3-(2-fluoro-3-methyl-phenyl)-propionic acid (2.39 g, 13.12 mmol) was reduced by borane in THF to give 1.82 g (82.5%) of 3-(2-fluoro-3-methyl-phenyl)-propan-1-ol. LC-MS: tR=0.86 min; [M+H]+=no ionization.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7]([OH:9])=O.[CH:10]1[C:15]([NH2:16])=[CH:14][CH:13]=[C:12]([NH2:17])[CH:11]=1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[NH2:16][C:15]1[CH:10]=[CH:11][C:12]([NH:17][C:7]([C:3]2[CH:4]=[N:5][O:6][C:2]=2[CH3:1])=[O:9])=[CH:13][CH:14]=1
Reactant: Cc1oncc1C(=O)O
Reactant: Nc1ccc(N)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: Cc1oncc1C(=O)Nc1ccc(N)cc1
Reaction time: 5 h

Procedure:
10.1 g (0.08 mol) of 5-methylisoxazole-4-carboxylic acid and 8.65 g (0.08 mol) of p-phenylenediamine are dissolved in 300 ml of tetrahydrofuran and 18.05 g (0.088 mol) of dicyclohexylcarbodiimide are added. After 5 hours (“h”), the deposited precipitate is filtered off with suction, the organic phase is concentrated and the product is chromatographed on silica gel by means of ethyl acetate/petroleum ether with addition of 1% glacial acetic acid and then crystallized from ethyl acetate/petroleum ether. The yield of the process was 6.8 g of acetate salt with a melting point of 123° C. to 128° C.