Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12][CH2:13][Cl:14])=[CH:10][C:9]2[C:4](=[C:5]([O:17][CH3:18])C=CC=2OC)[N:3]=1.CO[CH:21]([O:24]C)[O:22][CH3:23].S(=O)(=O)(O)[OH:27].O=[O+][O-]>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:5]([O:17][CH3:18])=[O:27])[C:9]([C:21]([O:22][CH3:23])=[O:24])=[CH:10][C:11]=1[CH2:12][CH2:13][Cl:14]
Reactant: COc1ccc(OC)c2nc(Cl)c(CCCl)cc12
Reactant: COC(OC)OC
Reactant: O=S(=O)(O)O
Agent: O=[O+][O-]
Solvent: CO
Product: COC(=O)c1cc(CCCl)c(Cl)nc1C(=O)OC

Procedure:
A solution of 2-chloro-3-(2-chloroethyl)-5,8-dimethoxyquinoline (22.0 g, 0.077 mole) in 1 L methanol containing 80 mL of trimethylorthoformate and 2 mL concentrated sulfuric acid is stirred at room temperature while ozone is bubbled in until TLC indicates the disappearance of starting material. The reaction is concentrated in vacuo, and the residue is partitioned between ether and saturated aqueous bicarbonate. The organic layer is washed further with bicarbonate, then with aqueous bisulfite. Drying and concentration in vacuo affords the desired product as an oil.
Reaction SMILES: C([O:7][CH2:8][C@@H:9]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:10]1[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[Cl:20])[N:16]=[C:15]([CH3:21])[CH:14]=[CH:13]2)(=O)C(C)(C)C.[OH-].[Na+]>C1COCC1.CO.O>[C:30]([O:29][C@@H:9]([C:10]1[C:11]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[Cl:20])[N:16]=[C:15]([CH3:21])[CH:14]=[CH:13]2)[CH2:8][OH:7])([CH3:33])([CH3:31])[CH3:32]
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](COC(=O)C(C)(C)C)OC(C)(C)C)c(Cl)cc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](CO)OC(C)(C)C)c(Cl)cc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.5 %

Procedure:
To a stirred solution of (S)-2-tert-butoxy-2-(7-chloro-5-(4-chlorophenyl)-2-methylquinolin-6-yl)ethyl pivalate (1J) (22 mg, 0.045 mmol) in THF and methanol (3 mL/1 mL) was added 1 M NaOH solution (1 mL, excess) at 0° C. The mixture was stirred at room temperature for 16 hours and diluted with water. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product 1K (11 mg, 61%). LCMS-ESI+ (m/z): 404.2, 406.2 (M+H)+.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.CN(C)C1C=CC=CC=1.O[C:16]1[NH:21][C:20]2=[CH:22][CH:23]=[CH:24][C:19]2=C(O)[N:17]=1.Cl[CH2:27][Cl:28]>>[Cl:3][C:16]1[NH:21][C:20]2=[CH:22][CH:23]=[CH:24][C:19]2=[C:27]([Cl:28])[N:17]=1
Reactant: Oc1nc(O)c2cccc-2[nH]1
Reactant: ClCCl
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Clc1nc(Cl)c2cccc-2[nH]1
Temperature: 25 °C
Yield: 15 %

Procedure:
A mixture solution of phosphorous oxychloride(49 ml), N,N-dimethylaniline(8.0 ml) and 2,4-dihydroxycyclopenta[d]pyrimidine(15.4 g, 0.1 mol) prepared in the above Step 2 was heated to reflux for 3 hours and cooled to a room temperature. After the reaction mixture was diluted with dichloromethane, the diluted solution was added to ice water, while maintaining the temperature of the reaction system below 10° C. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate and concentrated in vacuo to give 2.8 g of titled compound as an oily form. (Yield: 15%)
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][Br:5].[CH3:6][N:7]1[N:11]=[N:10][C:9]([C:12]2[CH:17]=[C:16]([CH3:18])[C:15](O)=[C:14]([CH3:20])[CH:13]=2)=[N:8]1.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O.CCOCC>[CH3:6][N:7]1[N:11]=[N:10][C:9]([C:12]2[CH:13]=[C:14]([CH3:20])[C:15]([O:1][CH2:2][CH2:3][CH2:4][Br:5])=[C:16]([CH3:18])[CH:17]=2)=[N:8]1
Reactant: Cc1cc(-c2nnn(C)n2)cc(C)c1O
Reactant: OCCCBr
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCBr
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
A mixture of (3-hydroxypropyl)-bromide (2.17 ml, 24 mmol), 4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenol (5.1 g, 25 mmol), and DEAD (4.18 g, 24 mmol) was dissolved in 50 ml of THF at 0° C. To the above solution was added dropwise triphenylphosphine (6.3 g, 24 mmol) at 0° C. and the mixture was allowed to stir at 0° C. for 0.5 h. The mixture was diluted with 500 ml of water and 100 ml of ether, and the aqueous layere was extracted with ether (2×400 ml). The combined organic layer was dried over sodium sulfate, and concentrated in vacuo. The residue was dissolved in 800 ml of ether, and the organic layer was washed with 10% NaOH solution (3×50 ml), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica column chromatography (7 cm column, ethyl acetate/hexane, 1/5) followed by recrystallization from methylene chloride/hexane to afford 6.4 g (82%) of 3-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxyl]-propylbromide, as a light yellow oil.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH:17]=[CH2:18])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:19])[C:6]([C:20]([OH:22])=[O:21])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:23][N:24]1[CH2:29][CH:28]2[CH2:30][CH:25]1[CH2:26][NH:27]2.C1N2CCN(CC2)C1.O>C(#N)C.CN(C)C=O>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH:17]=[CH2:18])[C:10]([F:16])=[C:11]([N:27]4[CH2:26][CH:25]5[CH2:30][CH:28]4[CH2:29][N:24]5[CH3:23])[C:12]=3[F:14])[C:7](=[O:19])[C:6]([C:20]([OH:22])=[O:21])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C=Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CN1CC2CC1CN2
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: C=Cc1c(F)c(N2CC3CC2CN3C)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 74.6 %

Procedure:
0.93 g of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-5-vinyl-3-quinolinecarboxylic acid, 0.5 g of 2-methyl-2,5-diazabicyclo[2.2.1]heptane and 0.36 g of DABCO are refluxed for 2 hours in a mixture of 6 ml of acetonitrile and 3 ml of dimethylformamide. At room temperature, the reaction mixture is treated with 2 ml of water, and the solid is filtered off with suction, washed with water and dried. 0.9 g of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(2-methyl-2,5-diazabicyclo[2.2.1]-hept-5-yl)-4-oxo-5-vinyl-3-quinolinecarboxylic acid is obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])(=[O:19])=[O:18].[N:27]1([CH2:36][C:37](O)=[O:38])[CH:35]=[C:33]([CH3:34])[C:31](=[O:32])[NH:30][C:28]1=[O:29].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:37](=[O:38])[CH2:36][N:27]2[CH:35]=[C:33]([CH3:34])[C:31](=[O:32])[NH:30][C:28]2=[O:29])[CH2:22][C:21]1=[O:26])(=[O:19])=[O:18]
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2ccccc2s1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cn(CC(=O)N2CCN(S(=O)(=O)c3nc4ccccc4s3)C(=O)C2)c(=O)[nH]c1=O
Reaction time: 4 h

Procedure:
To the mixture of 1-(benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt (0.83 g, 2.5 mmol), (thymin-1-yl)-acetic acid (0.46 g, 2.5 mmol), and PyBOP (1.43 g, 2.75 mmol) in DMF (12 mL) was added diisopropylethylamine (0.61 ml, 3.75 mmol) at ambient temperature. The resulting reaction mixture was stirred for 4 h at the same temperature and the solvent was removed in vacuo. The residue was dissolved in dichloromethane (20 mL) and the solution was washed with water, saturated sodium bicarbonate solution, 1N HCl solution, and saline. The resulting solution was dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo. The resulting residue was recrystallized in dichloromethane-ethyl ether to afford the title compound. 1H NMR MHz; DMSO-d6) δ 11.30 (d, 1H), 8.34 (d, 1H), 8.26 (m, 1H), 7.71 (m, 2H), 7.34 (s, 0.6H), 7.27 (s, 0.4H), 4.67 (s, 1.2H), 4.57 (s, 0.8H), 4.42 (s, 0.8H), 4.27 (s, 1.2H), 4.21 (t, 1.2H), 4.07 (t, 0.8H), 3.95 (t, 1.2H), 3.85 (t, 0.8H), 1.74 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])O.[Na+]>C(O)C>[C:9]([O:13][C:14]([N:16]1[CH2:17][CH2:18][N:19]([C:22]([CH:24]2[CH2:29][CH2:28][N:27]([C:2]3[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=3)[CH2:26][CH2:25]2)=[O:23])[CH2:20][CH2:21]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Clc1cc(Cl)ncn1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C2CCNCC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C2CCN(c3cc(Cl)ncn3)CC2)CC1
Yield: 89.5 %

Procedure:
A solution of 4,6-dichloropyrimidine (3.60 g), 1-(tert-butoxycarbonyl)-4-(-4-piperidylcarbonyl)piperazine (6.00 g) and sodium hydrogen carbonate (4.20 g) in ethanol (100 ml) was heated at reflux for 6 hours. Solvent was evaporated and the residue dissolved in ethyl acetate and washed with water, dried (Na2SO4) and evaporated. The residue was recrystallised from ethyl acetate to give, as a solid 1-(tert-butoxycarbonyl)-4-[1-(6-chloro-pyrimidin-4-yl)-piperidin-4-ylcarbonyl]piperazine (7.40 g).
Reaction SMILES: [C:1]1([C:7]2[N:22]=[C:10]3[CH:11]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:13]=[C:14]([NH2:15])[N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31](Cl)=[O:32])[CH:27]=[CH:28][CH:29]=1>>[Cl:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31]([NH:15][C:14]2[N:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:22]=[C:10]3[CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:13]=2)=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12
Reactant: O=C(Cl)Cc1cccc(Cl)c1
Product: O=C(Cc1cccc(Cl)c1)Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12

Procedure:
The title compound, MS m/e (%): 440 (M+H+, 100), was prepared in accordance with the general method of example 31 from 2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine and 3-chlorophenylacetyl chloride.
Reaction SMILES: [Si]([O:18][CH2:19][C@@H:20]([N:51]([CH2:64][CH2:65][CH:66]([CH3:68])[CH3:67])[S:52]([C:55]1[CH:60]=[CH:59][C:58]([N+:61]([O-:63])=[O:62])=[CH:57][CH:56]=1)(=[O:54])=[O:53])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30](=[O:50])[C@H:31]([CH:37]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[NH:32][C:33]([O:35][CH3:36])=[O:34])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.N1C=CC=CC=1>C1COCC1.CCOC(C)=O>[OH:18][CH2:19][C@@H:20]([N:51]([CH2:64][CH2:65][CH:66]([CH3:68])[CH3:67])[S:52]([C:55]1[CH:56]=[CH:57][C:58]([N+:61]([O-:63])=[O:62])=[CH:59][CH:60]=1)(=[O:53])=[O:54])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30](=[O:50])[C@H:31]([CH:37]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[NH:32][C:33]([O:35][CH3:36])=[O:34]
Reactant: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N(CCC(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1)C(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H](CO)N(CCC(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1)C(c1ccccc1)c1ccccc1
Yield: 69750.3 %

Procedure:
A solution of N-{2-[(3S)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-{(3-methylbutyl)[(4-nitrophenyl)sulfonyl]amino}butyl]phenyl}-Nα-(methoxycarbonyl)-β-phenyl-L-phenyl alaninamide (10, 141.3 mg, 0.148 mmol) in THF (1.5 ml) stirred at 0° C. in a plastic vial, was treated with a 70% solution of HF in pyridine (1.5 mL, 5.8 mmol), the plastic bottle was capped and the final mixture stirred at room temperature for 4 h. Diluted with EtOAc, washed with water followed by saturated NaHCO3, dried over MgSO4, filtered and concentrated. Purification made by passage through a chromatographic cartridge of silicagel (12 g) eluted with 20% to 60% EtOAc in hexane to give 74 g (69% yield) of title compound as white foam. MS: m/z=717.3 (MH+).
Reaction SMILES: C[C:2]([CH3:4])=[O:3].[C@@H:5]12[C:14](=[O:15])[O:13][C:11](=[O:12])[C@@H:6]1[CH2:7][CH2:8][CH2:9][CH2:10]2.[C:16]([OH:21])(=[O:20])[C:17]([CH3:19])=[CH2:18]>O>[C:16]([O:21][CH2:4][CH2:2][O:3][C:11]([CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]1[C:14]([OH:13])=[O:15])=[O:12])(=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: CC(C)=O
Reactant: C=C(C)C(=O)O
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Solvent: O
Product: C=C(C)C(=O)OCCOC(=O)C1CCCCC1C(=O)O
Reaction time: 1 h

Procedure:
Into acetone (1,000 ml) were dissolved cis-1,2-cyclohexane dicarboxylic anhydride (308.3 g), methacrylic acid (2-hydroxyethyl) (273.3 g) and 4-(dimethylamine) pyridine (4.9 g), and heated for 5 hours under reflux. After acetone had been distilled off under reduced pressure, 1N hydrochloric acid (500 ml) and ethyl acetate (2,000 ml) were added thereto so that an extracting process was carried out. After the organic layer had been washed with saturated saline solution (500 ml) twice, to this was added magnesium sulfuric anhydride (100 g) and this was allowed to stand for 1 hour to be dehydrated. After magnesium sulfate had been filtered and separated, ethyl acetate was distilled off under reduced pressure so that a white solid matter was obtained. After having been ground, this was added to water (2,000 ml), and after having been stirred for 2 hours, this was filtered and dried to obtain a white solid matter (518.9 g) of 2-[2-(methacryloyloxy)ethoxycarbonyl]cyclohexane carboxylic acid.
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][CH2:10][Mg+].[Br-].B(F)(F)F.CCOCC>C(Cl)Cl.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[C:2]1([C:1]2([NH2:8])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccccc1
Reactant: CC[Mg+]
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: FB(F)F
Agent: [Br-]
Solvent: CCOCC
Solvent: ClCCl
Product: NC1(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
To a solution of benzonitrile (1.03 g, 10 mmol) in DCM (50 mL) at −60° C. was added Ti(OiPr)4 (3.22 mL, 11 mmol) and EtMgBr (3M in ether, 7.34 mL, 22 mmol), the resulting dark brown solution was slowly warmed up to room temperature over 1 h. BF3.OEt2 (2.47 mL, 20 mmol) was added, and the solution was further stirred at room temperature for 2 h. The mixture was quenched with Sat. NH4Cl and 1N HCl, aqueous layer was separated and extracted with ether, and then neutralized with 5N NaOH to pH=10. The resulting precipitate was filtered off and the filtrate was extracted with EtOAc, EtOAc layer was combined, dried and concentrated to give 1-phenylcyclopropanamine as oil (600 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:28]([F:31])([F:30])[F:29])=[N:4][N:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)([C:17](NO)=[NH:18])[CH2:13][CH2:12]2)=[O:10])[C:6]=1[CH3:7].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=[O:39].C[C@H](NC([C@H]1N(C([C@@H](NC([C@@H](N)CC2C=CC(O)=CC=2)=O)CC(O)=O)=O)CCC1)=O)C(N1[C@H](C(N2[C@H](C(N3[C@H](C(N4[C@H](C(N5[C@H](C(N6[C@H](C(O)=O)CCC6)=O)CCC5)=O)CCC4)=O)CCC3)=O)CCC2)=O)CCC1)=O>>[Cl:1][C:2]1[C:3]([C:28]([F:31])([F:30])[F:29])=[N:4][N:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)([C:17]([NH2:18])=[O:39])[CH2:13][CH2:12]2)=[O:10])[C:6]=1[CH3:7]
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCC(C(=N)NO)(c2ccc(Cl)cc2)CC1
Agent: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(=O)O)NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCC(C(N)=O)(c2ccc(Cl)cc2)CC1

Procedure:
To the crude material from Example 21 was added 5 mg of CSA and 1 mL of TMOF. The mixture was heated to 100C overnight and the crude product was purified by reversed phase HPLC (acetonitrile—H2O with 0.1% TFA as the eluent) to yield 1-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-4-(4-chloro-phenyl)-piperidine-4-carboxylic acid amide. MS (ES) M+H expected=463.0, found=463.1
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11]1)=[O:7])(C)(C)C.[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[NH2:28][C:29]1[C:37]([Cl:38])=[CH:36][C:32](C(O)=O)=[C:31]([O:39][CH3:40])[CH:30]=1>>[NH2:28][C:29]1[C:37]([Cl:38])=[CH:36][C:32]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:26]([NH:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:27])[CH2:11]2)=[O:7])=[C:31]([O:39][CH3:40])[CH:30]=1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCN)C1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: O=C=Nc1ccccc1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCNC(=O)Nc2ccccc2)C1

Procedure:
3-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)propylamine (0.74 g) as starting compound was reacted and treated in the same manner as in Example 34 using phenyl isocyanate (0.33 ml) and 4-amino-5-chloro-2-methoxybenzoic acid (0.58 g) to give 4-amino-5-chloro-2-methoxy-N-(1-(3-(3-phenylureido)propyl)pyrrolidin-3-ylmethyl)-benzamide.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)#[N:2].[I:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]>>[I-:10].[C:13]([CH2:12][CH2:11][N+:7]1[CH:8]=[CH:9][C:4]([CH2:3][C:1]#[N:2])=[CH:5][CH:6]=1)([OH:15])=[O:14]
Reactant: N#CCc1ccncc1
Reactant: O=C(O)CCI
Product: N#CCc1cc[n+](CCC(=O)O)cc1
Product: [I-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 59 %

Procedure:
4-cyanomethyl-pyridine 475 milligrams (0.004) mole were mixed with 1.0 gram of 3-iodopropionic acid (excess) in 100 ml round bottom flask. The flask was closed using a rubber septem and heated at 130 degrees Celsius using an oil bath for six hours. The flask was allowed to cool to ambient temperature and the reaction product was washed by triturating with ether. Acetone 30 ml was added and kept at room temperaturea for 12 hours. The precipitated product was filtered and washed with acetone, 755 mg (79%) of product was obtained.
Reaction SMILES: Cl[CH:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[CH2:3]1.[N-:16]=[N+:17]=[N-:18].[Na+].O>CN(C)C=O>[N:16]([CH:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[CH2:3]1)=[N+:17]=[N-:18]
Reactant: CC1(C)CC(Cl)c2cc(C#N)ccc2O1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(N=[N+]=[N-])c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 4-chloro-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran(3g) and sodium azide (0.9g) in N,N-dimethylformamide (20 ml) was stirred for 3 days at room temperature. Water was added and the mixture extracted with ethyl acetate, the organic phase was separated and further washed with water, then dried over anhydrous sodium sulphate. Filtration and evaporation of the solvent in vacuo gave the title compound (3.03g) as a solid, which was used in the next step without further purification.
Reaction SMILES: [CH:1]1([C:5]2[C:12]([C:13]3[NH:17][C:16]([O:18][CH2:19][CH3:20])=[N:15][N:14]=3)=[CH:11][C:8]([C:9]#[N:10])=[C:7]([CH3:21])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[NH4+].[OH-:23].OO>CCO>[CH:1]1([C:5]2[C:12]([C:13]3[NH:17][C:16]([O:18][CH2:19][CH3:20])=[N:15][N:14]=3)=[CH:11][C:8]([C:9]([NH2:10])=[O:23])=[C:7]([CH3:21])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: [OH-]
Reactant: CCOc1nnc(-c2cc(C#N)c(C)cc2C2CCC2)[nH]1
Agent: OO
Agent: [NH4+]
Solvent: CCO
Product: CCOc1nnc(-c2cc(C(N)=O)c(C)cc2C2CCC2)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzonitrile (219.7, 0.15 g, 0.53 mmol) in EtOH (10 ml) was added NH4OH (0.18 ml, 2.66 mmol, 14.8 N in H2O) followed by H2O2 (1.8 ml, 26.6 mmol, 50% in H2O). The mixture was stirred at room temperature overnight. The mixture was cooled to 0° C. and quenched carefully with 1N Na2S2O3 solution (26 ml). The mixture was extracted with EtOAc (×2) and the combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified with prep-TLC (5% MeOH in CH2Cl2). Yield: 0.1 g, white solid, 62.5%. m/z (ES−) 299 (M−H)−.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[CH2:39][C:40](O)=[O:41])=[CH:33][C:32]=2[F:43])=[C:28]([CH:44]([CH3:46])[CH3:45])[NH:27][N:26]=1)(=O)C.[NH2:47][C:48]([CH3:68])([CH3:67])[C:49]([N:51]1[CH2:56][CH2:55][N:54](C(OCC2C=CC=CC=2)=O)[CH2:53][CH2:52]1)=[O:50].C(N1CCNCC1)C1C=CC=CC=1>>[F:43][C:32]1[CH:33]=[C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:41])[NH:47][C:48]([C:49]([N:51]2[CH2:52][CH2:53][NH:54][CH2:55][CH2:56]2)=[O:50])([CH3:68])[CH3:67])[CH:35]=[CH:36][C:31]=1[CH2:30][C:29]1[C:25]([O:24][C@@H:6]2[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]2[OH:4])=[N:26][NH:27][C:28]=1[CH:44]([CH3:46])[CH3:45]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CC(=O)O)cc2F)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CC(C)(N)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Agent: c1ccc(CN2CCNCC2)cc1
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCC(=O)NC(C)(C)C(=O)N2CCNCC2)cc1F

Procedure:
The title compound was prepared in a similar manner to that described in Example 99 using 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-2-fluorophenyl}methyl)-5-isopropyl-1H-pyrazole and 1-(2-amino-2-methylpropionyl)-4-(benzyloxycarbonyl)piperazine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-1-(methyl)ethylcarbamoyl]ethoxy}-2-methyl-phenyl)methyl]-5-isopropyl-1H-pyrazole and 1-benzyl-piperazine, respectively.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][N:3]=1.[CH3:14][N:15]1[CH:19]=[CH:18][C:17]([NH2:20])=[N:16]1>O1CCOCC1.Cl[Pd-](P(C1CC2CC1CC2)C1CC2CC1CC2)[C-]1C=CC=C1N(C)C.[CH-]1C=CC=C1.[Fe+2]>[CH:9]1([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH:20][C:17]3[CH:18]=[CH:19][N:15]([CH3:14])[N:16]=3)=[N:3][CH:4]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Cn1ccc(N)n1
Reactant: Brc1ccc(OC2CCCC2)cn1
Agent: CN(C)c1ccc[c-]1[Pd-](Cl)P(C1CC2CCC1C2)C1CC2CCC1C2
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: C1COCCO1
Product: Cn1ccc(Nc2ccc(OC3CCCC3)cn2)n1
Temperature: 80 °C
Yield: 29 %

Procedure:
2-Bromo-5-cyclopentyloxy-pyridine (0.97 mmol), sodium-tert.-butylate (1.4 eq.), and 1-methyl-1H-pyrazole-3-amine (1.2 eq.) are dissolved in degassed dioxane (2 ml) and heated to 80° C. Chloro-(di-2-norbornylphosphino)(2-dimethylaminoferrocene-1-yl)palladium (II) (3 mg) in degassed dioxane (1 ml) is added and the reaction mixture is heated for 1 hour at 150° C. in the microwave. The reaction is quenched with ethylacetate/methanol (30 ml, 9:1) and filtrated over celite. The solvent of the filtrate is removed in vacuo. (5-Cyclopentyloxy-pyridine-2-yl)-(1-methyl-1H-pyrazole-3-yl)-amine (“A25”) is obtained after reversed phase column chromatography (water/acetonitrile+0.1% TEA) as a colorless powder in a yield of 29%; HPLC (method C): 1.55 min; LC-MS (method A): 0.97 min, 259.15 (M+H+);