Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH:3]([NH:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=1)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][CH2:15][CH2:16]3)=[N:11]2)=[CH:6][C:5]=1[CH3:19].C1COCC1.[OH-].[Na+]>CO>[CH3:1][CH:2]([CH3:31])[CH:3]([NH:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][CH2:15][CH2:16]3)=[N:11]2)=[CH:6][C:5]=1[CH3:19]
Reactant: COC(=O)c1ccc(NC(c2ccc(-n3cc4c(n3)CCCC4)cc2C)C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(-n2cc3c(n2)CCCC3)ccc1C(Nc1ccc(C(=O)O)cc1)C(C)C
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a mixture of methyl 4-((2-methyl-1-(2-methyl-4-(4,5,6,7-tetrahydro-2H-indazol-2-yl)phenyl)propyl)amino)benzoate (137.3 mg), THF (0.6 mL) and methanol (0.6 mL) was added 1M aqueous sodium hydroxide solution (0.658 mL), and the mixture was stirred at 50° C. overnight. The solvent was evaporated under reduced pressure, the resulting mixture was neutralized with 1M hydrochloric acid (0.658 mL), and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a crudely purified product. This compound was used in step D without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][C:23]([OH:25])=O)[N:21]=1)=[CH:5]2.[CH3:26][N:27]([CH3:33])[CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][C:23]([N:30]3[CH2:31][CH2:32][CH:28]([N:27]([CH3:33])[CH3:26])[CH2:29]3)=[O:25])[N:21]=1)=[CH:5]2
Reactant: CN(C)C1CCNC1
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Product: CN(C)C1CCN(C(=O)C[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCCC5)c4[nH]3)=N2)C1
Yield: 48 %

Procedure:
The compound (40 mg, 0.11 mmol) prepared in Example 27 and 3-dimethylaminopyrrolidine instead of morpholine were reacted according to the same procedure as Example 73 to give the title compound (24 mg, Yield 48%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:5](=[O:8])[NH:6][CH:7]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:5](=[O:8])[N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cc(Br)c[nH]c1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(Br)cn(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
A round bottom flask was charged with methyl 5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylate (0.500 g, 2.2 mmol), phenylboronic acid (0.66 g, 5.4 mmol), and copper(II) acetate (0.78 g, 4.3 mmol). Dichloromethane (25 mL) was added, followed by 4 A molecular sieves (500 mg, activated) and pyridine (0.70 mL, 8.6 mmol). The reaction mixture was stirred overnight at room temperature in the presence of air. The reaction mixture was diluted with dichloromethane and filtered through a small pad of Celite, washing well with dichloromethane. The filtrate was concentrated under vacuum. The remaining residue was purified by silica gel chromatography (1% methanol/dichloromethane) to give methyl 5-bromo-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylate as a yellow foam/oil (0.655 g, 1.9 mmol, 89% yield). MS (ESI pos. ion) m/z: 309 (MH+). Calc'd exact mass for C13H10BrNO3: 308.
Reaction SMILES: [CH3:1][N:2]([CH:4]=[N:5][C:6]1[NH:7][C:8](=O)[C:9]2[NH:10][CH:11]=[N:12][C:13]=2[N:14]=1)[CH3:3].CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:27])=O.C(=O)([O-])O.[Na+]>>[CH3:1][N:2]([CH:4]=[N:5][C:6]1[N:14]=[C:13]2[C:9]([NH:10][CH:11]=[N:12]2)=[C:8]([Cl:27])[N:7]=1)[CH3:3]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=Nc1nc2nc[nH]c2c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)c1ccccc1
Product: CN(C)C=Nc1nc(Cl)c2[nH]cnc2n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
20.6 g (0.1 mol) of N-dimethylaminomethyleneguanine obtained in Example 15, and 12.1 g (0.1 mol) of N,N-dimethylaniline were added to 38.3 g (0.25 mol) of phosphorus oxychloride, followed by stirring at 80° C. for 2 hours. After cooling, the reaction mixture was added to 500 ml of ice water, and then neutralized with 126.0 g (1.5 mol) of sodium hydrogen carbonate. The precipitating crystal was collected by filtration and then washed with 50 ml of water, subsequently with 50 ml of methanol to yield 18.0 g (0.08 mol) of a crystal of 2-dimethylaminomethyleneamino-6-chloropurine (yield 80% ). Comparative Example (method disclosed in Japanese Patent Laid-Open No. 227583/1986)
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])C.[C:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1B(O)O)(=[O:37])[CH3:36]>>[C:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:27]1[CH:26]=[C:25]([C:28]([F:30])([F:31])[F:29])[CH:24]=[CH:23][C:22]=1[O:21][C:16]1[CH:15]=[C:14]([CH:19]=[C:18]([CH3:20])[CH:17]=1)[O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([OH:34])=[O:3])=[C:8]([CH3:33])[CH:9]=1)(=[O:37])[CH3:36]
Reactant: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Reactant: CC(=O)c1ccccc1B(O)O
Product: CC(=O)c1ccccc1-c1cc(C(F)(F)F)ccc1Oc1cc(C)cc(Oc2ccc(CCC(=O)O)c(C)c2)c1

Procedure:
The title compound is prepared by reacting the compound of 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester with 2-acetyl phenyl boronic acid as in Example 38 to afford 0.032 g (28%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[SH:10].[H-].[Na+].[CH2:13]([N:20]1[C:24]2[N:25]=[C:26]([NH2:30])[N:27]=[C:28](Cl)[C:23]=2[CH:22]=[CH:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN1C=CC=CC1=O>[CH2:13]([N:20]1[C:24]2[N:25]=[C:26]([NH2:30])[N:27]=[C:28]([S:10][C:3]3[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])[C:23]=2[CH:22]=[CH:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1cc(C)c(S)c(C)c1
Reactant: Nc1nc(Cl)c2ccn(Cc3ccccc3)c2n1
Agent: Cn1ccccc1=O
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(C)c(Sc2nc(N)nc3c2ccn3Cc2ccccc2)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.2 %

Procedure:
To a solution of 2,4,6-trimethylbenzene-1-thiol (231 mg, 1.52 mmol) in 1-methyl-2-pyridone (2 mL) was added NaH (58 mg, 1.52 mmol). The reaction mixture was stirred at room temperature for 15 min and a solution of 7-benzyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (131 mg, 0.51 mmol) in 1-methyl-2-pyridone (2 mL) was added to the mixture. The mixture was heated at 60° C. for 16 h and cooled to room temperature. The reaction was poured into ice water and extracted with EtOAc (2×20 mL). The combined organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=75:25) yielded 180 mg (94%) of 7-benzyl-4-(2,4,6-trimethyl-phenylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine.
Reaction SMILES: [BrH:1].[NH2:2][CH2:3][CH:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([OH:16])[CH:10]=[CH:9]2)C.Br.[CH3:18]C(NCCC1C=C2C(=CC=1)C=C(O)C(O)=C2)CCC1C=CC=CC=1>>[BrH:1].[NH2:2][CH:3]([CH3:18])[CH2:4][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([OH:16])[CH:10]=[CH:9]2
Reactant: CC(CCc1ccccc1)NCCc1ccc2cc(O)c(O)cc2c1
Reactant: CC(CN)c1ccc2cc(O)ccc2c1
Agent: Br
Product: CC(N)Cc1ccc2cc(O)ccc2c1

Procedure:
6-(2-amino-1-methylethyl)-2-naphthol hydrobromide, and 6-{2-[(1-methyl-3-phenylpropyl)amino]ethyl}-2,3-naphthalenediol hydrobromide;
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[OH-].[Na+].[C:17](OC(=O)C)(=[O:19])[CH3:18].Cl>C(OCC)C>[C:17]([O:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])c(O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(=O)Oc1cc(CC(=O)O)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h
Yield: 519.3 %

Procedure:
A stirred mixture of (3-hydroxy-4-nitro-phenyl)acetic acid (1 2.0 g), aqueous sodium hydroxide (152.3 mL, 1M) and diethyl ether (150 mL), cooled to 0° C. in an ice salt bath, was treated dropwise with acetic anhydride (8.1 g) at a rate to maintain the temperature at 0° C. When the addition was complete the mixture was stirred at 0° C. for a further 2 hours then acidified with dilute hydrochloric acid and then extracted with ethyl acetate. The extracts were dried over magnesium sulphate and then evaporated to give the title compound (12.6 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([Cl:7])[N:6]=1.[Cl:8][S:9](O)(=[O:11])=[O:10]>>[Cl:1][C:2]1([S:9]([Cl:8])(=[O:11])=[O:10])[NH:6][C:5]([Cl:7])=[CH:4][S:3]1
Reactant: Clc1csc(Cl)n1
Reactant: O=S(=O)(O)Cl
Product: O=S(=O)(Cl)C1(Cl)NC(Cl)=CS1

Procedure:
can be prepared in a process in which, in a first step, 2,4-dichloro-thiazole is reacted with chlorosulphonic acid to give 2,4-dichloro-thiazole-sulphonyl chloride, in which, in a second step, the 2,4-dichloro-thiazole-sulphonyl chloride is reacted with primary amines or with a primary and a secondary amine to give 2-amino-4-chloro-thiazolesulphonamides, and in which, in a third step, the sulphonamides mentioned are reacted with dichlorohalogenomethylsulphenyl chlorides to give the substances of the formula (I).
Reaction SMILES: CO[C:3](=[O:22])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([F:21])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:23][NH:24][C:25]([NH2:27])=[O:26].C[O-].[Mg+2].C[O-].CO>>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[C:13]([F:21])[CH:12]=2)[C:3]([NH:27][C:25]([NH:24][CH3:23])=[O:26])=[O:22])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: CNC(N)=O
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(F)c1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(F)c1
Temperature: 25 °C
Yield: 23 %

Procedure:
3-Cyclopentyl-2-(3-fluoro-4-methanesulfonyl-phenyl)-propionic acid methyl ester (90 mg, 0.274 mmol) and methyl urea (61 mg, 0.822 mmol) were treated with a solution of magnesium methoxide in methanol (7.4 wt %, 1.0 mL, 0.685 mmol). The reaction mixture was then concentrated in vacuo to approximately one-half the volume of methanol. The resulting reaction mixture was then heated under reflux for 24 h. The resulting cloudy, white reaction mixture was allowed to cool to 25° C. and then filtered through celite. The celite was thoroughly washed with ethyl acetate. The filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded 1-[3-cyclopentyl-2-(3-fluoro4-methanesulfonyl-phenyl)-propionyl]-3-methyl-urea (23.3 mg, 23%) as a white solid: mp 199-200° C.; EI-HRMS m/e calcd for C17H23FN2O4S (M+) 370.1362, found 370.1370.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20](OC1C=CC=CC=1)=[O:21].Cl.[OH:30][CH:31]1[CH2:34][NH:33][CH2:32]1>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20]([N:33]1[CH2:34][CH:31]([OH:30])[CH2:32]1)=[O:21]
Reactant: Cn1c(Nc2ccc(I)cc2F)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Reactant: OC1CNC1
Agent: Cl
Product: Cn1c(Nc2ccc(I)cc2F)c(C(=O)N2CC(O)C2)c(=O)n(C)c1=O
Yield: 52 %

Procedure:
The title compound was synthesized from compound 2A and 3-hydroxyazetidine hydrochloride in 52% yield following a similar procedure described in the synthesis of Example 5. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.83 (s, 1H) 7.65 (d, J=9.85 Hz, 1H) 7.52 (d, J=9.60 Hz, 1H) 6.90-6.99 (m, 1H) 5.64 (d, J=5.31 Hz, 1H) 4.25-4.34 (m, 1H) 3.96-4.04 (m, 1H) 3.69-3.75 (m, 1H) 3.39-3.47 (m, 1H) 3.35 (s, 3H) 3.17-3.23 (m, 1H) 3.16 (s, 3H). [M+H] calc'd for C16H16FIN4O4, 475. found, 475.
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[C:16]3[N:15]=[C:14]([CH2:17][OH:18])[N:13]([CH3:19])[C:12]=3[CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].O[C:23]1[CH:55]=[CH:54][C:26]([CH2:27][CH:28]2[S:32][C:31](=[O:33])[N:30]([C:34]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]2=[O:53])=[CH:25][CH:24]=1.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([CH2:17][O:18][C:23]4[CH:55]=[CH:54][C:26]([CH2:27][CH:28]5[S:32][C:31](=[O:33])[N:30]([C:34]([C:47]6[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=6)([C:41]6[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=6)[C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=6)[C:29]5=[O:53])=[CH:25][CH:24]=4)[N:13]([CH3:19])[C:12]=3[CH:16]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1c(CO)nc2c(Oc3ccc(C#N)cc3)cccc21
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Product: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2ccc(Oc3ccc(C#N)cc3)cc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.2 %

Procedure:
A mixture of 4-cyanophenoxy-2-hydroxymethyl-1-methyl-1H-benzimidazole (279 mg), 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione (558 mg), azodicarbonylpiperidine (378 mg), tri-n-butylphosphine (303 mg) and toluene (20 ml) was stirred at ambient temperature for 15 hours. The reaction mixture was purified by chromatography on a silica gel column using n-hexane/ethyl acetate=1/1 as the eluant to give the title compound (706 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12](Cl)[C:11]=2[N:10]=[C:9]1[OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:23]>CO>[NH2:23][C:12]1[C:11]2[N:10]=[C:9]([OH:22])[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:20]=2[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1
Reactant: Oc1nc2c(Cl)nc3ccccc3c2n1Cc1ccccc1
Reactant: N
Solvent: CO
Product: Nc1nc2ccccc2c2c1nc(O)n2Cc1ccccc1
Temperature: 170 °C

Procedure:
1-Benzyl-4-chloro-1H-imidazo[4,5-c]quinolin-2-ol (approximately 1.1 g) and ammonia (approximately 100 mL of a 7 N solution in methanol) were added to a high-pressure vessel, which was sealed and heated in an oven at 170° C. for five days. The resulting solution was concentrated under reduced pressure, and the residue was purified by automated flash chromatography (silica cartridge, eluting with aqueous ammonium hydroxide:methanol:dichloromethane in a gradient from 0:0:100 to 0.2:4.8:95). A solid was present on top of the column; the solid was collected, washed with acetonitrile (6×100 mL), and purified again by automated flash chromatography (silica cartridge, eluting with aqueous ammonium hydroxide:methanol:dichloromethane in a gradient from 0.2:4.8:95 to 1:19:80) to provide 70 mg of 4-amino-1-benzyl-1H-imidazo[4,5-c]quinolin-2-ol as a white solid, mp greater than 250° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:35]([O:38][CH2:39][CH3:40])(=[O:37])[CH3:36]>CN(C=O)C>[CH2:39]([O:38][C:35](=[O:37])[CH2:36][N:9]1[CH2:10][C@@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C@@:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[C@H:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[F:28])[CH3:40]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 21 h
Yield: 44.2 %

Procedure:
To a solution of rac (2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (42.1 mg, 0.10 mmol) in DMF (3 mL) was added potassium carbonate (43.3 mg, 0.313 mmol) and the reaction mixture was stirred at rt under argon for 21 hrs. The reaction mixture was diluted with ethyl acetate and washed with water (2×) and brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by flash chromatography to give rac [(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetic acid ethyl ester (22.3 mg, 44.2%,) as a white amorphous solid. HRMS (ES+) m/z Calcd for C26H28Cl2F2N2O2+H [(M+H)+]: 509.1569; Found: 509.1569.
Reaction SMILES: N12CCCN=C1CCCCC2.[F:12][C:13]([F:30])([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:24]2[NH:25][O:26][C:27](=[O:29])[N:28]=2)[CH:19]=1)[C:14]([F:17])([F:16])[F:15].[N:31]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1>N1C=CC=CC=1>[N:31]1([C:36]([N:28]2[C:27](=[O:29])[O:26][N:25]=[C:24]2[C:20]2[CH:19]=[C:18]([C:13]([F:12])([F:30])[C:14]([F:15])([F:17])[F:16])[CH:23]=[CH:22][N:21]=2)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=c1nc(-c2cc(C(F)(F)C(F)(F)F)ccn2)[nH]o1
Reactant: O=C(Cl)N1CCCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: O=C(N1CCCC1)n1c(-c2cc(C(F)(F)C(F)(F)F)ccn2)noc1=O
Reaction time: 4 h
Yield: 63.2 %

Procedure:
To 2 ml of pyridine were added 0.16 g of 1,8-diazabicyclo[5,4,0]undec-7-ene, and 0.2 g of 3-(4-pentafluoroethylpyridin-2-yl)-1,2,4-oxadiazol-5-one, and 0.14 g of 1-pyrrolidinecarbonyl chloride was added at room temperature. After stirring for 4 hours, the resultant solution was concentrated, and the residue was subjected to silica gel column chromatography to obtain 0.17 g of 4-(1-pyrrolidinecarbonyl)-3-(4-pentafluoroethylpyridin-2-yl)-1,2,4-oxadiazol-5-one (present compound (63)).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:3].Cl.[NH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH:21]([C:24]([N:26]2[CH2:35][C:34]3[CH:33]=[N:32][N:31]([CH3:36])[C:30]=3[NH:29][C:28]3[CH:37]=[C:38]([CH3:41])[CH:39]=[CH:40][C:27]2=3)=[O:25])[CH2:20][CH2:19]1>ClCCl.C(N(CC)CC)C>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][O:4][C:2](=[O:3])[NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH:21]([C:24]([N:26]3[CH2:35][C:34]4[CH:33]=[N:32][N:31]([CH3:36])[C:30]=4[NH:29][C:28]4[CH:37]=[C:38]([CH3:41])[CH:39]=[CH:40][C:27]3=4)=[O:25])[CH2:20][CH2:19]2)=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)C1CCC(CN)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)C1CCC(CNC(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-nitrobenzyl chloroformate (1.08 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of (4-Aminomethyl-cyclohexyl)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride (Compound number 149) (1.95 mg, 0.005 mmol) in dichloromethane (0.05 ml) and triethyl-amine (0.0035 ml). The mixture was stirred at room temperature for 1 h then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=533.3
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C@H:11]([OH:14])[CH2:12][Cl:13].[C:15](OC(=O)C)(=[O:17])[CH3:16]>C1COCC1>[C:15]([NH:9][CH2:10][C@H:11]([OH:14])[CH2:12][Cl:13])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: NC[C@H](O)CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NC[C@H](O)CCl
Reaction time: 0.08 h

Procedure:
Triethylamine (10.5ml, 75.3 mmol, 1.11 eq) is added to a slurry of (S)-1-amino-3-chloro-2-propanol hydrochloride (V, EXAMPLE 1, 9,938 g, 68.059 mmol) in THF (80 ml) at −40° and the mixture stirred for 5 min at −40°. Acetic anhydride (6.78 ml, 71.86 mmol, 1.056 eq) is then added at −40° and the mixture allowed to warm to 20-25° over 1.5 hrs. The precipitate is removed by filtration with reduced pressure and washed with THF. The filtrate is treated with magnesol (5.69 g), which is removed by filtration with reduced pressure and washed with THF (2×60 ml). The filtrate is then concentrated under reduced pressure. The concentrate is purified by flash chromatography (silica gel; eluting with a gradient of 75-100% ethyl acetate/cyclohexane) to give the title compound, NMR (CDCl3) 2.03, 3.32, 3.50-3.57, 3.55, 3.91-4.13, 5.01 and 7.09δ; CMR (CDCl3) 23.00, 43.31, 46.52, 70.65 and 172.40δ; MS (CI, NH3), M/Z (relative intensity), 171 (41.6), 169 (100), 154 (22.4), 152 (48.1); [α]25D=−7.44 (c=1.00, H2O).
Reaction SMILES: Br[CH2:2][CH:3]1[O:19][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[C:9]([CH3:17])=[C:8]3[CH3:18].[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C)C=O>[N:20]([CH2:2][CH:3]1[O:19][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[C:9]([CH3:17])=[C:8]3[CH3:18])=[N+:21]=[N-:22]
Reactant: Cc1c(C)c2c3c(cc(C)c2[nH]c1=O)CC(CBr)O3
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(C)c2c3c(cc(C)c2[nH]c1=O)CC(CN=[N+]=[N-])O3
Temperature: 25 °C
Reaction time: 4 h
Yield: 1 %

Procedure:
2-Bromomethyl-5,8,9-trimethyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (1.07 g, 3.32 mmol) was dissolved in N,N-dimethylformamide (30 ml). To the obtained solution, sodium azide (1.29 g, 19.9 mmol) was added. The mixture was stirred at room temperature for 4 hours. The reaction mixture was subjected to distillation under reduced pressure for removing the solvent. To the resultant residue, chloroform and water were added. The mixture was extracted, dried, and condensed. Recrystallization from chloroform--n-hexane yielded 8.99 mg of the title compound as yellow needles (95.2%).
Reaction SMILES: C1C[N:4]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:34]([O:38][C:39]([N:41]1[CH2:44][CH:43]([CH2:45][C:46]([OH:48])=O)[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]>CN(C=O)C>[NH2:4][C:46](=[O:48])[CH2:45][CH:43]1[CH2:44][N:41]([C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:40])[CH2:42]1
Reactant: CC(C)(C)OC(=O)N1CC(CC(=O)O)C1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(CC(N)=O)C1
Yield: 57.5 %

Procedure:
PyBOP (1.946 g, 3.74 mmol) was added to a solution of [1-(tert-Butoxycarbonyl)azetidin-3-yl]acetic acid (0.805 g, 3.74 mmol) in DMF (10 mL). The mixture was stirred in an ice-bath, ammonia gas was bubbled in for 3 mins and then the mixture was stirred at rt overnight. The reaction mixture was concentrated, water (15 mL) and saturated, aqueous NaHCO3 (5 mL) were added, and the mixture was extracted with EtOAc (20 mLx3). The extracts were combined, washed with water (20 mL) and brine (10mL), dried (Na2SO4) and evaporated. Column chromatography of the residue (ISOLUTE SI, 50 g/150 ml), eluting with EtOAc and heptane (50:50), then EtOAc and then MeOH and EtOAc (1:99, 2:98 and 5:95), gave the title compound (0.461 g, 57.5%) as a white solid. 1H NMR (400 MHz, CDCl3): 1.42 (s, 9H), 2.53 (d, 2H), 2.85-2.96 (m, 1H), 3.60 (dd, 2H), 4.09 (t, 2H), 5.78 (s, br, 2H); 13C NMR (100 MHz, CDCl3): 25.4, 28.3, 39.7, 54.3 (br), 79.4, 156.3, 173.2.