Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH:40][CH2:41][C@H:42]([N:46]2[CH2:51][CH2:50][N:49]([S:52]([CH3:55])(=[O:54])=[O:53])[CH2:48][CH2:47]2)[C:43](O)=[O:44])(=[O:39])=[O:38])=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Si](ON)(C(C)(C)C)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(OCC)(=O)C.O>[CH2:23]([O:30][C:31]1[CH:32]=[CH:33][C:34]([S:37]([NH:40][CH2:41][C@H:42]([N:46]2[CH2:51][CH2:50][N:49]([S:52]([CH3:55])(=[O:54])=[O:53])[CH2:48][CH2:47]2)[C:43]([NH:2][OH:1])=[O:44])(=[O:38])=[O:39])=[CH:35][CH:36]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CS(=O)(=O)N1CCN([C@@H](CNS(=O)(=O)c2ccc(OCc3ccccc3)cc2)C(=O)O)CC1
Reactant: On1nnc2ccccc21
Agent: CC(C)(C)[Si](C)(C)ON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N1CCN([C@@H](CNS(=O)(=O)c2ccc(OCc3ccccc3)cc2)C(=O)NO)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 39 %

Procedure:
224 mg (1.7 mmol) of 1-hydroxybenzotriazole and 318 mg (1.7 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride are added successively to 750 mg (1.5 mmol) of (S)-3-(4-benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoic acid in 20 ml of dimethylformamide. After stirring at ambient temperature for 20 min, a solution of 244 mg (1.7 mmol) of O-tert-butyldimethylsilylhydroxylamine in 3 ml of dimethylformamide is added. The reaction medium is then stirred at ambient temperature for 18 h and then 2 ml of a saturated aqueous solution of sodium hydrogen carbonate and finally 2 ml of water are added. After extraction with ethyl acetate, the organic phase is washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, filtered and concentrated. The crude residue obtained is taken up in 15 ml of ethyl acetate, heated to 70° C. and then brought back to ambient temperature, filtered and dried under vacuum. 300 mg (34%) of (S)-3-(4-benzyloxybenzenesulfonylamino)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)propionamide are obtained in the form of a white solid having a melting point of 165° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH:8][C:9]2[N:14]=[C:13]([C@@H:15]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:16][C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[C:12](Br)=[CH:11][N:10]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[C:34]([C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][C:42]=1[F:43])(=[O:36])[NH2:35].C([O-])([O-])=O.[K+].[K+]>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].C1(C)C=CC=CC=1.CC(O)C.O>[N:1]1([CH2:6][CH2:7][NH:8][C:9]2[N:14]=[C:13]([C@@H:15]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:16][C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[C:12]([C:39]3[CH:40]=[CH:41][C:42]([F:43])=[C:37]([C:34](=[O:36])[NH2:35])[CH:38]=3)=[CH:11][N:10]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(NCCn2ccnn2)ncc1Br
Reactant: NC(=O)c1cc(B(O)O)ccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(NCCn2ccnn2)ncc1-c1ccc(F)c(C(N)=O)c1
Temperature: 120 °C

Procedure:
In a microwave tube were charged with compound 23C (52 mg, 0.1 mmol), (3-carbamoyl-4-fluorophenyl)boronic acid (27 mg, 0.15 mmol), K2CO3 (41 mg, 0.3 mmol), Pd(dppf)Cl2 (5 mg). To the mixture was added 2 mL of Toluene/2-propanol/H2O (3/1/1). The mixture was heated up to 120° C. for 20 min in a Microwave Synthesizer. The mixture was partitioned between ethyl acetate and water. The organic layer was separated and concentrated to afford crude product used for next step without further purification. MS (m/z) 582.73 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][NH:10][C:11]([NH2:13])=[O:12])=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.O>C1(C)C=CC=CC=1>[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([N:9]([C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[NH:10][C:11]([NH2:13])=[O:12])=[O:27])=[CH:24][CH:23]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(NNC(N)=O)cn1
Solvent: O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)N(NC(N)=O)c2ccc(OC)nc2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 28.8 %

Procedure:
To a suspension of 2-(6-methoxypyridin-3-yl)hydrazinecarboxamide (17 g, 93.3 mmol) in 100 mL of toluene, pyridine (15.1 mL, 187 mmol) and then a solution of 4-methoxybenzoyl chloride (15.9 g, 93.3 mmol) in 50 mL of toluene were added. The mixture was refluxed with stirring for 1 hour. After cooling at 80° C., 75 mL of water was added to the mixture. After vigorous shaking, an insoluble material was isolated by filtration, washed with water and toluene, dried in vacuo to give 2-(4-methoxybenzoyl)-2-(6-methoxypyridin-3-yl)hydrazinecarboxamide (8.5 g, 28.8% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:11](=[O:18])[N:10]([CH2:19][C:20]3[CH:32]=[CH:31][CH:30]=[CH:29][C:21]=3[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:9]2)=[CH:4][CH:3]=1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:42][CH2:43][CH2:44][N:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:47]2([CH2:55][CH2:54]2)[C:46]1=[O:56]>CC(=O)CC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3([CH2:13][CH2:14][N:15]([CH2:42][CH2:43][CH2:44][N:45]4[C:53]5[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=5)[C:47]5([CH2:55][CH2:54]5)[C:46]4=[O:56])[CH2:16][CH2:17]3)[C:11](=[O:18])[N:10]([CH2:19][C:20]3[CH:32]=[CH:31][CH:30]=[CH:29][C:21]=3[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1N(CCCCl)c2ccccc2C12CC2
Reactant: CC(C)(C)OC(=O)c1ccccc1CN1CN(c2ccc(F)cc2)C2(CCNCC2)C1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)c1ccccc1CN1CN(c2ccc(F)cc2)C2(CCN(CCCN3C(=O)C4(CC4)c4ccccc43)CC2)C1=O
Temperature: 78 °C
Reaction time: 5 h
Yield: 44.2 %

Procedure:
To a solution of tert-butyl 2-((1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.2 g, 0.46 mmol), sodium iodide (0.021 g, 0.14 mmol) and potassium carbonate (0.095 g, 0.7 mmol) in 2-butanone (5 mL), was added 1′-(3-chloropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one (0.107 g, 0.46 mmol). After stirring at 78° C. for 5 hours, the reaction mixture was filtered and isolated by Biotage flash chromatography (1-10% methanol/dichloromethane) and preparatory TLC (10% methanol/dichloromethane) to obtain the title compound (0.13 g, 44%); 1H NMR (DMSO-d6): δ 1.50 (t, 2H, J=6.4 Hz), 1.56-1.60 (m, 11H), 1.69 (d, 2H, J=9.2 Hz), 1.75 (t, 2H, J=6.4 Hz), 2.32-2.34 (m, 4H), 2.64-2.67 (m, 4H), 3.79 (t, 2H, J=6.4 Hz), 4.58 (s, 2H), 4.82 (s, 2H), 6.91-6.92 (m, 2H), 6.97-6.99 (m, 2H), 7.08-7.15 (m, 3H), 7.19 (d, 1H, J=6.8 Hz), 7.25-7.31 (m, 1H), 7.41 (t, 1H, J=8 Hz), 7.57 (t, 1H, J=7.6 Hz), 7.82 (dd, 1H, J=8 and 1.2 Hz); MS for C38H43FN4O4 m/z 639.4 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([NH:5][C@H:6]1[C:15]2[C:10](=[CH:11][C:12]([CH:19]=O)=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:4].[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[F:1][C:2]([F:22])([F:21])[C:3]([NH:5][C@H:6]1[C:15]2[C:10](=[CH:11][C:12]([CH2:19][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:4]
Reactant: C1CCNCC1
Reactant: O=Cc1cc2c(cc1[N+](=O)[O-])[C@H](NC(=O)C(F)(F)F)CCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(N[C@@H]1CCCc2cc(CN3CCCCC3)c([N+](=O)[O-])cc21)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ((R)-2,2,2-trifluoro-N-(6-formyl-7-nitro-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide (350 mg, 1.1 mmol) in 6 mL of 1,2-dichloroethane was added piperidine (187 mg, 2.2 mmol) and NaBH(OAc)3 (350 mg, 1.65 mmol). After stirring at RT overnight, the reaction was quenched with Sat. NaHCO3, extracted with EtOAc, dried over Na2SO4, filtered, and evaporated to dryness. Flash chomatography (SiO2, EtOAc/hexane=1:1) afforded (R)-2,2,2-trifluoro-N-(7-nitro-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide as a white solid.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][CH3:17])[S:15][C:9]=2[NH:8][C:7]1=[O:18].O[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[C:34]([C:40]#[N:41])=[CH:35][CH:36]=[C:37]([F:39])[CH:38]=2)=[CH:29][CH:28]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C(OCC)(=O)C.O1CCCC1>[CH2:16]([C:14]1[S:15][C:9]2[N:8]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[C:34]([C:40]#[N:41])=[CH:35][CH:36]=[C:37]([F:39])[CH:38]=4)=[CH:29][CH:28]=3)[C:7](=[O:18])[NH:6][C:11](=[O:12])[C:10]=2[CH:13]=1)[CH3:17]
Reactant: N#Cc1ccc(F)cc1-c1ccc(CO)cc1
Reactant: CCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)[nH]c2s1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4cc(F)ccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.5 %

Procedure:
A mixture of 3-(2,4-dimethoxybenzyl)-6-ethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.5 g), 4′-(hydroxymethyl)-5-fluorobiphenyl-2-carbonitrile (1.3 g), 1,1′-(azodicarbonyl)dipiperidine (1.6 g), tributylphosphine (1.3 mL) and tetrahydrofuran (16 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in trifluoroacetic acid (15 mL) and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was concentrated under reduced pressure. To the obtained residue was added ethyl acetate, and insoluble material was filtered off. The filtrate was concentrated and recrystallized from diethyl ether to give the title compound as a colorless solid (1.8 g, 100%).
Reaction SMILES: [I:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C@H:20](OS(C)(=O)=O)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH:20]([O:10][C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:9][C:6]=2[CH:7]=[O:8])[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=Cc1cc(I)ccc1O
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(I)cc2C=O)C1
Yield: 59.9 %

Procedure:
In a manner similar to the method described in example 4a, 5-iodosalicylaldehyde (5 g, 20 mmol) (Aldrich) reacted with (S)-3-methanesulfonyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester (7 g, 26 mmol) prepared in Example 48a and K2CO3 in N,N-dimethylformamide to give (R/S)-3-(2-formyl-4-iodo-phenoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester as a white foam (Yield 5 g, 60%).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[N:10]=[C:11]([CH:20]([NH:22][CH:23]3[C:32]4[C:27](=[C:28]([OH:33])[CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]3)[CH3:21])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]>CN(C=O)C>[C:3]1([C:9]2[N:10]=[C:11]([CH:20]([NH:22][CH:23]3[C:32]4[C:27](=[C:28]([O:33][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]3)[CH3:21])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)CBr
Reactant: CC(NC1CCCc2c(O)cccc21)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc2c1CCCC2NC(C)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 7 h
Yield: 57.1 %

Procedure:
A solution of NaH (60% oil, 66 mg) and 1-[1-(4,5-diphenyloxazol-2-yl)ethylamino]-1,2,3,4-tetrahydro-5-hydroxynaphthalene (0.55 g) in DMF (10 ml) was stirred for 30 minutes at room temperature. To the reaction mixture was added ethyl bromoacetate (0.26 g). After being stirred for 7 hours at room temperature, the solution was partitioned between ethyl acetate and sat. NaHCO3. The organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give 1-[1-(4,5-diphenyloxazol-2-yl)ethylamino]-1,2,3,4-tetrahydro-5-ethoxycarbonylmethoxynaphthalene (0.38 g). MS (m/z): 497 (M+ +1) IR (Film): 1740 cm-1NMR (CDCl3, δ): 1.29 (3H, t, J=7.1 Hz), 1.60 (3H, t, J=6.6 Hz), 1.70-1.85 (3H, m), 1.90-2.15 (1H, m), 2.44-2.98 (2H, m), 3.89 (1H, m), 4.24-4.31 (3H, m), 4.60 (2H, s), 6.55-6.60 (1H, m), 7.08-7.11 (2H, m), 7.32-7.40 (6H, m), 7.58-7.69 (4H, m)
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:31]([C:34]([NH:36][C:37]2[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=2[F:44])=[O:35])=[CH:30][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16]([NH:18][CH:19]([CH2:24][CH2:25][C:26]([O:28]C)=[O:27])[C:20]([O:22]C)=[O:21])=[O:17])[CH:12]=2)[CH:6]=1.[OH-].[Na+].O.Cl>CO>[F:1][C:2]1[CH:33]=[CH:32][C:31]([C:34]([NH:36][C:37]2[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=2[F:44])=[O:35])=[CH:30][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16]([NH:18][CH:19]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C:20]([OH:22])=[O:21])=[O:17])[CH:12]=2)[CH:6]=1
Reactant: COC(=O)CCC(NC(=O)c1c[nH]c(-c2cc(Oc3cc(C(=O)Nc4cc(C)ccc4F)ccc3F)ccn2)c1)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)NC(CCC(=O)O)C(=O)O)c[nH]4)c3)c2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of dimethyl 2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]pentanedioate (320 mg, 0.53 mmol) in MeOH (20 ml) was added 1M NaOH solution (2 ml, 2 mmol). The mixture was stirred at room temperature for 16 hours and poured into 100 ml of water. 1M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give 2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]pentanedioic acid as white solid. Yield: 305 mg, 100%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:17][C:18]([CH3:26])([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:19]#[N:20]>>[C:19]([C:18]([NH:17][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])([CH3:26])[CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])#[N:20]
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(Cl)cn1
Reactant: CC(C)(C)CC(C)(N)C#N
Product: CC(C)(C)CC(C)(C#N)NC(=O)c1cc(OCC(F)(F)F)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 78e, using 5-Chloro-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 24c) and 2-amino-2,4,4-trimethylpentanenitrile (CAN 65260-84-6) as starting materials and isolated (643 mg, 87%) as a yellow oil; MS (ESI, m/z): 378.4 (M+H+).
Reaction SMILES: [Cl:1][CH:2]([CH2:5][C:6]([Cl:10])(Cl)[CH:7]=O)[C:3]#[N:4].[Al+3].[Cl-:12].[Cl-].[Cl-]>>[Cl:12][C:7]1[C:6]([Cl:10])=[CH:5][C:2]([Cl:1])=[CH:3][N:4]=1
Reactant: N#CC(Cl)CC(Cl)(Cl)C=O
Reactant: [Cl-]
Agent: [Al+3]
Product: Clc1cnc(Cl)c(Cl)c1
Temperature: 60 °C

Procedure:
13.6 g of 2,4,4-trichloro-4-formylbutyronitrile obtained according to (a), with the addition of 1.0 g of AlCl3, is heated in an enamel autoclave for 1 hour at 60° C. The dark crude product is afterwards distilled with steam, in the process of which the 2,3,5-trichloropyridine precipitates, in the distillate, in the form of white crystals. The yield is 9.1 g (83% of theory) of 2,3,5-trichloropyridine, m.p. 49°-50° C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:4]([F:7])([F:6])[F:5].[H][H]>[C].[Ru].C(O)(C)C>[F:1][C:2]([F:22])([F:23])[C:3]([CH:15]1[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]1)([CH:8]1[CH2:9][CH2:10][CH:11]([OH:14])[CH2:12][CH2:13]1)[C:4]([F:5])([F:7])[F:6]
Reactant: Oc1ccc(C(c2ccc(O)cc2)(C(F)(F)F)C(F)(F)F)cc1
Reactant: [H][H]
Agent: [Ru]
Solvent: CC(C)O
Product: OC1CCC(C(C2CCC(O)CC2)(C(F)(F)F)C(F)(F)F)CC1
Temperature: 130 °C
Yield: 56 %

Procedure:
Into a stainless steel autoclave were placed 500 g of 4,4'-(perfluoroisopropylidene)diphenol, 100 ml of isopropanol and 2 g of 5% ruthenium-carbon. The mixture was maintained at a temperature of 130° C. and a hydrogen pressure of 50 kg/cm2G for 40 minutes and then at 160° to 170° C. and a hydrogen pressure of 60 to 70 kg/cm2G for 40 minutes. After cooled to room temperature, the catalyst is filtered off and isopropanol was removed at a reduced pressure. The residue was recrystallized from toluene to obtain 290 g of 4,4'-(perfluoroisopropylidene)dicyclohexanol in the form of white solid.
Reaction SMILES: [C:1]1([C:7]23[CH2:12][CH:11]2[CH2:10][NH:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1.CCOCC.C(Cl)Cl>[C:13]([N:9]1[CH2:10][CH:11]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([CH2:12]2)[CH2:8]1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc(C23CNCC2C3)cc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CC2CC2(c2ccccc2)C1
Reaction time: 8 h

Procedure:
To 15.9 g of 1-phenyl-3-azabicyclo[3.1.0]hexane in 20 ml of pyridine is added 20 ml of acetic anhydride. The mixture is allowed to stand overnight at room temperature and then evaporated to give an oil. This oil is dissolved in a mixture of ether and methylene chloride, washed with dilute hydrochloric acid and then sodium bicarbonate and dried over magnesium sulfate and evaporated to a pale amber liquid. This liquid is crystallized from hexane to give the product 3-acetyl-1-phenyl-3-azabicyclo[3.1.0]hexane mp 63°-65° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([OH:8])[CH:3]=1.[CH3:9]I>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[CH:3]=1
Reactant: Oc1cc(Cl)ccn1
Reactant: CI
Product: COc1cc(Cl)ccn1
Yield: 58.3 %

Procedure:
4-Chloro-2-hydroxy-pyridine (247 mg, 1.91 mmol), Ag2CO3 (1.58 g, 5.74 mmol) and MeI (0.13 ml, 2.11 mmol) were heated in a sealed tube at 50° C. for 16 hours and then filtered through celite and concentrated at reduced pressure. The residue was purified by FCC (Pentane/Diethyl ether with gradient, 99:1 to 95:5) to provide the title compound as colourless oil (160 mg, 58%).
Reaction SMILES: N1C=CC=CC=1.[ClH:7].[NH2:8][N:9]=[CH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1.Cl.[C:21]([C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[C:30]([CH2:34][C:35](=[O:37])[NH2:36])=[C:29](O)[CH:28]=[CH:27]2)(=[NH:23])[NH2:22].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(C(C)=O)C.O.C(O)=O.CN(C=O)C>[ClH:7].[ClH:7].[NH2:8][N:9]=[CH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([O:17][C:29]2[CH:28]=[CH:27][C:26]3[C:31](=[CH:32][CH:33]=[C:24]([C:21](=[NH:22])[NH2:23])[CH:25]=3)[C:30]=2[CH2:34][C:35](=[O:37])[NH2:36])=[O:16])=[CH:13][CH:12]=1
Reactant: N=C(N)c1ccc2c(CC(N)=O)c(O)ccc2c1
Reactant: NN=Cc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCC(C)=O
Solvent: O=CO
Solvent: O
Product: N=C(N)c1ccc2c(CC(N)=O)c(OC(=O)c3ccc(C=NN)cc3)ccc2c1
Reaction time: 2 h
Yield: 7 %

Procedure:
20 Milliliters of 20% hydrous pyridine and 6 ml of DMF were added to 1.0 g of 4-aminoiminomethylbenzoic acid.hydrochloride, 1.39 g of 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 1.23 g of DCC and 60.8 mg of DMAP, followed by stirring for 2 hours under cooling with ice and then 24 hours at room temperature. Then, the precipitate was filtered and the filtrate was concentrated under reduced pressure. To the residue was added 20 ml of DMF, and the resulting solution was added dropwise to 400 ml of acetone, followed by stirring for 24 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain a crude product. Then, the product was subjected to silica gel column chromatography using methyl ethyl ketone-water-formic acid (80:15:5) as an eluent, and the desired fractions were collected and the solvent was distilled off under reduced pressure. To the residue were added 10 ml of methanol and 0.9 ml of concentrated hydrochloric acid, and the resulting solution was added dropwise to 200 ml of acetone, followed by stirring for 2 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain 80.2 mg of the desired product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[C:9]([CH2:14][NH:15][CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][O:26][C:27](=[O:38])[C:28]1[CH:33]=[C:32]([C:34]#[N:35])[CH:31]=[CH:30][C:29]=1[CH2:36]Br.CCN(C(C)C)C(C)C>CC#N>[CH3:25][O:26][C:27](=[O:38])[C:28]1[CH:33]=[C:32]([C:34]#[N:35])[CH:31]=[CH:30][C:29]=1[CH2:36][N:15]([CH2:14][C:9]1[C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:24])=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:16][C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: Cc1cccnc1CNCc1ncccc1NC(=O)OC(C)(C)C
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(C#N)ccc1CN(Cc1ncccc1C)Cc1ncccc1NC(=O)OC(C)(C)C
Yield: 90.2 %

Procedure:
Using General Procedure A: A solution (2-{[(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-pyridin-3-yl)-carbamic acid tert-butyl ester (0.220 g, 0.65 mmol), 2-bromomethyl-5-cyano-benzoic acid methyl ester (0.245 g, 0.97 mmol), and DIPEA (0.23 mL, 1.32 mmol) in CH3CN (7 mL) was stirred at room temperature for 21 hours. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2-MeOH—NH4OH) provided 0.294 g (88%) of 2-{[(3-tert-Butoxycarbonylamino-pyridin-2-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-5-cyano-benzoic acid methyl ester as a colorless oil. 1H NMR (CDCl3) δ 1.58 (s, 9H), 2.20 (s, 3H), 3.76 (s, 2H), 3.86 (s, 3H), 4.05 (s, 2H), 4.09 (s, 2H), 7.09-7.16 (m, 2H), 7.44 (d, 1H, J=7.8 Hz), 7.55 (dd, 1H, J=8.1, 1.5 Hz), 7.89 (d, 1H, J=8.1 Hz), 8.04 (d, 1H, J=1.5 Hz), 8.09 (dd, 1H, J=1.5, 4.8 Hz), 8.51 (d, 1H, J=7.8 Hz), 8.63 (d, 1H, J=4.8 Hz).
Reaction SMILES: C(O[C:6]1[C:7](=[O:16])[C:8](=[O:15])[C:9]=1[NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])CCC.[CH3:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[CH3:26])[CH2:21][NH2:22]>O1CCCC1>[C:11]([NH:10][C:9]1[C:8](=[O:15])[C:7](=[O:16])[C:6]=1[NH:22][CH2:21][C:20]1[CH:23]=[CH:24][C:25]([CH3:26])=[C:18]([CH3:17])[CH:19]=1)([CH3:12])([CH3:13])[CH3:14]
Reactant: CCCCOc1c(NC(C)(C)C)c(=O)c1=O
Reactant: Cc1ccc(CN)cc1C
Solvent: C1CCOC1
Product: Cc1ccc(CNc2c(NC(C)(C)C)c(=O)c2=O)cc1C
Yield: 74 %

Procedure:
Tetrahydrofuran (17 mL), 3-butoxy-4-tert-butylamino-cyclobut-3-ene-1,2-dione (1.13 g, 5 mmol, Example 1) and 3,4-dimethylbenzylamine (0.68 g, 5 mmol) were stirred together at room temperature for 2 days. Removal of solvent and trituration of the residue with diethyl ether gave 1.06 g of a light yellow solid. Four recrystallizations of this material from acetonitrile provided 0.394 g of the tide compound as a white solid: mp 264°-264° C. (softens 260° C.). MS (m/z) 286 (M+). HPLC indicates a major component (96%).