Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[C:16]([F:21])[C:17]([NH:19][CH3:20])=[CH:18][C:11]=3[O:10][CH2:9]2)=[CH:4][CH:3]=1.C([O:24][C:25](=O)[NH:26][S:27]([C:30]1[S:31][C:32]([Cl:35])=[CH:33][CH:34]=1)(=[O:29])=[O:28])C>O1CCOCC1>[Cl:35][C:32]1[S:31][C:30]([S:27]([NH:26][C:25]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[C:13](=[O:14])[C:12]4[CH:15]=[C:16]([F:21])[C:17]([NH:19][CH3:20])=[CH:18][C:11]=4[O:10][CH2:9]3)=[CH:6][CH:7]=2)=[O:24])(=[O:29])=[O:28])=[CH:34][CH:33]=1
Reactant: CNc1cc2c(cc1F)C(=O)N(c1ccc(N)cc1)CO2
Reactant: CCOC(=O)NS(=O)(=O)c1ccc(Cl)s1
Solvent: C1COCCO1
Product: CNc1cc2c(cc1F)C(=O)N(c1ccc(NC(=O)NS(=O)(=O)c3ccc(Cl)s3)cc1)CO2
Temperature: 110 °C
Yield: 37.4 %

Procedure:
A mixture of 3-(4-aminophenyl)-6-fluoro-7-(methylamino)-2,3-dihydrobenzo[e][1,3]oxazin-4-one (Ex. 4) (130 mg, 0.45 mmol) and (5-Chloro-thiophene-2-sulfonyl)-carbamic acid ethyl ester (150 mg, 0.53 mmol, 1.2 eq) in dry 1,4-dioxan (3 mL) was heated at 110° C. for 2 hr. Upon cooling, the reaction was concentrated in vacuo and the crude residue was purified by HPLC (C-18) to give 86 mg (37%) of pure 1-(5-chlorothiophen-2-ylsulfonyl)-3-(4-(6-fluoro-7-(methylamino)-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)phenyl)urea. RP-HPLC: 2.49 min; ES-MS (M+H)+=511.0; 1H-NMR (MeOH-d4) δ (ppm): 2.8 (s, 3 H), 5.4 (s, 2 H), 6.2 (d, 1 H), 6.9 (d, 2 H), 7.1 (d, 2 H), 7.3 (d, 1 H), 7.4 (d, 1 H), 7.5 (d, 2 H).
Reaction SMILES: [OH:1][N:2]=[C:3]1[C:15]2[CH:14]=[CH:13][C:12]([O:16][CH3:17])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[C:7]([O:18][CH3:19])[CH:8]=2.C(N(CC)CC)C.[CH2:27]([C:39]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>C1COCC1>[CH2:27]([C:39]1[CH:40]=[CH:41][C:42]([S:45]([O:1][N:2]=[C:3]2[C:4]3[CH:5]=[CH:6][C:7]([O:18][CH3:19])=[CH:8][C:9]=3[C:10]3[C:15]2=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=3)(=[O:47])=[O:46])=[CH:43][CH:44]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc2c(c1)-c1cc(OC)ccc1C2=NO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCc1ccc(S(=O)(=O)ON=C2c3ccc(OC)cc3-c3cc(OC)ccc32)cc1
Yield: 51.4 %

Procedure:
As described under 11.3., 5.1 g (0.02 mol) of 9-hydroxyimino-3,6-dimethoxyfluorene are reacted at 0° C., in the presence of 3.0 g (0.03 mol) of triethylamine in 100 ml THF, with 5.6 g (0.022 mol) of 4-dodecylbenzenesulfonyl chloride. The crude product obtained after isolation is purified by flash chromatography on silica gel (eluant: petroleum ether/ethyl acetate 4:1). 5.8 g (51.3%) of 9-(4-dodecyl-phenylsulfonyloxyimino)-3,6-dimethoxyfluorene are obtained in the form of a viscous yellow oil. The UV spectrum (acetonitrile) of the substance shows absorption bands with a maximum at 315 nm (ε=21100) that extend to 443 nm. Elemental analysis: C33H41NO5S (563.76)
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][Si:28]([CH3:32])([CH3:31])[C:29]#[CH:30]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[C:30]#[C:29][Si:28]([CH3:32])([CH3:31])[CH3:27]
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: C#C[Si](C)(C)C
Product: C[Si](C)(C)C#Cc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Yield: 66.1 %

Procedure:
Use a method similar to the General Procedure 3 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (425 mg, 1 mmol) with 2-trimethylsilylacetylene (0.28 mL, 2 mmol). Purify by chromatography on silica gel eluting with isohexane/EtOAc (100:0 to 85:15 gradient over 40 min) to give the desired intermediate (247 mg, 81%). MS (ES+) m/z: 306 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][NH2:21])[CH:9]=1)([CH3:3])[CH3:2].[F:24][C:25]([F:39])([F:38])[C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:29]Br.C[Si]([N-][Si](C)(C)C)(C)C.[K+].O>C1COCC1.C1(C)C=CC=CC=1>[F:24][C:25]([F:38])([F:39])[C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([C:34]([F:37])([F:35])[F:36])[CH:33]=1)[CH2:29][NH:21][CH2:20][C:11]1[CH:12]=[C:13]([C:16]([F:17])([F:18])[F:19])[CH:14]=[CH:15][C:10]=1[C:8]1[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=[CH:6][C:7]=1[O:22][CH3:23]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1-[5′-Isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanamine (94.1 mg, 0.291 mmol) was dissolved in THF (4 mL). 3,5-B is(trifluoromethyl)benzyl bromide (320 μL, 1.75 mmol) was added followed by potassium bis(trimethylsilyl)amide (2.33 mL of a 0.5 M solution in toluene, 1.164 mmol). The reaction was stirred at room temperature for 72 hours and then poured into H2O (30 mL). The mixture was extracted with EtOAc (75 mL). The organic layer was washed with brine (25 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 0 to 15% EtOAc/hexanes, then a second column with 50% CH2Cl2, then a third column with 25% EtOAc/hexanes afforded [3,5-bis(trifluoromethyl)benzyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amine as a light yellow oil. Rf=0.18 (40% CH2Cl2/hexanes). LCMS=550.3 (M+1)+. 1H NMR (CDCl3, 600 MHz) δ 7.75 (s, 1H), 7.74 (s, 1H), 7.70 (s, 2H), 7.58 (d, J=7.9 Hz, 1H), 7.34 (d, J=7.8 Hz, 1H), 7.24 (dd, J=8.5, 2.2 Hz, 1H), 6.99 (d, J=2.2 Hz, 1H), 6.90 (d, J=8.5 Hz, 1H), 3.68-3.76 (m, 4H), 3.68 (s, 3H), 2.88 (m, 1H), 1.22 (d, J=6.4 Hz, 6H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.CN(C)CCN(C)C.C([Li])CCC.[CH:20]12[O:26][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25]2>C1COCC1.O>[CH3:1][N:2]1[C:6]([C@H:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]2[OH:26])=[CH:5][CH:4]=[N:3]1
Reactant: Cn1cccn1
Reactant: C1CCC2OC2C1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cn1nccc1[C@H]1CCCC[C@@H]1O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
To a solution of 1-methylpyrazole (9.34 g, 114 mmol) and N,N,N′,N′-tetramethylethylenediamine (17.1 mL, 114 mmol) in THF (300 mL), butyl lithium (1.63 M solution in hexane; 81.7 mL, 133 mmol) was added at −78° C. The reaction solution was stirred at −78° C. for 30 minutes. Then, cyclohexene oxide (13.9 mL, 137 mmol) was added thereto, and the mixture was stirred at room temperature for 15 hours. To the reaction solution, water (1 L) was added, followed by extraction with ethyl acetate (500 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (ethyl acetate) to yield the title compound (11.2 g, 55%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:27]OS(C)(=O)=O)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:33]1[CH:37]=[CH:36][N:35]=[CH:34]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([CH2:27][N:33]2[CH:37]=[CH:36][N:35]=[CH:34]2)[C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:21]=2)=[O:14])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)c1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Product: CCOC(=O)c1ccc(NC(=O)C(Cn2ccnc2)NS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
The procedure described in Example 79 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-methanesulfonyloxypropanamide (600 mg) was reacted with imidazole to obtain the desired (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-(1H-imidazol-1-yl)propanamide (115.5 mg) together with a by-product having lower polarity. The by-product was not investigated further.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][C:19]1[O:23][C:22]([C:24](O)=[O:25])=[CH:21][CH:20]=1>>[CH3:18][C:19]1[O:23][C:22]([C:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:25])=[CH:21][CH:20]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: Cc1ccc(C(=O)O)o1
Product: Cc1ccc(C(=O)Nc2ccc3[nH]cc(C4CCN(C)CC4)c3c2)o1
Yield: 86.9 %

Procedure:
Beginning with 7.0 mg (0.03 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 11.3 mg (0.09 mMol) 5-methyl-2-furoic acid, 8.8 mg (87%) of the title compound were recovered.
Reaction SMILES: [CH2:1]=[C:2]1[S:6][C:5](=[NH:7])[N:4]([C:8]2[CH:21]=[CH:20][C:11]3[O:12][C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[O:15][C:10]=3[CH:9]=2)[CH2:3]1.CCN(C(C)C)C(C)C.[C:31](Cl)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33]>C(#N)C.C(Cl)Cl>[CH3:33][C:32]([CH3:35])([CH3:34])[C:31](/[N:7]=[C:5]1\[S:6][C:2]([CH3:1])=[CH:3][N:4]\1[C:8]1[CH:21]=[CH:20][C:11]2[O:12][C:13]([F:19])([F:18])[C:14]([F:16])([F:17])[O:15][C:10]=2[CH:9]=1)=[O:36]
Reactant: C=C1CN(c2ccc3c(c2)OC(F)(F)C(F)(F)O3)C(=N)S1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)/c(=N/C(=O)C(C)(C)C)s1
Temperature: 65 °C

Procedure:
To a solution of 5-methylene-3-(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thiazolidin-2-imine (Example 22C, 0.14 g, 0.44 mmol) in acetonitrile (3 mL) was added Hunig's base (0.062 g, 0.48 mmol) followed by pivaloyl chloride (0.064 g, 0.54 mmol). The mixture was heated for 12 hours at 65° C. The mixture was cooled down and more pivaloyl chloride (0.064 g, 0.54 mmol) was added. The mixture was heated again at 65° C. for 12 hours. After cooling, the reaction mixture was diluted with CH2Cl2 (50 mL) and washed with water and brine. The organic phase was dried over sodium sulfate, filtered and dried. After evaporation under reduced pressure, the residue was chromatographed over silica using CH2Cl2-5% MeOH/CH2Cl2 to supply the titled compound. 1H NMR (CDCl3) δ ppm 1.05 (9 H), 2.30 (3 H), 6.80 (1 H), 7.20 (1 H), 7.40 (1 H), 7.50 (1 H); MS (ESI) m/z 405(M+H)+.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([F:22])([C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=1)[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].S(=O)(=O)(O)O.[I:30]N1C(=O)CCC1=O.[OH-].[Na+]>C(OCC)(=O)C.C(O)C>[I:30][C:16]1[CH:17]=[C:11]([C:3]([F:22])([C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6])[C:2]([F:23])([F:24])[F:1])[CH:12]=[C:13]([C:18]([F:19])([F:20])[F:21])[C:14]=1[NH2:15]
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1ccc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc1C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1c(I)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc1C(F)(F)F
Temperature: 40 °C
Reaction time: 4 h
Yield: 64.5 %

Procedure:
To 100 mL of ethanol was added 17.0 g (44.8 mmol) of 4-(perfluorobutan-2-yl)-2-(trifluoromethyl)aniline, and 5.28 g (53.8 mmol) of concentrated sulfuric acid and 12.6 g (55.8 mmol) of N-iodosuccinimide were added thereto under ice-cooling, followed by stirring at room temperature for 1 hour and 30 minutes and at 40° C. for 4 hours. To the reaction solution was added a 4 M aqueous sodium hydroxide solution to neutralize the reaction solution, and then ethyl acetate was added thereto to extract the organic phase. The organic phase was washed with saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent solvent; hexane:ethyl acetate=10:1) to prepare 14.6 g (yield 65%) of a target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9]O)[N:6]=[C:5](CO)[CH:4]=1.C(N(CC)CC)C.[CH:20]([Cl:23])(Cl)Cl.CS([Cl:28])(=O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][Cl:28])[N:6]=[C:5]([CH2:20][Cl:23])[CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(CO)nc(CO)c1
Reactant: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(CCl)nc(CCl)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-methoxy-2,6-bis(hydroxymethyl)pyridine (2.89 g, 17.10 mmol)-and triethylamine (9.6 ml, 68.40 mmol) at 0° C. in 100 ml of anhydrous dichloromethane and 50 ml of chloroform under an argon atmosphere was added methanesulphonyl chloride (3.9 ml, 51.30 mmol). The solution was stirred at 0° C. for 30 minutes, warmed to room temperature and stirred a further 24 hours. Additional methanesulphonyl chloride (1.5 ml, 19.38 mmol) was added and the mixture was stirred at 50° C. for 24 hours. The reaction mixture was quenched with H2O (50 ml), the aqueous phase extracted with CH2Cl2, dried over MgSO4 and concentrated to afford an orange oil. The residual oil was passed through a short plug of silica gel using dichloromethane as eluent thus affording after concentration a pale yellow solid which was identified by 1H NMR as 4-methoxy-2,6-bis-(chloromethyl)pyridine (2.3 g, 66%).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[CH:15]=[C:14]([CH2:16][N:17]2[C:25]3[C:20](=[CH:21][C:22]([C:26]([OH:28])=O)=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)[C:13]2[CH2:12][CH:11]=[CH:10][CH2:9][C:8]=2[N:7]=1>C(Cl)Cl>[CH3:5][C:6]1[CH:15]=[C:14]([CH2:16][N:17]2[C:25]3[C:20](=[CH:21][C:22]([C:26]([Cl:3])=[O:28])=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)[C:13]2[CH2:12][CH:11]=[CH:10][CH2:9][C:8]=2[N:7]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(Cn2ccc3cc(C(=O)O)ccc32)c2c(n1)CC=CC2
Solvent: ClCCl
Product: Cc1cc(Cn2ccc3cc(C(=O)Cl)ccc32)c2c(n1)CC=CC2
Temperature: 25 °C
Yield: 80 %

Procedure:
Thionyl chloride (5 ml) was added to a suspension of the 1-[(2-methyl-5,8-dihydro-4-quinolinyl)methyl]-1H-indole-5-carboxylic acid from step (402a) (0.67 g, 2.1 mmol) in methylene chloride (15 ml) and was heated to reflux for 2 hs. The reaction was cooled to room temperature, concentrated in vacuo to give the 1-[(2-methyl-5,8-dihydro-4-quinolinyl)methyl]-1H-indole-5-carbonyl chloride (0.68 g, 80%) as a yellow solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][C@@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1.[C:18](=O)([O:29]C1C=CC([N+]([O-])=O)=CC=1)[O:19][CH2:20][C:21]1[O:25][N:24]=[C:23]([C:26](=[O:28])[NH2:27])[CH:22]=1.CN1CCOCC1.O>ClCCl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][C@@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:19][CH2:20][C:21]2[O:25][N:24]=[C:23]([C:26](=[O:28])[NH2:27])[CH:22]=2)=[O:29])[CH2:14]1
Reactant: NC(=O)c1cc(COC(=O)Oc2ccc([N+](=O)[O-])cc2)on1
Reactant: c1ccc2cc(OC[C@@H]3CCNC3)ccc2c1
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: NC(=O)c1cc(COC(=O)N2CC[C@@H](COc3ccc4ccccc4c3)C2)on1
Temperature: 25 °C
Reaction time: 20 h
Yield: 38.5 %

Procedure:
0.21 g (0.92 mmol) of (R)-3-(naphth-2-yloxymethyl)-pyrrolidine is dissolved in 3.80 ml of dichloromethane and then 0.31 g (1.01 mmol) of 3-carbamoylisoxazol-5-ylmethyl 4-nitrophenyl carbonate and 0.15 ml (1.38 mmol) of N-methylmorpholine are added. The mixture is stirred at ambient temperature for 20 hours and then water is added to the reaction medium. After extraction of the aqueous phase with dichloromethane, the organic phases are successively washed three times with a 1M aqueous sodium hydroxide solution and then twice with a saturated aqueous ammonium chloride solution. After having dried the organic phases over sodium sulphate, they are filtered and the filtrate is evaporated to dryness. 0.14 g of the desired product is thus obtained in the form of a white solid after purification on a column of silica gel, elution being carried out with a dichloromethane/methanol mixture, and then taken up in isopropyl ether.
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].[C:12]([O:19][CH3:20])(=[O:18])[CH2:13][C:14]([O:16][CH3:17])=[O:15]>C1(C)C=CC=CC=1>[CH3:17][O:16][C:14]([CH:13]([C@H:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][N+:1]([O-:3])=[O:2])[C:12]([O:19][CH3:20])=[O:18])=[O:15]
Reactant: COC(=O)CC(=O)OC
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)C(C(=O)OC)[C@@H](C[N+](=O)[O-])c1ccccc1
Temperature: 30 °C
Reaction time: 24 h

Procedure:
[(S,S)-N-(2,4,6-triisopropylbenzenesulfonyl)-1,2-diphenylethylenediamine](hexamethylbenzene)ruthenium (14.8 mg, 0.02 mmol, S/C=50), trans-β-nitrostyrene (149 mg, 1.0 mmol), dimethyl malonate (114 μl, 1.0 mmol) and toluene (1 ml) were added into Schlenk (20 ml) under an argon atmosphere, and stirred at 30° C. for 24 hours. 1HNMR determination of the solution showed that the yield of the product was 94%. The reaction solution was purified by flash column chromatography (hexane/acetone=80/20, SiO2), and the optical purity was measured by HPLC (CHIRALPACK AD manufactured by Daicel Co., Ltd., hexane:2-propanol=90:10, flow rate 0.5 ml/min, detection by 210 nm), resulting to 87% ee.
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=[O:10])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.F[B-](F)(F)F.[CH3:17][N:18]([CH3:30])[C:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][CH:21]=[N+](C)C.CC[O-].[Na+].C(OCC)C>C(O)C>[CH:19]([O:10][CH:9]([CH3:8])[CH3:11])([CH3:25])[CH3:20].[CH3:17][N:18]([CH3:30])[C:19](=[CH:20][CH:21]=[C:11]1[CH2:1][CH2:2][C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:9]1=[O:10])[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)C(=CC=[N+](C)C)N(C)C
Reactant: O=C1CCCc2ccccc21
Agent: CC[O-]
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CC(C)OC(C)C
Product: CCOC(=O)C(=CC=C1CCc2ccccc2C1=O)N(C)C
Temperature: 20 °C
Yield: 33.5 %

Procedure:
α-Tetralone (51 g) is added dropwise in the course of 45 minutes, at a temperature in the region of 15° C., to a mixture of N-(3-dimethylamino-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (100 g) in ethanol (500 cc) and a 2M ethanolic solution of sodium ethylate (210 cc). The mixture is maintained for 1 hour 45 minutes at a temperature in the region of 20° C. and is then heated for 4 hours 45 minutes to 70° C. The reaction ethanol is evaporated off to dryness and the oil obtained is pounded with ethyl ether (4×300 cc). The ethereal extracts are concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa). After recrystallization of the solid obtained in a boiling mixture (60 cc) of isopropyl ether and ethyl acetate (90:10 by volume), ethyl 2-dimethylamino-4-(1-oxo-1,2,3,4-tetrahydro-2-naphthylidene)-2-butenoate (17.5 g), m.p. 84° C., is obtained.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:14]=[C:15]([CH2:19][CH2:20][C:21]#[N:22])[CH:16]=[CH:17][CH:18]=3)[N:6]2[N:5]=1)=O.[N:23]1([CH:29]2[CH2:35][CH2:34][C:33]3[CH:36]=[C:37]([NH2:40])[CH:38]=[CH:39][C:32]=3[CH2:31][CH2:30]2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.COCC(O)C.C(N(CC)C(C)C)(C)C>>[N:23]1([CH:29]2[CH2:35][CH2:34][C:33]3[CH:36]=[C:37]([NH:40][C:4]4[N:9]=[CH:8][C:7]5=[CH:10][CH:11]=[C:12]([C:13]6[CH:14]=[C:15]([CH2:19][CH2:20][C:21]#[N:22])[CH:16]=[CH:17][CH:18]=6)[N:6]5[N:5]=4)[CH:38]=[CH:39][C:32]=3[CH2:31][CH2:30]2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: Nc1ccc2c(c1)CCC(N1CCOCC1)CC2
Reactant: CS(=O)c1ncc2ccc(-c3cccc(CCC#N)c3)n2n1
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: N#CCCc1cccc(-c2ccc3cnc(Nc4ccc5c(c4)CCC(N4CCOCC4)CC5)nn23)c1

Procedure:
Into a microwave vial, 3-[3-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-propionitrile (0.0964 g, 0.310 mmol), 7-Morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (0.168 g, 0.683 mmol), 1-Methoxy-2-propanol (0.747 mL) and N,N-Diisopropylethylamine (0.119 mL) were added. The reaction was microwaved on 300 watts, 170° C. for 50 minutes. The solvent was removed under vacuum. The desired product was isolated via ISCO column chromatography with DCM and methanol as eluant (0 to 10% methanol). The collected fractions afforded 3-{3-[2-(7-Morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-propionitrile as a yellow solid (35 mg, 23%). LCMS (E/I+) 493.20 (M+H). MP 184-186° C. NMR 1H (DMSO-d6)-9.34 (s, 1H), 8.97 (s, 1H), 8.18 (d, 1H, J=8.44 Hz), 8.02 (s, 1H), 7.56 (s, 1H), 7.97 (d, 2H, J=7.23 Hz), 7.35 (d, 1H, J=7.23 Hz), 7.18 (d, 1H, J=4.51 Hz), 7.05 (d, 1H, J=7.89), 6.95 (d, 1H, J=4.51 Hz), 3.54 (bs, 4H), 2.98 (t, 2H, J=7.32 Hz), 2.87 (t, 2H, J=7.04 Hz), 2.53-2.81 (m, 5H), 2.43-2.48 (m, 4H), 1.89-2.07 (m, 2H), 1.22-1.43 (m, 2H).
Reaction SMILES: [I:1][C:2]1[N:9]2[C:5]([S:6][C:7](S(C)=O)=[N:8]2)=[N:4][CH:3]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[CH2:13]([NH:20][C:7]1[S:6][C:5]2=[N:4][CH:3]=[C:2]([I:1])[N:9]2[N:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: CS(=O)c1nn2c(I)cnc2s1
Solvent: ClCCl
Product: Ic1cnc2sc(NCc3ccccc3)nn12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.8 %

Procedure:
5-Iodo-2-methanesulfinyl-imidazo[2,1-b][1,3,4]thiadiazole (500.00 mg; 1.60 mmol; 1.00 eq.) was dissolved in dichloromethane (1.60 ml) and benzylamine (622.18 μl; 4.79 mmol; 3.00 eq.) was added. Then, the reaction was refluxed overnight. The reaction was concentrated in vacuo. Then, 5 ml of isopropanol were added and the suspended solution was heated under reflux for 15 min. The mixture was allowed to cool to room temperature and then cooled to 0° C. After 15 min at 0° C., the solid was filtered and washed with isopropanol to give a white solid. The solid was dried at 60° C. for 1 h to give 460.2 mg of the desired product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][NH2:16])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[C:27]1([S:37](Cl)(=[O:39])=[O:38])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][NH:16][S:37]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)(=[O:39])=[O:38])[CH2:13][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CN)CC1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CNS(=O)(=O)c2cccc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of trans-(4-aminomethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester (17 g) and ethyldiisopropylamine (14.41 ml) in N,N-dimethylformamide (350 ml) is cooled to 0° C. and treated with a solution of naphthalene-1-sulfonylchloride (15.9 g) in N,N-dimethylformamide (100 ml). The reaction is stirred at ambient temperature for 2 h, concentrated in vacuo. The residue is taken up in dichloromethane, washed with a 0.5 N HCl solution, a saturated aqueous sodium carbonate solution and water, dried and concentrated. Crystallization from hexanes-ethyl acetate gives trans-{4-[(naphthalene-1-sulfonylamino)-methyl]-cyclohexylmethyl}-carbamic acid tert-butyl ester as a white powder, melting at 199-200° C. Rf(A1) 0.42.