Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:20][C@@H:19]2[N:11]([C:12]3[N:13]=[C:14]4[CH2:23]OC(=O)[C:15]4=[CH:16][C:17]=3[CH2:18]2)[C@H:10]([CH3:25])[CH2:9]1)=O)(C)(C)C.[CH3:26][Mg]Br.[O:29]1[CH2:33][CH2:32]CC1>C(OCC)C>[CH3:26][C:33]1([CH3:32])[C:15]2=[CH:16][C:17]3[CH2:18][C@H:19]4[N:11]([C:12]=3[N:13]=[C:14]2[CH2:23][O:29]1)[C@H:10]([CH3:25])[CH2:9][NH:8][CH2:20]4
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc4c(nc3N21)COC4=O
Reactant: C[Mg]Br
Reactant: C1CCOC1
Solvent: CCOCC
Product: C[C@@H]1CNC[C@H]2Cc3cc4c(nc3N21)COC4(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 0.345 g (5R,8aR)-5-methyl-1-oxo-3,5,6,8,8a,9-hexahydro-1H-2-oxa-4,4b,7-triaza-cyclopenta[b]fluorene-7-carboxylic acid tert-butyl ester in 5 ml tetrahydrofuran was added at 0° C. 2.00 ml of a 2M solution of methylmagnesium bromide in diethyl ether. The mixture was stirred at 0° C. for 30 min and at room temperature for 1 h. The reaction mixture was partitioned between 10% aqueous ammonium chloride and ethyl acetate, the phases were separated and the organic phase was washed with 10% aqueous citric acid 10% aqueous sodium bicarbonate and brine dried over sodium sulfate and evaporated. The residue was taken up in 5 ml trifluoroacetic acid and kept at room temperature for 2 h. The solvent was evaporated and the residue was partitioned between water and ethyl acetate. The phases were separated and the aqueous phase was mixed with dichloromethane. The pH of the mixture was adjusted to 12.00 by addition of 2N aqueous sodium hydroxide. The phases were separated and the organic phase was washed with half concentrated brine dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica gel with dichloromethane:methanol:ammonia; 90:10:1 to yield 0.18 g of the title compound as slightly yellow oil (MS: 260.2 (M+H+))
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][C:7](=O)[CH:3]([CH2:4]2)[CH2:2]1.C(N(CC)CC)C.[NH2:16][C:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=1[C:23]#[N:24]>C(Cl)Cl>[NH2:24][C:23]1[C:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C:17]=2[N:16]=[C:7]2[C:6]=1[CH:5]1[CH2:4][CH:3]2[CH2:2][CH2:1]1
Reactant: O=C1CC2CCC1C2
Reactant: N#CC1=C(N)CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1c2c(nc3c1C1CCC3C1)CCCC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 12.8 %

Procedure:
To a stirred solution of norcamphor (0.9 g, 8.2 mmole) in methylene chloride (8.0 ml) at -20° C., a mixture of triethylamine (1.7 g, 16.4 mmole) and 2-amino-1-cyano-1-cyclohexene (1.0 g, 8.2 mmole) in methylene chloride (24 ml) was added and the resulting mixture was stirred at 25° C. for 15 hours. The reaction mixture was then quenched with 12% aqueous NaCH (60 ml) and was stirred vigorously with methylene chloride (60 ml). The reaction mixture was then filtered through a 2" pad of diatomaceous earth (Celite (trademark)). The organic phase was separated, washed with water (2×50 ml) and then dried (anhydrous MgSO4). Methylene chloride was then removed under reduced pressure to afford an oil which was triturated with pentane to give the title compound as a off-white solid (225 mg, 13%, m.p. 131°-133° C.). 1H-NMR (CDCl3, 300 MHz, δ): 2H, m, 1.15-2.38 ppm; 1H, d, 1.5 ppm; 7H, m, 165-2.0 ppm; 2H, bs, 2.4 ppm; 2H, bd, 2.8 ppm; 2H, bd 3.3 ppm; 2H, s, 3.95 ppm. HRMS: Calculated--214.3096; Found--214.1466. TLC: (90:10:1-methylene chloride: methanol:28% aqueous ammonia) Rf =0.25
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([CH3:23])[CH:3]=1.C1[CH2:28][O:27][CH2:26]C1.C([Li])CCC.ICOC>CCOC(C)=O>[CH2:17]([CH:16]([C:15]1[C:10]2[N:11]([C:7]([C:5]3[S:6][C:2]([CH2:26][O:27][CH3:28])=[CH:3][C:4]=3[CH3:23])=[C:8]([CH3:22])[N:9]=2)[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C)c(C)nc12
Reactant: C1CCOC1
Agent: COCI
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)nn2c(-c3sc(COC)cc3C)c(C)nc12
Temperature: 25 °C
Yield: 44 %

Procedure:
To a −78° C. solution of 3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.30 g, 0.76 mmol) and THF (3 mL) is added 1.34 M n-Bu-Li (0.50 mL, 0.80 mmol). After 30 minutes iodo-methoxy-methane (0.097 mL, 1.15 mmol) is added and the solution warmed to ambient temperature. After 1 hour the solution is diluted with EtOAc (40 mL) washed with water (30 mL), brine (30 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (15%-20% EtOAc/hexane gradient) furnish the title compound (0.12 g, 0.34 mmol, 44%). 1H NMR (CDCl3), δ 0.87 (t, J=7.5 Hz, 6H), 1.72-1.90 (m, 4H), 2.09 (s, 3H), 2.45 (s, 3H), 2.49 (s, 3H), 3.28-3.37 (m, 1H), 3.44 (s, 3H), 4.61 (s, 2H), 6.65 (s, 1H), 6.93 (s, 1H). LC/MS (m/z): calcd. for C20H27N3OS (M+H)+: 358.3; found: 358.3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:10][C:9]2=[O:23])=[CH:4][C:3]=1[NH:24][CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH:59]1([C:63](O)=O)[CH2:62][CH2:61][CH2:60]1>CN(C=O)C>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][O:14][C:11]2[CH:12]=[CH:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]4[N:1]=[C:63]([CH:59]5[CH2:60][CH2:61][CH2:62]5)[N:24]([CH3:25])[C:3]=4[CH:4]=3)[C:9](=[O:23])[CH:10]=2)=[CH:21][CH:20]=1
Reactant: CNc1cc(-n2ccc(OCc3ccc(Cl)cc3)cc2=O)ccc1N
Reactant: O=C(O)C1CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(C2CCC2)nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(4-amino-3-(methylamino)phenyl)-4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (90 mg), HATU (101 mg), N,N-diisopropylethylamine (0.130 ml), cyclobutanecarboxylic acid (0.024 ml) and DMF (2 ml) was stirred at room temperature for 2 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in AcOH (2 ml), and the mixture was stirred at 90° C. for 1 h. After evaporation, the residue was purified by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from EtOH to give the title compound (22.72 mg) as an off-white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[Br:13]Br>C(OCC)C>[CH2:11]([O:10][C:8]([C:3]1[CH2:4][CH2:5][CH2:6][CH:7]([Br:13])[C:2]=1[OH:1])=[O:9])[CH3:12]
Reactant: BrBr
Reactant: CCOC(=O)C1CCCCC1=O
Solvent: CCOCC
Product: CCOC(=O)C1=C(O)C(Br)CCC1
Temperature: 0 °C
Yield: 82.5 %

Procedure:
Ethyl 2-oxocyclohexanecarboxylate (5.0 g, 29 mmol, 4.7 mL) was dissolved in diethyl ether (5 mL) and cooled to 0° C. under N2. Bromine (4.6 g, 29 mmol, 4.2 mL) was added dropwise over 15 min and the reaction mixture was allowed to warm to room temperature over 90 min. The mixture was slowly poured into ice-cold saturated aqueous sodium carbonate solution (40 mL) and extracted with ethyl acetate (3×40 mL). The combined organic layers were dried and concentrated in vacuo to afford 5.96 g (81%) of 3-bromo-2-hydroxy-cyclohex-1-enecarboxylic acid ethyl ester (29) as a pale yellow oil which was used in the next step without purification. The structure was confirmed by 13C NMR (75 MHz, DMSO-d6) δC 14.14, 17.65, 21.77, 32.02, 59.95, 60.83, 99.70, 166.33, 172.81.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH:12]1[CH:24]([NH:26][C:27]1[N:32]=[C:31]([N:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34]2)[CH:30]=[CH:29][N:28]=1)[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:42]1([N:52]=[C:53]=[O:54])[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44][CH:43]=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:53](=[O:54])[NH:52][C:42]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH:45]=[CH:44][CH:43]=2)[CH2:13][CH:12]1[CH:24]([NH:26][C:27]1[N:32]=[C:31]([N:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34]2)[CH:30]=[CH:29][N:28]=1)[CH3:25])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(Nc1nccc(-n2ccc3ccccc32)n1)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Reactant: O=C=Nc1cccc2ccccc12
Product: CC(Nc1nccc(-n2ccc3ccccc32)n1)C1CN(C(=O)Nc2cccc3ccccc23)CCN1C(=O)OCc1ccccc1

Procedure:
The title compound was prepared from 2-[1-(1-(benzyloxycarbonyl)-4-(tert-butyloxycarbonyl)-piperazine-2-yl)-ethylamino]-4-(indol-1-yl)pyrimidine (68 mg) and naphthyl isocyanate (24 mg) according to the procedure described in EXAMPLE 14, Step F. Mass spectrum (ESI) 626.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[C:42]([CH3:44])[N:41]=[C:40]([CH2:45][CH3:46])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[C:42]([CH3:44])[N:41]=[C:40]([CH2:45][CH3:46])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C)n1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)nc(CC)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J8) (240 mg, 0.75 mmol) and 3-[3-(2-ethyl-6-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K34) (255 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous light yellow substance (336 mg, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C:11]([O:13][C@@H:14]1[CH2:18][C@@H:17]([C:19](=[O:35])[NH:20][C@:21]3([C:26](=[O:34])[NH:27][S:28]([CH:31]4[CH2:33][CH2:32]4)(=[O:30])=[O:29])[CH2:23][C@H:22]3[CH2:24][CH3:25])[N:16](C(OC(C)(C)C)=O)[CH2:15]1)=[O:12])[CH2:6]2.[ClH:43].O1CCOCC1>C(Cl)Cl>[ClH:1].[ClH:43].[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C:11]([O:13][C@@H:14]1[CH2:18][C@@H:17]([C:19](=[O:35])[NH:20][C@:21]3([C:26](=[O:34])[NH:27][S:28]([CH:31]4[CH2:32][CH2:33]4)(=[O:30])=[O:29])[CH2:23][C@H:22]3[CH2:24][CH3:25])[NH:16][CH2:15]1)=[O:12])[CH2:6]2
Reactant: CC[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](OC(=O)N2Cc3cccc(Cl)c3C2)CN1C(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](OC(=O)N2Cc3cccc(Cl)c3C2)CN1)C(=O)NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
(3R,5S)-1-(tert-butoxycarbonyl)-5-((1R,2R)-1-(cyclopropylsulfonylcarbamoyl)-2-ethylcyclopropylcarbamoyl)pyrrolidin-3-yl 4-chloroisoindoline-2-carboxylate (1.35 g, 2.16 mmol) in DCM (5 mL) was added 4 N HCl in dioxane (4.32 ml, 17.3 mmol). The reaction mixture was stirred at rt for 2 hours. The solvent was removed and the residue was suspended in ethyl ether (30 mL) and stirred for 30 min. The solid was collected by filtration to give (3R,5S)-5-((1R,2R)-1-(cyclopropylsulfonylcarbamoyl)-2-ethylcyclopropylcarbamoyl)pyrrolidin-3-yl 4-chloroisoindoline-2-carboxylate dihydrochloride (1.10 g, 91%) as white solid. LCMS (APCI+): 525.2.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C1C=CC=CC=1.C[N:23]([C:25]([O:29]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C)C[C@@H]1CC[C@H](C2C=CC=CC=2)N1>CN(C=O)C.CCOC(C)=O>[C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6]([C:25]([NH2:23])=[O:29])=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: c1ccc(-c2ccccc2)cc1
Agent: CN(C)C[C@@H]1CC[C@H](c2ccccc2)N1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)c1ccccc1-c1ccccc1
Reaction time: 2 h
Yield: 45 %

Procedure:
Biphenyl acid 10 (40 mg, 0.064 mmol, 1 eq) and HBTU (49 mg, 0.13 mmol, 2 eq) were dissolved in DMF (1 mL) followed by the addition of N,N-dimethyl-1-((2S,5R)-5-phenylpyrrolidin-2-yl)methanamine 250 (23 mg, 0.13 mmol, 2 eq). The reaction mixture was stirred for 2 h, diluted with EtOAc and quenched with a saturated aqueous NaHCO3 solution. The reaction mixture was extracted with EtOAc (3×100 mL) and the combined organics were dried over MgSO4, filtered and concentrated in vacuo to afford an oil. The crude oil was purified by silica gel chromatography (2-5% MeOH/DCM, 0.1% Et3N) to afford 23 mg of biphenyl amide 247. Yield 45%.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][C:15]=1Cl)[C@H:11]([NH:17][C:18](=[O:51])[C:19]([C:25]1[N:26]=[C:27]([NH:31][C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[S:28][C:29]=1[Cl:30])=[N:20][O:21][CH2:22][CH2:23][F:24])[C:10]2=[O:52])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:53][C:54]1[S:58][C:57]([S-:59])=[N:56][N:55]=1.[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][C:15]=1[S:59][C:57]1[S:58][C:54]([NH2:53])=[N:55][N:56]=1)[C@H:11]([NH:17][C:18](=[O:51])[C:19]([C:25]1[N:26]=[C:27]([NH:31][C:32]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[S:28][C:29]=1[Cl:30])=[N:20][O:21][CH2:22][CH2:23][F:24])[C:10]2=[O:52])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C1=C(Cl)CSC2[C@H](NC(=O)C(=NOCCF)c3nc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)sc3Cl)C(=O)N12
Reactant: Nc1nnc([S-])s1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C1=C(Sc2nnc(N)s2)CSC2[C@H](NC(=O)C(=NOCCF)c3nc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)sc3Cl)C(=O)N12

Procedure:
A solution of (7R)-3-chloro-7-[2-[5-chloro-2-(tritylamino)-thiazol-4-yl]-2-(2-fluoroethoxyimino)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid t-butyl ester XV (45 mg, 0.057 mmol) and sodium 5-amino-[1,3,4]thiadiazole-2-thiolate (10 mg, 0.064 mmol) in DMF (0.5 mL) was stirred at room temperature for 3 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure the title compound (8 mg, 16%) was isolated by radial chromatography on silica gel (dichloromethane/methanol 50:1).
Reaction SMILES: [Cl:1][C:2]1[N:3]([NH2:13])[CH:4]=[C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:6]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:23])[CH3:22]>ClCCl>[Cl:1][C:2]1[N:3]([NH:13][C:21](=[O:23])[CH3:22])[CH:4]=[C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:6]=1
Reactant: Nn1cc(-c2cccnc2)nc1Cl
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nn1cc(-c2cccnc2)nc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.2 %

Procedure:
To a solution of 2-Chloro-4-(pyridin-3-yl)-1H-imidazol-1-amine (30 mg, 0.15 mmol) and triethylamine (15 mg, 0.15 mmol) in dichloromethane (5 mL) was added acetyl chloride (12 mg, 0.15 mmol) at 0° C. The reaction mixture was stirred for 30 minutes at 0° C. The solvent was removed in vacuum and the residue was purified by prep-TLC (petroleum ether:ethyl acetate=1:2) to give the title compound (10 mg, 27%) as a yellow solid: mp 129-131° C.; 1H NMR (300 MHz, CDCl3) δ 10.69 (br, 1H), 8.81-8.80 (m, 1H), 8.44-8.43 (m, 1H), 8.02-8.00 (m, 1H), 7.33 (br s, 2H), 2.20 (s, 3H); ESIMS m/z 237 [(M+H)]+.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][CH:34]=1)[CH2:6][O:7][C:8]1[CH:31]=[CH:30][C:11]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]4[O:27][C:26]([CH:28]=O)=[CH:25][CH:24]=4)[CH:21]=3)[N:16]=[CH:15][N:14]=2)=[CH:10][CH:9]=1.[CH3:37][S:38]([CH2:41][CH2:42][NH2:43])(=[O:40])=[O:39]>>[CH3:37][S:38]([CH2:41][CH2:42][NH:43][CH2:28][C:26]1[O:27][C:23]([C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]=[C:13]3[NH:12][C:11]2[CH:10]=[CH:9][C:8]([O:7][CH2:6][C:5]3[CH:32]=[CH:33][CH:34]=[C:3]([C:2]([F:36])([F:1])[F:35])[CH:4]=3)=[CH:31][CH:30]=2)=[CH:24][CH:25]=1)(=[O:40])=[O:39]
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(C(F)(F)F)c5)cc4)c3c2)o1
Reactant: CS(=O)(=O)CCN
Product: CS(=O)(=O)CCNCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(C(F)(F)F)c5)cc4)c3c2)o1

Procedure:
Prepared according to Procedure D from 5-(4-{4-(3-trifluoromethylbenzyloxy)anilino}-6-quinazolinyl)-furan-2-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). 1H NMR 300 MHz (DMSO-d6) 11.63 (bs, 1H); 9.88 (bs, 1H); 9.59 (bs, 1H); 8.88 (s, 1H); 8.43 (d, 1H); 7.97 (d, 1H); 7.90-7.67 (m, 6H); 7.34 (d, 1H); 7.19 (d, 2H); 6.89 (d, 1H); 5.30 (s, 2H); 4.45 (s, 2H); 3.78 (m, 2H); 3.45 (m, 2H, obscured by water peak); 3.19 (s, 3H); MS m/z 597 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:15]=[N:16][C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[C:19]([O:24][CH3:25])[CH:18]=4)[N:11]([C@H:26]([C:28]3[CH:45]=[CH:44][C:31]([C:32]([NH:34][CH2:35][CH2:36][C:37]([O:39]C(C)(C)C)=[O:38])=[O:33])=[CH:30][CH:29]=3)[CH3:27])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:15]=[N:16][C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[C:19]([O:24][CH3:25])[CH:18]=4)[N:11]([C@H:26]([C:28]3[CH:29]=[CH:30][C:31]([C:32]([NH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:44][CH:45]=3)[CH3:27])[N:10]=2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: COc1ccc2cc(-c3cc(-c4cc(Cl)cc(Cl)c4)nn3[C@@H](C)c3ccc(C(=O)NCCC(=O)OC(C)(C)C)cc3)cnc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2cc(-c3cc(-c4cc(Cl)cc(Cl)c4)nn3[C@@H](C)c3ccc(C(=O)NCCC(=O)O)cc3)cnc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the intermediate from step I (64 mg) in CH2Cl2(2 mL) was added TFA (2 mL). After the reaction was stirred at room temperature for 30 minutes it was concentrated in vacuo and azeotroped with toluene (3×). The resulting light yellow solid was dissolved in 1,4-dioxane and lyophilized overnight to afford the product as a white solid. 1H NMR (DMSO, 500 MHz) 8.8 (d, J=1.6 Hz, 1H), 8.45 (t, J=5.5 Hz, 1H), 8.38 (s, 1H), 7.94 (s, 2H), 7.92 (d, J=8.4 Hz, 2H), 7.72 (d, J=8.0 Hz, 2H), 7.58 (s, 1H), 7.45 (d, J=2.1 Hz, 1H), 7.37 (dd, J=2.3, 8.7 Hz, 1H), 7.28 (s, 1H), 7.2 (d, J=8.0 Hz, 2H), 5.8 (q, J=6.9 Hz, 1H), 3.95 (s, 3H), 3.41 (q, J=6.9 Hz, 2H), 2.45 (t, J=7.1 Hz, 2H), 1.93 (d, J=6.9 Hz, 3H). LC-MS: 3.53 min; (M+H)=588.9.
Reaction SMILES: [H-].[Na+].[CH:3]1([C:8]([N:10]2[CH2:17][CH2:16][C@:15]3([CH3:19])[CH2:18][C@@H:11]2[CH2:12][C:13]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:14]=23)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:25]N(C)C=O.CI>O1CCCC1.O>[CH:3]1([C:8]([N:10]2[CH2:17][CH2:16][C@:15]3([CH3:19])[CH2:18][C@@H:11]2[CH2:12][C:13]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:14]=23)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CN(C)C=O
Reactant: C[C@]12CCN(C(=O)C3CCCC3)[C@@H](Cc3ccc(O)cc31)C2
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)[C@]1(C)CCN(C(=O)C3CCCC3)[C@@H](C2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (0.01 g) is added to a solution of cyclopentyl-[(2R,6R)-8-hydroxy-6-methyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone (0.10 g) in tetrahydrofuran (6 mL; alternatively N,N-dimethylformamide may be used). The mixture is stirred for 30 min at room temperature before methyl iodide (25 μL) is added. The resulting solution is stirred at room temperature overnight. Then, water is added and the resulting mixture is extracted with dichloromethane. The combined extracts are dried (Na2SO4) and the solvent is evaporated. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[N:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:8][CH:7]=1.C([O-])(O)=O.[Na+]>>[N:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][C:14]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:15][CH:16]=2)=[CH:8][CH:7]=1
Reactant: c1csc(-c2ccncc2)c1
Reactant: O=S(=O)(O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=S(=O)(Cl)c1ccc(-c2ccncc2)s1
Temperature: 25 °C
Reaction time: 120 h
Yield: 32.7 %

Procedure:
Chlorosulfonic acid (1.4 ml) was added to 2-(4-pyridyl)thiophene (500 mg) at 0° C. and the mixture was stirred for 5 days at room temperature. Ice-water was carefully added to this mixture at 0° C. to decompose excess reagent. This solution was poured into saturated aqueous NaHCO3 solution (ca. pH 7) and extracted with AcOEt (20 ml×3). The combined organic layer was washed with brine, and dried over MgSO4. After 4N HCl-AcOEt (10 ml) was added to the solution, the solvent was removed in vacuo to give 300 mg of 5-(4-pyridyl)-thiophenesulfonyl chloride as a white solid (yield 32.7%).
Reaction SMILES: [Br-].[C:2]1([CH2:8][CH2:9][CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:37]2[CH:41]=[C:40](C=O)[N:39]=[CH:38]2)C=CC=CC=1.[K].[C:57]([O-])(C)(C)C>C1COCC1>[NH:37]1[CH:41]=[C:40]([CH:9]([CH2:8][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=[CH2:57])[N:39]=[CH:38]1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: c1ccc(CCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K]
Solvent: C1CCOC1
Product: C=CC(Cc1ccccc1)c1c[nH]cn1
Reaction time: 1 h

Procedure:
10 mmol of 3-phenylpropyltriphenylphosphonium bromide, 10 mmol of (1-triphenylmethyl-1H-imidazol-4-yl)methanal (J. L. Kelley, C. A. Miller, E. W. Mc Lean, J. Med. Chem. 1977, 20, 721) and 12 mmol of potassium of t-butanolate are stirred for 24 hours in 50 ml THF. The solvent is evaporated off under reduced pressure, hydrolysed with water and extracted using chloroform. The concentrated organic extract is heated from reflux in 30 ml 2N HCl and 30 ml of acetone for 1 hour. The solvent is evaporated off under reduced pressure and triphenylmethanol is extracted using diethyl ether. The aqueous phase is alkalized using ammonia and the crude product is extracted using diethyl ether. The aqueous phase is alkalized using diethyl ether and crystallized as hydrogen maleate from diethyl ether and ethanol.
Reaction SMILES: [C:1]([N:5]=[C:6]=[S:7])([CH3:4])([CH3:3])[CH3:2].[CH:8]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9]1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[C:1]([NH:5][C:6]([NH:13][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[S:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CCCC1
Reactant: CC(C)(C)N=C=S
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)NC(=S)NC1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a solution of tert-butyl isothiocyanate (5.0 mL; 39.4 mmoL) in DCM (200 mL) was added cyclopentylamine (4.67 mL; 47.3 mmoL) followed by DIPEA and the reaction mixture was stirred at R.T. for 2 h. The mixture was diluted with EtOAc, and washed with a 10% aqueous solution of citric acid (2×), saturated NaHCO3 (2×), H2O (2×) and brine (1×). The organic layer was dried over anhydrous MgSO4, filtered and evaporated to yield N-tert-butyl-N′-cyclopentylthiourea as a white solid (3.70 g; 47% yield). The N-tert-butyl-N′-cyclopentylthiourea (3.70 g) was dissolved in concentrated HCl (46 mL). The dark yellow solution was heated at a gentle reflux. After 40 min the reaction mixture was allowed to cool to R.T. and thereafter cooled in ice and rendered basic to pH 9.5 with solid and a saturated aqueous solution of NaHCO3. The product was extracted into EtOAc (3×). The combined EtOAc extracts were washed with H2O (2×) and brine (1×). The organic layer was dried (MgSO4), filtered and concentrated to yield a beige solid (2.46 g crude). Trituration of the crude material in hexane/EtOAc 95/5 provided, after filtration, the N-cyclopentythiourea 8a as a white solid (2.38 g; 90% yield).