Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[CH2:4][N:5]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][C:10]=1[O:18][CH3:19].C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[CH3:40][S:41]([O:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([N:5]([CH2:4][C:3]2[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:2]=2[F:1])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:20])=[C:10]([O:18][CH3:19])[CH:11]=1)(=[O:43])=[O:42]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)COc1ccc(CCO)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)COc1ccc(CCOS(C)(=O)=O)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(2,4-difluorobenzyl)-N-heptyl-2-[4-(2-hydroxyethyl)-2-methoxyphenoxy]acetamide (A)(132 mg, 0.294 mmol) was dissolved in DCM (10 ml). It was cooled in an ice-bath. Triethylamine (0.05 ml, 0.352 mmol) was added and then methanesulfonyl chloride (37 mg, 0.323 mmol) was dropped in. The cooling-bath was removed after 30 minutes. The mixture was stirred at room temperature overnight. LS-MS showed that ca 50% of A was not reacted. The mixture was cooled in an ice-bath and 0.05 ml of triethylamine was added, followed by 0.025 ml of methanesulfonyl chloride. After addition, the cooling-bath was removed and the mixture was stirred for 5 hours more. It was then washed with water (×2) and brine, dried (magnesium sulphate) and evaporated. Oil product 138 mg was left and used for next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH:26]1[C:31]([C@H:32]([OH:35])[CH2:33][NH2:34])=[CH:30][C:29]([OH:36])=[C:28]([OH:37])[CH:27]=1>>[OH:36][C:29]1[CH:30]=[C:31]([C@@H:32]([OH:35])[CH2:33][NH:34][CH:22]2[CH2:23][CH2:24][N:19]([C:16]3[CH:15]=[CH:14][C:13]([NH:12][S:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)(=[O:10])=[O:11])=[CH:18][CH:17]=3)[CH2:20][CH2:21]2)[CH:26]=[CH:27][C:28]=1[OH:37]
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Reactant: NC[C@@H](O)c1ccc(O)c(O)c1
Product: COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)c4ccc(O)c(O)c4)CC3)cc2)cc1

Procedure:
The title compound was prepared from 4-methoxy-N-[4-(4-oxo-piperidine-1-yl)-phenyl]-benzenesulfonamide (which was obtained in Example 218) and L-norepinephrine according to the procedure of Example 255 as a white solid; 1 H NMR (300 MHz, DMSO-d6) δ 1.40-1.55 (m, 2H), 1.90-2.05 (m, 2H), 2.50-3.00 (m, 5H), 3.50-3.75 (m, 2H), 3.79 (s, 3H), 4.50-4.65 (m, 1H), 6.60 (d, J=8.0 Hz, 1H), 6.68 (d, J=8.0 Hz, 1H), 6.76-6.80 (m, 3H), 6.88 (d, J=9.0 Hz, 2H), 7.04 (d, J=7.8 Hz, 2H), 7.61 (d, J=7.8 Hz, 2H), 8.85 (s, 1H); MS (ES) m/z: 513.9 (MH+); HRMS Calcd. for C26H32N3O6S(MH+): 514.2011. Found: 514.2000.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]3[CH2:13][CH2:14][O:15][C:7]3([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1.[H-].[Na+].Br[CH2:27][C:28](OCC)=[O:29].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CN(C)C=O.O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:27][CH2:28][OH:29])[C:10](=[O:12])[CH2:9][N:8]3[CH2:13][CH2:14][O:15][C:7]3([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1
Reactant: CCOC(=O)CBr
Reactant: O=C1CN2CCOC2(c2ccccc2F)c2cc(Cl)ccc2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: O=C1CN2CCOC2(c2ccccc2F)c2cc(Cl)ccc2N1CCO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 33.3g (0.1 M) of 10-chloro-11b-(2-fluorophenyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one in 100 ml of dry N,N-dimethylformamide was treated with 6.6g (0.138 M) of a 50 percent dispersion of sodium hydride in mineral oil. The mixture was stirred for 0.5 hour at room temperature, was then cooled to 5°-10° and treated with a solution of 31g (0.186 M) of ethyl bromoacetate in 25 ml of dry N,N-dimethylformamide. The resulting mixture was allowed to stir at room temperature for 18 hours when 3 ml of water was carefully added. The solution was next evaporated to dryness under reduced pressure. The residue was next treated with 50 ml of toluene and evaporated to dryness. This procedure was repeated twice in order to azeotrope any remaining water or N,N-dimethylformamide. The crude ester thus obtained was dissolved in 250 ml of dry tetrahydrofuran, cooled to 0° and was treated by the portionwise addition of 1.9g (0.05 M) of lithium aluminium hydride. The cooling bath was removed and the mixture was allowed to stir for 3 hours. Enough saturated sodium bicarbonate solution was added to coagulate the solids and the mixture was filtered. The filtrates were concentrated to dryness and dissolved in dichloromethane. The solution was washed with 1N hydrochloric acid, water, saturated brine, dried over anhydrous sodium sulfate and evaporated. The residue was crystallized from toluene to give the above named product as white prisms, m.p. 142°-147°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:9]1[C:14]([C:15]2[O:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:22][CH:21]=3)=[N:17][N:16]=2)=[CH:13][C:12](Br)=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:44]([S:47]([C:50]1[CH:55]=[CH:54][C:53](B2OC(C)(C)C(C)(C)O2)=[CH:52][CH:51]=1)(=[O:49])=[O:48])([CH3:46])[CH3:45].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:9]1[C:14]([C:15]2[O:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:22][CH:21]=3)=[N:17][N:16]=2)=[CH:13][C:12]([C:53]2[CH:52]=[CH:51][C:50]([S:47]([CH:44]([CH3:46])[CH3:45])(=[O:49])=[O:48])=[CH:55][CH:54]=2)=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CN(Cc1ccc(-c2nnc(-c3cc(Br)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3nnc(-c4ccc(CN(C)C(=O)OC(C)(C)C)cc4)o3)c2)cc1
Temperature: 80 °C
Yield: 98 %

Procedure:
tert-Butyl N-[[4-[5-[2-[bis(tert-butoxycarbonyl)amino]-5-bromo-3-pyridyl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (120 mg, 0.1817 mmol) was dissolved in DMF (1.2 mL) and 2-(4-isopropylsulfonylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (84.57 mg, 0.2726 mmol) and Pd(PPh3)2Cl2 (7.516 mg, 0.01817 mmol) were added. 2M aqueous Na2CO3 (272.6 μL, 0.5451 mmol) was added and the reaction heated at 80° C. for 1 hour in a sealed tube. The reaction mixture was cooled to ambient temperature and diluted with EtOAc/water. The layers were separated and the aqueous layer extracted with EtOAc (×2). The combined organic extracts were washed with water (×3), brine (×2), dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was purified by column chromatography (ISCO Companion™, 4 g column, 0-50% EtOAc/Petroleum ether) to give the impure sub-title compound as a yellow oil (136 mg). This was used directly in the next step with no further purification.
Reaction SMILES: [N-:1]=[C:2]=[O:3].[C:4]1([CH2:10][CH2:11][CH2:12][CH2:13]N)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>>[N:1]([CH2:13][CH2:12][CH2:11][CH2:10][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[C:2]=[O:3]
Reactant: [N-]=C=O
Reactant: NCCCCc1ccccc1
Product: O=C=NCCCCc1ccccc1
Yield: 84 %

Procedure:
Following the synthetic procedure of 4b′ as described in Example 17, isocyanate 4c′ (84% yield) was synthesized from 4-(phenyl)butylamine as an oil. 1H-NMR (CDCl3) δ1.61-1.78 (m, 4H), 2.66 (t, J=7.5 Hz, 2H), 3.32 (t, J=6.5 Hz, 2H), 7.17-7.23 (m, 3H), 7.26-7.32 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>C1(C)C=CC=CC=1>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:32]
Reactant: O=C=Nc1ccccc1F
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccc4F)cc3)c2cc1OC
Yield: 73 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (51 mg) was dissolved in toluene (5 ml) with heat, 2-fluorophenyl isocyanate (0.2 ml) was added, and the admixture was refluxed with heat for 15 minutes. The resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 54 mg of the title compound (yield: 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:37]#[N:38])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:34][CH3:35])[C:17]([NH:19][C:20]3[CH:21]=[CH:22][C:23]4[N:27]=[C:26]([C:28]([O:30]CC)=[O:29])[NH:25][C:24]=4[CH:33]=3)=[O:18])[C:10](=[O:36])[CH:9]=2)[CH:7]=1.[OH-].[Li+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:37]#[N:38])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:34][CH3:35])[C:17]([NH:19][C:20]3[CH:21]=[CH:22][C:23]4[N:27]=[C:26]([C:28]([OH:30])=[O:29])[NH:25][C:24]=4[CH:33]=3)=[O:18])[C:10](=[O:36])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1nc2ccc(NC(=O)C(CC)n3cc(OC)c(-c4cc(Cl)ccc4C#N)cc3=O)cc2[nH]1
Agent: [Li+]
Agent: [OH-]
Product: CCC(C(=O)Nc1ccc2nc(C(=O)O)[nH]c2c1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
86 mg (0.16 mmol) of ethyl 6-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-1H-benzimidazole-2-carboxylate (racemate) were hydrolysed with lithium hydroxide according to General Method 3. Yield: 67 mg (82% of theory)
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Li]CCCC.[C:15]1(=[O:20])[CH2:19][CH2:18][CH2:17][CH2:16]1.O>O1CCCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:15]1([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C1CCCC1
Reactant: c1ccc2scnc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: OC1(c2nc3ccccc3s2)CCCC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 70.5 %

Procedure:
To a solution of 2 mL (18.3 mmol) of benzothiazole in 20 mL of tetrahydrofuran was added 11.4 mL (18.2 mmol) of 1.6 M n-BuLi at −78° C. After 45 min, 1.6 mL (18.1 mmol) of cyclopentanone was added at the same temperature. The reaction was let warm to room temperature over 1 h. Water was added to quench the reaction and the mixture was extracted with ether (3×). The ether layer was washed with brine (3×) and dried over magnesium sulfate. After removal of solvent, purification by silica gel column chromatography eluting with hexane:ethyl acetate (4:1) gave 2.8 g (71%) of 1-(1,3-benzothiazol-2-yl)cyclopentanol as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.02 (d, J=8 Hz, 1H), 7.92 (d, J=8 Hz, 1H), 7.51 (t, J=8 Hz, 1H), 7.41 (t, J=8 Hz, 1H), 2.25 (m, 4H), 2.00 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:15]([NH2:18])(=[O:17])=[O:16])=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=2)[N:7]=1.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:15]([N:18]=[CH:21][N:22]([CH3:24])[CH3:23])(=[O:17])=[O:16])=[C:9]([C:11]([F:12])([F:14])[F:13])[N:10]=2)[N:7]=1
Reactant: NS(=O)(=O)c1c(C(F)(F)F)nc2ccc(Cl)nn12
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)C=NS(=O)(=O)c1c(C(F)(F)F)nc2ccc(Cl)nn12
Reaction time: 3.5 h

Procedure:
6-Chloro-2-trifluoromethylimidazo[1,2-b]pyridazin-3-ylsulfonamide (1.70 g, 5.65 mmol) was suspended in toluene (10.0 ml), and N,N-dimethylformamide dimethyl acetal (90%, 1.84 ml, 12.4 mmol) was added thereto and stirred for 3.5 hours under reflux. The reaction mixture was concentrated under reduced pressure. To the residue concentrated was added diisopropyl ether, and the crystals were collected by filtration to give the title compound as brown crystals. The yield was 1.96 g (97.4%).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]([O:13]C)[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([CH3:26])[C:7]1[N:8]2[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])=[N:16][C:17]=1[CH3:18].B(Br)(Br)Br.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[OH:2][C:3]1[CH:12]=[C:11]([OH:13])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([CH3:26])[C:7]1[N:8]2[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])=[N:16][C:17]=1[CH3:18]
Reactant: COc1cc(OC)c2nc(C)c3c(C)nc(-c4ccccc4C)n3c2c1
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccccc1-c1nc(C)c2c(C)nc3c(O)cc(O)cc3n12
Temperature: 0 °C

Procedure:
0.3 g 6,8-Dimethoxy-3,4-dimethyl-1-(2-methylphenyl)-imidazo[1,5-a]quinoxaline, 30 mL dichloromethane and 5 mL BBr3 were heated in a closed vessel for 3 hours at 130° C. After cooling the suspension was given in 250 mL ice-cooled aqueous potassium carbonate solution. After stirring for 30 min at pH 7-9 the precipitate was filtered off, washed with water and purified with silica gel, dichloromethane/methanol 9/1.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]([C:20]1[C:24](=[O:25])[CH2:23][CH2:22][C:21]=1[NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1)[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=1[Cl:19].[C:37](N1C=CN=C1)(N1C=CN=C1)=[O:38].O>C(#N)C.ClCCl>[Cl:19][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:11]=1[CH:10]1[NH:9][C:37](=[O:38])[N:26]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=2)[C:21]2[CH2:22][CH2:23][C:24](=[O:25])[C:20]1=2)[C:15]#[N:16]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N#Cc1ccc(C(N)C2=C(Nc3cccc(C(F)(F)F)c3)CCC2=O)c(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC3)c(Cl)c1
Temperature: 25 °C

Procedure:
Triethylamine (0.38 mL, 2.70 mmol) is added to a mixture of 4-(amino(5-oxo-2-(3-(tri-fluoromethyl)phenylamino)cyclopent-1-enyl)methyl)-3-chlorobenzonitrile hydrochloride (intermediate 20.1, 660 mg, 1.34 mmol based on 90% purity) and 1,1′-carbonyldiimidazole (270 mg, 1.68 mmol) in acetonitrile (5 mL), and the mixture is stirred at room temperature over night. Water and dichloromethane are added, and the phases are separated. The organic layer is concentrated under reduced pressure and purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 290 mg. ESI mass spectrum: [M+H]+=432; Retention time HPLC: 0.61 min (X012_S01).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)([O-:17])=[O:16].[CH:26]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[OH-].[Na+]>C(O)(=O)C.C(Cl)Cl>[CH:26]1([NH:32][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: NC1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(CNC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Sodium triacetoxyborohydride (11.0 mmol, 2.33 g) was added to a mixture of 4-nitro-benzaldehyde Compound 4a (10.0 mmol, 1.51 g), cyclohexylamine Compound 10a (10.5 mmol, 1.2 mL) and glacial acetic acid (5 drops) in CH2Cl2 (40 mL) and the resulting suspension was allowed to stir at room temperature for 12 hrs. An aliquot of the reaction mixture showed the formation of product (MS m/e 235, 100%). The reaction mixture was basified with 2N NaOH solution and was extracted with CH2Cl2. The organic layer was washed with brine, separated and dried over Na2SO4. The drying agent was filtered and the solvent was removed in vacuo to yield cyclohexyl-(4-nitro-benzyl)-amine Compound 14a (1.56 g, 67%) as a yellow oil, which was used in the next step without further purification.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[K+].[F:11][C:12]([F:22])([F:21])[C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1>CO>[F:11][C:12]([F:21])([F:22])[C:13]1[CH:20]=[CH:19][C:16]([CH2:17][S:1][C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: Oc1ccc(S)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Oc1ccc(SCc2ccc(C(F)(F)F)cc2)cc1
Reaction time: 0.5 h
Yield: 37.5 %

Procedure:
10 ml of methanol solution containing 2.8 g of 4-mercaptophenol was dropped with ice cooling into 20 ml of methanol solution containing 1.4 g of potassium hydroxide, followed by further stirring for 30 minutes. To this reaction mixture, 10 ml of methanol solution containing 5.0 g of 4-trifluoromethyl benzyl bromide was added with ice cooling, followed by stirring for 18 hours at room temperature. After concentrating the reaction mixture, ethyl acetate and water were added, followed by fractionating an organic layer. After the organic layer was dried with anhydrous magnesium sulfate, it was concentrated. The concentrate was purified by silica gel column chromatography (eluant: n-hexane/ethyl acetate/gradation) to produce 2.23 g of the desired product.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[C:6]([N:12]3[CH2:16][CH2:15][CH2:14][C:13]3=[O:17])[CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[C:3]1=[O:24].[C:25]([O:29][C:30]([NH:32][C@@H:33]([C:44](O)=[O:45])[CH2:34][C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[NH:37][CH:36]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[NH:37]1[C:38]2[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:35]([CH2:34][C@@H:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:27])([CH3:26])[CH3:28])[C:44](=[O:45])[NH:1][CH:2]2[CH2:11][C:10]3[C:5](=[C:6]([N:12]4[CH2:16][CH2:15][CH2:14][C:13]4=[O:17])[CH:7]=[CH:8][CH:9]=3)[N:4]([CH2:18][C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)[C:3]2=[O:24])=[CH:36]1
Reactant: NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Product: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O

Procedure:
The procedure of Example 14(a) was repeated, except that (−)-3-amino-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-3,4-dihydroquinolin-2(1H)-one (300 mg) and N-tert-butoxycarbonyl-D-tryptophan (294 mg) were used, whereby tert-butyl (2R)-3-(1H-indol-3-yl)-1-oxo-1-[2-oxo-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-ylamino]propan-2-ylcarbamate was yielded. Subsequently, the procedure of Example 15(a) was repeated, except that the compound prepared as described above was used, whereby the title compound (438 mg) was yielded.
Reaction SMILES: [Cl:1][SiH:2]([Cl:4])[Cl:3].[CH3:5][C:6]([CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH2:7].CC(C)=CC(C)(C)C.C(Cl)C=C>>[CH3:5][CH:6]([CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:7][Si:2]([Cl:4])([Cl:3])[Cl:1]
Reactant: Cl[SiH](Cl)Cl
Reactant: C=C(C)CC(C)(C)C
Agent: CC(C)=CC(C)(C)C
Solvent: C=CCCl
Product: CC(CC(C)(C)C)C[Si](Cl)(Cl)Cl

Procedure:
The process described in Example 2 is repeated, except that 1.2 liters of trichlorosilane, 1.8 liters of diisobutylene (a mixture of 2,4,4-trimethylpentene-1 and 2,4,4-trimethylpentene-2) and 10 ml of the catalytic solution are substituted for the trichlorosilane, allyl chloride and catalytic solution. About 98.6 mol percent of the trichlorosilane employed is reacted and 11.6 moles per hour of 2,4,4-trimethylpentyltrichlorosilane are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[N:8]=[CH:7][N:6]=[C:5]2[OH:11].BrC1C=C(C(OC)=O)NC=1.CC1(C)C(C)(C)OB([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[CH:31]=2)O1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:39]1[CH2:40][CH2:41][N:36]([C:32]2[CH:31]=[C:30]([C:2]3[CH:3]=[C:4]4[N:9]([CH:10]=3)[N:8]=[CH:7][N:6]=[C:5]4[OH:11])[CH:35]=[CH:34][N:33]=2)[CH2:37][CH2:38]1
Reactant: Oc1ncnn2cc(Br)cc12
Reactant: CC1(C)OB(c2ccnc(N3CCOCC3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COC(=O)c1cc(Br)c[nH]1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Oc1ncnn2cc(-c3ccnc(N4CCOCC4)c3)cc12
Temperature: 100 °C
Yield: 82 %

Procedure:
To a solution of 6-bromopyrrolo[2,1-f][1,2,4]triazin-4-ol (100 mg, 0.47 mmol, prepared from methyl 4-bromo-1H-pyrrole-2-carboxylate: see, generally, Kitamura, C. and Yamashita, Y. J. Chem. Soc. Perkin Trans. 1, 1997, 1443, the disclosure of which is herein incorporated by reference, using a similar procedure outlined in the PCT Appl. WO 00/71129) and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (290 mg, 1.0 mmol) in DMF (2 mL) were added saturated aq. K2CO3 solution (2.0 mL) and Pd(PPh3)4 (60 mg, 0.05 mmol). The reaction mixture was purged with N2 for 10 min and then was heated at 80° C. for 5 h and 100° C. for 12 h. After cooling, the mixture was diluted with H2O and filtered to afford the crude product, which was triturated with DCM to provide the title compound (114 mg, 82% yield). MS(ESI) m/z 298.2 (M+H)+.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[N:12]1([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:16][CH2:15][CH2:14][CH2:13]1>CS(C)=O.O.C(OCC)(=O)C>[N:12]1([CH:17]2[CH2:22][CH2:21][N:20]([C:2]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=3)[CH2:19][CH2:18]2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COC(=O)c1ccc(F)cc1
Reactant: C1CCN(C2CCNCC2)C1
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N2CCC(N3CCCC3)CC2)cc1
Temperature: 150 °C
Reaction time: 4 h
Yield: 73.4 %

Procedure:
Commercially available methyl 4-fluorobenzoate (1.5 g, 9.73 mmol) was added to a solution of commercially available 4-(1-pyrrolidinyl)piperidine (3.0 g, 19.5 mmol) in dimethylsulfoxide (15 mL) at room temperature and then the mixture was stirred under nitrogen atmosphere and under irradiation with microwave at 150° C. for 4 hours. The reaction liquid was allowed to stand to cool to room temperature and then diluted with water and ethyl acetate. The organic layer was washed with water and then dried by a conventional method. The drying agent was separated by filtration and then the filtrate was concentrated under vacuum. The residue was purified with NH silica gel column chromatography (n-heptane:ethyl acetate=1:1) to obtain the title compound (2.06 g, 73%).
Reaction SMILES: [Cl-].[Cl:2][CH2:3][C:4]([N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[NH2+:5].C(N(CC)CC)C.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(#N)C.ClCCl>[Cl:2][CH2:3][C:4](=[N:5][S:25]([C:22]1[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=1)(=[O:27])=[O:26])[N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: [NH2+]=C(CCl)N1CCOCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N=C(CCl)N2CCOCC2)cc1
Temperature: 7.5 °C
Reaction time: 2 h
Yield: 25.2 %

Procedure:
To 1 g (5.02 mmol) 2-chloro-1-morpholine-4-ylethaniminium chloride and 0.7 ml triethylamine in 25 ml acetonitrile were added 0.96 g p-toluene sulfonic acid chloride at 10° C. and the mixture was stirred for 2 hours at 5-10° C. For workup, the mixture was diluted with dichlormethane, was washed with water and saturated NaCl-solution, was dried with MgSO4, was filtered and was evaporation-concentrated. Chromatography on silica gel (dichlormethane/methanol 0-3%) yielded 400 mg of the target products; ESI-MS [M+H+]=317.05.