Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[C:11]2[CH:10]=[C:9]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([O:19][CH2:20][C:21]4[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=4)[CH:14]=[N:13]3)[CH:8]=[CH:7][C:6]=2[C:5]2[CH2:31][N:32](C(OC(C)(C)C)=O)[CH2:33][CH2:34][CH2:35][C:4]1=2>CO>[ClH:1].[CH3:2][N:3]1[C:11]2[CH:10]=[C:9]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([O:19][CH2:20][C:21]4[CH:22]=[N:23][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:26]=4)[CH:14]=[N:13]3)[CH:8]=[CH:7][C:6]=2[C:5]2[CH2:31][NH:32][CH2:33][CH2:34][CH2:35][C:4]1=2
Reactant: Cn1c2c(c3ccc(-n4ncc(OCc5ccc(C(F)(F)F)nc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CCC2
Agent: Cl
Solvent: CO
Product: Cn1c2c(c3ccc(-n4ncc(OCc5ccc(C(F)(F)F)nc5)cc4=O)cc31)CNCCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
1.25 M HCl in MeOH (4.0 mL) was added to tert-butyl 6-methyl-8-(6-oxo-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridazin-1(6H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (43 mg, 0.075 mmol), and the resulting solution was stirred under N2 at ambient temperature for 18 h. The solution was concentrated under reduced pressure, and the resulting residue was diluted with MeOH (1.0 mL) and Et2O (10 mL). The resulting solids were collected by filtration to provide the title compound (23 mg, 61%) as an off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 8.91 (d, J=1.5 Hz, 1H), 8.87 (s, 2H), 8.22 (dd, J=8.5, 1.5 Hz, 1H), 8.02-8.00 (m, 2H), 7.64 (d, J=8.5 Hz, 1H), 7.57 (d, J=1.5 Hz, 1H), 7.13 (dd, J=8.5, 2.0 Hz, 1H), 6.56 (d, J=3.0 Hz, 1H), 5.41 (s, 2H), 4.44 (s, 2H), 3.72 (s, 3H), 3.47-3.43 (m, 2H), 3.10 (t, J=5.5 Hz, 2H), 2.08-2.04 (m, 2H); ESI MS m/z 470 [M+H]+; HPLC (Method A)>99% (AUC), tR=14.1 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[Cl:36][C:37]1[CH:38]=[C:39]([CH:44]2[CH2:48][NH:47][CH2:46][CH:45]2[CH:49]([O:51][C:52]2[CH:59]=[CH:58][C:55]([C:56]#[N:57])=[CH:54][N:53]=2)[CH3:50])[CH:40]=[CH:41][C:42]=1[Cl:43]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([C:12]([N:47]2[CH2:48][C@H:44]([C:39]3[CH:40]=[CH:41][C:42]([Cl:43])=[C:37]([Cl:36])[CH:38]=3)[C@@H:45]([C@@H:49]([O:51][C:52]3[CH:59]=[CH:58][C:55]([C:56]#[N:57])=[CH:54][N:53]=3)[CH3:50])[CH2:46]2)=[O:14])[CH2:11]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: CC(Oc1ccc(C#N)cn1)C1CNCC1c1ccc(Cl)c(Cl)c1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: C[C@H](Oc1ccc(C#N)cn1)[C@H]1CN(C(=O)C2CN(C(=O)OC(C)(C)C)C2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a stirred solution of azetidine-1,3-dicarboxylic acid mono-tert-butyl ester (0.072 g, 0.36 mmol) in 15 mL of CH2Cl2 was added (0.069 g, 0.36 mmol) of EDC, (0.048 g, 0.36 mmol) of HOBt and Et3N (0.06 mL, 0.42 mmol). After one hour at RT, was added 6-{(SR)-1-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethoxy}-nicotinonitrile (VII-B-2, 0.10 g, 0.27 mmol). The mixture was stirred at RT over night and then poured onto water and extracted with CH2Cl2. The combined organic phases were dried over Na2SO4 and concentrated under vacuo. Column chromatography (SiO2, EtOAc/H, 1:1) yielded 0.14 g (98%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8](CCCCCCCCCCCCCCC)[C:4]=1[C:5](Cl)=[O:6].[NH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([C:36]([F:39])([F:38])[F:37])[CH:29]=1.C(N(CC)CC)C>ClCCl>[C:32]([C:31]1[CH:34]=[CH:35][C:28]([NH:27][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[O:2][CH3:1])=[CH:29][C:30]=1[C:36]([F:37])([F:38])[F:39])#[N:33]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: CCCCCCCCCCCCCCCc1cccc(OC)c1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1

Procedure:
2-Methoxy-6-pentadecyl-benzoyl chloride was condensed with 4-Amino-2-trifluoromethyl benzonitrile in dichloromethane in presence of triethylamine as acid scavenger to yield N-(4-Cyano-3-trifluoromethyl-phenyl)-2-methoxy-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH3:23][C:24]([O:27][C:28](ON=C(C1C=CC=CC=1)C#N)=[O:29])([CH3:26])[CH3:25].C(OCC)(=O)C>O1CCOCC1.O>[C:28]([NH:10][C@H:9]([C:11]([OH:13])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][CH:14]=1)([O:27][C:24]([CH3:26])([CH3:25])[CH3:23])=[O:29]
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
p-Nitrophenylalanine (7.94 g, 37.8 mmol) was dissolved in 50% aqueous dioxane solution (60 ml) and triethylamine (0.9 ml, 56.7 mmol) added. BOC-ON (10.24 g, 41.6 mmol) (Aldrich Chemical Co.) was added and the solution stirred for two hours. Ethyl acetate (100 ml) and H2O (50 ml) were next added and the contents poured into a separatory funnel. The aqueous layer was retained and extracted twice with ethyl acetate (100 ml). The aqueous layer was cooled to 0° C. and the pH was adjusted to 2.0 with 3N HCl, whereupon a precipitate formed which was collected and dried under vacuum. The filtrate was extracted with ethyl acetate twice (100 ml), dried (MgSO4) and stripped to dryness. The two fractions provided to be identical and were combined (11.0 g, 94.0%). The melting point of the compound was 165° C.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([C:9]3([OH:16])[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1.[NH:19]1[CH2:22][CH:21]([NH:23][C:24]([CH2:26][NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)=[O:25])[CH2:20]1>>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([C:9]3([OH:16])[CH2:14][CH2:13][CH:12]([N:19]4[CH2:22][CH:21]([NH:23][C:24]([CH2:26][NH:27][C:28](=[O:39])[C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:36])[F:37])[CH:30]=5)=[O:25])[CH2:20]4)[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(O)(c2nc3ccc(Br)cc3s2)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3nc4ccc(Br)cc4s3)CC2)C1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-(6-Bromo-benzothiazol-2-yl)-4-hydroxy-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]1[CH:13]([C:14]([O:16]C)=[O:15])[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]1.Cl>C1COCC1.CO>[O:3]=[C:4]1[CH:13]([C:14]([OH:16])=[O:15])[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]1
Reactant: COC(=O)C1Cc2ccccc2NC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1Cc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.7 %

Procedure:
1N Aqueous sodium hydroxide solution (80 ml) was added dropwise to the mixed solution of methyl 2-oxo-1,2,3,4-tetrahydro-3-quinolinecarboxylate (8.322 g) in THF (80 ml) and methanol (80 ml) at 0° C. The reaction mixture was stirred at room temperature for 4 hours. 1N Hydrochloric acid (90 ml) was added dropwise to the reaction mixture at 0° C., which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried and concentrated to obtain crude crystals of the entitled compound (7.032 g). The obtained crude crystals were put to use in the following reaction without purification.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>[Pd].C(O)C>[C:1]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[CH2:21][CH2:20][CH2:19][NH:18][C:17]=3[N:16]=2)[CH2:12][CH2:13]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc3cccnc3n2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc3c(n2)NCCC3)CC1
Reaction time: 20 h

Procedure:
A mixture of 3-3 (2.1 g, 6.4 mmol), 10% Pd/C (210 mg), and ethanol (32 mL) was stirred under a hydrogen atmosphere (1 atm) for 20 hrs. The reaction mixture was then filtered through a celite pad and the filtrate was concentrated. Flash chromatography (silica, 70% hexanes/EtOAc) gave 3-4 as a colorless oil.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].C(N(CC)CC)C.[CH2:24]([CH:26]([CH2:30][CH2:31][CH2:32][CH3:33])[C:27](Cl)=[O:28])[CH3:25]>C(Cl)(Cl)Cl>[CH2:24]([CH:26]([CH2:30][CH2:31][CH2:32][CH3:33])[C:27]([N:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:28])[CH3:25]
Reactant: CCCCC(CC)C(=O)Cl
Reactant: O=C1CC[C@@H](C(=O)OCc2ccccc2)N1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCC(CC)C(=O)N1C(=O)CC[C@H]1C(=O)OCc1ccccc1

Procedure:
39.4 g (180 mmol) of benzyl (L)-pyroglutamate, prepared according to Example II(1), are dissolved in 160 ml of chloroform and 28.4 g (28 mmol) of triethylamine at ordinary temperature. A solution of 29.3 g (180 mmol) of 2-ethylhexanoyl chloride in 40 ml of chloroform is run in and the mixture is heated under reflux for 5 hours.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].O=C1CCC(=O)N1[O:41][C:42]([NH:44][C:45]1[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=1)=O>C(#N)C>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:42]([NH:44][C:45]3[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=3)=[O:41])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Nc1cccnc1)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)Nc4cccnc4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 30.5 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.29 g, 1.9 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in acetonitrile (50 mL). After stirring for 20 min, (2,5-dioxopyrrolidinyloxy)-N-(3-pyridyl)carboxamide (0.44 g, 1.85 mmol) was added. The mixture was stirred at room temperature for 17 hours. The mixture was filtered and the solid was recrystallized from methanol (25 mL) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}(3-pyridylamino)carboxamide (0.23 g 30%). 2N HCl/ether was added to a stirred solution of N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}(3-pyridylamino)carboxamide (0.23 g) in methanol (5 mL) and ethyl acetate (10 mL). The mixture was stirred for 2 hours and filtered to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}(3-pyridylamino)carboxamide hydrochloride (0.2 g) as a white solid: mp 263-265° C.; 1H NMR (DMSO-d6) δ 11.17 (s, 1H), 10.43 (s, 1H), 9.08 (d, J=1.7 Hz, 1H), 8.44 (d, J=5.4 Hz, 1H), 8.33-8.29 (dd, J=1.2 and 8.5 Hz, 1H), 7.93-7.78 (m, 4H), 7.55 (t, J=6.0 Hz, 1H), 5.21-5.14 (dd, J=5.a and 12.5 Hz, 1H), 4.80 (d, J=5.9 Hz, 2H), 2.97-2.84 (m, 1H), 2.65-2.50 (m, 2H), 2.10-2.06 (m, 1H); 3C NMR (DMSO-d6) δ 172.78, 169.83, 167.54, 166.96, 154.78, 139.97, 139.51, 134.80, 134.37, 133.35, 132.34, 131.60, 130.43, 127.17, 127.10, 121.99, 48.88, 38.68, 30.94, 21.99; Anal. Calcd. For C20H18N5O5Cl: C, 54.12; H, 4.09; N, 15.78; Cl, 7.99. Found: C, 54.11; H, 4.10; N, 15.44; Cl, 7.81.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4](=[CH2:28])[CH2:5][O:6][C:7]1[C:16]([C:17](=[O:19])[CH3:18])=[C:15]2[C:10]([C:11](=[O:27])[C:12]([CH3:26])=[C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:14]2)=[CH:9][CH:8]=1.[CH:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(O)C.O>[CH3:26][C:12]1[C:11](=[O:27])[C:10]2[C:15](=[C:16]([C:17](=[O:19])[CH:18]=[CH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:7]([O:6][CH2:5][C:4]([CH3:3])=[CH2:28])=[CH:8][CH:9]=2)[O:14][C:13]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C=C(C)COc1ccc2c(=O)c(C)c(-c3ccccc3)oc2c1C(C)=O
Reactant: O=Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=C(C)COc1ccc2c(=O)c(C)c(-c3ccccc3)oc2c1C(=O)C=Cc1ccccc1
Temperature: 25 °C
Yield: 85.5 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 7-(2-methylallyloxy) 8acetyl-3methylflavone (2.61 g, 0.0075 mol) and benzaldehyde (0.8 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 2.8 g of product m.p. 145-47° C., 1H-NMR (CDCl3)δ:1.78 (s, 3H); 2.20 (s, 3H); 4.62 (s, 2H); 4.98 (d, 2H, J=18 Hz); 7.06 (d,1H, J=16 Hz); 7.09 (d, 1H, J=8.9 Hz); 7.35-7.45 (m,7H); 7.50-7.55(m, 4H); 8.32 (d, 1H, J=8.9 Hz).
Reaction SMILES: [OH-].[Li+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:20][CH2:21][C@H:22]([N:27]2[CH2:32][CH2:31][N:30]([S:33]([CH3:36])(=[O:35])=[O:34])[CH2:29][CH2:28]2)[C:23]([O:25]C)=[O:24])(=[O:19])=[O:18])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1.O>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([S:17]([NH:20][CH2:21][C@H:22]([N:27]2[CH2:32][CH2:31][N:30]([S:33]([CH3:36])(=[O:34])=[O:35])[CH2:29][CH2:28]2)[C:23]([OH:25])=[O:24])(=[O:19])=[O:18])=[CH:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)[C@H](CNS(=O)(=O)c1ccc(OCc2ccccc2)cc1)N1CCN(S(C)(=O)=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)N1CCN([C@@H](CNS(=O)(=O)c2ccc(OCc3ccccc3)cc2)C(=O)O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.7 %

Procedure:
2.6 ml (2.6 mmol) of an aqueous solution of lithium hydroxide having a concentration of 1M are added to a solution of 900 mg (1.8 mmol) of methyl (S)-3-(4-benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoate in 20 ml of tetrahydrofuran and 0.5 ml of water. The reaction medium is stirred at ambient temperature for 18 h and then the THF is evaporated off under vacuum. 2.8 ml of an aqueous solution of acetic acid having of concentration of 1M and then 30 ml of water are added and the product precipitates. The suspension is stirred for 30 min at 100° C. and 20 then brought back to ambient temperature, filtered and dried under vacuum. 750 mg (86%) of (S)-3-(4-benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoic acid are obtained in the form of a white solid.
Reaction SMILES: [CH2:1]([CH:3]1[CH:20]([OH:21])[CH:19]([CH3:22])[CH:18]=[C:17]([CH3:23])[CH:16]=[C:15]([O:24][CH3:25])[C:14](=[O:26])[O:13][CH:12]([CH:27]([CH:29]([OH:48])[CH:30]([CH3:47])/[C:31](=[N:41]\[O:42][CH2:43][C:44](O)=[O:45])/[CH:32]=[CH:33]/[CH:34]([CH3:40])[CH:35]([OH:39])/[CH:36]=[CH:37]/[CH3:38])[CH3:28])[CH:11]([O:49][CH3:50])[CH:10]=[CH:9][CH:8]=[C:7]([CH3:51])[CH2:6][CH:5]([CH3:52])[CH:4]1[OH:53])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[CH2:64]([CH2:66][NH2:67])[OH:65].O>ClCCl>[CH2:1]([CH:3]1[CH:20]([OH:21])[CH:19]([CH3:22])[CH:18]=[C:17]([CH3:23])[CH:16]=[C:15]([O:24][CH3:25])[C:14](=[O:26])[O:13][CH:12]([CH:27]([CH:29]([OH:48])[CH:30]([CH3:47])/[C:31](=[N:41]\[O:42][CH2:43][C:44]([NH:67][CH2:66][CH2:64][OH:65])=[O:45])/[CH:32]=[CH:33]/[CH:34]([CH3:40])[CH:35]([OH:39])/[CH:36]=[CH:37]/[CH3:38])[CH3:28])[CH:11]([O:49][CH3:50])[CH:10]=[CH:9][CH:8]=[C:7]([CH3:51])[CH2:6][CH:5]([CH3:52])[CH:4]1[OH:53])[CH3:2]
Reactant: NCCO
Reactant: C/C=C/C(O)C(C)/C=C/C(=N/OCC(=O)O)C(C)C(O)C(C)C1OC(=O)C(OC)=CC(C)=CC(C)C(O)C(CC)C(O)C(C)CC(C)=CC=CC1OC
Agent: C/C=C/C(O)C(C)/C=C/C(=N/OCC(=O)NCCO)C(C)C(O)C(C)C1OC(=O)/C(OC)=C/C(C)=C/C(C)C(O)C(CC)C(O)C(C)C/C(C)=C/C=C/C1OC
Agent: C/C=C/C(O)C(C)/C=C/C(=N/OCC(=O)O)C(C)C(O)C(C)C1OC(=O)/C(OC)=C/C(C)=C/C(C)C(O)C(CC)C(O)C(C)C/C(C)=C/C=C/C1OC
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: C/C=C/C(O)C(C)/C=C/C(=N/OCC(=O)NCCO)C(C)C(O)C(C)C1OC(=O)C(OC)=CC(C)=CC(C)C(O)C(CC)C(O)C(C)CC(C)=CC=CC1OC
Reaction time: 0.33 h

Procedure:
To a solution of compound of example 10 (10 mg) in dichloromethane (2 mL) dicyclohexylcarbodiimide (3 mg), and HOBt (2 mg) were added. After 20 min, ethanol amine (1 mg) was added. The reaction mixture was stirred for 18 h under nitrogen atmosphere. Cold water was added to the reaction mixture, the organic layer was separated. The reaction mixture was extracted with dichloromethane (3×5 mL). The combined organic layer was washed with water (2×5 mL). The organic layer was dried over sodium sulphate, and was concentrated. The crude product was purified by preparative HPLC [Eurospere-100, C18 column (250 mm×8 mm), mobile phase: acetonitrile-water (1:1 isocratic)] to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:34]=[C:35]([Cl:44])[C:36]=1[NH:37][C:38](=[O:43])[CH2:39][N:40]([CH3:42])[CH3:41])[CH2:5][NH:6][C:7]([NH:16][C:17]([C@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)=[O:18])=[N:8]C(=O)OC(C)(C)C.[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46]>>[NH2:8]/[C:7](/[NH:6][CH2:5][C:4]1[CH:34]=[C:35]([Cl:44])[C:36]([NH:37][C:38](=[O:43])[CH2:39][N:40]([CH3:41])[CH3:42])=[C:2]([Cl:1])[CH:3]=1)=[N:16]\[C:17]([C@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=1)=[O:18].[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46]
Reactant: CN(C)CC(=O)Nc1c(Cl)cc(CNC(=NC(=O)OC(C)(C)C)NC(=O)[C@H]2CCCN2c2ccc(C(F)(F)F)cc2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CC(=O)Nc1c(Cl)cc(CN/C(N)=N/C(=O)[C@H]2CCCN2c2ccc(C(F)(F)F)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of: (R)-tert-butyl (3,5-dichloro-4-(2-(dimethylamino)-acetamido)benzylamino)(1-(4-(trifluoromethyl)phenyl)-pyrrolidine-2-carboxamido)-methylenecarbamate (4 mg) in dichloromrthane (0.10 mL) was added TFA (0.50 μL), and the resulting mixture was stirred at room temperature for 12 h. The solvents were removed in vacuo to give the title compound as its TFA salt (3 mg). retention time: 1.52 min (method A). MS (ESI) (M+H)+ 559.13.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[N:3]=1.[NH2:23][C@H:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([NH:12][C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[CH:10]=[CH:11][C:2]([NH:23][C@H:24]2[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25]2)=[N:3]3)(=[O:15])=[O:14])=[CH:17][CH:18]=1
Reactant: N[C@@H]1CCc2ccccc21
Reactant: O=S(=O)(Nc1cccc2nc(Cl)ccc12)c1ccc(F)cc1
Product: O=S(=O)(Nc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12)c1ccc(F)cc1

Procedure:
N-(2-Chloro-quinolin-5-yl)-4-fluoro-benzenesulfonamide (300 mg, 0.891 mmol) and (R)-1-aminoindane (254 mg, 1.91 mmol) were stirred in a sealed tube at 120° C. overnight. The reaction mixture was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0->50:50 gradient). The title compound was obtained as a yellow solid (287 mg, 74%), MS:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[CH3:17][CH:18]([CH3:26])[CH2:19][C:20](=[O:25])[CH2:21][C:22](=O)[CH3:23]>>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:22]([CH3:23])[C:21]([C:20](=[O:25])[CH2:19][CH:18]([CH3:26])[CH3:17])=[C:9]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)CC(=O)CC(C)C
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1
Product: Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1C(=O)CC(C)C
Yield: 55 %

Procedure:
The title compound was prepared from (2-Amino-5-bromo-phenyl)-phenyl-methanone [example A16] and 6-methyl-2,4-heptanedione according to the procedure of example 1. Yield: 55%. MS: m/z=381 (M).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([N+:11]([O-])=O)[CH:5]=1.O.O.Cl[Sn]Cl>C(O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([NH2:11])[CH:5]=1
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc(Cl)c(N)c1
Temperature: 80 °C

Procedure:
To a solution of 4-Chloro-3-nitro-benzoic acid methyl ester (5.0 g, 23.19 mmol) in 100 ml of ethanol was added SnCl2.2H2O (26.0 g, 115.96 mmol) and the reaction mixture was heated at 80° C. for 2 h. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure. Water (100 mL) was added, basified the reaction mixture with NaOH solution and extracted with hot EtOAc (3×250 mL).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:16]=[CH:15][C:14]2[NH:13][CH:12]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:11]3[CH2:23][CH2:24][CH2:25][O:26][CH:10]3[C:9]=2[CH:8]=1)[CH2:2][CH:3]([CH3:5])[CH3:4].[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:27]([N:20]1[CH2:21][CH2:22][CH:17]([CH:12]2[CH:11]3[CH2:23][CH2:24][CH2:25][O:26][CH:10]3[C:9]3[CH:8]=[C:7]([O:6][CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])[CH:16]=[CH:15][C:14]=3[NH:13]2)[CH2:18][CH2:19]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)CCOc1ccc2c(c1)C1OCCCC1C(C1CCNCC1)N2
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)CCOc1ccc2c(c1)C1OCCCC1C(C1CCN(Cc3ccccc3)CC1)N2
Temperature: 90 °C
Yield: 38.5 %

Procedure:
A Microwave vial was charged with (4aSR*,5RS*,10bSR*)-9-(isopentyloxy)-5-(piperidin-4-yl)-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinoline (80 mg, 0.22 mmol, 1 equiv.), benzaldehyde (24 mg, 22 μL, 0.22 mmol, 1 equiv.), NaBH(OAc)3 (95 mg, 0.44 mmol, 2 equiv.) followed by DCE (2.5 mL) under argon atmosphere. This reaction mixture was heated under microwave heating at 90° C. for 10 min. After cooling back to r.t., the reaction mixture was quenched with sat. NaHCO3 solution and diluted with CH2Cl2. The phases were separated and the organic phase additional extracted with CH2Cl2 twice. The combined organic phases were dried over MgSO4 and the solvent removed under reduced pressure after filtration. The residue was purified by Combiflash chromatography (SiO2, c-Hexane/AcOEt) to afford (4aSR*,5RS*,10bSR*)-5-(1-benzylpiperidin-4-yl)-9-(isopentyloxy)-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinoline (38 mg, 38%). The compound was prepared as hydrochloride salt following the method described in example 1.