Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:14][CH:13]([OH:15])[CH2:12]1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][C:28]=1Cl>CN(C=O)C.O>[Br:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][C:28]=1[O:15][CH:13]1[CH2:12][N:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH2:14]1
Reactant: Clc1ccncc1Br
Reactant: OC1CN(c2ccc3ccccc3n2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cnccc1OC1CN(c2ccc3ccccc3n2)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
To a solution of 1-(quinolin-2-yl)azetidin-3-ol (see PREPARATION P1.2, step 1; 320 mg, 1.60 mmol) in DMF (10 mL) was added Cs2CO3 (1.04 g, 3.2 mmol) and 3-bromo-4-chloropyridine (307 mg, 1.60 mmol). The mixture was stirred at 90° C. overnight and then diluted with water (20 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (5% to 30% EtOAc in petroleum ether) to give the title product (350 mg, 0.98 mmol, 61% yield) as white solid. ESI-MS (M+1): 356 calc. for C17H14BrN3O 355.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[C:3]=1[CH3:19].[CH2:20]([NH2:22])[CH3:21]>CN1CCCC1=O.O>[CH3:19][C:3]1[C:4]([O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])=[N:5][C:6]([CH3:8])=[CH:7][C:2]=1[NH:22][CH2:20][CH3:21]
Reactant: Cc1cc(C)c(Oc2nc(C)cc(Cl)c2C)c(C)c1
Reactant: CCN
Solvent: O
Solvent: CN1CCCC1=O
Product: CCNc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C
Temperature: 150 °C
Yield: 60 %

Procedure:
A mixture of 4-chloro-3,6-dimethyl-2-(2,4,6-trimethylphenoxy)-pyridine (1.330 g, 4.822 mmol) and 20 ml of ethyl amine in 13 ml of 1-methyl-2-pyrrolidinone was heated at 150° C. at 250 psi overnight in a pressure reactor. The reaction was heated an additional 24 hours at 175° C. and 300 psi. The reaction mixture cooled to room temperature and diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give a brown oil. The oil residue was purified through silica gel column chromatography using chloroform to 2% methanol in chloroform as eluent to give 0.820 g (60%) of the title compound as a white solid, mp 115-116° C.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([I:23])[CH:20]=[CH:19][C:15]=3[C:16](O)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.Cl.[NH2:25][C@H:26]([CH3:36])[C@H:27]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[OH:28]>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([I:23])[CH:20]=[CH:19][C:15]=3[C:16]([NH:25][C@H:26]([CH3:36])[C@H:27]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[OH:28])=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: C[C@@H](N)[C@@H](O)c1ccc(Cl)cc1
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12
Agent: Cl
Product: C[C@@H](NC(=O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12)[C@@H](O)c1ccc(Cl)cc1
Yield: 67 %

Procedure:
The title compound (42 mg, 67%) was obtained from 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodobenzoic acid (EXAMPLE 101, Part D) and (1S,2R)-2-amino-1-(4-chloro-phenyl)-propan-1-ol hydrochloride salt as in Example 1, Part C. HPLC: RT=10.13 min. MS (ESI−): mass calcd. for C22H18ClIN4O4S2, 628.89; m/z found, 627/629 [M−H]−. 1H NMR (500 MHz, CDCl3): 11.49 (s, 1H), 8.37 (dd, J=7.0, 0.8, 1H), 8.23 (dd, J=8.8, 0.8, 1H), 8.07 (d, J=1.5, 1H), 7.73 (dd, J=8.8, 7.1, 1H), 7.37-7.27 (m, 5H), 6.98 (d, J=8.3, 1H), 6.20 (d, J=8.1, 1H), 4.95 (d, J=2.7, 1H), 4.42-4.38 (m, 1H), 2.65 (s, 1H), 1.03 (d, J=6.9, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:13]#[N:14])=[CH:7]2.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]>CC(C)=O>[Cl:1][C:2]1[C:3]2[C:8](=[CH:7][C:6]([C:13]#[N:14])=[CH:5][CH:4]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: N#Cc1ccc2c(Cl)c(O)ccc2c1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NCCOc1ccc2cc(C#N)ccc2c1Cl
Yield: 81 %

Procedure:
To a solution of 5-chloro-6-hydroxynaphthalene-2-carbonitrile (1.5 mmol) and K2CO3 (3 mmol) in acetone was added tert-butyl (2-bromoethyl)carbamate (2.1 mmol). The resulting mixture was heated at reflux overnight. After TLC control (n-hexane/ethyl acetate 65:35), solvent was evaporated in vacuo and the residue was dissolved in 15 mL of ethyl acetate and washed with water (3×5 mL), brine (10 mL) and dried over Na2SO4. The evaporation of solvent afforded tert-butyl {2-[(1-chloro-6-cyanonaphthalen-2-yl)oxy]ethyl}carbamate as a brown solid (81% yield) which was used without further purification.
Reaction SMILES: [C:1]1([C@H:7]2[C@H:16]3[CH2:17][CH2:18][N:19]([C:20]([C@H:22]4[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]4[NH:28][C:29]([C:31]4[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=4[C:33]([OH:35])=O)=[O:30])=[O:21])[C@H:15]3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.CCOC(OC(OCC)=O)=O.O>CN(C=O)C>[C:1]1([C@H:7]2[C@H:16]3[CH2:17][CH2:18][N:19]([C:20]([C@H:22]4[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]4[N:28]4[C:33](=[O:35])[C:32]5[C:31](=[CH:39][CH:38]=[CH:37][CH:36]=5)[C:29]4=[O:30])=[O:21])[C@H:15]3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccccc1C(=O)N[C@@H]1CCCC[C@@H]1C(=O)N1CC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21
Agent: CCOC(=O)OC(=O)OCC
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C([C@H]1CCCC[C@H]1N1C(=O)c2ccccc2C1=O)N1CC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.2 %

Procedure:
To a solution of the compound (70 mg, 0.13 mmol) of Example 123 and triethylamine (20.9 μl, 0.15 mmol) in DMF (5 ml) was added DEPC (24.5 μl, 0.15 mmol) under ice-cooling, and the mixture was stirred at room temperature for 4 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate, the extract was washed with saturated brine and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (3:1-1:1, v/v) to give the title compound (54 mg, 71%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27](=[O:30])[NH:28][CH3:29])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[B:36]([OH:38])[OH:37].[OH:39][CH2:40][C:41]([CH2:45]O)([CH2:43]O)[CH3:42].CC(C)([O-])C.[K+:52].C1COCC1>C1COCC1>[K+:52].[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27](=[O:30])[NH:28][CH3:29])=[C:18]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[B-:36]12[O:39][CH2:40][C:41]([CH3:45])([CH2:43][O:37]1)[CH2:42][O:38]2
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(B(O)O)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Reactant: CC(CO)(CO)CO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([B-]45OCC(C)(CO4)CO5)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C

Procedure:
To a stirred solution of (2-chloro-4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenyl)boronic acid (0.0750 g, 0.135 mmol) and 1,1,1-tris(hydroxymethyl)ethane (0.0180 g, 0.148 mmol) in anhydrous THF (6 mL) was added activated 3 angstrom molecular sieves (0.400 g). The resulting mixture was heated to reflux for 4 hours and cooled to RT. The mixture was filtered to remove solids and the filtrate concentrated to dryness at reduced pressure. The residue was dissolved in 5 mL of anhydrous THF and the solution cooled to 0° C. The solution was treated with 1M potassium t-butoxide/THF (135 μL, 0.135 mmol) by dropwise addition. After warming to RT the solution was concentrated to dryness at reduced pressure to afford the title compound as a light yellow solid in quantitative yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.48 (d, J=4.0 Hz, 1H) 8.09 (s, 1H) 7.98 (dd, J=8.9, 5.5 Hz, 2H) 7.51 (d, J=7.9 Hz, 1H) 7.39 (t, J=8.9 Hz, 2H) 7.07-7.18 (m, 3H) 3.55 (s, 6H) 3.28 (s, 3H) 2.82 (d, J=3.4 Hz, 3H) 2.10-2.23 (m, 1H) 0.73-1.04 (m, 4H) 0.45 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]#[N:8])[CH2:3][CH2:2]1.[OH-:9].[NH4+]>S(=O)(=O)(O)O>[NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:8])=[O:9])[CH2:3][CH2:2]1
Reactant: [OH-]
Reactant: N#CC1CCNCC1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: NC(=O)C1CCNCC1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
4-(4-chloro-phenyl-amino)-1-phenylmethyl)-4-piperidine-carbonitrile (29.3 g) was dissolved in 150 ml conc. sulfuric acid and stirred for 1 h at room temperature and 1 h at 70° C. Then the reaction mixture was cooled to room temperature and poured on ice, adjusted to pH 10 by addition of 30% aqueous ammonium hydroxide and extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and evaporated to yield 4-(4-chloro-phenyl-amino)-1-phenylmethyl)-4-piperidine-carboxamide as an brownish oil which crystallized upon addition of 50 ml diethyl ether and 50 ml pentane. Off-white powder (11.84 g), m.p. 167-170° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:17])([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:31][NH:32][O:33][CH3:34].O>ClCCl.C(OCC)(=O)C>[CH3:34][O:33][N:32]([CH3:31])[C:14]([C:11]1([F:17])[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC(F)(C(=O)O)CC1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CON(C)C(=O)C1(F)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.6 %

Procedure:
After dissolving 2.19 g of 1-(tert-butoxycarbonyl)-4-fluoropiperidine-4-carboxylic acid in 30 ml of dichloromethane, 2.16 g of 1,1′-carbonyldiimidazole was added and the mixture was stirred at room temperature for 1.5 hours. Next, 1.30 g of N-methyl-O-methylhydroxylamine hydrochloride was added and the mixture was stirred overnight at room temperature. Water was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with aqueous sodium carbonate solution, water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (2.33 g, 90% yield).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8](=[O:20])[N:9]([CH2:16][C:17]([OH:19])=[O:18])[C:10]2=[O:15])(=[O:4])=[O:3].[Cl:21][C:22]1[CH:23]=[N+:24]([O-:47])[CH:25]=[C:26]([Cl:46])[C:27]=1[CH2:28][C@@H:29]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH:38]([F:40])[F:39])=[C:33]([O:41][CH2:42][CH:43]2[CH2:45][CH2:44]2)[CH:32]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C1COCC1.O>[Cl:21][C:22]1[CH:23]=[N+:24]([O-:47])[CH:25]=[C:26]([Cl:46])[C:27]=1[CH2:28][C@@H:29]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH:38]([F:40])[F:39])=[C:33]([O:41][CH2:42][CH:43]2[CH2:45][CH2:44]2)[CH:32]=1)[O:18][C:17](=[O:19])[CH2:16][N:9]1[C:8](=[O:20])[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[C:10]1=[O:15]
Reactant: CS(=O)(=O)Nc1cccc2c1C(=O)N(CC(=O)O)C2=O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cccc2c1C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 21.29 %

Procedure:
A mixture of 2-(4-(methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetic acid (78 mg, 0.262 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)-2-hydroxyethyl)pyridine 1-oxide (110 mg, 0.262 mmol), DMAP (15.97 mg, 0.131 mmol) and EDC (125 mg, 0.654 mmol) in 15 ml of THF was stirred at room temperature for 2 days. The mixture was diluted with water, acidified and extracted twice with EtOAc; the organic layer was then washed with brine, dried over sodium sulfate and evaporated. The residue was triturated with methanol and the title compound was obtained as a pale yellow solid (39 mg, 0.056 mmol, 21.29% yield, MS/ESI+ 700.11 [MH]+, [αD]=−63.94, c=0.355 in DCM). 1H NMR (300 MHz, DMSO-d6) δ ppm 9.29 (br. s., 1H), 8.47 (s, 2H), 7.86 (dd, 1H), 7.81 (dd, 1H), 7.63 (dd, 1H), 7.19 (d, 1H), 7.10 (d, 1H), 6.97 (dd, 1H), 7.08 (t, 1H), 6.02 (dd, 1H), 4.46 (d, 1H), 4.38 (d, 1H), 3.93 (d, 2H), 3.41 (dd, 1H), 3.30 (s, 3H), 3.24 (dd, 1H), 1.10-1.31 (m, 1H), 0.48-0.66 (m, 2H), 0.27-0.48 (m, 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:15][C:14](=[O:16])[O:13][C:11](=[O:12])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CN[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH2:25]([N:27](CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:10][C:11]([NH:27][CH2:25][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:12])[CH2:15][C:14]([OH:13])=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCN(CC)CC
Reactant: O=C1CC(c2ccc(Cl)c(Cl)c2)CC(=O)O1
Reactant: CNc1ccccc1
Solvent: ClCCl
Product: O=C(O)CC(CC(=O)NCc1ccccc1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-(3,4-Dichlorophenyl)glutaric anhydride in CH2Cl2 (20 mL) at 0° C. was treated sequentially with N-methylaniline (0.518 g), triethylamine (0.489 g) and N,N-dimethylaminopyridine (trace). The mixture was stirred at 0° C. for two hours then allowed to warm to room temperature and stirred for 12 hours. The reaction mixture was washed with 1N HCl (2×20 mL) and water (20 mL). The organic layers were dried over MgSO4, filtered and concentrated to afford the title compound (1.2 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][NH:22][C:23]([C:25]3[C:33]4[N:32]=[C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])[NH:30][C:29]=4[CH:28]=[CH:27][CH:26]=3)=[O:24])[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:9][CH2:10][CH:11]([CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([CH2:21][NH:22][C:23]([C:25]3[C:33]4[N:32]=[C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])[NH:30][C:29]=4[CH:28]=[CH:27][CH:26]=3)=[O:24])[CH2:19][CH2:20]2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCC(CNC(=O)c3cccc4[nH]c(C(C)(C)C)nc34)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1nc2c(C(=O)NCC3CCN(CC4CCNCC4)CC3)cccc2[nH]1
Yield: 88 %

Procedure:
Crude 4-(4-{[(2-tert-butyl-1H-benzoimidazole-4-carbonyl)amino]methyl}-piperidin-1-ylmethyl)piperidine-1-carboxylic acid tert-butyl ester, prepared as in the previous step (5.1 g, 10 mmol) was treated with a mixture of trifluoroacetic acid (40 mL) and dichloromethane (40 mL) at room temperature for 0.5 h. The mixture was concentrated in vacuo, redissolved in dichloromethane (25 mL) and basified with 1M aqueous sodium hydroxide (15 mL). The organic layer was removed, and the aqueous layer re-extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo to afford the desired product as a brown foam (3.6 g, 8.8 mmol, 88%). (m/z): [M+H]+ calcd for C24H37N5O 412.31, found 412.6.
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]([CH3:30])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]2[CH:22]=[C:23]([C:27]([NH2:29])=[O:28])[C:24]([NH2:26])=[N:25][C:14]1=2)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:26][C:24]1[C:23]([C:27]([NH2:29])=[O:28])=[CH:22][C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]([CH2:12][C@H:11]([NH2:10])[CH3:30])[C:14]=2[N:25]=1
Reactant: C[C@H](Cn1c2ccccc2c2cc(C(N)=O)c(N)nc21)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: C[C@@H](N)Cn1c2ccccc2c2cc(C(N)=O)c(N)nc21
Reaction time: 8 h
Yield: 86.5 %

Procedure:
To a solution of benzyl{(1R)-2-[2-amino-3-(aminocarbonyl)-9H-pyrido[2,3-b]indol-9-yl]-1-methylethyl}carbamate (xxiv-a, 13 mg, 0.031 mmol) in ethanol (10 mL) was added palladium on carbon (10 mg, 0.094 mmol). The reaction mixture was stirred under a hydrogen atmosphere overnight. Solids were removed by filtration and the filtrate was concentrated in vacuo to afford 2-amino-9-[(2R)-2-aminopropyl]-9H-pyrido[2,3-b]indole-3-carboxamide (35, 7.6 mg, 86%). NH4OAc standard conditions. DAD Retention time =4.90 min. M+H=284. 1H NMR (300 MHz, MeOD-d4): Δ 8.66 (s, 1H), 7.90 (d, J=7.7 Hz, 1H) 7.49 (d, J=8.1 Hz, 1H), 7.23 (ddd, J=7.4, 6.9, 1.2 Hz, 1H), 7.17 (ddd, J1=7.8, 7.7, 1.2 Hz, 1H), 4.33 (d, J=6.1 Hz, 2H), 3.63-3.71 (m, 1H), 1.23 (d, J=6.5 Hz, 3H).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Cl:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.Cl>O1CCOCC1>[Cl:6][C:7]1[CH:13]=[CH:12][C:10]([NH:11][C:3](=[O:4])[CH2:2][Cl:1])=[CH:9][CH:8]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: C1COCCO1
Product: O=C(CCl)Nc1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
3.4 g (30 mol) of 2-chloroacetyl chloride were dissolved in anhydrous dioxane and a solution containing 3.8 g (30 mol) of 4-chloroaniline was added dropwise. After an hour, the batch was poured into ice water, acidified using dilute hydrochloric acid, the supernatant was removed by suction and the residue was washed with water until neutral. The reaction product was recrystallized from ethanol. The yield was 3.2 g.
Reaction SMILES: COC(N([C@@H](C1C=CC=CC=1)C)C(=O)[CH:7]([CH2:14][CH:15]=[CH2:16])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=O.[CH3:26][O-:27].[Na+].C1C[O:32][CH2:31]C1>>[CH2:11]([CH:10]([CH2:9][CH2:8][CH2:7][CH2:14][CH2:15][CH3:16])[C:26]([O:32][CH3:31])=[O:27])[CH:12]=[CH2:13]
Reactant: C1CCOC1
Reactant: C=CCC(CCCCCC)C(=O)N(C(=O)OC)[C@H](C)c1ccccc1
Reactant: C[O-]
Agent: [Na+]
Product: C=CCC(CCCCCC)C(=O)OC
Reaction time: 22 h
Yield: 55 %

Procedure:
A solution of 0.345 g (1.0 mmol) of N-methyloxycarbonyl-N-(2-allyloctanoyl)-1-(R)-phenylethylamine in 5 ml of THF was cooled to 0° C., 0.386 g (2.0 mmol) of NaOMe (28% solution in methanol) was added, and the mixture was stirred for 22 hours. The reaction was terminated by addition of 2 ml of 1 N hydrochloric acid, and the product was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was quantitated by GC. Thus was obtained 0.109 g (55%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]([C:19]3[S:20][CH:21]=[CH:22][C:23]=3Br)=[O:18])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.[C:25]1(OB(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CO.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17](=[O:18])[C:19]3[S:20][CH:21]=[CH:22][C:23]=3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1CN1CCC(CC(=O)c2sccc2Br)CC1
Reactant: OB(O)Oc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: COc1ncccc1CN1CCC(CC(=O)c2sccc2-c2ccccc2)CC1
Yield: 100.7 %

Procedure:
290 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-(3-bromo-2-thienyl)-2-oxoethyl]piperidine obtained in Example 73, 173 mg of phenylboric acid and 42 mg of tetrakis(triphenylphosphine)palladium were suspended in 5.6 ml of toluene, 1.4 ml of methanol and 2.8 ml of 2 M sodium carbonate, and the mixture was heated under reflux for 3 hours under nitrogen flow. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (ethyl acetate), to give 290 mg of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2>CO.O=[Pt]=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7][CH2:6]2
Reactant: COc1ccc2ncccc2c1
Agent: O=[Pt]=O
Solvent: CO
Product: COc1ccc2c(c1)CCCN2
Temperature: 40 °C

Procedure:
6-Methoxyquinoline (48 g, 0.30 mol) was dissolved in 500 mL methanol and mix with PtO2 (12 g, 52.8 mmol), the mixture was put in a Parr shaker heated to 40° C. under hydrogen (40 psi (275 kPa)) for 24 h. The reaction was cool to room temperature, released the pressure, and then removed the catalyst. The solvent was concentrated resulting the title compound: 1H NMR (300 MHz, CDCl3) 1.90-1.97 (m, 2), 2.75 (t, 2H, J=6.4 Hz), 3.25 (t, 2H, J=5.5 Hz), 3.72 (s, 3H), 6.44-6.60 (m, 3H). cl PREPARATION 36
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2>Br>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: Br
Product: O=C1CCCc2cc(O)ccc21
Yield: 85 %

Procedure:
A solution of 6-methoxy- 1-tetralone (5.0 g) in 48% hydrobromic acid (62 ml) was refluxed for 8 hours. The mixture was cooled, filtered and washed with water (50 ml) to give 6-hydroxy-1-tetralone (3.91 g): NMR 5 (d6 DMSO) 1.9-2.05(m,2H), 2.4-2.55(m,2H), 2.8-2.9(m,2H), 6.65(d, 1H), 6.7(dd,1H), 7.75(d,1H), m/e 163(M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)=[CH:11]C=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:23]([CH:28]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:25][CH2:26][CH3:27])=[O:24].[CH2:48](O)C>>[CH2:26]([O:25][C:23](=[O:24])/[CH:28]=[CH:48]/[CH:11]=[C:10]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:27]
Reactant: O=CC=C(c1cccc([N+](=O)[O-])c1)c1cccc([N+](=O)[O-])c1
Reactant: CCO
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)/C=C/C=C(c1cccc([N+](=O)[O-])c1)c1cccc([N+](=O)[O-])c1

Procedure:
As in Example 99, a solution of 3,3-bis(3-nitrophenyl)-2-propenal (7.9 g) and (carboethoxymethylene)triphenylphosphorane (9.75 g) in ethanol was stirred at room temperature for 1 hour. The usual work up gave a mixture of esters which was crystallized from dichloromethane-hexane to furnish 6.7 g of (E)-5,5-bis(3-nitrophenyl)-2,4-pentadienoic acid ethyl ester, mp 121°-123° C. Recrystallization from the same solvent gave the analytical sample, mp 122°-123° C. Anal. Calculated for C19H16N2O6 : C, 61.96; H, 4.38; N, 7.60 Found: C, 62.63; H, 4.60; N, 7.79.