Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:40]1[S:44][N:43]=[CH:42][CH:41]=1)CCC.O>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>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:40]2[S:44][N:43]=[CH:42][CH:41]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccns1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(-c2ccns2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O

Procedure:
A solution of tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (60 mg, 0.120 mmol), 5-(tributylstannyl)isothiazole (67.5 mg, 0.180 mmol) and tetrakis(triphenylphosphine)palladium(0) (69.5 mg, 0.060 mmol) in toluene (2.0 mL) was heated to 120° C. for 45 minutes via microwave irradiation. The reaction mixture was subsequently poured into water and was extracted with EtOAc. The extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (Flash 60 column) eluting with hexane/EtOAc (1:1) to give the title compound as a yellow solid. ESI-MS m/z [M+H]+ calc'd for C26H34FN5O5S, 548. found, 548.
Reaction SMILES: C(N(CC)CC)C.Cl.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[CH:12][C:11]=1[N+:20]([O-:22])=[O:21].[NH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)(Cl)Cl>[N+:20]([C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:10]=1[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: NCCCCCNC(=O)c1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NCCCCCNc1c([N+](=O)[O-])cnc2ccccc12)c1ccccc1
Yield: 84.3 %

Procedure:
Triethylamine (1 eq.) was added to a suspension of 4-chloro-3-nitroquinoline hydrochloride (13 g, 53 mmol) in chloroform. A suspension of N-(5-aminopentyl)benzamide (11 g, 53 mmol) in chloroform was added and the reaction mixture was heated to reflux. Progress of the reaction was monitored by HPLC. The reaction mixture was concentrated under vacuum. The residue was diluted with toluene, heated to reflux and then filtered while still hot. The filtrate was allowed to cool. The resulting precipitate was isolated by filtration to provide 16.9 g of N1-{5-[(3-nitroquinolin-4-yl)amino]pentyl}benzamide as a yellow solid, m.p. 130-132-C. 1H NMR (500 MHz, DMSO-d6) δ 9.07 (s, 1H), 9.02 (broad s, 1H), 8.53 (d, J=8.0 Hz, 1H), 8.43 (t, J=6.0 Hz, 1H), 7.89 (dd, J=8.0, 1.2 Hz, 1H), 7.83 (dt, J=8.0, 1.2 Hz, 1H), 7.80 (d, J=8.0 Hz, 2H), 7.57 (dt, J=8.0, 1.2 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.43 (t, J=8.0 Hz, 2H), 3.63 (q, J=6.0 Hz, 2H), 3.25 (q, J=6.0 Hz, 2H), 1.77 (quintet, J=7.0 Hz, 2H), 1.55 (quintet, J=7.0 Hz, 2H), 1.39 (quintet, J=7.0 Hz, 2H).
Reaction SMILES: C(=O)=O.CC(C)=O.[NH3:8].C([O:11][C:12]([C:14]1[O:25][C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]([CH3:26])[C:16]=2[C:15]=1[O:27][CH3:28])=O)C>O1CCCC1>[CH3:28][O:27][C:15]1[C:16]2[N:17]([CH3:26])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[C:24]=2[O:25][C:14]=1[C:12]([NH2:8])=[O:11]
Reactant: N
Reactant: CCOC(=O)c1oc2c3ccccc3n(C)c2c1OC
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COc1c(C(N)=O)oc2c3ccccc3n(C)c12
Temperature: 0 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
A flask fitted with a Dewar condenser containing dry ice/acetone was cooled in a dry ice/acetone bath and charged with 350 ml of anhydrous ammonia. A few crystals of hydrated ferric nitrate catalyst were added, and the cooling bath was removed. Lithium amide was then generated by the addition, over one hour, of 1.78 g (0.26 mole) of freshly cut lithium metal ribbon. After the addition of 65 ml of cold tetrahydrofuran, a solution of 16.5 g (0.060 mole) of 3-methoxy-4-methyl-4H-furo[3,2-b]indole-2-carboxylic acid ethyl ester in 75 ml of tetrahydrofuran was added over 30 minutes. The Dewar condenser was removed, and the mixture was stirred for 16 hours as the excess ammonia evaporated. The total reaction mixture was added to 600 g of ice/water, and the crude amide product was filtered and washed with water. Recrystallization from aqueous ethanol yielded 11.7 g (79% yield) of final product, mp 174°-177° C. An additional recrystallization as above yielded an analytically pure sample, mp 179°-182° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH3:31])[CH2:12][O:11][S:10](=[O:13])[N:9]1[CH:14]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH2:32]>CC#N>[C:1]([O:5][C:6]([C:8]1([CH3:31])[CH2:12][O:11][S:10](=[O:32])(=[O:13])[N:9]1[CH:14]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C(c2ccc(OC)cc2)N2S(=O)OCC2(C)C(=O)OC(C)(C)C)cc1
Reactant: O
Solvent: CC#N
Product: COc1ccc(C(c2ccc(OC)cc2)N2C(C)(C(=O)OC(C)(C)C)COS2(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89 %

Procedure:
A solution of the diastereomeric sulfamidites 13a (97 mg, 0.22 mmol) in 4 mL of CH3CN was cooled in an ice bath and treated successively with 1.1 eq of NaIO4 (51 mg), a catalytic amount of RuO2H2O (˜1 mg) and 2.4 mL of H2O. After 5 minutes of stirring the ice bath was removed, and the reaction was continued for 20 minutes. The reaction mixture was diluted in 10 mL of EtOAc and washed with 10 mL of saturated NaHCO3 solution. The aqueous layer was extracted with 2×10 mL of EtOAc, and the combined organic layers were washed with 10 mL brine followed by usual work up. The crude product was purified by silica gel column chromatography (30% EtOAc in hexane) to provide the cyclic sulfamidate 14a as a light yellow solid (90 mg, 89%): mp 143.5-145 EC (EtOAc.hexane); 1H NMR (CDCl3) δ 1.29 (3H, s), 1.51 (9H, s), 3.77 (3H, s), 3.80 (3H, s), 4.16 (1H, d, J=8.8), 4.73 (1H, d, J=8.8), 5.98 (1H, s), 6.82-6.89 (4H, m), 7.38-7.44 (4H). Anal. (C23H29NO7S) C, H, N.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[O:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:23]3[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[O:4][N:3]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1cc(NS(=O)(=O)c2ccc(Br)cc2)on1
Product: COc1ccc(-c2ccc(S(=O)(=O)Nc3cc(C)no3)cc2)cc1
Yield: 82 %

Procedure:
N-(3-methyl-5-isoxazolyl)-4-(4-methoxyphenyl)benzenesulfonamide was prepared in the same manner as described in Example 206b, using N-(3-methyl-5-isoxazolyl)-4-bromobenzenesulfonamide (Example 206a) and 4-methoxybenzeneboronic acid resulting in an 82% yield of the final product, m.p. 1 94-1 96° C. The product was recrystallized using hexane/ethyl acetate.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]([C@@H:12]([CH2:21][CH2:22][CH3:23])[CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]2)[CH3:11])=[O:9])=[CH:6][CH:5]=1.[CH3:26]I>C1COCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]([C@@H:12]([CH2:21][CH2:22][CH3:23])[CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([O:20][CH3:26])[CH2:16][CH2:15]2)[CH3:11])=[O:9])=[CH:24][CH:25]=1
Reactant: CI
Reactant: CCC[C@@H](CN1CCC(O)CC1)N(C)C(=O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC[C@@H](CN1CCC(OC)CC1)N(C)C(=O)c1ccc(Cl)cc1
Reaction time: 0.08 h
Yield: 50.9 %

Procedure:
NaH (21.24 mg, 0.89 mmol) was added to a solution of (S)-4-chloro-N-(1-(4-hydroxypiperidin-1-yl)pentan-2-yl)-N-methylbenzamide (Example 44) (200 mg, 0.59 mmol) in dry THF (10 mL) at room temperature under N2. After 5 min was MeI (0.037 mL, 0.59 mmol) added. The reaction was stirred overnight and was then quenched by addition of NH3 saturated H2O (2 mL). The resulting solution was evaporated and the remainder was dissolved in EtOAc and poured on an SCX-2 column (5 g). The column was washed with MeOH and the product was eluted by NH3 saturated MeOH. The crude product was purified by preparative HPLC to yield the title product (106 mg, 51.0%). 1H NMR (600 MHz, DMSO-d6) δ 0.78, 0.91, 1.05-1.51, 1.70-1.84, 1.91-2.03, 2.09-2.13, 2.17-2.23, 2.33-2.39, 2.41-2.54, 2.58-2.64, 2.76, 2.82, 3.12, 3.19-3.22, 3.53-3.59, 4.71-4.79, 7.31-7.35, 7.36-7.40, 7.47-7.53. HRMS (M+H)+: calculated 353.1996. found 353.2006.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH2:3][C:4]([CH3:27])([CH3:26])[C:5]([N:7]([CH:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C@@H:8]1[CH2:12][NH:11][C@H:10]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH2:9]1)=[O:6].[C:29]([N:33]1[CH2:37][C@@H:36]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=2)[C@H:35]([C:45](O)=[O:46])[CH2:34]1)([CH3:32])([CH3:31])[CH3:30]>>[ClH:44].[C:29]([N:33]1[CH2:37][C@@H:36]([C:38]2[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=2)[C@H:35]([C:45]([N:11]2[CH2:12][C@@H:8]([N:7]([C:5](=[O:6])[C:4]([CH3:27])([CH3:26])[CH2:3][N:2]([CH3:1])[CH3:28])[CH:18]3[CH2:23][CH2:22][C:21]([CH3:24])([CH3:25])[CH2:20][CH2:19]3)[CH2:9][C@H:10]2[C:13]([N:15]([CH3:16])[CH3:17])=[O:14])=[O:46])[CH2:34]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CN(C)CC(C)(C)C(=O)N(C1CCC(C)(C)CC1)[C@@H]1CN[C@H](C(=O)N(C)C)C1
Reactant: CC(C)(C)N1C[C@@H](C(=O)O)[C@H](c2ccc(Cl)cc2)C1
Product: CN(C)CC(C)(C)C(=O)N(C1CCC(C)(C)CC1)[C@H]1C[C@@H](C(=O)N(C)C)N(C(=O)[C@@H]2CN(C(C)(C)C)C[C@H]2c2ccc(Cl)cc2)C1
Product: Cl

Procedure:
The title compound was prepared according to the procedure described in Step F, G of Example A1, using (4S)-4-{[3-(dimethylamino)-2,2-dimethylpropanoyl](4,4-dimethylcyclohexyl)amino)}-N,N-dimethyl-L-prolineamide (82 mg, 0.18 mmol) prepared in Step B and (3S,4R)-1-t-butyl-4-(4-chlorophenyl)pyrrolidine-3-carboxylic acid prepared in Preparation Example A9-2 (105 mg, 89%).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:14]([O:18][C:19]([N:21]([C:29]1[CH:34]=[C:33]([CH3:35])[C:32]([CH2:36]Br)=[CH:31][N:30]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:20])([CH3:17])([CH3:16])[CH3:15].C(OCC)(=O)C>CN(C=O)C>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([CH2:36][C:32]1[CH:31]=[N:30][C:29]([N:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])=[CH:34][C:33]=1[CH3:35])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: Cc1cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc1CBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1C)C(=O)OCC
Reaction time: 0.25 h
Yield: 47.9 %

Procedure:
To a suspension of NaH (0.24 g, 6.0 mmol, 60%) in DMF (5 mL) was added diethyl malonate (0.91 mL, 6.0 mmol) and the mixture was stirred for 15 min. A solution 2-[N,N-bis(tert-butoxycarbonyl)amino]-5-bromomethyl-4-methyl-pyridin (2.0 g, 5.0 mmol) in DMF (5 mL) was added and the resulting solution stirred for 120 min at 60 ° C. Ethyl acetate was added and the mixture was washed with water and brine and dried. After evaporation of the solvent, the crude product was purified by flash chromatography (CH3OH/CH2Cl2, 1:100→1:20) to give a pure fraction 2-(6-[N,N-bis(tert-butoxycarbonyl)amino]-4-methyl-pyridin-3-ylmethyl)-malonic acid diethyl ester (1.15 g, 48%) and an impure fraction 2-(6-[N,N-bis(tert-butoxycarbonyl)amino]4-methyl-pyridin-3-ylmethyl)-malonic acid diethyl ester (1.1 g).
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[CH2:11]Br.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[CH2:14]([N:21]1[CH2:11][C:5]2[C:4](=[CH:9][CH:8]=[C:7]([Cl:10])[CH:6]=2)[C:3]1=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(Cl)cc1CBr
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1c2ccc(Cl)cc2CN1Cc1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 39.6 %

Procedure:
A mixture of 2-bromomethyl-4-chloro-benzoic acid methyl ester (0.120 g, 0.46 mmol), benzylamine (0.106 mL, 1.0 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-benzyl-5-chloro-2,3-dihydro-isoindol-1-one (0.047 g, 40%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.26 (m, 2H), 4.80 (m, 2H), 7.32 (m, 7H), 7.83 (m, 1H). GC-MS: m/z 257 (M)+, 180 (M−77)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([CH:18]([O:20][CH2:21][C:22]3([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH3:19])[N:9]=2)=[CH:4][CH:3]=1.C=O.[C:36](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:11]=[C:10]([CH:18]([O:20][CH2:21][C:22]3([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:27][CH2:26][N:25]([CH3:36])[CH2:24][CH2:23]3)[CH3:19])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(OCC1(c2ccccc2)CCNCC1)c1cc(C(F)(F)F)cc(-c2ccc(F)cc2)n1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(OCC1(c2ccccc2)CCN(C)CC1)c1cc(C(F)(F)F)cc(-c2ccc(F)cc2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-(4-fluorophenyl)-6-(1-((4-phenylpiperidin-4-yl)methoxy)ethyl)-4-(trifluoromethyl)pyridine (40 mg, 0.08 mmol), and formaldehyde (37 wt. % solution in water, 0.2 mL, 7.5 mmol) were combined in dichloromethane (2.0 mL) and cooled to 0° C. The reaction was treated with sodium triacetoxyborohydride (74 mg, 0.3 mmol) and a drop of acetic acid. The reaction was stirred at 0° C. for 30 min and at room temperature for 1 h. The solvent was removed in vacuo and the resulting crude mixture was concentrated and purified by preparative HPLC which afforded 10.0 mg (27%) 1H-NMR (CD3OD, 400 MHz) δ 8.09 (m, 1H), 7.93 (m, 1H), 7.14-7.58 (m, 9H), 4.51 (q, 1H), 3.36-3.52 (m, 2H), 2.80-2.93 (m, 2H), 2.59-2.79 (m, 5H), 2.04-2.24 (m, 2H), 1.42 (d, 3H), LC: Tr=1.952 min HPLC Method 1. Mass spec.: 473.36 (MH)+.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][NH:12][CH3:13].C(Cl)(Cl)Cl>C(N(CC)CC)C>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]([CH3:13])[CH3:11])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CNC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)c1ccc(I)cc1
Reaction time: 1 h
Yield: 94 %

Procedure:
4-Iodobenzoyl chloride (10.0 g) was added portionwise to dimethylamine (1.8 g) in triethylamine (40 ml) at 0°. The suspension was stirred at 0° for 1 h, treated with chloroform (200 ml), washed with aqueous sodium bicarbonate (1 M; 100 ml), dried and evaporated to give the title compound (9.7 g) m.p. 103°-106°.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:18])[CH2:12][CH:13]([OH:17])[C:14]([OH:16])=[O:15])=[C:6]([O:19][CH3:20])[CH:5]=1)[CH:2]=[CH2:3].[C:21]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.C(OCC)(=O)C>[CH3:21][O:15][C:14](=[O:16])[CH:13]([OH:17])[CH2:12][C:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:1][CH:2]=[CH2:3])=[CH:5][C:6]=1[O:19][CH3:20])=[O:18]
Reactant: O=C([O-])[O-]
Reactant: C=CCc1ccc(OC(=O)CC(O)C(=O)O)c(OC)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: C=CCc1ccc(OC(=O)CC(O)C(=O)OC)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To a solution of 2-Hydroxy-succinic acid 4-(4-allyl-2-methoxy-phenyl)ester (0.1 g, 0.35 mmol) in dry DMF (2.0 mL) was added dry K2CO3 followed by methyl iodide (0.024 mL) at 0° C. and the reaction mixture was stirred at room temperature (25° C.) over a period of 60 min. The resulting mixture was diluted with ethyl acetate (50.0 mL) and filtered. The filtrate was washed with water (4×200 mL) and dried over sodium sulphate. The crude product obtained upon evaporation of volatiles was purified by column chromatography to obtain orange colour viscuss liquid (0.05 g, 47%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7](Br)[CH:8]=[N:9][CH:10]=1)([CH3:3])[CH3:2].[CH3:12][C@H:13]([OH:17])[CH2:14][CH:15]=[CH2:16].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(#N)C>[CH:1]([O:4][C:5]1[CH:6]=[C:7](/[CH:16]=[CH:15]/[CH2:14][C@@H:13]([OH:17])[CH3:12])[CH:8]=[N:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cncc(Br)c1
Reactant: C=CC[C@H](C)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)Oc1cncc(/C=C/C[C@H](C)O)c1
Temperature: 25 °C
Yield: 60.7 %

Procedure:
A mixture of 5-isopropoxy-3-bromopyridine (12.56 g, 58.13 mmol), (2S)-4-penten-2-ol (5.00 g, 58.05 mmol), palladium(II) acetate (130 mg, 0.58 mmol), tri-o-tolylphosphine (706 mg, 2.32 mmol), triethylamine (35 mL, 252 mmol) and acetonitrile (35 mL) were heated in a sealed glass tube at 130–140° C. for 8 h. The reaction mixture was cooled to ambient temperature. The solvent was removed under reduced pressure on a rotary evaporator. Water (50 mL) was added and the mixture was extracted with chloroform (3×50 mL). The combined chloroform extracts were dried (K2CO3), filtered, and concentrated by rotary evaporation. The crude product was purified by column chromatography over silica gel, eluting with chloroform-acetone (95:5, v/v). Selected fractions were combined and concentrated by rotary evaporation, producing 7.80 g (60.7%) of a pale-yellow oil.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:11]=1[CH2:12][NH:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]([CH2:21][C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[C:25]#[N:26])[C:16](=[O:30])[CH:15]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:15]1[C:16](=[O:30])[N:17]([CH2:21][C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[C:25]#[N:26])[C:18]([CH3:20])=[CH:19][C:14]=1[NH:13][CH2:12][C:11]1[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:10]=1[F:9]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(NCc2ccc(F)cc2F)cc(=O)n1Cc1cccc(C#N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(NCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1cccc(C#N)c1
Reaction time: 2 h
Yield: 19.2 %

Procedure:
N-Chloro succinimide (36 mg, 0.27 mmol) was added to a solution of the product of Step 5 (0.125 g, 0.26 mmol) in methylene chloride (10 mL). After stirring at 25 C for 2 h, the reaction was complete by LC-MS. The reaction mixture was poured into saturated aqueous NaHCO3. The aqueous mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried with anhydrous Na2SO4, and concentrated in vacuo. The residue was triturated with acetonitrile to give the title compound as a tan solid (20 mg, 13%). 1H NMR (400 MHz, CD3OD) δ 7.61 (d, J=8.4 Hz, 1H), 7.49 (m, 2H), 7.40 (d, J=8.4 Hz, 1H), 7.33 (q, J=8.4 and 14.8 Hz, 1H), 6.94 (m, 2H), 6.00 (s, 1H), 5.34 (s, 2H), 4.56 (s, 2H), 2.21 (s, 3H) ppm. 19F NMR (400 MHz, CD3OD) δ −114.00 (1F), −116.89 (1F) ppm. LC/MS, tr=5.49 minutes (5 to 95% acetonitrile/water over 8 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 400 (M+H).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:24](O)=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2N=CC=CC=2N=N1.[F:60][C:61]([F:92])([F:91])[CH2:62][CH:63]([NH:69][CH2:70][C:71]1[C:86]([O:87][CH3:88])=[CH:85][C:74]([O:75][CH2:76][CH2:77][CH2:78][CH2:79][C:80]([O:82][CH2:83][CH3:84])=[O:81])=[CH:73][C:72]=1[O:89][CH3:90])[CH:64]([O:67][CH3:68])[O:65][CH3:66].C(N(C(C)C)CC)(C)C>ClCCl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:24]([N:69]([CH2:70][C:71]3[C:72]([O:89][CH3:90])=[CH:73][C:74]([O:75][CH2:76][CH2:77][CH2:78][CH2:79][C:80]([O:82][CH2:83][CH3:84])=[O:81])=[CH:85][C:86]=3[O:87][CH3:88])[CH:63]([CH:64]([O:65][CH3:66])[O:67][CH3:68])[CH2:62][C:61]([F:91])([F:92])[F:60])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CCOC(=O)CCCCOc1cc(OC)c(CNC(CC(F)(F)F)C(OC)OC)c(OC)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCCOc1cc(OC)c(CN(C(=O)[C@H](CC(C)C)NC(=O)OCC2c3ccccc3-c3ccccc32)C(CC(F)(F)F)C(OC)OC)c(OC)c1
Yield: 79.6 %

Procedure:
A solution of 6.6 g (18.7 mmol) of N-[(9-fluorenyl)-methoxycarbonyl]-L-leucine and 9.7 g (18.7 mmol) of 7-azabenzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate in 50 ml of anhydrous dichloromethane was stirred at room temperature for 15 minutes. To this mixture were then added 6.0 g (12.4 mmol) of ethyl 5-[4-[[3,3,3-trifluoro-1(RS)-(dimethoxymethyl)propylamino]methyl]-3,5-dimethoxyphenoxy]valerate and 4.3 ml of (24.8 mmol) diisopropylethylamine. After stirring overnight at 250C the mixture was diluted with dichloromethane and washed in sequence with water, 10% citric acid solution, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, then dried over anhydrous magnesium sulphate andfiltered. The solvent was removed by evaporation and the residue was chromatographed on silica gel using 30% ethyl acetate in hexane for the elution. There were obtained 8.06 g of ethyl 5-[4-[[N-[N-[(9-fluorenyl)methoxycarbonyl]-L-leucyl]-N-[3,3,3-trifluoro-1(RS)-(dimethoxymethyl)propyl]amino]methyl]-3,5-dimethoxyphenoxy]valerate; MS: m/e 839.4 [M+Na], 855.3 [M+K].
Reaction SMILES: [NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1.[N+:27]([C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1)([O-:29])=[O:28]>>[NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:34][C:33]3[CH:36]=[CH:37][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN)CC1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2ccc([N+](=O)[O-])cc2)CC1
Yield: 85 %

Procedure:
4-Amino-N-(1-(5-aminopentyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (2 g) as starting compound and 4-nitrobenzaldehyde (0.87 g) were reacted and treated in the same manner as in Example 121 to give 2.3 g of 4-amino-5-chloro-2-methoxy-N-((1-(5-(4-nitrobenzylamino)pentyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: C[Si](C)(C)CC[O:5][C:6]1[CH:13]=[N:12][CH:11]=[CH:10][C:7]=1[C:8]#[N:9].[F-].C([N+](CCCC)(CCC)CCCC)CCC>C1COCC1>[OH:5][C:6]1[CH:13]=[N:12][CH:11]=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: C[Si](C)(C)CCOc1cnccc1C#N
Agent: CCCC[N+](CCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: N#Cc1ccncc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
A flask was charged with 3-(2-(trimethylsilyl)ethoxy)isonicotinonitrile (1.30 g, 5.90 mmol), THF (5 mL) and N,N-dibutyl-N-propylbutan-1-aminium fluoride (11.8 mL, 11.8 mmol) in THF was added. The reaction mixture was stirred at ambient temperature for 1 hour and then concentrated. The crude product was purified by silica gel chromatography, eluting with DCM and 5% methanol in DCM to give the desired product (0.7 g, 99% yield) as dark brown oil.