Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.C1(NC(C)C)CCCCC1.[C:16]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH3:17].[Cl:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28]Cl>C1COCC1.Cl>[Cl:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:17][C:16]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: CC(=O)OC(C)(C)C
Reactant: ClC/C=C\CCl
Agent: CC(C)NC1CCCCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC/C=C\CCl
Reaction time: 0.08 h

Procedure:
n-BuLi (1.6M, 6 ml) was added over 5 min. to a stirred, cooled (-10°) solution of cyclohexylisopropylamine (1.64 ml) in dry THF (10 ml) under nitrogen. After 5 min., the solution was cooled to -78° and 15 min. later tert-butyl acetate (1.35 ml) was added over 5 min. After 20 min. cis-1,4-dichloro-2-butene (4 ml) was added and the mixture was allowed to warm to 10° over 4 h. The mixture was diluted with 1N HCl (25 ml) and extracted with ER (2×30 ml). The combined extracts were successively washed with 1N HCl (20 ml), brine (20 ml) and 8% NaHCO3 solution (20 ml) then dried and evaporated. The excess of dichloromethane was removed in vacuo and the residue was purified by chromatography (A) using PE, followed by 1:1 CH2Cl2 -PE increasing to CH2Cl2 as eluant to give the title compound as an oil (0.66 g)
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([OH:10])[N:5]=[C:4]([CH3:11])[CH:3]=1.O.NN>C(O)C.[Ni]>[NH2:1][C:2]1[CH:3]=[C:4]([CH3:11])[N:5]=[C:6]([OH:10])[C:7]=1[CH2:8][NH2:9]
Reactant: Cc1cc(N)c(C#N)c(O)n1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1cc(N)c(CN)c(O)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 54.4 %

Procedure:
4-amino-2-hydroxy-6-methylnicotinonitrile (350 mg, 2.4 mmol) was dissolved in ethanol (15 mL) and warmed to 50° C. before it was treated with raney nickel (1 ml slurry in water) followed by addition of hydrazine monohydrate (2 ml). The resulting mixture was allowed to stir at 50° C. for 2 hours. The cooled reaction mixture was filtered through celite, rinsed with methanol. The filtrate was concentrated in vacuo to provide crude product which was purified by silica gel column chromatography with dichloromethane/methanol=10:1 to afford 4-amino-3-(aminomethyl)-6-methylpyridin-2-ol (200 mg, 56% yield) as a yellow solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[N:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][N:14]=3)[CH2:9][CH2:8]2)[C:3]1=[O:21].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(O[C:74]1[CH:83]=[C:82]2[C:77]([C:78](=[O:84])[CH2:79][CH2:80][O:81]2)=[CH:76][C:75]=1[Cl:85])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:85][C:75]1[CH:76]=[C:77]2[C:82](=[CH:83][C:74]=1[NH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH:7]3[CH2:12][CH2:11][N:10]([C:13]4[N:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][N:14]=4)[CH2:9][CH2:8]3)[C:3]1=[O:21])[O:81][CH2:80][CH2:79][C:78]2=[O:84]
Reactant: CCc1cnc(N2CCC(N3CC[C@H](N)C3=O)CC2)nc1
Reactant: O=C1CCOc2cc(OS(=O)(=O)C(F)(F)F)c(Cl)cc21
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCc1cnc(N2CCC(N3CC[C@H](Nc4cc5c(cc4Cl)C(=O)CCO5)C3=O)CC2)nc1
Temperature: 25 °C
Yield: 5 %

Procedure:
(S)-3-Amino-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one (Example 34, Steps A-D; 120 mg, 0.42 mmol) was dissolved in toluene (3 mL). 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (26 mg, 0.042 mmol), 6-chloro-4-oxochroman-7-yl trifluoromethanesulfonate (206 mg, 0.62 mmol) and Cs2CO3 (162 mg, 0.498 mmol) were added and the reaction was bubbled through with nitrogen for 5 minutes. Pd2 dba3 (19.0 mg, 0.021 mmol) was added and the reaction plunged into 95° C. oil bath overnight. The reaction was cooled to ambient temperature, partitioned between water and EtOAc, dried over Na2SO4, filtered and concentrated. The residue was purified over silica gel (75 to 100% EtOAc in hexanes) to afford a mixture. The mixture was further purified by reverse phase chromatography (25 to 95% ACN in water) to afford (S)-3-(6-chloro-4-oxochroman-7-ylamino)-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one (10 mg, 0.022 mmol, 5% yield. Mass spectrum (apci) m/z=470.3 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][CH3:25])[CH:6]=1.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[CH2:22][N:23]([C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][CH3:25])[CH:6]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1
Product: CCN(Cc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1)C(=O)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 15, Step 7, using the following starting materials: [3-(2-ethylaminomethyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester and benzoyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH3:21][S:22]([O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33]O)=[CH:28][CH:27]=1)(=[O:24])=[O:23].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3](=[O:20])[CH:4]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:33][CH2:32][C:29]2[CH:28]=[CH:27][C:26]([O:25][S:22]([CH3:21])(=[O:23])=[O:24])=[CH:31][CH:30]=2)=[CH:8][CH:7]=1
Reactant: CS(=O)(=O)Oc1ccc(CCO)cc1
Reactant: CCCCCCOC(Cc1ccc(O)cc1)C(=O)OC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCOC(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)OC
Reaction time: 18 h
Yield: 66.9 %

Procedure:
2-Hexyloxy-3-(4-hydroxyphenyl)propanoic acid methyl ester (0.33 g, 1.19 mmole) and 2-(4-methanesulfonyloxyphenyl)ethanol (0.2578 g; 1.19 mmole) was dissolved in dichloromethane (5 ml) under argon. Azodicarbonyl dipiperidine (0.451 g; 1.789 mmole) was added followed by addition of triphenylphosphine (0.375 g; 1.423 mmole). The reaction mixture was stirred at room temperature and after 2 hours more dichloromethane (2 ml) was added. The reaction mixture was stirred for another 18 hours and then filtered. The filtrate was washed with water, sodium hydrogen carbonate solution, diluted potassium hydrogen sulfate solution and brine, dried with sodium sulfate and evaporated. Chromatography of the residue on silica gel using heptane:ethyl acetat (2:1 to 1:1) as eluant gave 0.381 g (67% yield) of 2-hexyloxy-3-[4-(2-{4-methanesulfonyloxyphenyl}-ethoxy)phenyl]propanoic acid methyl ester.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:21])[CH3:20])[C:13]([O:15]CC)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[N:30]=[C:31]=[O:32]>>[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[NH:30][C:31]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:20])[CH3:21])[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])=[O:32]
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CO)c1)OC(C)C
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1COC(=O)Nc1ccc(Cl)cc1Cl

Procedure:
Using ethyl 3-[3-(hydroxymethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and 2,4-dichlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:4][CH:3]=1.F[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1.[H-].[Na+]>O1CCCC1>[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(CCO)n1
Reactant: N#Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc(CCOc2ccc(C#N)cc2)n1
Temperature: 0 °C

Procedure:
To a mixture of 6-methyl-2-pyridineethanol (97.2 g), p-fluorobenzonitrile (85.8 g) and dry tetrahydrofuran (600 ml) was added 60% sodium hydride in oil (29.0 g) in small portions with ice-cooling and stirring and the mixture was further stirred for 2 hours. The reaction mixture was poured in ice-water and extracted with ethyl ether. The ethyl ether layer was washed with water, dried (MgSO4) and concentrated, and the residue was crystallized from hexane to give 4-[2-(6-methyl-2-pyridyl)ethoxy]benzonitrile. Yield: 85.9 g (50.1%); m.p.: 66°-67° C.
Reaction SMILES: N(OCCC(C)C)=O.[CH2:9]([O:16][C:17]1[CH:44]=[CH:43][C:20]([O:21][C:22]2[CH:28]=[C:27]([N:29]3[C:34](=[O:35])[CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[N:31]([CH3:40])[C:30]3=[O:41])[C:26]([F:42])=[CH:25][C:23]=2N)=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[ClH:45]>[Cu]Cl.[Cu](Cl)Cl.C(#N)C>[Cl:45][C:23]1[CH:25]=[C:26]([F:42])[C:27]([N:29]2[C:34](=[O:35])[CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[N:31]([CH3:40])[C:30]2=[O:41])=[CH:28][C:22]=1[O:21][C:20]1[CH:43]=[CH:44][C:17]([O:16][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:18][CH:19]=1
Reactant: Cl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccc(OCc4ccccc4)cc3)c(N)cc2F)c1=O
Agent: Cl[Cu]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccc(OCc4ccccc4)cc3)c(Cl)cc2F)c1=O
Reaction time: 1 h

Procedure:
0.46 g of isoamyl nitrite was added dropwise to a mixture of 1.0 g of 2-(4-benzyloxyphenoxy)-5-fluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]aniline, 0.38 g of copper (I) chloride, 0.78 g of copper (II) chloride, and 14 ml of acetonitrile at room temperature, and the mixture was stirred for 1 hour. This reaction solution was poured into 2% hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.73 g of ([4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]methyl)benzene.
Reaction SMILES: [CH:1]1([CH:4]([NH:8][CH2:9][C:10]2[C:18]3[C:17]([C:19]([O:21]C)=O)=[CH:16][CH:15]=[N:14][C:13]=3[N:12](C(OC(C)(C)C)=O)[CH:11]=2)[CH2:5][CH2:6][OH:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CO>[CH:1]1([CH:4]([N:8]2[CH2:9][C:10]3=[CH:11][NH:12][C:13]4[C:18]3=[C:17]([CH:16]=[CH:15][N:14]=4)[C:19]2=[O:21])[CH2:5][CH2:6][OH:7])[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccnc2c1c(CNC(CCO)C1CC1)cn2C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Product: O=C1c2ccnc3[nH]cc(c23)CN1C(CCO)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.1 %

Procedure:
1-tert-Butyl 4-methyl 3-((1-cyclopropyl-3-hydroxypropylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylate (50 mg, 0.12 mmol) was stirred in MeOH (3 mL) with 1N NaOH (1 mL) at rt for 16 h. The reaction was neutralized with 1N HCl and concentrated in vacuo. The residue was dissolved in DMF (3 mL). HATU (47 mg, 0.12 mmol) was added, and the reaction stirred at room temperature for 2 h. The solution was concentrated in vacuo and purified by preparative HPLC eluting with a gradient of 15% to 70% Solvent B in Solvent A to give 16 mg of the title compound as an off-white solid. 1H NMR (400 MHz, CD3OD) δ 8.34 (d, 1H, J=4.8 Hz), 7.35 (d, 1H, J=4.8 Hz), 7.28 (s, 1H), 5.10 (AB q, 2H, J=76.4, 16.8 Hz), 4.08-4.20 (m, 1H), 3.59 (t, 2H, J=6.4 Hz), 2.02-2.14 (m, 2H), 1.17-1.30 (m, 1H), 0.73-0.79 (m, 1H), 0.42-0.54 (m, 2H), 0.24-0.33 (m, 1H). [M+H] found 272.
Reaction SMILES: [Si]([O:8][C:9]1[C:14]([CH2:15][CH2:16][CH3:17])=[CH:13][C:12]([CH2:18][CH2:19][OH:20])=[CH:11][C:10]=1[CH2:21][CH2:22][CH3:23])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:21]([C:10]1[CH:11]=[C:12]([CH2:18][CH2:19][OH:20])[CH:13]=[C:14]([CH2:15][CH2:16][CH3:17])[C:9]=1[OH:8])[CH2:22][CH3:23]
Reactant: CCCc1cc(CCO)cc(CCC)c1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCc1cc(CCO)cc(CCC)c1O
Reaction time: 0.25 h
Yield: 170.6 %

Procedure:
To a solution of 1.0 g (2.98 mmol) of the product of Step C in 3.0 mL of THF was added 3.57 mL (3.57 mmol) of 1.0N solution of tetrabutylammonium fluoride in THF. After 15 minutes TLC indicated that the reaction was complete. The reaction mixture was concentrated and then purified by flash chromatography (silica gel, hexane/ethyl acetate 3:1) to give 1.13 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N+:23]([O-])=O)[CH:21]=2)[N:16]([CH3:26])[CH:15]=1)[C:6]([O:8][CH3:9])=[O:7]>O1CCCC1.[Pd]>[NH2:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:26])[CH:15]=[C:14]2[CH2:13][C:12]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc([N+](=O)[O-])cc23)c(OC)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc(N)cc23)c(OC)c1
Yield: 109.2 %

Procedure:
A solution of methyl 3-methoxy-4-(1-methyl-5-nitroindol-3-ylmethyl)benzoate (1.5 grams) in 50 mL of tetrahydrofuran was hydrogenated at 40 p.s.i. in the presence of 10% palladium-on-carbon (0.3 grams) for 3 hours. The reaction was filtered and the filtrate evaporated to give 1.5 grams of title compound. NMR (CDCl3) δ:3.35, (broad s, 2H), 3.65 (s, 3H), 3.95 (s, 3H), 4.05 (s, 2H), 6.85 (m, 3H), 7.10 (m, 2H), 7.50 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26]>CC(CC(C)C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:11][CH:10]=2)=[O:16])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)Br
Reactant: O=C(c1ccc(O)cc1)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)C(C)Oc1ccc(C(=O)c2ccc(Cl)cc2)cc1

Procedure:
0.75 mole (175 g) of 4'-chloro-4-hydroxy-benzophenone, 1.5 l of methylisobutylketone, 0.975 mole (134 g) of K2CO3 and 0.8 mole (145 g) of ethyl 2-bromopropionate are placed in a 2-liter flask. The mixture is heated at reflux for 8 hours with vigorous agitation whereupon the reaction mixture is cooled and filtered on a Buchner funnel. The solvent is then evaporated under vacuum and the residue distilled; the desired ester is recovered at 198° to 201° C. under 0.1 mm of mercury. Yield 190 g (76%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][N:3]=1.CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>>[C:8]([C:7]1[C:2]([N:1]=[CH:12][N:13]([CH3:15])[CH3:14])=[N:3][CH:4]=[N:5][CH:6]=1)#[N:9]
Reactant: COC(OC)N(C)C
Reactant: N#Cc1cncnc1N
Product: CN(C)C=Nc1ncncc1C#N

Procedure:
The title compound was prepared from the reaction of 4-Amino-5-pyrimidinecarbonitrile (Aldrich) with N,N-dimethylformamide dimethyl acetal using the procedure from Example 156B to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([S:20](Cl)(=[O:22])=[O:21])=[CH:5]2.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C.O>ClCCl>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([S:20]([C:6]2[N:7]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)(=[O:22])=[O:21])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1cc2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3n2S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-chloro-1-phenylsulfonylindole-2-sulfonyl chloride (4.41 g) in dichloromethane (75 ml), tert-butyl-1-piperazine carboxylate (2.21 g) and triethylamine (1.65 ml) were added under ice cooling. The resulting mixture was stirred at room temperature for 3 hours. After completion of the reaction, water and dichloromethane were added to the reaction mixture. The organic layer so separated was dried over anhydrous sodium sulfate and then distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (ethyl acetate:n-hexane=1:20), whereby the title compound (3.63 g, 60%) was obtained as colorless crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]1[CH:19]=[C:18]([CH:20]=O)[N:17]=[CH:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.C(O)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:20][C:18]2[N:17]=[CH:16][NH:15][CH:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1c[nH]cn1
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: c1ccc(CN2CCC(NCc3c[nH]cn3)CC2)cc1
Yield: 86.3 %

Procedure:
To a solution of 1-benzyl-4-piperidinamine (3.4 g), imidazole-4-carbaldehyde (1.4 g) and acetic acid (1.7 ml) in 1,2-dichloroethane (100 ml) was added sodium triacetoxyborohydride (4.7 g), and mixed at room temperature for 15 hours. A 1 N aqueous sodium hydroxide solution was added to the reaction solution and pH of the aqueous layer was adjusted to about 12, and then extracted with chloroform (100 ml). The extract was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain the title compound as a yellow oil (3.4 g).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([NH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=1.C([O:21][CH2:22][C:23]1[CH:27]=[CH:26][O:25][C:24]=1[C:28](=[O:31])[CH2:29]Br)(=O)C.O>CN(C=O)C>[NH2:9][C:8]1[C:7]2[C:6](=[CH:5][C:4]([Cl:3])=[CH:11][CH:10]=2)[N:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:29]=1[C:28]([C:24]1[O:25][CH:26]=[CH:27][C:23]=1[CH2:22][OH:21])=[O:31]
Reactant: CC(=O)OCc1ccoc1C(=O)CBr
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)n1c(C(=O)c2occc2CO)c(N)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 15.8 %

Procedure:
To a suspension of sodium hydride (60% w/w dispersion in mineral oil, 390 mg, 8.8 mmol) in DMF (20 ml) was added a solution of 4-chloro-2-(ethoxycarbonylamino)benzonitrile (step 1, 2 g, 8.8 mmol) in DMF (5 ml) at 0° C. After stirring for 1 h at 0° C., 3-acetoxymethyl-2-(bromoacetyl)furan (step 1, 2.3 g, 8.8 mmol) was added and the resulting mixture was stirred at room temperature for an additional 6 h. The mixture was poured into water (100 ml), and extracted with ethyl acetate (300 ml). The organic extract was washed with saturated aqueous sodium bicarbonate (100 ml), brine (100 ml), and then dried (MgSO4) and concentrated. The residue was diluted with a mixture of ethanol (20 ml) and water (10 ml), and then potassium carbonate (ca. 2 g) was added. After stirring for 6 h, the mixture was poured into a saturated aqueous ammonium chloride (100 ml) and the mixture extracted with ethyl acetate (300 ml). The organic extract was washed with brine (100 ml), dried (MgSO4) and concentrated. The residue was purified by flash column chromatography eluting with ethyl acetate/hexane (2/1) to give 505 mg (16%) of the titled compound as yellow solids. Mass; M+=362
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:6][C:7]2[C:12]([C:13]=1[C:14]([OH:16])=O)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:2].C1C=C2N=NN(O)C2=CC=1.O.CN1CCOCC1.C(Cl)CCl.[C:45]1([C@@H:51]([NH2:54])[CH2:52][CH3:53])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C(Cl)Cl>[CH2:1]([S:3][C:4]1[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:6][C:7]2[C:12]([C:13]=1[C:14]([NH:54][C@H:51]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:52][CH3:53])=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:2]
Reactant: CC[C@H](N)c1ccccc1
Reactant: CCSc1c(-c2ccccc2)nc2ccccc2c1C(=O)O
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CCSc1c(-c2ccccc2)nc2ccccc2c1C(=O)N[C@@H](CC)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.9 %

Procedure:
A solution of 3-(ethylthio)-2-phenylquinoline-4-carboxylic acid (4) (269 mg, 0.87 mmol), HOBT hydrate (230 mg, 1.5 mmol), 4-methylmorpholine (164 μL, 1.5 mmol) in DCM (30 ml) was added EDC (289 mg, 1.5 mmol) at RT under N2. (S)-1-Phenyl propylamine (202 mg, 1.5 mmol) was then added and the reaction mixture stirred at RT for 12 h. All solvent was removed in vacuo and the residue was partitioned between ethyl acetate and 0.5 N HCl aqueous solution. The organic phase was washed with 10% aqueous sodium bicarbonate solution, brine, and dried over sodium sulfate. The organic solution was then concentrated in vacuo. The residue was purified by chromatography eluting with 15-25% ethyl acetate/hexane to give the title compound (315 mg, 85% yield) as a solid. 1H NMR (300 MHz, CDCl3) δ 0.96 (t, 3H), 1.22 (t, 3H), 2.0 (m, 2H), 2.40 (m, 2H), 5.28 (q, 1H), 7.20 (d, 2H), 7.34 (d, 2H), 7.39 (m, 2H), 7.78 (m, 2H), 7.84 (m, 2H), 8.00 (m, 1H), 8.11 (m, 2H), 8.15 (m, 2H). MS APCI, m/z=427 (M+1). LCMS: 2.82 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:20])[C:10]([O:12]N1C(=O)CCC1=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26]1[N:30]([C:31]2[CH:32]=[C:33]([CH2:36][NH2:37])[S:34][CH:35]=2)[N:29]=[C:28]([C:38]([F:41])([F:40])[F:39])[CH:27]=1.CCN(CC)CC.Cl>C(Cl)Cl.CN(C=O)C>[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26]1[N:30]([C:31]2[CH:32]=[C:33]([CH2:36][NH:37][C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:20])[S:34][CH:35]=2)[N:29]=[C:28]([C:38]([F:40])([F:41])[F:39])[CH:27]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: NCc1cc(-n2nc(C(F)(F)F)cc2-c2ccco2)cs1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1cc(-n2nc(C(F)(F)F)cc2-c2ccco2)cs1
Temperature: 25 °C
Reaction time: 36 h
Yield: 49 %

Procedure:
(S)-2,5-Dioxopyrrolidin-1-yl 2-(tert-butoxycarbonylamino)propanoate (130 mg, 0.45 mmol) was added to amine 5 (110 mg, 0.35 mmol) and Et3N (94.4 mg, 130 μL, 0.93 mmol) in DCM (2 mL) and DMF (0.2 mL) and the mixture was stirred at room temperature for 36 h. DCM was added followed by 1N HCl and the organic layer was separated and washed with H2O, then with saturated NaHCO3, dried over MgSO4, filtered and concentrated. The crude material was purified by chromatography (Biotage, 25+S column) eluting with 0-50% EtOAc/hexanes. Compound 6 was obtained in 49% yield as a white solid. LRMS (ESI): calc. 484.5; found 507.1 (MNa)+.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][CH2:21][CH2:22][O:23][Si](C(C)(C)C)(C)C)[C:9]([C:11]1[NH:12][C:13](=[O:19])[C:14]([Br:18])=[CH:15][C:16]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1.Cl>[CH2:1]([N:8]([CH2:20][CH2:21][CH2:22][OH:23])[C:9]([C:11]1[NH:12][C:13](=[O:19])[C:14]([Br:18])=[CH:15][C:16]=1[CH3:17])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(Br)c(=O)[nH]c1C(=O)N(CCCO[Si](C)(C)C(C)(C)C)Cc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(Br)c(=O)[nH]c1C(=O)N(CCCO)Cc1ccccc1
Reaction time: 16 h

Procedure:
To a stirred solution of N-benzyl-5-bromo-N-(3-((tert-butyldimethylsilyl)oxy) propyl)-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (3, 3.0 g, 6.0 mmol) in dioxane (20 mL), hydrogenchloride in dioxane (20 mL) was added at room temperature and the mixture was stirred for 16 h. After completion, the solvent was removed and the reaction was basified with aqueous sodium bicarbonate solution and extracted with 5% methanol/dichloromethane (3×200 mL). The organic layer was dried over sodium sulfate and solvent was removed under reduced pressure to get N-benzyl-5-bromo-N-(3-hydroxypropyl)-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (4) as brown liquid. Yield: 2.2 g, 95%; MS (ESI) m/z 381.22 [M−1]−.