Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[SH:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(OCC)(=O)C>CN(C)C=O>[CH:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[S:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:5]
Reactant: CCOC(=O)CCCS
Reactant: O=Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCSc1ccccc1C=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 67 %

Procedure:
Under an argon atmosphere, 2-fluorobenzaldehyde (5 g) was dissolved in 15 ml of dimethylformamide and potassium carbonate (8.35 g) was added. Ethyl 4-mercaptobutyrate (8.6 ml) was added at room temperature and was stirred at room temperature for 14 hours. After the addition of 100 ml of ethyl acetate, the mixture was washed with 50 ml of water twice, 50 ml of a 0.5N hydrochloric acid, and 50 ml of water three times. After drying with anhydrous sodium sulfate, the mixture was concentrated. The concentrated matter was subjected to silica gel chromatography (hexane/ethyl acetate=4/1) purification. The resulting effective fractions were concentrated to yield ethyl 4-(2-formylphenylthio)butyrate (6.86 g, Yield 67%).
Reaction SMILES: [CH2:1]([N:5]([CH2:21][CH2:22][CH2:23][CH3:24])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[C:8]([O:19][CH3:20])[CH:7]=1)[CH2:2][CH2:3][CH3:4].C([Li])CCC.CN(C)[CH:32]=[O:33]>O1CCCC1>[CH2:21]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:15][C:16]([CH:32]=[O:33])=[CH:17][CH:18]=2)=[C:8]([O:19][CH3:20])[CH:7]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCN(CCCC)c1ccc(C=Cc2cccs2)c(OC)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(OC)c1
Temperature: -71.5 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
In a stream of argon, in 25 ml of tetrahydrofuran was dissolved 1.5 g (4.37 mmol) of dibutyl[3-methoxy-4-[2-(thiophene-2-yl)vinyl]phenyl]amine, and 4.1 ml of n-butyllithium (1.6 mol solution in hexane) (6.56 mmol) was added dropwise thereto under cooling at −70 to −73° C. After the mixture was stirred for 1 hour, 0.43 ml (5.54 mmol) of N,N-dimethylformamide was added dropwise. After the reaction mixture was stirred for 1 hour, the bath was removed and the temperature was allowed to rise. To this mixture, 10 ml of water was added dropwise. After the reaction mixture was poured into water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residual liquid was dissolved in 200 ml of ether and 70 mg of iodine pieces were added thereto. After stirred at room temperature, the mixture was washed with a 5% sodium bisulfite solution and then with a saturated saline solution. After drying over anhydrous sodium sulfate and concentration were performed, the residue was purified by silica gel column chromatography to give 1.27 g of a reddish orange crystal (yield: 79.2%).
Reaction SMILES: [ClH:1].CC([CH:6]1[CH2:11][CH:10]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([N:27]3[CH:31]=[CH:30][N:29]=[CH:28]3)[CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:17][CH:16]=2)=[O:13])[CH2:9][CH2:8][N:7]1C([O-])=O)(C)C.[OH-].[Na+]>CCOC(C)=O>[ClH:1].[CH2:25]([CH:22]([CH2:23][CH3:24])[CH:21]([C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:12]([CH:10]2[CH2:9][CH2:8][NH:7][CH2:6][CH2:11]2)=[O:13])=[CH:16][CH:17]=1)[N:27]1[CH:31]=[CH:30][N:29]=[CH:28]1)[CH3:26]
Reactant: CCC(CC)C(c1ccc(NC(=O)C2CCN(C(=O)[O-])C(C(C)(C)C)C2)cc1)n1ccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCC(CC)C(c1ccc(NC(=O)C2CCNCC2)cc1)n1ccnc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
HCl conc. (3.6 ml) was added at RT to a mixture of (±)-1,1-dimethylethyl4-[[[4-[2-ethyl-1-(1H-imidazol-1-yl)butyl]phenyl]amino]carbonyl]-1-piperidinecarboxylate (0.0032 mol) in EtOAc (30 ml). The mixture was stirred at RT for 4 hours, then basified with a concentrated NaOH solution and extracted with EtOAc and then CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue (1 g) was converted into the hydrochloric acid salt (1:1) in 2-propanol. The precipitate was filtered off and dried, yielding 0.85 g (68%) (±)—N-[4-[2-ethyl-1-(1H-imidazol-1-yl)butyl]-phenyl]-4-piperidinecarboxamide monohydrochloride (compound 57).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[N:10]([O-])=O.[Na+].[H+].[B-:15]([F:19])([F:18])([F:17])[F:16]>O>[F:16][B-:15]([F:19])([F:18])[F:17].[Br:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[N+:5]#[N:10]
Reactant: Nc1ccccc1Br
Reactant: O=N[O-]
Agent: Cl
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: O
Product: N#[N+]c1ccccc1Br
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 47.5 %

Procedure:
9.5 mL of concentrated hydrochloric acid, 65 mL of pure water, and 6.0 g (35 mmol) of 2-bromoaniline were added to a 200-mL four-necked flask, and they were then dissolved by heating. The obtained solution was cooled to 0° C. Thereafter, an aqueous solution of 2.46 g (35.1 mmol) of sodium nitrite that had previously been dissolved in 7.5 mL of pure water was added dropwise thereto over approximately 10 minutes. The reaction solution that was first in a gruel-like state was converted to a light yellow transparent liquid by stirring it for 30 minutes. Subsequently, 12.5 g (59.8 mmol) of a 42-mass-% HBF4 aqueous solution was added dropwise thereto over approximately 5 minutes. As a result, light yellow crystals were immediately precipitated. The reaction solution was stirred for 30 minutes, and the crystals were then filtrated with a glass filter. The resultant was washed with 30 mL of pure water, and was then washed with a mixed solution of 8 mL of methanol and 32 mL of ether. Thereafter, the resultant was dried under a reduced pressure, so as to obtain 4.5 g of 2-bromobenzenediazonium tetrafluoroborate in the form of white crystals (yield: 48%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](OC)([O:9]C)[CH3:8])=[N:4][CH:3]=1.FC(F)(F)C(O)=O.O>ClCCl>[Cl:1][C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[N:4][CH:3]=1
Reactant: COC(C)(OC)c1ncc(Cl)s1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1ncc(Cl)s1
Reaction time: 8 h

Procedure:
To a solution of 5-Chloro-2-(1,1-dimethoxy-ethyl)-thiazole (3.5 g) in dichloromethane (20 ml) was added trifluoroacetic acid (30 ml) and water (1 ml). The resulting mixture was stirred overnight at ambient, concentrated to an oil, diluted with diethyl ether, washed with 10% sodium bicarbonate, water and brine, dried (magnesium sulfate), filtered and concentrated to afford the sub-titled compound as a yellow solid in quantitative yield (2.6 g); 1H NMR (400 Mhz, CDCl3) δ 2.7 (3H, s), 7.8 (1H, s).
Reaction SMILES: [Cl-].[NH4+].[CH:3]1[C:20]2[C:19]3[C:10](=[C:11]([C:21]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:22])[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[N:18]=3)[CH:9]=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1>C(O)C.C(OCC)(=O)C.[Zn]>[CH:3]1[C:20]2[C:19]3[NH:18][C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[CH:11]([C:21]([O:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[O:22])[C:10]=3[CH:9]=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Oc1ccccc1)c1c2ccccc2nc2c1ccc1ccccc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(Oc1ccccc1)C1c2ccccc2Nc2c1ccc1ccccc21
Reaction time: 2 h

Procedure:
Ammonium chloride (10 g) and 10 g of zinc were added to an Ar-purged suspension of 1.0 g of the ester from step (b) in ethanol. The mixture was stirred for 2 h, filtered and the solids washed with CH2Cl2. The combined solutions were evaporated to dryness producing a white solid which was dissolved in ethyl acetate and washed with 3×25 mL of water. The product was purified by chromatography using 10% ethyl acetate/hexane. 1H NMR (CDCl3) δ 5.48 (s, 1H), 5.69-7.27 (m, 9H), 7.41-7.55 (m, 5H), 7.83-7.88 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])[CH2:5]2.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:23][C:24]1[C:28]([CH3:30])([CH3:29])[O:27][C:26](=O)[CH:25]=1>C1COCC1>[Br:23][C:24]1[C:28]([CH3:30])([CH3:29])[O:27]/[C:26](=[C:5]2/[C:6](=[O:12])[NH:7][C:8]3[C:4]/2=[CH:3][C:2]([F:1])=[C:10]([F:11])[CH:9]=3)/[CH:25]=1
Reactant: O=C1Cc2cc(F)c(F)cc2N1
Reactant: CC1(C)OC(=O)C=C1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)c(F)cc32)C=C1Br
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5,6-difluorooxindole (450 mg, 2.66 mmol) in THF (20 mL) at 0° C., was added 1M LiHMDS in THF (5.3 mL, 5.3 mmol). The reaction mixture was stirred at 0° C. for 10 minutes. 4-bromo-5,5-dimethyl-5H-furan-2-one (340 mg, 1.78 mmol) was then added. The reaction mixture was stirred at 0° C. for 30 min., and then at room temperature for an additional 30 min and quenched with 2.5M aqueous H2SO4 (3 mL). The resulting mixture was stirred at room temperature for 16 hours and poured into water (100 mL). The precipitates were filtered, washed with water and dried in vacuo to yield (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-5,6-difluoro-1,3-dihydro-2H-indol-2-one as yellow solid. Yield: 547 mg, 90%.
Reaction SMILES: [C:1]1(=[O:8])[O:7][CH:4]([CH2:5][CH3:6])[CH2:3][CH2:2]1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1>C(OCC)(=O)C>[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:16][C:1](=[O:8])[CH2:2][CH2:3][CH:4]([OH:7])[CH2:5][CH3:6])=[CH:13][CH:12]=1
Reactant: COc1ccc(CN)cc1
Reactant: CCC1CCC(=O)O1
Solvent: CCOC(C)=O
Product: CCC(O)CCC(=O)NCc1ccc(OC)cc1
Temperature: 82.5 °C
Reaction time: 16 h
Yield: 72.8 %

Procedure:
Gamma-caprolactone (28.745 Kg, 251.8 moles) and 4-methoxybenzylamine (38.0 Kg, 277 moles) were placed in a 100 gallon glass lined tank. The solution was heated to 80-85° C. and held at that temperature for 16 hours. TLC on silica gel plates showed the reaction was complete. The TLC system comprised: ethyl acetate with detection at 254 nm. Ethyl acetate (18 gal, 68 L) was slowly charged to the reaction pot after cooling to 60° C. Hexanes (a total of 18 gal, 68 L) were added until a haze was achieved. After ½ hour, to allow crystallization to start, the remainder of the hexanes was added. The slurry was cooled to 25° C. and granulated for 3 hours. The solid was collected by filtration and washed with a 1:1 mixture of ethyl acetate and hexanes. The wet cake was vacuum dried with no additional heat to produce 46.05 Kg (72.8%) of the desired amide; mp 81-82° C.
Reaction SMILES: [C:1]([C:3]1([OH:9])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[CH:2].[C:10]([C:13]1[CH:14]=[C:15](/[CH:18]=[C:19]2\[C:20](=[O:30])[NH:21][C:22]3[C:27]\2=[C:26](I)[C:25]([F:29])=[CH:24][CH:23]=3)[NH:16][CH:17]=1)(=[O:12])[CH3:11]>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[C:10]([C:13]1[CH:14]=[C:15](/[CH:18]=[C:19]2\[C:20](=[O:30])[NH:21][C:22]3[C:27]\2=[C:26]([C:2]#[C:1][C:3]2([OH:9])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[C:25]([F:29])=[CH:24][CH:23]=3)[NH:16][CH:17]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(I)c32)c1
Reactant: C#CC1(O)CCOCC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(C#CC4(O)CCOCC4)c32)c1

Procedure:
Using Method C above, 4-Ethynyl-tetrahydro-pyran-4-ol (0.16 g, 1.26 mmol) (Example 85A) was coupled with (Z)-3-[(4-acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one (0.2 g, 0.50 mmol) (Example 90B above) using (Ph3P)4Pd (58.4 mg) and CuI (9.6 mg) as catalyst in DMF (15 mL) and Et3N (15 mL) as solvent at 85° C. for 18 h. (Yield 102 mg, 52%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:28]=[CH:29][CH:30]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[CH:9]=2)[N:4]([S:31]([C:34]2[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH:3]=1.[CH2:41]([N:49]1[CH:53]=[C:52](B2OC(C)(C)C(C)(C)O2)[CH:51]=[N:50]1)[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:41]([N:49]1[CH:53]=[C:52]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([CH:28]=[CH:29][CH:30]=4)[CH2:14][CH:15]4[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20]4)[CH:9]=3)[N:4]([S:31]([C:34]3[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=3)(=[O:33])=[O:32])[CH:3]=2)[CH:51]=[N:50]1)[CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4cccc(CC5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc32)cc1
Reactant: CC1(C)OB(c2cnn(CCc3ccccc3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4cccc(CC5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc32)cc1
Yield: 84.9 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 4-(3-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzyl)piperidine-1-carboxylate (intermediate 66G) (100 mg, 0.148 mmol) was coupled with 1-phenethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 59) (67 mg, 0.223 mmol) using Pd(PPh3)2Cl2 (6 mg, 0.007 mmol) and sodium carbonate (40 mg, 0.372 mmol) in toluene/ethanol/water (5/2/1 ml) to afford 90 mg (84.1% yield) of the titled compound after column purification using 50% ethyl acetate in hexane as eluent. MS: m/z=659.8 (M+1) (de t-butyl).
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=1.[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:14]([N:16]([CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=1)[CH2:17][CH3:18])[CH3:15]
Reactant: CCNCC
Reactant: CCOC(=O)c1cccc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(CN(CC)CC)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 63.5 %

Procedure:
To a suspension of ethyl 6-(chloromethyl)picolinate (200 mg, 1.00 mmol) and KI (166 mg, 1.00 mmol) in DMF was added N,N-diethyl amine (73 mg, 1.00 mmol) and K2CO3 (304 mg, 2.20 mmol). The reaction mixture was stirred at rt for 5 h. LC-MS indicated the presence of product. The solvent was evaporated under reduced pressure and the residue was partitioned between EtOAc (20 mL) and water (20 mL). The organic layer was washed with water (15 mL) and dried over Na2SO4. The solvent was evaporated under reduced pressure to give ethyl 6-((diethylamino)methyl)picolinate (150 mg, 64%) as an oil. LC-MS (ESI) m/z 237 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:57][CH3:58])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][C:34]([OH:36])=O)[CH:16]=[CH:17][CH:18]=2)=[O:12])=[C:6]([C:37]2[CH:42]=[C:41]([C:43](=[O:56])[NH:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([C:52]([F:55])([F:54])[F:53])[CH:47]=3)[CH:40]=[CH:39][N:38]=2)[CH:5]=1)[CH3:2].[N:59]1([C:65]2[CH:70]=[CH:69][C:68]([OH:71])=[CH:67][CH:66]=2)[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([N:3]([CH2:57][CH3:58])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:12])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][C:34]([N:62]3[CH2:61][CH2:60][N:59]([C:65]4[CH:66]=[CH:67][C:68]([OH:71])=[CH:69][CH:70]=4)[CH2:64][CH2:63]3)=[O:36])[CH:14]=2)=[C:6]([C:37]2[CH:42]=[C:41]([CH:40]=[CH:39][N:38]=2)[C:43]([NH:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([C:52]([F:54])([F:53])[F:55])[CH:47]=2)=[O:56])[CH:5]=1)[CH3:2]
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(CCCOCCOCCOCCOCCC(=O)O)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)c1ccc(NC(=O)c2cccc(CCCOCCOCCOCCOCCC(=O)N3CCN(c4ccc(O)cc4)CC3)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reaction time: 0.5 h
Yield: 105.7 %

Procedure:
To a solution of 16-(3-(4-(diethylamino)-2-(4-(3-(trifluoromethyl)benzylcarbamoyl)pyridin-2-yl)phenylcarbamoyl)phenyl)-4,7,10,13-tetraoxahexadecan-1-oic acid (300 mg, 0.37 mmol), 4-(piperazin-1-yl)phenol (71 mg, 0.40 mmol) and DIPEA (142 mg, 1.1 mmol) in DMF (3 mL) was added HATU (160 mg, 0.42 mmol). After 30 minutes, the solvent was removed under vacuum and the residue was dissolved in DCM (50 mL). This was washed with water (4×25 mL), dried (Na2SO4) and concentrated to give the title compound (379 mg).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:16]1([P:22]2[C:27]([CH3:29])([CH3:28])[CH2:26][C:25](=O)[CH2:24][C:23]2([CH3:32])[CH3:31])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH2:2]1[CH2:1][O:4][C:25]2([CH2:26][C:27]([CH3:29])([CH3:28])[P:22]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:23]([CH3:32])([CH3:31])[CH2:24]2)[O:3]1
Reactant: OCCO
Reactant: CC1(C)CC(=O)CC(C)(C)P1c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(C)CC2(CC(C)(C)P1c1ccccc1)OCCO2
Yield: 78 %

Procedure:
A flask equipped with a Dean-Stark trap was charged with a mixture of 150 mls of ethylene glycol, 0.73 grams p-toluenesulfonic acid and 800 mls toluene and then purged with nitrogen for one hour. To this mixture, 10 grams of 1-phenyl-2,2,6,6-tetramethyl-4-phosphorinanone (0.04 mole) were added. The two phase system was heated to reflux and 26 mls of a water-ethylene glycol azeotrope were collected over a 20 hour period. The reaction mixture was washed with saturated sodium bicarbonate, water, dried over anhydrous potassium carbonate, the solvent removed in vacuo, and the residue distilled under reduced pressure to give 9.2 grams (78%) of a colorless liquid, bp 134°-140° C. (0.3 mm Hg).
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]2[C:8]3[C:17]4[C:12](=[CH:13][C:14](/[CH:18]=[CH:19]/[S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:16]=4)[N:11]=[CH:10][C:9]=3[N:24]=[C:6]2[CH2:5][O:4][CH2:3]1>[Pd].C(O)C>[CH3:1][C@@H:2]1[N:7]2[C:8]3[C:17]4[C:12](=[CH:13][C:14]([CH2:18][CH2:19][S:20]([CH3:23])(=[O:21])=[O:22])=[CH:15][CH:16]=4)[N:11]=[CH:10][C:9]=3[N:24]=[C:6]2[CH2:5][O:4][CH2:3]1
Reactant: C[C@H]1COCc2nc3cnc4cc(/C=C/S(C)(=O)=O)ccc4c3n21
Agent: [Pd]
Solvent: CCO
Product: C[C@H]1COCc2nc3cnc4cc(CCS(C)(=O)=O)ccc4c3n21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
A 250-mL, glass Parr bottle was charged with palladium on carbon (10%, 0.04 g) and 2 mL of ethanol. A solution of (11S)-11-methyl-3-[(E)-2-(methylsulfonyl)ethenyl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline (0.45 g, 1.31 mmol) dissolved in 125 mL of ethanol was then added. The reaction mixture was placed on Parr apparatus and shaken under H2 at 50 PSI (3.4×105 Pa) overnight at ambient temperature. The reaction mixture was then filtered through a pad of CELITE filter agent. The pad rinsed with ethanol and the combined filtrates were concentrated under reduced pressure to give 0.45 g of (11S)-11-methyl-3-[2-(methylsulfonyl)ethyl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([S:13]([CH3:16])(=[O:15])=[O:14])=[C:5]2O.CN(C)C1C=CC(C)=CC=1.P(Cl)(Cl)([Cl:30])=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([S:13]([CH3:16])(=[O:15])=[O:14])=[C:5]2[Cl:30]
Reactant: Cc1nc2ccc(Br)cc2c(O)c1S(C)(=O)=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: Cc1ccc(N(C)C)cc1
Product: Cc1nc2ccc(Br)cc2c(Cl)c1S(C)(=O)=O
Temperature: 20 °C
Reaction time: 6.5 h
Yield: 18 %

Procedure:
6-Bromo-3-methanesulfonyl-2-methyl-quinolin-4-ol (example C.1) (6 g, 19 mmol) and N,N-dimethyl-p-toluidine (5.5 mL, 38 mmol) were dissolved in toluene (60 mL) and heated under argon to reflux. The phosphorous oxychloride (1.9 mL, 20.9 mL) was added and heating at reflux continued for 6.5 h. The product precipitated spontaneously upon cooling to 20° C., the crystals were filtered off and washed with little toluene. One obtained 4.19 g (66%) of light brown crystals. Since the product is somewhat soluble in toluene, the mother liquor was extracted with 3 N HCl (2×), sat. NaCl (2×). The residue was purified by chromatography on silica gel in dichloromethane. One obtained 1.17 g (18%) of additional material. MS: m/z=333/335 (M).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([CH:18]3[C:27]([CH3:29])([CH3:28])[CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:30](O)=[O:31])[CH:24]=4)[NH:19]3)[CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:33][S:34]([NH2:37])(=[O:36])=[O:35]>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([CH:18]3[C:27]([CH3:29])([CH3:28])[CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:30]([NH:37][S:34]([CH3:33])(=[O:36])=[O:35])=[O:31])[CH:24]=4)[NH:19]3)[CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2cc(F)cc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)cc1
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(-c2cc(F)cc(C3Nc4ccc(C(=O)NS(C)(=O)=O)cc4CC3(C)C)c2)cc1
Yield: 30.9 %

Procedure:
A mixture of 2-(4′-tert-butyl-5-fluoro-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (30 mg, 0.07 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (20 mg, 0.10 mmol), 4-dimethylaminopyridine (12.2 mg, 0.10 mmol), methane sulfonamide (20 mg, 0.21 mmol) in dichloromethane (10 mL) was refluxed for 12 hours. Removal of the solvent afforded an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-[2-(4′-tert-butyl-5-fluoro-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (11 mg, 30%) as a light yellow solid: LC/MS m/e calcd for C29H33FN2O3S (M+H)+: 509.66, observed: 509.2.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[S:23][C:22]([CH2:24][N:25]4[CH2:28][CH:27]([C:29]([O:31]CC)=[O:30])[CH2:26]4)=[CH:21][CH:20]=3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[S:23][C:22]([CH2:24][N:25]4[CH2:26][CH:27]([C:29]([OH:31])=[O:30])[CH2:28]4)=[CH:21][CH:20]=3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CN(Cc2ccc(-c3noc(-c4ccc(Oc5ccccc5)cc4)n3)s2)C1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1CN(Cc2ccc(-c3noc(-c4ccc(Oc5ccccc5)cc4)n3)s2)C1
Yield: 79.6 %

Procedure:
The title compound (69 mg) was synthesized in a yield of 80% as a white crystalline solid by conducting the similar reaction to that mentioned in Example 3 (3e) using ethyl 1-({5-[5-(4-phenoxyphenyl)-1,2,4-oxadiazol-3-yl]-2-thienyl}methyl)azetidine-3-carboxylate (90 mg, 0.20 mmol) that was obtained in Example 5 (5b) and a 1N aqueous solution of sodium hydroxide (0.60 ml, 0.60 mmol).