Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][NH:13][CH2:12][C@@H:11]([C:15]([OH:17])=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH2:27]([O:34][C:35](ON1C(=O)CCC1=O)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[CH2:27]([O:34][C:35]([N:13]1[CH2:14][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10][C@H:11]([C:15]([OH:17])=[O:16])[CH2:12]1)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CNC[C@@H](C(=O)O)C1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of cis-(+/−)-5-(tert-butoxycarbonylamino)piperidine-3-carboxylic acid (1.0 eq.) in dichloromethane (0.2 M) was added DIEA(1.1 eq.), followed by N-(benzyloxycarbonyloxy)succinimide (1.0 eq.); the reaction was stirred at r.t. overnight. The solvent was removed under reduced pressure. To the crude was added EtOAc and 1N HCl. After extraction, the organic layer was washed with brine, dried and filtered, and concentrated to yield cis-(+/−)-1-(benzyloxycarbonyl)-5-(tert-butoxy-carbonylamino)piperidine-3-carboxylic acid (99% yield) LCMS (m/z): 379.2 (MH+); LC Rt=3.55 min.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].[CH3:10][C:11]([O:18][OH:19])([CH3:17])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14].C1(O)C=CC=CC=1>>[C:11]([O:18][O:19][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:1])[CH3:3])([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:17])[CH3:10]
Reactant: C=C(C)c1ccccc1
Reactant: CC(C)(C)CC(C)(C)OO
Solvent: Oc1ccccc1
Product: CC(C)(C)CC(C)(C)OOC(C)(C)c1ccccc1
Temperature: 25 °C
Yield: 81.5 %

Procedure:
Into the 200 ml jacketed reactor described in Example II were added 18.0 grams (0.152 m) alpha-methylstyrene, 18.4 grams (0.11 m) 87.6% 1,1,3,3-tetramethylbutyl hydroperoxide and 4.6 grams (0.048 m) phenol. The mixture was stirred to obtain a clear solution and the temperature was adjusted to 20° C. To this solution was added 1.7 grams (0.011 m) of t-cumyl chloride from the addition funnel over 5 minutes while holding the temperature at 20°-21° C. The reaction was stirred 5 minutes at 21°-22° C., warmed to 25° C. and stirred 1/2 hour at 25° C., 1/2 hour at 30° C., 1/2 hour at 35° C., 11/2 hours at 40° C. and finally 1/2 hour at 45° C. At this point the t-octyl hydroperoxide had been completely consumed and the reaction was terminated by adding 50 mls of water, stirring 5 minutes, adding 10 mls of 50% NaOH, stirring another 5 minutes and separating the aqueous caustic layer. The organic layer was successively washed with 50 mls 15% NaOH, saturated NaHCO3 solution, H2O, 15% NaHSO3 solution, saturated NaHCO3 solution and water. After drying over anhydrous sodium sulfate the crude product weighed 32.6 grams and contained 72.6% cumyl t-octyl peroxide for a corrected yield of 23.7 grams and a 81.5% yield.
Reaction SMILES: Br[CH:2]([C:4]1[S:8][C:7]([S:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[C:6]([N+:18]([O-:20])=[O:19])[CH:5]=1)[CH3:3].[CH3:21][NH:22][CH3:23]>>[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[S:9][C:7]1[S:8][C:4]([CH:2]([N:22]([CH3:23])[CH3:21])[CH3:3])=[CH:5][C:6]=1[N+:18]([O-:20])=[O:19]
Reactant: CC(Br)c1cc([N+](=O)[O-])c(Sc2ccc(Cl)cc2Cl)s1
Reactant: CNC
Product: CC(c1cc([N+](=O)[O-])c(Sc2ccc(Cl)cc2Cl)s1)N(C)C

Procedure:
Prepared according to the procedure described for example 28 from 5-(1-bromoethyl)-2-(2,4-dichlorophenyl)sulfanyl-3-nitro-thiophene (0.1 g, 0.25 mmol) and dimethylamine (0.19 mL, 0.8 mmol). The title compound was obtained as a solid (15 mg, 16% yield). 1H NMR (400 MHz, MeOD) δ: 7.92 (1H, m), 7.88 (1H, m), 7.85 (1H, m) 7.58 (1H, m), 4.74 (1H, q), 2.81 (3H, m), 2.78 (3H, m), 1.67 (3H, d). MS m/z: 376.9 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:18][N:19]([CH3:24])[S:20](Cl)(=[O:22])=[O:21]>C1COCC1>[CH3:18][N:19]([CH3:24])[S:20]([N:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)(=[O:22])=[O:21]
Reactant: C1CC2(CCN1)OCCO2
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)N1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a solution of 1,4-dioxa-8-azaspiro[4,5]decane (5.0 g, 35 mmol) in THF (25 mL) was added triethylamine (5 mL, 36 mmol) followed by N,N-dimethylsulfamoyl chloride (3.7 mL, 35 mmol). The resulting white mixture was stirred at room temperature for 1 h. The solids were removed by filtration and the solution was concentrated to give the title compound as a white solid (8.7 g, 100% yield). 1H NMR (300 MHz, CDCl3) δ: 3.93 (4H, s), 3.35 (4H, t, J=5.8 Hz), 2.78 (6H, s), 1.73 (4H, t, J=5.8 Hz). LCMS (M+H) calcd for C9H19N2O4S: 251.10; found: 251.24.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]([C:16]2[CH:17]=[C:18]([S:22]([C:25]3[CH:26]=[C:27]4[C:32](=[C:33]([CH3:35])[CH:34]=3)[N:31]=[CH:30][C:29]([C:36]([NH2:38])=[O:37])=[C:28]4[NH:39][C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[CH:41]=3)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=2)=[O:15])[CH:10]=[CH:11][CH:12]=1.C(Br)(Br)(Br)[Br:49].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.O1CCCC1>[Br:49][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]([C:16]2[CH:17]=[C:18]([S:22]([C:25]3[CH:26]=[C:27]4[C:32](=[C:33]([CH3:35])[CH:34]=3)[N:31]=[CH:30][C:29]([C:36]([NH2:38])=[O:37])=[C:28]4[NH:39][C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[CH:41]=3)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=2)=[O:15])[CH:10]=[CH:11][CH:12]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5cccc(C#CCCCO)c5)c4)cc23)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5cccc(C#CCCCBr)c5)c4)cc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
A suspension of Intermediate 77 (0.65 g, 1.0 mmol) and carbon tetrabromide (1.0 g, 3.0 mmol) in dichloromethane (14 mL) was sonicated for 5 minutes and then cooled in an ice-water bath. Following the addition, via syringe, of a triphenylphosphine (0.52 g, 2.0 mmol) solution in tetrahydrofuran, the cooling bath was removed, allowing the mixture to stir overnight at room temperature. The mixture was quenched with ethanol and concentrated to foam under reduced pressure. The foam was taken up in tetrahydrofuran (15 mL) and treated as before with carbon tetrabromide (3.0 mmol) and triphenylphosphine (2.0 mmol). After stirring overnight at room temperature, the mixture was concentrated under reduced pressure. The crude material was again taken up in tetrahydrofuran (15 mL) and treated as before with carbon tetrabromide (3.0 mmol) and triphenylphosphine (2.0 mmol). After stirring overnight at room temperature, the mixture was concentrated under reduced pressure. The residue was taken up a suspension in acetone and filtered. The concentrated filtrate was purified via automated flash silica gel chromatography, using a 40 g Silicycle SiliSep flash column (hexanes/ethyl acetate). Concentration of the desired fractions under reduced pressure provided the title compound as straw-colored foam (0.35 g, 48%). ES/MS calcd. for C36H32BrN4O5S+ 711.1. Found m/z=711.2 (M+H)+.
Reaction SMILES: [OH-:1].[K+].[CH3:3][C:4]1[N:8]([CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[C:7]2[CH:20]=[C:21]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:22]=[C:23]([C:24]#[N:25])[C:6]=2[N:5]=1.OO>O.C1COCC1>[CH3:3][C:4]1[N:8]([CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[C:7]2[CH:20]=[C:21]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:22]=[C:23]([C:24]([NH2:25])=[O:1])[C:6]=2[N:5]=1
Reactant: [OH-]
Reactant: Cc1nc2c(C#N)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Agent: OO
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2c(C(N)=O)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 35 °C
Yield: 72 %

Procedure:
A solution of KOH (45 mg, 0.8 mmol) in water (10 mL) was added dropwise to solution of 2-methyl-6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-1H-benzimidazole-4-carbonitrile (prepared using the same procedure as Example 24, 150 mg, 0.4 mmol) and 30% H2O2 (3 ml) in THF (15 mL) at rt. The mixture was heated to 35° C. for 1 h. When TLC showed no starting material remaining, water (50 mL) was added, then it was filtered. The filter cake was purified by silica gel chromatography eluted with petroleum ether:EtOAc=1:2 to give the product (115 mg, 72%), as a white solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 2.47 (s, 3H), 3.05 (t, 4H, J=4.8 Hz), 3.69 (t, 4H, J=4.8 Hz), 6.05 (s, 2H), 6.34 (d, 1H, J=7.2 Hz), 7.25 (d, 1H, J=2.4 Hz), 7.34 (t, 1H, J=7.8 Hz), 7.53 (d, 1H, J=2.4 Hz), 7.63-7.70 (m, 2H,), 7.77 (d, 1H, J=3.0 Hz), 7.86 (d, 1H, J=8.1 Hz), 8.01 (d, 1H, J=7.2 Hz), 8.24 (d, 1H, J=8.1 Hz), 9.24 (d, 1H, J=3.0 Hz); LC-MS: m/e=401 [M+1]+
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[Cl:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=1[F:27])[CH:19]=[CH:20][C:21](O)=O>>[Cl:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=1[F:27])/[CH:19]=[CH:20]/[C:21]1[NH:1][C:2]2[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=2[N:8]=1
Reactant: O=C(O)C=Cc1ccc(F)c(Cl)c1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(F)c(Cl)c3)nc2n(CC)c1=O
Yield: 12.3 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 2.50 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 3.01 g (15.1 mmol) of 3-chloro-4-fluorocinnamic acid. Then, the resultant crude crystals were recrystallized from tetrahydrofuran/water to give 560 mg (yield 32%) of Compound 176 as a white powder.
Reaction SMILES: [Cl-].[CH2:2]([N+:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCOC(C)=O.CO.N>>[CH2:2]([N:9]1[CH2:10][CH:11]=[C:12]([CH3:15])[CH2:13][CH2:14]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cc[n+](Cc2ccccc2)cc1
Agent: N
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1=CCN(Cc2ccccc2)CC1

Procedure:
The product was obtained analogously to IP 5b starting from 10.0 g (45.5 mmol) of 1-benzyl-4-methylpyridinium chloride. Yield: 7.15 g (84% of theoretical); C13H17N (M=187.281); calc.: molpeak (M+H)+: 188; found: molpeak (M+H)+: 188; Rf value: 0.95 (silica gel, EtOAc/MeOH/NH3 9:1:0.1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[C:21]#[N:22])=[CH:4][C:5](=[O:13])[N:6]([CH:8]([CH3:12])[C:9]([OH:11])=O)[CH:7]=1.[NH2:23][C:24]1[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[C:3]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[C:21]#[N:22])=[CH:4][C:5](=[O:13])[N:6]([CH:8]([CH3:12])[C:9]([NH:23][C:24]2[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])=[CH:26][CH:25]=2)=[O:11])[CH:7]=1
Reactant: CC(C(=O)O)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
135 mg (purity 93%, 0.37 mmol) of 2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) and 1.2 eq. of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 281 mg (purity 58%, 85% of theory)
Reaction SMILES: [N:1]1([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:6][CH2:5][CH:4]([N:7]2[C@@H:15]3[C@H:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)[CH2:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25].Cl>>[O:16]=[C:8]1[CH2:9][C@@H:10]2[C@H:15]([CH2:14][CH2:13][CH2:12][CH2:11]2)[N:7]1[CH:4]1[CH2:3][CH2:2][N:1]([CH:17]2[CH2:18][CH2:19][N:20]([C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:21][CH2:22]2)[CH2:6][CH2:5]1
Reactant: O=C1C[C@H]2CCCC[C@@H]2N1C1CCN(C2CCNCC2)CC1
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Product: CC(C)OC(=O)N1CCC(N2CCC(N3C(=O)C[C@H]4CCCC[C@@H]43)CC2)CC1

Procedure:
Following procedure similar to Example 82, the title compound was prepared from (3aR,7aS)-1-(1,4′-bipiperidin-4-yl)octahydro-2H-indol-2-one and isopropyl chloroformate. 1H NMR (400 MHz, METHANOL-D4) HCl salt: 6 ppm 1.24 (d, J=5.86 Hz, 6H), 1.27-1.53 (m, 4H), 1.53-1.83 (m, 4H), 1.84-2.00 (m, 4H), 2.04-2.17 (m, 3H), 2.26 (d, J=6.64 Hz, 1H), 2.28-2.37 (m, 1H), 2.35-2.68 (m, 2H), 2.74-2.95 (m, 2H), 3.03-3.23 (m, 3H), 3.34-3.46 (m, 1H), 3.60 (d, J=12.89 Hz, 2H), 3.78-3.94 (m, 1H), 4.29 (d, J=14.06 Hz, 2H), 4.76-4.88 (m, 1H). MS (M+1): 392.3
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[CH:9][CH:8]=[C:7]([Br:27])[CH:6]=2.[C:28](OC)(OC)(OC)[CH2:29][CH2:30][CH3:31]>>[Br:27][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([CH2:13][CH:14]4[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]4)[C:28]([CH2:29][CH2:30][CH3:31])=[N:1][C:2]=3[CH:3]=[N:4][C:5]=2[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2c(N)cnc3cc(Br)ccc23)CC1
Reactant: CCCC(OC)(OC)OC
Product: CCCc1nc2cnc3cc(Br)ccc3c2n1CC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 77.9 %

Procedure:
The method described in Part A of Examples 142–144 was used to treat tert-butyl 4-[(3-amino-7-bromoquinolin-4-ylamino)methyl]piperidine-1-carboxylate (15.0 g, 34.5 mmol) with trimethyl orthobutyrate (5.62 g, 37.9 mmol). After completion, the reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (eluting with 95:5 chloroform:CMA) followed by recrystallization from ethyl acetate to provide 13.1 g of tert-butyl 4-[(7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate as a white solid, mp 215–216° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[Br:11]Br>CC(O)=O.CCOC(C)=O>[Br:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][N:3]=[C:2]2[Cl:1]
Reactant: Clc1n[nH]c2ccccc12
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Clc1n[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a room temperature solution of 3-chloro-1H-indazole (10.0 g, 65.5 mmol) in AcOH (250 ml) was added Br2 (3.54 ml, 68.8 mmol) dropwise. The reaction mixture was stirred at room temperature for 18 hours, then diluted with EtOAc (500 ml), washed with aqueous NaOH solution (10%), saturated aqueous NaHCO3 and brine. The organic layer was dried over MgSO4, filtered, concentrated, and the residue was recrystallized from toluene. The solid was washed with hexanes and dried in vacuo affording 5-Bromo-3-chloro-1H-indazole CCXIV as a white solid (54% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N+:11]([O-])=O)=[CH:4][N:3]=1.[H][H]>CCOC(C)=O>[Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([NH2:11])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: [H][H]
Solvent: CCOC(C)=O
Product: Nc1cnc(Cl)c(N)c1
Reaction time: 3 h
Yield: 65 %

Procedure:
A tablespoonful of Raney nickel catalyst in water was washed first with 95% EtOH and then with EtOAc; it was added to a solution of 2-chloro-3,5-dinitropyridine (4.00 g, 0.0196 mol) in EtOAc (150 ml) and the mixture was hydrogenated at an initial hydrogen pressure of 47.5 p.s.i. for 3 hours. The mixture was filtered through celite and the filtrate was concentrated. The residue was crystallized from CH2Cl2 -pentane to give 1.83 g of the titled product.
Reaction SMILES: [C:1]1([C:7](=[N:14][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:25])[F:24])[C:16]=2[CH3:27])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Br:35])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:35][CH2:27][C:16]1[C:17]([C:23]([F:24])([F:25])[F:26])=[C:18]([CH:21]=[CH:22][C:15]=1[N:14]=[C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:19]#[N:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(N=C(c2ccccc2)c2ccccc2)ccc(C#N)c1C(F)(F)F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: N#Cc1ccc(N=C(c2ccccc2)c2ccccc2)c(CBr)c1C(F)(F)F
Temperature: 25 °C
Yield: 95 %

Procedure:
To a stirred solution of the benzonitrile (3.53 g, 9.69 mmol) from step D in CCl4 (90 mL) was added NBS (1.98 g, 11.14 mmol) and benzoyl peroxide (70%, 0.352 g, 1.45 mmol). The mixture was heated at reflux for 3 h. After cooling to ambient temperature, the reaction was diluted with CH2Cl2 (100 mL), washed with 1N NaOH (100 mL), brine (100 mL), dried (MgSO4) and concentrated. Purification by SiO2 chromatography (10% EtOAc in hexanes) afforded 3-(bromomethyl)-4-[(diphenylmethylidene)amino]-2-(trifluoromethyl)benzonitrile (4.08 g, 95%) as a light yellow solid: 1H NMR (400 MHz, DMSO-d6): δ 7.78 (d, J=8.3 Hz, 1H), 7.78-7.11 (m, 10H), 6.91 (d, J=8.6 Hz, 1H), 4.78 (s, 2H).
Reaction SMILES: [CH2:1]([O:19][CH2:20][C:21]([CH2:58][O:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH3:77])([CH2:38][O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:22][O:23][C:24]1[CH:36]=[CH:35][C:34]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27](=[O:37])[C:26]=2[CH:25]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Cl:78][C:79]1[CH:84]=[CH:83][C:82]([Mg]Br)=[CH:81][CH:80]=1>C1COCC1>[CH2:40]([O:39][CH2:38][C:21]([CH2:58][O:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH3:77])([CH2:20][O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:22][O:23][C:24]1[CH:36]=[CH:35][C:34]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([C:82]3[CH:83]=[CH:84][C:79]([Cl:78])=[CH:80][CH:81]=3)([OH:37])[C:26]=2[CH:25]=1)[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57]
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CCCCCCCCCCCCCCCCCCOCC(COCCCCCCCCCCCCCCCCCC)(COCCCCCCCCCCCCCCCCCC)COc1ccc2c(c1)C(=O)c1ccccc1-2
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOCC(COCCCCCCCCCCCCCCCCCC)(COCCCCCCCCCCCCCCCCCC)COc1ccc2c(c1)C(O)(c1ccc(Cl)cc1)c1ccccc1-2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
Under a nitrogen atmosphere, 2-(3-octadecyloxy-2,2-bis-octadecyloxymethyl-propoxy)-9-fluorenone (75 mg, 73 μmol) was suspended in THF (1 ml) to allow dissolution at 50° C. 4-Chlorophenylmagnesium bromide solution (0.15 ml, 0.15 mmol) was added dropwise, and the mixture was stirred for 30 minutes. After completion of the reaction, the reaction mixture was cooled to room temperature, extracted with chloroform (3 ml), and washed 3 times with 1N hydrochloric acid (1 ml), 3 times with 5% NaHCO3 solution (1 ml) and once with 20% NaCl solution (1 ml). The organic layer was dried over Na2SO4, the solvent of the filtrate was evaporated, and the obtained residue was separated and purified by silica gel column chromatography and crystallized from methanol (1 ml) to give 2-(3-octadecyloxy-2,2-bis-octadecyloxymethyl-propoxy)-9-(4-chlorophenyl)-9-fluorenol (66 mg, 56μ mmol, 77%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:16][CH2:17][CH2:18][O:19][CH3:20]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:16][CH2:17][CH2:18][O:19][CH3:20])[CH:3]=1
Reactant: COCCCCl
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCCOc1cccc(Br)c1
Temperature: 100 °C
Reaction time: 4.5 h
Yield: 99.9 %

Procedure:
A mixture of 5.0 g of 3-bromophenol, 7.99 g of potassium carbonate and 3.77 g of 1-chloro-3-methoxypropane in 90 ml of dimethylformamide is stirred at 100° C. for 4.5 hours. The reaction mixture is clarified by filtration and the filtrate is evaporated in vacuo. The residue is taken up in 100 ml of tert-butyl methyl ether, and the organic phase is washed once each wit 50 ml of 1N NaOH, 50 ml of water and 50 ml of brine. The organic phase is dried with sodium sulphate, filtered and evaporated. 7.08 g of the title compound are obtained as an orange oil. Rt=4.91.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:12][C:11]([N:13]2[CH2:18][CH2:17][N:16]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C@@H:15]([C:33]([OH:35])=O)[CH2:14]2)=[N:10][C:9]=1[CH3:36])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:37]([C:40]1[N:45]=[CH:44][C:43]([CH2:46][NH2:47])=[CH:42][CH:41]=1)([CH3:39])[CH3:38].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:1]([O:5][C:6]([C:8]1[S:12][C:11]([N:13]2[CH2:18][CH2:17][N:16]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:30])[F:31])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C@@H:15]([C:33](=[O:35])[NH:47][CH2:46][C:43]3[CH:44]=[N:45][C:40]([CH:37]([CH3:39])[CH3:38])=[CH:41][CH:42]=3)[CH2:14]2)=[N:10][C:9]=1[CH3:36])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc(N2CCN(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)[C@@H](C(=O)O)C2)sc1C(=O)OC(C)(C)C
Reactant: CC(C)c1ccc(CN)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(N2CCN(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)[C@@H](C(=O)NCc3ccc(C(C)C)nc3)C2)sc1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 86.5 %

Procedure:
To a mixed solution of the compound (55 mg) obtained in Step 6, [(6-isopropylpyridin-3-yl)methyl]amine (24 mg) and 1-hydroxybenzotriazole hydrate (23 mg) in N,N-dimethylformamide (660 μl) was added, with stirring at room temperature, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (29 mg). After stirring at room temperature for 3 hr, the reaction mixture was partitioned by adding saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by thin layer chromatography (ethyl acetate:n-hexane=3:2) to give the title compound (59 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:22]=2[NH:21][CH:20]=[CH:19]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:22]=2[NH:21][CH:20]=[CH:19]3)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cccc3cc[nH]c23)CC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc3cc[nH]c23)CC1
Reaction time: 24 h
Yield: 90.6 %

Procedure:
To a solution of 4-hydroxy-4-(1H-indol-7-yl)-piperidine-1-carboxylic acid tert-butyl ester (117 mg, 0.37 mmol) in pyridine (5 mL) was added POCl3 (70 μL, 0.74 mmol) in a single portion. The reaction was stirred for 24 h, quenched with the slow addition of water (10 mL) and extracted with EtOAc (3×10 mL). The combined acetate layers were washed with brine, dried (MgSO4) and concentrated to afford 4-(1H-indol-7-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a light yellow oil (100 mg).