Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)C(C)C)C.[NH2:10][C:11]1([C:17]([NH:19][C@H:20]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:21][CH2:22][OH:23])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.Cl[C:32]1[C:33]2[CH:40]=[CH:39][NH:38][C:34]=2[N:35]=[CH:36][N:37]=1>C(O)CCC.CCOC(C)=O>[NH2:10][C:11]1([C:17]([NH:19][C@H:20]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:21][CH2:22][OH:23])=[O:18])[CH2:16][CH2:15][N:14]([C:32]2[C:33]3[CH:40]=[CH:39][NH:38][C:34]=3[N:35]=[CH:36][N:37]=2)[CH2:13][CH2:12]1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: NC1(C(=O)N[C@@H](CCO)c2ccc(Cl)cc2)CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: NC1(C(=O)N[C@@H](CCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 60 °C
Reaction time: 18 h
Yield: 61.2 %

Procedure:
N-Ethyldiisopropylamine (1.676 ml, 9.62 mmol) was added to (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)piperidine-4-carboxamide (Intermediate 49) (1 g, 3.21 mmol) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.493 g, 3.21 mmol) in butan-1-ol (15 ml). The resulting solution was stirred at 60° C. for 18 hours. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (25 mL) and saturated brine (25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 6% MeOH with ammonia in DCM. Pure fractions were evaporated to dryness to afford (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (842 mg) as a white foam. (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide was stirred in ethyl acetate (7 mL) for 18 hours. The solid was collected by filtration, washed with a small amount of ethyl acetate and vacuum oven dried at 55° C. for 18 hours to afford (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (0.585 g, 42.5%) as a white solid. m/z (ES+) (M+H)+=429; HPLC tR=1.60 min.
Reaction SMILES: [CH2:1]([Li])CCC.[F:6][C:7]([F:19])([F:18])[CH2:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][N:11]=1.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[F:6][C:7]([F:19])([F:18])[CH2:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[CH2:1])=[CH:12][N:11]=1
Reactant: [Li]CCCC
Reactant: O=Cc1ccc(OCC(F)(F)F)nc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1ccc(OCC(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.5 %

Procedure:
n-Butyllithium (5.14 mL, 13.4 mmol) is added to a suspension of methyltriphenylphosphonium bromide (4.41 g, 12.34 mmol) in tetrahydrofuran (51 mL) at −78° C. under nitrogen atmosphere. The reaction mixture is warmed to room temperature to yield deep red ylide solution. To ylide solution, cooling in ice, is introduced 6-(2,2,2-trifluoroethoxy)nicotinaldehyde (2.11 g, 10.3 mmol, Step-1) in tetrahydrofuran (10 mL) and stirred at room temperature for 3 hours. The reaction mixture is poured into water, extracted with ethyl acetate and dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (10:1) to give 1.56 g (75% yield) of the title compound as colorless oil.
Reaction SMILES: [OH:1][CH:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][CH2:4][CH2:5][C:6]([N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][O:10][C:9]1=[O:19])=[O:7].N1C=CN=C1.[C:31]([Si:35](Cl)([CH3:37])[CH3:36])([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C>[C:31]([Si:35]([CH3:37])([CH3:36])[O:1][CH:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][CH2:4][CH2:5][C:6]([N:8]1[CH:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:11][O:10][C:9]1=[O:19])=[O:7])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(CCCC(O)c1ccccc1)N1C(=O)OCC1c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC(CCCC(=O)N1C(=O)OCC1c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
30 g of 3-(5-Hydroxy-5-phenyl-pentanoyl)-4-phenyl-oxazolidin-2-on are solved in 50 ml of DMF. After addition of 14.3 g of imidazol and 19 g of tert. -Butyl-dimethylsilylchlorid in 25 ml of DMF the reaction is stirred at room temperature until all components are dissolved (2-4 h). The reaction solution is evaporated, and after water was added extracted by acetic acid ethylester. After drying of the organic phase by magnesium sulfate and evaporation compound I (product 1) is obtained: C26H35NO4Si (453.6) MS (ESI+) 476 (M+Na+).
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[C:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[C:13]([O:21][CH3:22])=[CH:12][C:4]=1[O:5][C:6]([CH3:11])([CH3:10])[C:7]([OH:9])=[O:8])=O.[C:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)(=[O:25])[CH3:24].C[O-].[Li+].Cl>CN(C)C=O.CO.O>[C:7]([C:6]([CH3:11])([O:5][C:4]1[CH:12]=[C:13]([O:21][CH3:22])[C:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:15][C:3]=1/[CH:1]=[CH:24]/[C:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)=[O:25])[CH3:10])([OH:9])=[O:8]
Reactant: COc1cc(OC(C)(C)C(=O)O)c(C=O)cc1-c1cccs1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Agent: C[O-]
Agent: Cl
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: COc1cc(OC(C)(C)C(=O)O)c(/C=C/C(=O)c2ccc(C(=O)O)cc2)cc1-c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
2-(2-Formyl-5-methoxy-4-thiophen-2-yl-phenoxy)-2-methyl-propionic acid (Ex-59B, 0.12 g, 0.39 mmol) and 4-acetylbenzoic acid (0.064 g, 0.39 mmol) were dissolved in a dimethylformamide-methanol solution (2.7 mL, 7:3). After complete dissolution, lithium methoxide (0.060 g, 1.6 mmol) was added and the resulting bright orange slurry was stirred in the dark at room temperature for 2 h. Upon completion, as determined by HPLC, the mixture was diluted with water (15 mL), acidified with a 1 N hydrochloric acid solution, and extracted with ethyl acetate (3×15 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The crude oil was taken up in ethyl alcohol (5 mL) and warmed to 60° C. to obtain complete dissolution and allowed to cool to room temperature. The resulting precipitate was collected on filter paper and dried in vacuo to yield 0.15 g (85%) of the title compound as a dark yellow solid, mp 223–225° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.23 (d, 2H, J=8.1 Hz), 8.10 (d, 2H, J=8.1 Hz), 8.06 (s, 1H), 7.95 (d, 1H, J=16.2 Hz), 7.69 (d, 1H, J=3.0 Hz), 7.55 (d, 1H, J=5.1 Hz), 7.14 (dd, 1H, J=5.1, 3.0 Hz), 6.58 (s, 1H), 3.88 (s, 3H), 1.66 (s, 6H). MS (ESI) m/z=467 ([M+H]+, 100%). Anal. Calcd. for C25H22O7S.⅓H2O: C, 63.55; H, 4.84; S, 6.79. Found: C, 63.39; H, 5.02; S, 6.53.
Reaction SMILES: [C:1]([C:3]1[C:4](Br)=[C:5](C)[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[C:17]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:11]1([CH2:17][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C([O-])[O-]
Reactant: C1CCNCC1
Reactant: Cc1cccc(C#N)c1Br
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1CN1CCCCC1
Yield: 100 %

Procedure:
A solution of 35 g (0.18 mole) of cyanobromotoluene and 16.18 g (0.19 mole) of piperidine in 300 mL of anhydrous DMF was treated with 73 g (0.5 mole) of K2CO3 at 50° C. for 2 hr. The reaction mixture was filtered through a plug of Celite, washed with 400 mL of ethyl acetate, and the filtrate was partitioned between ethyl acetate and ½ saturated brine. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo, yielding 36 g (0.18 mole) 100% of 2-Piperidin-1-ylmethyl-benzonitrile. 1H NMR (300 MHz, CDCl3) 7.6 (m, 3H), 7.24 (m, 1H), 3.6 (s, 2H), 2.4 (m, 4H), 1.5 (m, 6H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.CCN(CC)CC.[CH:22]1[CH:27]=[CH:26][C:25]([CH2:28][O:29][C:30](Cl)=[O:31])=[CH:24][CH:23]=1.O>C(Cl)Cl>[C:10]([O:9][C:8]([NH:7][C@H:3]1[CH2:4][CH2:5][CH2:6][N:1]([C:30]([O:29][CH2:28][C:25]2[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=2)=[O:31])[CH2:2]1)=[O:14])([CH3:11])([CH3:13])[CH3:12]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.1 %

Procedure:
To a solution of (S)-tert-butyl piperidin-3-ylcarbamate (5 g, 24.9 mmol) and Et3N (3.8 mL, 27.4 mmol) in CH2Cl2 (75 mL) was added Cbz-Cl (3.92 mL, 27.4 mmol) at 0° C., after the addition was complete the reaction was warmed to rt and stirred for 4 h. The reaction was diluted with ice cooled water (30 mL) and the CH2Cl2 layer was separated and dried over Na2SO4 and concentrated in vacuo to give (7.5 g, 89%) of the tilted compound. 1H NMR (400 MHz, CDCl3): δ 7.40-7.24 (m, 5H), 5.18 (s, 2H), 4.58 (bs, 1H), 3.80-3.62 (m, 2H), 3.55-3.41 (m, 1H), 3.37-3.21 (m, 2H), 1.82-1.78 (m, 1H), 1.75-1.69 (m, 1H), 1.61-1.53 (m, 2H), 1.42 (s, 9H). ES-MS: m/z [M+1]=335.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:5]2O.P(Cl)(Cl)([Cl:25])=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:5]2[Cl:25]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1c(-c2ccccc2)c(C(F)(F)F)nc2ccc(Br)cc12
Product: FC(F)(F)c1nc2ccc(Br)cc2c(Cl)c1-c1ccccc1

Procedure:
A solution of 6-bromo-3-phenyl-2-(trifluoromethyl)quinolin-4-ol (8.29 g, 22.5 mmol, Intermediate 19: step a) in phosphoryl trichloride (25 mL, 269 mmol) was heated at 110° C. for 2 hours, and concentrated in vacuo. Dichloromethane and ice-water were added, and the mixture was basified at 4° C. with concentrated NH4OH until pH˜10. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic phases were dried (Na2SO4), concentrated, and purified by flash column chromatography (120 g silica gel column, 2-9% EtOAc in heptanes) to afford the title compound as a light yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.[N:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[N:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:22][CH2:23][N:24]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[N:8]=[CH:7]3)[CH2:25][CH2:26]2)=[CH:17][CH:16]=1
Reactant: ClCCCCn1cnc2ccccc21
Reactant: c1cc(N2CCNCC2)ccn1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: c1ccc2c(c1)ncn2CCCCN1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.6 %

Procedure:
1-(4-chlorobutyl)-1H-benzimidazole (7.51 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 4-(4-pyridyl) piperazine (4.9 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred for 10 min at ambient temperature, and then heated and refluxed to react for 20 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3, eluted with dichloromethane/methanol mixture to produce 6.3 g compound (I-13) with a yield of 62.1%. ESI-MS [M+H]+: m/z 336.2.
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[NH2:13][C:14]1[CH:15]=[C:16]([CH:35]=[CH:36][CH:37]=1)[O:17][C:18]1[CH:32]=[CH:31][C:21]2[N:22]=[C:23]([NH:25][C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[S:24][C:20]=2[C:19]=1[C:33]#[N:34].C(N(CC)CC)C.[F:45][C:46]([F:55])([F:54])[C:47]1[CH:48]=[CH:49][C:50]([NH2:53])=[N:51][CH:52]=1>O1CCCC1.C(OCC)(=O)C>[C:33]([C:19]1[C:20]2[S:24][C:23]([NH:25][C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])=[N:22][C:21]=2[CH:31]=[CH:32][C:18]=1[O:17][C:16]1[CH:35]=[CH:36][CH:37]=[C:14]([NH:13][C:1](=[O:12])[NH:53][C:50]2[CH:49]=[CH:48][C:47]([C:46]([F:54])([F:45])[F:55])=[CH:52][N:51]=2)[CH:15]=1)#[N:34]
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: N#Cc1c(Oc2cccc(N)c2)ccc2nc(NC(=O)C3CC3)sc12
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1c(Oc2cccc(NC(=O)Nc3ccc(C(F)(F)F)cn3)c2)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.9 %

Procedure:
To a solution of bis(trichloromethyl) carbonate (59.3 mg, 0.200 mmol) in tetrahydrofuran (2 mL) were added N-[6-(3-aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (200 mg, 0.571 mmol) produced in Example 3(vi) and triethylamine (158 μL, 1.14 mmol) at 4° C., and the mixture was stirred at the same temperature for 30 min. 5-(Trifluoromethyl)pyridin-2-amine (185 mg, 1.14 mmol) was added to the reaction mixture, and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (methanol/ethyl acetate=0/100→10/90), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-heptane (1/1) to give the title compound (113 mg, 37%) as a white powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][O:22][CH3:23].[N:24]1([C:29]2[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25]1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][O:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:29]([N:24]4[CH:28]=[CH:27][CH:26]=[CH:25]4)=[CH:30][CH:31]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(O)c1ccc(-n2cccc2)cc1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)c1ccc(-n2cccc2)cc1

Procedure:
According to the general method of Example 50, 1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine and 4-(1-pyrrolyl)benzoic acid were combined to provide N1-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}-4-(1-pyrrolyl)benzamide as an off white powder, m.p. 173.0-174.9° C. 1H NMR (300 MHz, DMSO-d6) δ 8.52 (t, J=5.5 Hz, 1H), 8.02 (d, J=7.9 Hz, 1H), 7.90 (d, J=8.7 Hz, 2H), 7.67 (d, J=8.7 Hz, 2H), 7.61 (dd, J=8.4, 1.1 Hz, 1H), 7.48 (t, J=2.2 Hz, 2H), 7.39 (m, 1H), 7.19 (dt, J=7.6, 1.1 Hz, 1H), 6.53 (broad s, 2H), 6.30 (t, J=2.2 Hz, 2H), 4.57 (t, J=7.0 Hz, 2H), 3.82 (t, J=6.7 Hz, 2H), 3.33 (m, 2H), 3.26 (s, 3H), 3.20 (t, J=6.7 Hz, 2H), 1.87 (m, 2H), 1.71 (m, 2H); MS (EI) m/e 482.2421 (482.2430 calcd for C28H30N6O2).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7](=[O:9])[CH3:8])[CH2:2]1.CCN(C(C)C)C(C)C.[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25][O:26][C:27](Cl)=[O:28])=[CH:21][CH:20]=1>C(Cl)Cl>[C:7]([CH:3]1[CH2:4][CH2:5][CH2:6][N:1]([C:27]([O:26][CH2:25][C:22]2[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=2)=[O:28])[CH2:2]1)(=[O:9])[CH3:8]
Reactant: CC(=O)C1CCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 1-(piperidin-3-yl)ethanone (53, 2.6 g, 20 mmol) in DCM (100 ml) at room temperature was added DIEA (5.2 ml, 30 mmol). A solution of Cbz-Cl (4.4 ml, 30 mmol) in DCM (20 ml) was added dropwise over 2 hrs. The mixture was stirred at room temperature for 17 hrs, washed with water, saturated sodium bicarbonate (aq.), water, 1N HCl (aq.) and brine, dried over anhydrous sodium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under vacuum to give the benzyl 3-acetylpiperidine-1-carboxylate (54) which was used in the next step without further purification. LC-MS for C15H19NO3 calcd: 261; found: 262.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[O:6])[CH2:4][C:3]1=[O:7].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[C:26]2[CH3:32]>>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:4]1[C:3](=[O:7])[C:2]([CH3:1])([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]=1[OH:6])=[C:26]2[CH3:32]
Reactant: Cc1c[nH]c2ccc(F)cc12
Reactant: CC1(c2ccccc2)C(=O)CC1=O
Reactant: O=Cc1ccccc1
Product: Cc1c(C(C2=C(O)C(C)(c3ccccc3)C2=O)c2ccccc2)[nH]c2ccc(F)cc12

Procedure:
Using general procedure C, 2-methyl-2-phenyl-cyclobutane-1,3-dione (Lit. 1) was reacted with benzaldehyde and 5-fluoro-3-methyl-1H-indole to give the title compound as a colorless solid. MS: 410.3 ([M−H]−).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([OH:21])=O)[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:22]([F:25])([F:24])[F:23])([O-:3])=[O:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[F:55][C:56]([F:69])([F:68])[C:57]1[CH:58]=[C:59]2[C:64](=[CH:65][CH:66]=1)[N:63]=[C:62]([NH2:67])[CH:61]=[CH:60]2>ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:12][CH2:13][CH:14]([O:17][CH2:18][C:19]([NH:67][C:62]3[CH:61]=[CH:60][C:59]4[C:64](=[CH:65][CH:66]=[C:57]([C:56]([F:68])([F:55])[F:69])[CH:58]=4)[N:63]=3)=[O:21])[CH2:15][CH2:16]2)=[CH:6][C:5]=1[C:22]([F:24])([F:23])[F:25])([O-:3])=[O:2]
Reactant: Nc1ccc2cc(C(F)(F)F)ccc2n1
Reactant: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)Nc1ccc2cc(C(F)(F)F)ccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
To a solution of 2-[[4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]oxy]acetic acid (100 mg, 0.28 mmol) in dichloromethane (30 ml) was added EDAC.HCl (81 mg, 0.42 mmol), HOBt (57 mg, 0.42 mmol) and triethylamine (85 mg, 0.84 mmol). After 15 minutes 6-(trifluoromethyl)quinolin-2-amine (68 mg, 0.32 mmol) was added and the resulting solution was stirred overnight at room temperature. The contents were then quenched with water (100 ml) and extracted with dichloromethane (3×50 ml). The organic layers were combined and dried over anhydrous magnesium sulfate. The solids were filtered off and the filtrate was concentrated under vacuum to give a residue, which was purified by silica gel column chromatography using 3% methanol in dichloromethane to afford 2-[[4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]-oxy]-N-[6-(trifluoromethyl)quinolin-2-yl]acetamide as a yellow solid (80.6 mg, 52%). (ES, m/z): [M+H]+ 557.20; 1H NMR (300 MHz, CD3OD): δ 8.51-8.47 (m, 2H), 8.29 (s, 1H), 8.05-7.99 (m, 2H), 7.93 (dd, J=1.8, 9.0 Hz, 1H), 7.01 (d, J=2.4 Hz, 1H), 6.83 (dd, J=2.4, 9.0 Hz, 1H), 4.27 (s, 2H), 3.63-3.45 (m, 2H), 2.27-2.14 (m, 4H), 1.70-1.56 (m, 2H), 1.46-1.34 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:11])[CH3:10].N1C=CN=C1.Cl[Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])=[CH:4][C:3]=1[CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)c1cc(O)ccc1Br
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1cc(O[Si](C(C)C)(C(C)C)C(C)C)ccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-3-isopropylphenol (880.0 mg, 4.09 mmols) and imidazole (417.0 mg, 6.13 mmols) in 10 mL DMF was added chloro-triisopropylsilane (946.0 mg, 4.90 mmols). After stirring overnight at room temperature the solution was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The title compound, 1.30 g (92%), was isolated by column chromatography (1-2% EtOAc-hexanes) as a colorless oil.
Reaction SMILES: C1C=CC(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)=CC=1.O[CH:19]([C:32]1[CH:33]=[C:34]([Si:37]([CH2:42][CH3:43])([CH2:40][CH3:41])[CH2:38][CH3:39])[O:35][CH:36]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[N:15]([CH:19]([C:32]1[CH:33]=[C:34]([Si:37]([CH2:42][CH3:43])([CH2:40][CH3:41])[CH2:38][CH3:39])[O:35][CH:36]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCC(O)c1coc([Si](CC)(CC)CC)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(N=[N+]=[N-])c1coc([Si](CC)(CC)CC)c1
Reaction time: 48 h

Procedure:
A solution of diphenylphosphonyl azide (143 mg, 0.52 mmol in THF (2 ml) was added over a period of 15 minutes to a solution of 4-(1-hydroxytridecyl)-2-triethylsilylfuran (200 mg, 0.52 mmol), triphenylphosphine (140 mg, 0.52 mmol) and diethyl azidocarboxylate (90 mg, 0.52 mmol) in THF (10 ml) at room temperature, After stirring for 2 days, the mixture was evaporated in the presence of a minimum amount of silica gel. The residue was purified by flash chromatography on silica using 5% ethyl ether/hexane to give the titled azide.
Reaction SMILES: [CH2:1]([C@H:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH2:6][C@H:5]([C:16]([OH:18])=[O:17])[NH:4]1)[CH3:2].C(N(CC)CC)C.[C:26](=[S:28])=[S:27].[CH3:29]I>O.CO>[CH2:1]([C@H:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH2:6][C@H:5]([C:16]([OH:18])=[O:17])[N:4]1[C:26]([S:28][CH3:29])=[S:27])[CH3:2]
Reactant: CC[C@@H]1N[C@@H](C(=O)O)Cc2c1[nH]c1ccccc21
Reactant: CI
Reactant: S=C=S
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: CC[C@H]1c2[nH]c3ccccc3c2C[C@H](C(=O)O)N1C(=S)SC
Yield: 69.8 %

Procedure:
In the same manner as described in Example 43, (1RS,3SR)-trans-1-ethyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (733 mg), triethylamine (707 mg), carbon disulfide (305 mg), methyl iodide (568 mg), methanol (20 ml) and water (2 ml) are reacted and treated. The product is recrystallized from aqueous ethanol to give the title compound (700 mg, 70%) as colorless prisms, m.p. 155°-157° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[C:6]1([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH2:5]2.Br[CH2:18][C:19]([OH:21])=[O:20].C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[C:6]1([CH2:11][CH2:10][N:9]([CH2:18][C:19]([OH:21])=[O:20])[CH2:8][CH2:7]1)[CH2:5]2
Reactant: O=C(O)CBr
Reactant: O=C1c2ccc(F)cc2CC12CCNCC2
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)CN1CCC2(CC1)Cc1cc(F)ccc1C2=O
Temperature: 25 °C
Yield: 100 %

Procedure:
A stirred solution of 5-fluorospiro[indene-2,4′-piperidin]-1(3H)-one (160 mg, 0.626 mmol), bromoacetic acid (113 mg, 0.813 mmol) and triethylamine (0.436 mL, 3.13 mmol) in acetonitrile (2 mL) was heated at 80° C. for 3 h, then cooled to 25° C. The reaction mixture was diluted with 20 mL of ethyl acetate and washed with 5 mL of water, dried over Na2SO4 and concentrated to dryness without any further purification to give the title compound (174 mg, 0.626 mmol, 100% yield). MS calculated for C15H17FNO3 278.3. found (ESI) m/z 278.4 (M+H)+, retention time 0.81 min.