Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].N1C=CC=CC=1.[CH2:16]([N:23]1[CH2:28][CH2:27][CH:26]([C:29](Cl)=[O:30])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[CH2:16]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]([NH:1][C:2]2[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=2[OH:9])=[O:30])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)C1CCN(Cc2ccccc2)CC1
Reactant: Nc1cc(Br)ccc1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cc(Br)ccc1O)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.9 %

Procedure:
1-Benzylpiperidine-4-carboxylic acid (29 g, 0.13 mol) dissolved in DCM (300 ml), cooled to 0° C. and added oxalyl chloride (17.3 ml, 0.2 mol). Catalytic amount of DMF was added to this mixture and stirred at rt for 2 h. After 2 h, DCM removed on rotavapour and co-distilled the residue two times with DCM to obtain 1-benzylpiperidine-4-carbonyl chloride quantitatively. 2-Amino-4-bromophenol (23 g, 0.12 mol) dissolved in DCM and added pyridine (11.5 g, 0.15 mol) under nitrogen atmosphere. This mixture stirred at rt for 30 mins and added 1-benzylpiperidine-4-carbonyl chloride (29 g, 0.12 mol) in DCM (100 ml). After continuing stirring at rt for 2 h, DCM was removed on the rotavapour to obtain the titled compound (47.6 g), which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([F:22])=[CH:24][CH:25]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(O)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(OCc2ccc(F)cc2)cc1
Yield: 49.8 %

Procedure:
Followed the same procedure as that of step 2 in Example 91 with the use of (R)-2-(4-hydroxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 0.5 mmol) and 4-fluoro-benzyl bromide (150 mg, 0.75 mmol) to afford the title product (100 mg, 50% yield); LCMS, 100% APCI+, Calcd. 401.48. Found: 402.34 m/z (M+1). 1H NMR (400 MHz, CDCl3); δ 1.47 (s, 9H), 1.80-2.10 (m, 4H), 3.39 (br, 2H), 3.70-3.90 (m, 1H), 4.02-4.19 (m, 2H), 4.97 (s, 2H), 6.82-6.89 (m, 2H), 7.06 (t, J=8.0 Hz, 2H), 7.23-7.28 (m, 2H), 7.35-7.42 (m, 2H).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][N:7]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.CN(C=O)C>[CH2:15]([NH:22][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:6]([Cl:5])=[N:7][CH:8]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C(NCc1ccccc1)c1ccc(Cl)nc1
Temperature: 80 °C
Yield: 78.4 %

Procedure:
3.5 ml (47.6 mMol) Thionylchloride and 50 □l DMF were added to a suspension of 5.0 g (31.7 mMol) 6-chloronicotinic acid in 50 ml toluene and the reaction mixture was heated at 80° C. for 2 hours. The solvent and excess thionyl chloride were removed under reduced pressure and the residue was dissolved in 50 ml dichloromethane. After cooling to 0° C., 10.4 ml (95.2 mMol) benzylamine were added over 20 minutes and after 30 minutes further stirring at room temperature, the reaction mixture was poured onto 50 ml aqueous saturated sodium bicarbonate solution. Extraction with dichloromethane, followed by crystallization from ethyl acetate/n-hexane 2:1 gave 6.13 g (78%) N-benzyl-6-chloro-nicotinamide as light brown crystals of m.p.=113-114° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:6][N:5]=[C:4]([N:17]=CN(C(C)C)C(C)C)[N:3]=1.[CH2:26]([CH2:28][NH2:29])[OH:27]>C(O)C>[NH2:17][C:4]1[N:3]=[C:2]([NH:29][CH2:28][CH2:26][OH:27])[C:7]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[CH:6][N:5]=1
Reactant: CC(C)N(C=Nc1ncc(C#Cc2ccc(Cl)cc2)c(Cl)n1)C(C)C
Reactant: NCCO
Solvent: CCO
Product: Nc1ncc(C#Cc2ccc(Cl)cc2)c(NCCO)n1

Procedure:
A mixture of 0.7 g of 4-chloro-5-(4-chlorophenylethynyl)-2-diisopropylaminomethyleneamino-pyrimidine, 20 mL ethanol and 0.6 mL ethanolamine was refluxed for 18 hours. The green solution was evaporated in vacuo and triturated with water. The insoluble yellow residue was recrystallized by dissolving in 35 mL hot methanol, concentrating to 10 mL and chilling. The pale yellow powdery precipitate was filtered and dried to yield 0.34 g of 2-amino-5-(4-chlorophenylethynyl)-4-(2-hyroxyethylamino)pyrimidine, m.p. 197–200° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[C:11]([C:14]([F:17])([F:16])[F:15])[NH:10][C:9]=2[C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:19])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[F:32][C:33]1[CH:42]=[CH:41][C:36]([O:37][CH2:38][CH2:39]Br)=[CH:35][CH:34]=1>CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[C:11]([C:14]([F:15])([F:16])[F:17])[N:10]([CH2:39][CH2:38][O:37][C:36]3[CH:41]=[CH:42][C:33]([F:32])=[CH:34][CH:35]=3)[C:9]=2[C:18]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)=[O:19])=[CH:4][CH:3]=1
Reactant: Cc1c(C(F)(F)F)[nH]c(C(=O)N2CCOCC2)c1-c1ccc(Cl)cc1
Reactant: Fc1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(-c2ccc(Cl)cc2)c(C(=O)N2CCOCC2)n(CCOc2ccc(F)cc2)c1C(F)(F)F
Temperature: 80 °C
Reaction time: 48 h

Procedure:
(3-(4-Chlorophenyl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone [for synthesis see SC-25] (130 mg, 0.349 mmol) was dissolved in dry MeCN (4 mL). The solution was mixed with K2CO3 (120 mg, 0.872 mmol) and KI (8.7 mg, 0.052 mmol), followed by addition of 4-fluorophenoxy-ethylbromide (153 mg, 0.697 mmol). The reaction mixture was stirred vigorously at 80° C. for 2 d. The temperature was lowered to room temperature; the reaction mixture was combined with the reaction mixture of another identical reaction (starting from 20 mg or 0.054 mmol (3-(4-chlorophenyl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone), followed by concentration in vacuo. The residue was used for flash chromatography (silica, gradient heptane/EtOAc, 1:0→1:1). The product was purified by preparative TLC (silica, DCM twice) to result in 60 mg (29%) of SC-51.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]1[CH2:33][CH:32]([OH:34])[CH2:31][CH:30]1[CH:35]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[O:36][CH:37]([C:46]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=1)[C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)=[O:28]>>[CH3:45][O:44][C:41]1[CH:42]=[CH:43][C:38]([CH:37]([C:46]2[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=2)[O:36][CH:35]([C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH:30]2[CH2:31][CH:32]([OH:34])[CH2:33][N:29]2[C:27](=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:21][C:1](=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:39][CH:40]=1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: COc1ccc(C(OC(c2ccccc2)C2CC(O)CN2C(=O)CCCCCN)c2ccc(OC)cc2)cc1
Product: CCCCCCCCC=CCCCCCCCC(=O)NCCCCCC(=O)N1CC(O)CC1C(OC(c1ccc(OC)cc1)c1ccc(OC)cc1)c1ccccc1
Yield: 98 %

Procedure:
Using the above described procedure, oleic acid 101f (2.83 g, 10 mmol) was coupled with the amine 100 and after work-up and column purification the pure amide was isolated as aa oil (7.7 g, 98%). 1H NMR (DMSO-d6, 400 MHz) δ 7.71-7.67 (m, 1H), 7.34-7.10 (m, 9H), 6.90-6.79 (m, 4H), 5.33-5.26 (m, 2H), 4.98 (d, J=3.90 Hz, 0.7H), 4.88 (d, J=3.90 Hz, 0.3H), 4.40-4.05 (m, 2H), 3.71 (s, 6H), 3.59-3.42 (m, 1H), 3.34-3.20 (m, 2H), 3.18-3.10 (m, 1H), 3.02-2.92 (m, 3H), 2.20-1.80 (m, 6H), 1.50-1.04 (m, 39H), 0.83 (t, J=6.1 Hz, 3H). 13C NMR (DMSO-d6, 400 MHz) δ=171.81, 170.92, 170.83, 158.09, 157.96, 145.08, 144.74, 135.87, 135.72, 135.42, 129.61, 129.54, 127.86, 127.74, 127.57, 126.56, 113.18, 113.09, 85.78, 85.10, 68.57, 67.44, 65.19, 63.32, 54.97, 54.92, 48.59, 45.71, 40.12, 38.21, 38.02, 36.29, 35.41, 34.16, 32.53, 31.28, 29.09, 28.84, 28.69, 28.66, 28.59, 28.55, 26.58, 26.56, 26.19, 25.32, 24.54, 24.14, 22.10, 13.94.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[OH:19].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>C1(C)C=CC=CC=1.O.CC#N.CC#N.CC#N.CC#N.F[P-](F)(F)(F)(F)F.[Cu+]>[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[O:19][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: O=C(O)c1cccnc1Cl
Agent: [Cu+]
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CC#N
Solvent: Cc1ccccc1
Product: O=C(O)c1cccnc1Oc1ccc(Cl)cc1Cl

Procedure:
To a solution of 2-chloro-nicotinic acid (2.15 g, 13.65 mmol, 1.0 equiv; [CAS RN 2942-59-8]) and 2,4-dichloro-phenol (2.22 g, 13.65 mmol, 1.0 equiv; [CAS RN 120-83-2]) in toluene (40 mL) was added caesium carbonate (8.89 g, 27.29 mmol, 2.0 equiv; [CAS RN 534-17-8]) and tetrakis(acetonitrile)copper(I) hexafluorophosphate (1.02 g, 2.73 mmol, 0.2 equiv; [CAS RN 64443-05-6]). The reaction mixture was heated to reflux over night. The solvent was evaporated under reduced pressure and the crude reaction product taken up in water (100 mL) acidified to pH 1 by addition of a solution of 1 M HCl and extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4 and the product purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of dichloromethane/methanol affording 1.69 g (44%) of the title compound as an off-white solid. 1H NMR (400 MHz, DMSO): δ7.26 (dd, J=7.6 Hz, J=4.8 Hz, 1H), 7.36 (d, J=8.7 Hz, 1H), 7.49 (dd, J=8.7 Hz, J=2.6 Hz, 1H), 7.76 (d, J=2.4 Hz, 1H), 8.25 (dd, J=4.8 Hz, J=2.2 Hz, 1H), 8.30 (dd, J=7.5 Hz, J=2.2 Hz, 1H), 13.33 (s, 1H). MS (ISN): 282.3 [M−H]−.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][OH:24])([CH2:18][CH2:19]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>C1(C)C=CC=CC=1.O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][O:24][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([CH2:18][CH2:19]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OCCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)COCCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 2-(1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethanol (60 mg, 0.185 mmol) in toluene (5 mL) was added tetrabutylammonium chloride hydrate (16.4 mg, 0.055 mmol). The reaction mixture was cooled to 0° C. and added 35% NaOH (5 mL), followed by tert-butyl bromoacetate (0.041 mL, 0.277 mmol). The reaction was stirred at rt for 4 h. The organic layer was separated, washed with 1 N aqueous HCl (3×5 mL) and brine (5 mL), dried, and concentrated in vacuo to afford tert-butyl 2-(2-(1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethoxy)acetate. The above ester was stirred with 1 N aqueous NaOH (3 mL) and MeOH (5 mL) under reflux for 2 h. The mixture was concentrated in vacuo. The residue was dissolved in EtOAc (5 mL), washed with 1 N aqueous HCl (5 mL) and H2O (3×5 mL), and concentrated in vacuo. The crude product was purified by preparative HPLC (PHENOMENEX® Axia 5μ C18 30×100 mm column; detection at 220 nm; flow rate=40 mL/min; continuous gradient from 30% B to 100% B over 10 min+2 min hold time at 100% B, where A=90:10:0.1 H2O:MeOH:TFA and B=90:10:0.1 MeOH:H2O:TFA) to afford the title compound (50 mg, 67% yield) as a clear oil. LCMS, [M+H]+=383.2. 1H NMR (500 MHz, CDCl3) δ 9.59 (s, 1H), 7.35-7.21 (m, 3H), 7.17-7.02 (m, 3H), 7.02-6.92 (m, 2H), 6.85 (ddd, J=8.1, 2.4, 1.0 Hz, 1H), 4.10 (s, 2H), 3.87 (s, 2H), 3.59 (t, J=6.9 Hz, 2H), 2.16-1.92 (m, 4H), 1.72 (q, J=7.6 Hz, 4H), 1.53 (t, J=6.9 Hz, 2H). HPLC-1: RT=11.0 min, purity=92.1%; HPLC-2: RT=9.7 min, purity=91.1%.
Reaction SMILES: [C:1]([C:4]1[C:18]([OH:19])=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])=[C:6]([CH2:20]Cl)[CH:5]=1)(=[O:3])[CH3:2].[CH3:22][OH:23]>Cl([O-])(=O)(=O)=O.[Ag+]>[C:1]([C:4]1[C:18]([OH:19])=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])=[C:6]([CH2:20][O:23][CH3:22])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CO
Reactant: CC(=O)c1cc(CCl)c(OCCCCCCC#N)cc1O
Agent: [Ag+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: COCc1cc(C(C)=O)c(O)cc1OCCCCCCC#N
Temperature: 25 °C

Procedure:
Approximately 3 millimoles of the chloro compound of Example 127 were treated with 0.62% g of silver perchlorate in 50 ml of methanol at 0° C. The reaction mixture was allowed to warm to room temperature over a 2 hour period. The mixture was then partitioned between ethyl acetate and an acidic sodium chloride solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative thin layer chromatography over silica gel eluting with 1:1 ethyl acetate/hexane providing 50 mg of the title compound. NMR, MS.
Reaction SMILES: COC[O:4][C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C@@H:11]2[CH2:13][O:12]2)=[CH:7][CH:6]=1.[C:16]1([C:22]2[C:30]3[C:29]([N:31]4[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]4)=[N:28][CH:27]=[N:26][C:25]=3[S:24][CH:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[OH:12][C@@H:11]([CH2:13][NH:37][CH:34]1[CH2:35][CH2:36][N:31]([C:29]2[C:30]3[C:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:23][S:24][C:25]=3[N:26]=[CH:27][N:28]=2)[CH2:32][CH2:33]1)[CH2:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([OH:4])=[CH:15][CH:14]=1
Reactant: NC1CCN(c2ncnc3scc(-c4ccccc4)c23)CC1
Reactant: COCOc1ccc(OC[C@@H]2CO2)cc1
Product: Oc1ccc(OC[C@@H](O)CNC2CCN(c3ncnc4scc(-c5ccccc5)c34)CC2)cc1
Yield: 58 %

Procedure:
Synthesis followed SP6 (4 h), using 250 μmol (S)-2-((4-(methoxymethoxy)phenoxy)methyl)oxirane and 1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine to give O-MOM intermediate upon purification by prep. TLC (2 mm silica gel, PE/CH2Cl2/MeOH 4:6:1) with 58% yield. Product was obtained by MOM removal according to SP8 (1.5 eq. TosOH, 10 h) and purification by prep. TLC (1 mm silica gel, CH2Cl2/MeOH 90:10) with 61% yield.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[F:27][C:28]([F:38])([F:37])[C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][N:22]([CH2:33][C:32]5[CH:31]=[CH:30][C:29]([C:28]([F:27])([F:37])[F:38])=[CH:36][CH:35]=5)[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)CC1
Yield: 74 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and 4-(trifluoromethyl)benzyl bromide, to give the desired product as a white solid (74%).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:13]=1[NH2:14]>>[CH3:20][O:19][C:17]1[CH:16]=[CH:15][C:13]([NH:14][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[C:12]([C:11]([F:10])([F:21])[F:22])[CH:18]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: COc1ccc(N)c(C(F)(F)F)c1
Product: COc1ccc(Nc2ccc(C#N)cc2)c(C(F)(F)F)c1
Yield: 60.5 %

Procedure:
Analogously to Example 1a), 4-bromobenzonitrile was reacted with 2-trifluoromethyl-4-methoxy-aniline. After chromatographic purification through silica gel (petroleum ether with 10 to 30% ethyl acetate) the 4-(4-methoxy-2-trifluoromethyl-phenylamino)-benzonitrile was obtained in a yield of 60.5% of theory.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[CH2:6][NH:7][C:8](=[O:27])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([S:21][CH2:22][CH3:23])[CH:18]=[CH:17][C:16]=2[N+:24]([O-])=O)[CH:10]=1>CO.[Pd]>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[CH2:6][NH:7][C:8](=[O:27])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([S:21][CH2:22][CH3:23])[CH:18]=[CH:17][C:16]=2[NH2:24])[CH:10]=1
Reactant: CCSc1ccc([N+](=O)[O-])c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: [Pd]
Solvent: CO
Product: CCSc1ccc(N)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(5-(ethylthio)-2-nitrophenyl)isonicotinamide (300 mg, 0.65 mmol, 1.00 equiv) in methanol (5 mL). The solution was treated with Pd/C (300 mg), and stirred under an atmosphere of hydrogen for 2 h at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 200 mg (71%) of N-(3-(trifluoromethyl)benzyl)-2-(2-amino-5-(ethylthio)phenyl)isonicotinamide as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:45]=[CH:44][C:6]2[O:7][C:8]([CH3:43])([CH3:42])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH:17](OC(OC4C=CC=CC=4)=S)[CH2:18][CH2:19][CH2:20][O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)=[CH:13][C:12]3=[O:41])[C:5]=2[CH:4]=1)#[N:2].N(C(C)(C)C#N)=NC(C)(C)C#N.C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:45]=[CH:44][C:6]2[O:7][C:8]([CH3:42])([CH3:43])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][C:23]4[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=4)=[CH:13][C:12]3=[O:41])[C:5]=2[CH:4]=1)#[N:2]
Reactant: COc1ccc(COCCCC(OC(=S)Oc2ccccc2)c2ccn(C3=CC(C)(C)Oc4ccc(C#N)cc43)c(=O)c2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: COc1ccc(COCCCCc2ccn(C3=CC(C)(C)Oc4ccc(C#N)cc43)c(=O)c2)cc1
Yield: 94.7 %

Procedure:
In 46 ml of anhydrous toluene, is dissolved 1.44 g of 6-cyano-2,2-dimethyl-4-(1,2-dihydro-2-oxo-4-(1-phenoxythiocarbonyloxy-4-p-methoxybenzyloxybutyl)-1-pyridinyl}-2H-benzo[b]pyran obtained in Example 45. Then, 0.76 g of 2,2'-azobisisobutyronitrile and 1.35 g of tri-n-butyltin hydride are added and reacted at 100° C. for 15 minutes. After the reaction, the reaction mixture is directly purified by silica gel column chromatography using 3/2 mixture of ethyl acetate/n-hexane as a developing solvent. Thus, 1.03 g of 6-cyano-2,2-dimethyl-4-{1,2-dihydro-2-oxo-4-(4-p-methoxybenzyloxybutyl)-1pyridinyl-}-2H-benzo[b]pyran is obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:6]([O:8]CC)=O)[CH2:5][CH2:4]1.[C:11](=O)([O:17]C(C)(C)C)[O:12][C:13]([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C.[Li+].[BH4-].C1COCC1>CCO.CN(C1C=CN=CC=1)C>[OH:8][CH2:6][C:3]1([NH:2][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CCOC(=O)C1(N)CC1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: [BH4-]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(CO)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 1-aminocyclopropanecarboxylate hydrochloride (1 eq) in EtOH (0.3 M) at room temperature was added di-tert-butyl carbonate (1.5 eq), triethylamine (2 eq), and DMAP (0.05 eq). The reaction was stirred at room temperature overnight. The reaction mixture was concentrated en vaccuo; and the residue was diluted in ethyl acetate. The organic solution was washed 1:1 saturated aqueous NH4Cl/water, brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The material was taken up in THF (0.3 M) and cooled to 0° C. To this solution was added 2 M LiBH4 in THF (4 eq). The reaction was warmed to room temperature and stirred for 4 hours, at which time more 2 M LiBH4 (1.3 eq) was added, and stirred overnight. The reaction mixture was cooled to 0° C. and slowly quenched with MeOH over 10 minutes and then water. The solution was stirred for 10 minutes; and precipitates appeared. The precipitates were filtered and rinsed with ethyl acetate. The filtrate was washed with water, brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-75% ethyl acetate in hexanes to give the product.
Reaction SMILES: [CH3:1][N:2]([C:10]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:24]=[N:25][N:26]([C:28]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:27]=3)=[CH:19][CH:18]=2)[CH:13]=[CH:12][C:11]=1[N+:47]([O-])=O)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]>[Pd].C(OCC)(=O)C>[CH3:1][N:2]([C:10]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:24]=[N:25][N:26]([C:28]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:27]=3)=[CH:19][CH:18]=2)[CH:13]=[CH:12][C:11]=1[NH2:47])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)ccc1N
Yield: 74.9 %

Procedure:
In a similar manner to that described in Reference Example 7, a reaction was carried out using t-butyl N-methyl-N-{2-nitro-5-[4-(2-triphenylmethyltetrazol-5-yl)phenoxy]phenyl}carbamate (0.98 g), palladium on carbon (10%, 0.13 g) and ethyl acetate (100 ml) and the reaction mixture was purified to give the title compound (0.70 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=1.[Li+].CC([N-]C(C)C)C.[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1>C1COCC1>[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]([OH:28])[CH:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:25][CH:24]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: c1cncc(Cc2cccnc2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1)C(c1cccnc1)c1cccnc1
Reaction time: 1 h

Procedure:
To the solution of 3-(pyridin-3-ylmethyl)pyridine (0.195 g, 1.15 mmol) in THF (5 mL) at −78° C. was added LDA (0.7 mL, 1.8 M) and stirred for 1 h. 4-Fluorobenzaldehyde (0.171 g, 1.37 mmol) in THF (1 mL) was added. The mixture was stirred at −78° C. for 10 min and at −45° C. for 0.5 h. The reaction was quenched with ice and extracted with CH2Cl2. The combined organic layer was dried, filtered, and concentrated to give a solid. The solid was triturated with CH2Cl2 to give 1-(4-fluorophenyl)-2,2-dipyridin-3-ylethanol. 1H-NMR (500 MHz, CDCl3) δ 8.60 (d, 1H, J=1.7), 8.45 (d, 1H, J=1.9), 8.38 (dd, 1H, J=4.7, 1.2), 8.27 (dd, 1H, J=4.6, 1.2), 7.91 (d, 1H, J=7.8), 7.76 (d, 1H, J=8.0), 7.34-7.29 (m, 3H), 7.19 (dd, 1H, J=7.8, 4.9), 7.02 (t, 2H, J=8.8), 5.68 (d, 1H, J=4.9), 5.45 (dd, 1H, J=8.5, 4.8), 4.34 (d, 1H, J=8.8). LRMS m/z (M+H) Calcd: 295.3. found: 295.1.