Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7]O)[N:6]=1.BrC1C=C(F)C(C[N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=C(F)C=1>>[Br:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:6]=1
Reactant: Fc1cc(Br)cc(F)c1CN1CCCCC1
Reactant: OCc1csc(Br)n1
Product: Brc1nc(CN2CCCCC2)cs1

Procedure:
The title compound was prepared from (2-bromothiazol-4-yl)-methanol, following the procedure outlined above for 1-(4-bromo-2,6-difluoro-benzyl)-piperidine, to afford the title compound as a yellow oil. 1H NMR (CDCl3, 300 MHz): 7.09 (s, 1H), 3.61 (d, J=0.9 Hz, 2H), 3.19 (t, J=5.4 Hz, 1H), 2.45 (t, J=5.1 Hz, 4H), 1.69-1.62 (m, 4H), 1.48-1.41 (m, 2H). LCMS (Method B): RT=0.8 min, M+H+=261/263.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]1[CH:4]=[C:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1.C1C(=O)N([Br:19])C(=O)C1>CC(N=NC(C#N)(C)C)(C#N)C.ClC1C=CC=CC=1>[CH3:1][Si:2]([CH3:10])([CH3:11])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[CH2:9][Br:19]
Reactant: Cc1cccc([Si](C)(C)C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Product: C[Si](C)(C)c1cccc(CBr)c1
Temperature: 0 °C
Yield: 99.1 %

Procedure:
A mixture of m-trimethylsilyltoluene (8.22 g, 50 mmol), NBS (8.90 g, 50 mmol), AIBN (0.05 g) and chlorobenzene (50 ml) was heated by means of a heating bath preheated to 110° C. An exothermic reaction started when the reaction mixture reached 80-90° C. and the orange suspension became a colorless solution within minutes. The mixture was cooled down with the aid of an ice-bath, ice water was added and the resulting mixture was extracted with hexane. The organic phase was washed with water, then brine and dried (MgSO4). Filtration through a silica plug (10 g) followed by evaporation of solvents yielded 12.05 g (99%) of 37 as a colorless liquid. Spectroscopic data were identical to those reported in the literature.43
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:27][C:28]([NH:30][C@@H:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C@H:34]([O:41][C:42]3[CH:43]=[CH:44][C:45]4[N:46]([C:48]([N:51]5[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]5)=[N:49][N:50]=4)[CH:47]=3)[CH2:33][CH2:32]2)=[O:29])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH2:18][CH2:19][O:20]C3CCCCO3)[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO>[C:1]([C:5]1[CH:6]=[C:7]([NH:27][C:28]([NH:30][C@@H:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C@H:34]([O:41][C:42]3[CH:43]=[CH:44][C:45]4[N:46]([C:48]([N:51]5[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]5)=[N:49][N:50]=4)[CH:47]=3)[CH2:33][CH2:32]2)=[O:29])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH2:18][CH2:19][OH:20])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2ccc(Cl)c(OCCOC3CCCCO3)c2)n1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2ccc(Cl)c(OCCO)c2)n1
Yield: 82.7 %

Procedure:
A solution of Intermediate 53c (830 mg, 1.06 mmol) and pyridinium p-toluenesulphonate (799 mg, 3.18 mmol) in methanol (7 mL) was stirred at 40-45° C. for 18.5 h. The cooled mixture was concentrated in vacuo, diluted with sat. sodium hydrogen carbonate solution and extracted with DCM (3×15 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-12% MeOH in DCM, to give the product as a solid (613 mg, 83%). An aliquot (50 mg) was further purified by HPLC (XBridge C18 column, 30-90% MeCN in H2O, 0.1% NH4OH) to give the title compound (38 mg). LCMS (Method 5): Rt 4.42 min, m/z 699.5 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.28 (9H, s), 1.57-1.65 (2H, m), 1.68-1.77 (4H, m), 1.80-1.97 (2H, m), 1.98-2.17 (2H, m), 3.11-3.17 (4H, m), 3.74 (2H, q, J=5.0 Hz), 4.12 (2H, t, J=5.0 Hz), 4.76-4.85 (1H, m), 4.90 (1H, t, J=5.1 Hz), 5.54 (1H, t, J=4.3 Hz), 6.34 (1H, s), 7.05-7.11 (2H, m), 7.16 (1H, dd, J=2.0, 9.9 Hz), 7.21-7.41 (5H, m), 7.54 (1H, d, J=8.5 Hz), 7.59-7.65 (2H, m), 8.14 (1H, br s).
Reaction SMILES: [H][H].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[O:8][C@@H:9]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:10][CH2:11][N:12]1[CH2:17][CH:16]=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)[CH2:14][CH2:13]1>[Pd].C(O)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[O:8][C@@H:9]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:10][CH2:11][N:12]1[CH2:13][CH2:14][CH:15]([C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)[CH2:16][CH2:17]1
Reactant: COc1ccc(O[C@H](CCN2CC=C(c3ccc([N+](=O)[O-])cc3)CC2)c2ccccc2)cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(O[C@H](CCN2CCC(c3ccc(N)cc3)CC2)c2ccccc2)cc1OC

Procedure:
A 25-mL RB flask, equipped with a hydrogen-filled balloon, was charged with 1-[(3R)-3-(3,4-dimethoxyphenoxy)-3-phenylpropyl]-4-(4-nitrophenyl)-1,2,3,6-tetrahydropyridine (63.0 mg, 0.133 mmol), palladium on carbon (5.0 mol-eq%, 0.00665 mmol, 7.04 mg) and ethanol (2.0 mL) at room temperature. After 1 hr the reaction mixture was filtered through a plug of Celite 545 and concentrated under reduced pressure. The crude product (54.1 mg, 89.4%) was used in next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[CH:14][C:13]=2[N+:22]([O-])=O)=[CH:5][CH:4]=1.[H][H]>C1(C)C=CC=CC=1.[Pt]>[NH2:22][C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:12]=1[NH:11][CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: [H][H]
Reactant: COc1ccc(CCNc2c([N+](=O)[O-])cnc3ccccc23)cc1
Agent: [Pt]
Solvent: Cc1ccccc1
Product: COc1ccc(CCNc2c(N)cnc3ccccc23)cc1

Procedure:
Using the method of Example 26, 20.4 g (0.063 mole) of 4-[2-(4-methoxyphenyl)ethylamino]-3-nitroquinoline was reduced by hydrogen in 300 ml of toluene with 5% platinum on charcoal. The solvent was then evaporated to provide a residue of 3-amino-4-[2-(4-methoxyphenyl)ethylamino]quinoline. To this residue was added 28 g (0.19 mole) of triethyl orthoformate and the mixture was heated at about 125° C. for two hours. To this mixture was added about 100 ml of aqueous hydrochloric acid and the mixture was heated on a steam bath for thirty minutes. After cooling, the precipitate was separated by filtration, washed sequentially with isopropanol and diethyl ether, and dried. To the solid was added water and ammonium hydroxide, after which the mixture was cooled and the solid was separated by filtration. A portion (3.5 g) of the solid was dissolved in isopropanol, and acidified with hydrochloric acid. The solid was separated by filtration, washed with isopropanol and dried to provide 1-[2-(4-methoxyphenyl)ethyl]-1H-imidazo[4,5-c]quinoline hydrochloride hydrate, m.p. 209°-213° C. Analysis: Calculated for C19H17N3O.HCl.1/3H2O: %C, 66.0; %H, 5.4; %N, 12.2; Found: %C, 66.1; %H, 5.3; %N, 12.3.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[C:7]([OH:24])=[C:8]2[C:13]3=[C:14]([C:16](=[O:22])[C:17]([C:19]([OH:21])=[O:20])=[CH:18][N:12]3[N:11]([CH3:23])[CH2:10][CH2:9]2)[CH:15]=1.[CH3:25]O>>[F:5][C:6]1[C:7]([OH:24])=[C:8]2[C:13]3=[C:14]([C:16](=[O:22])[C:17]([C:19]([O:21][CH3:25])=[O:20])=[CH:18][N:12]3[N:11]([CH3:23])[CH2:10][CH2:9]2)[CH:15]=1
Reactant: CO
Reactant: CN1CCc2c(O)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cn2c3c(c(O)c(F)cc3c1=O)CCN2C
Reaction time: 0.5 h

Procedure:
To 100 ml of methanol, while cooling on ice, 9 ml of thionyl chloride was added, and the solution was stirred for 30 minutes at the same temperature. 2.60 g of the compound (166) obtained in Example 43 was added to the solution, and the solution was heated at reflux for 24 hours. After air-cooling, insoluble matter was removed by filtering, and the filtrate was removed by distillation. To the residue, chloroform was added, and the formed solid matter was filtered off to obtain 2.20 g of the subject compound (167).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[CH:8]=[C:9]([N:14]2[C:18](=[O:19])[CH:17]=[C:16]([CH3:20])[NH:15]2)[CH:10]=[CH:11][C:12]=1[CH3:13].O.CN(C)[CH:24]=[O:25]>>[CH3:6][C:7]1[CH:8]=[C:9]([N:14]2[C:18]([OH:19])=[C:17]([CH:24]=[O:25])[C:16]([CH3:20])=[N:15]2)[CH:10]=[CH:11][C:12]=1[CH3:13]
Reactant: Cc1cc(=O)n(-c2ccc(C)c(C)c2)[nH]1
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(-n2nc(C)c(C=O)c2O)cc1C
Temperature: 100 °C
Yield: 79 %

Procedure:
Phosphorus oxychloride (4.82 mL, 51.6 mmol) was added dropwise to an ice-cooled, stirred suspension of 1-(3,4-dimethylphenyl)-3-methyl-3-pyrazolin-5-one (8.70 g, 43.0 mmol) in dimethylformamide (18.0 mL) at such a rate as to maintain the temperature below 20° C. After the addition, the mixture was heated at 100° C. for 2 h, then cooled, poured into iced water (200 mL). The resulting mixture was stirred for 18 h, then filtered. The solid was washed with water and dried to give the title compound (7.83 g, 79%) as a cream-coloured powder. MS (ES) m/e 231 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]([OH:20])=O)=[N:10]1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:34][NH:35][O:36][CH3:37].CCN(C(C)C)C(C)C>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]([N:35]([O:36][CH3:37])[CH3:34])=[O:20])=[N:10]1
Reactant: COc1cn(-c2cc(I)ccc2F)nc(C(=O)O)c1=O
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cn(-c2cc(I)ccc2F)nc(C(=O)N(C)OC)c1=O
Temperature: 50 °C
Reaction time: 1.17 h
Yield: 82.5 %

Procedure:
A mixture of 1-(2-fluoro-5-iodophenyl)-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (9.96 g, 25.5 mmol) and CDI (4.55 g, 28.1 mmol) in THF (200 mL) was heated to 40° C. for 30 min and 50° C. for 90 min. To the mixture was added DMF (20 mL). The mixture was stirred at 50° C. for 70 min. To the solution were added N,O-dimethylhydroxylamine hydrochloride (3.74 g, 38.3 mmol) and i-Pr2NEt (6.67 mL, 38.3 mmol) at room temperature. The solution was stirred at room temperature for 16 h. The mixture was concentrated in vacuo, diluted with water and 1 M HCl aqueous solution, extracted with EtOAc, washed with saturated NaHCO3 aqueous solution, dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on silica gel (hexane/EtOAc=20/80 to 0/100 and EtOAc/MeOH=100/0 to 0/100) and triturated with MeOH/EtOH/hexane to yield the title compound (9.11 g, 82% yield) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.24 (3H, s), 3.56 (3H, s), 3.80 (3H, s), 7.36 (1H, dd, J=10.6, 8.7 Hz), 7.93 (1H, ddd, J=8.7, 4.5, 2.3 Hz), 8.12 (1H, dd, J=7.4, 2.1 Hz), 8.53 (1H, s).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])=O.C1(P(=[CH:32][C:33]#[N:34])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N>C1(C)C=CC=CC=1>[C:33]([CH:32]=[CH:1][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])#[N:34]
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccccc1C=O
Agent: N
Solvent: Cc1ccccc1
Product: COC(=O)c1ccccc1C=CC#N
Temperature: 110 °C

Procedure:
Methyl 2-formylbenzoate (10 g, 60.9 mmol) was dissolved in toluene (200 mL). (Triphenylphosphoranylidene)acetonitrile (20.19 g, 67.0 mmol) was then added to the mixture. The reaction was heated at 110° C. for 20 hours, then cooled to room temperature, concentrated under vacuum and the residue was triturated with ether (2×). The ether solution was passed though a plug of silica gel to provide Example 1A (mixture of E and Z isomers). The mixture of E and Z isomers was used directly for the next step. MS (DCI+) m/z 205.0 [M+NH3]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24].[CH3:33][NH:34][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1>>[CH3:33][N:34]([C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1)[C:17](=[O:19])[C:16]1[CH:15]=[CH:14][C:13]([C:11]2[O:12][C:8]([CH3:7])=[C:9]([CH2:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:24])=[O:25])[N:10]=2)=[CH:21][CH:20]=1
Reactant: CNc1cccnc1
Reactant: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)N(C)c4cccnc4)cc3)oc2C)cc1
Yield: 73.4 %

Procedure:
Reaction of oxalyl chloride (100 λL, 1.1 mmol) and benzoic acid 4 (275 mg, 0.7 mmol) with subsequent coupling to N-methyl-N-(3-pyridinyl)amine (88 mg, 0.8 mmol) gave benzamide 7 (237 mg, 69%) as a white powder: mp (MeOH) 195-197° C.; 1H NMR δ 8.37 (d, J=2.4 Hz, 1H, H-2′), 8.35 (dd, J=4.7, 1.5 Hz, 1H, H-6′), 7.72 (ddd, J=8.2, 2.4, 1.5 Hz, 1H, H-4′), 7.67 (br d, J=8.5 Hz, 2H, H-2, H-6), 7.63 (br d, J=8.2 Hz, 2H, H-2″, H-6″), 7.37-7.42 (m, J=8.2 Hz, 4H, H-3, H-5, H-3″, H-5″), 7.34 (ddd, J=8.2, 4.7 Hz, 1H, H-5′), 4.58 (s, 2H, CH2SO2), 3.42 (s, 3H, NCH3), 2.34 (s, 3H, CH3), 2.06 (s, 3H, CH3); 13C NMR δ 168.8, 157.8, 149.8, 148.1, 147.3, 144.4, 140.7, 137.4, 135.5, 134.2, 129.6 (2), 129.0 (2), 128.2 (2), 127.2, 125.9, 125.0 (2), 123.8, 52.9, 37.6, 21.0, 9.6; MS m/z 462.6 (MH+, 100%). Anal. calcd for C25H23N3O4S: C, 65.06; H, 5.02; N, 9.10. Found: C, 64.90; H, 4.92; N, 8.83%.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[CH:2]([CH3:4])[CH3:3].[C:22]1([CH2:28][S:29](Cl)(=[O:31])=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C>ClCCl>[CH2:1]([N:5]([CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[S:29]([CH2:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:31])=[O:30])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CNCc1ccc(-c2cccc(S(C)(=O)=O)c2)s1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(=O)(=O)Cc1ccccc1

Procedure:
In analogy to example 13, step 2, isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amine (example 15, step 2) was reacted with alpha-toluenesulfonyl chloride and N,N-diisopropyl ethyl amine in dichloromethane to give N-isobutyl-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-C-phenyl-methanesulfonamide as an off-white solid. MS: 495.2 ([M+NH4]+)
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])([O-])=O.[K+].[K+].[O:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23](=[O:26])[CH2:24]Br)=[CH:22][C:17]=2[O:16][CH2:15]1.O>CC(C)=O.C(OCC)C>[O:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23](=[O:26])[CH2:24][S:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:22][C:17]=2[O:16][CH2:15]1
Reactant: CCOC(=O)CS
Reactant: O=C(CBr)c1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)CSCC(=O)c1ccc2c(c1)OCO2

Procedure:
Ethyl 2-mercaptoacetate (9.68 mL, 88.3 mmol) was added dropwise to a suspension of K2CO3 (12.2 g, 88.3 mmol) and 1-(1,3-benzodioxol-5-yl)-2-bromoethanone (21.4 g, 88.3 mmol) in dry acetone (100 mL). The mixture was stirred at reflux for seven hours, cooled at an icebath and added 200 mL water. Diethyl ether (400 mL) was added and the phases were separated. The aqueous layer was extracted with diethyl ether (200 mL) and the combined organic layers were washed with brine (200 mL), dried (MgSO4) and concentrated. This afforded the title compound.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:24]=[CH:23][C:6]([O:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)=[N:13][CH:14]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl[CH2:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([CH2:45][C:46]2[CH:54]=[CH:53][C:52]3[O:51][CH2:50][O:49][C:48]=3[CH:47]=2)[CH2:41][CH2:40]1)=[O:38]>CN(C=O)C>[CH2:45]([N:42]1[CH2:41][CH2:40][N:39]([C:37](=[O:38])[CH2:36][NH:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][C:12]3[CH:11]=[CH:10][C:9]([CH2:8][O:7][C:6]4[CH:23]=[CH:24][C:3]([C:2]([F:25])([F:1])[F:26])=[CH:4][CH:5]=4)=[CH:14][N:13]=3)=[CH:17][CH:18]=2)[CH2:44][CH2:43]1)[C:46]1[CH:54]=[CH:53][C:52]2[O:51][CH2:50][O:49][C:48]=2[CH:47]=1
Reactant: O=C(CCl)N1CCN(Cc2ccc3c(c2)OCO3)CC1
Reactant: Nc1ccc(Oc2ccc(COc3ccc(C(F)(F)F)cc3)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CNc1ccc(Oc2ccc(COc3ccc(C(F)(F)F)cc3)cn2)cc1)N1CCN(Cc2ccc3c(c2)OCO3)CC1
Temperature: 80 °C
Reaction time: 11 h

Procedure:
4-[5-(4-trifluoromethylphenoxymethyl)pyridin-2-yloxy]phenylamine (4.50 g, 12.5 mmol) was dissolved in DMF (150 mL). To the resulting solution were added potassium carbonate (2.60 g, 18.8 mmol) and sodium iodide (1.87 g, 12.5 mmol), and then to this solution was added 2-chloro-1-(4-piperonylpiperazin-1-yl)ethanone (4.21 g, 12.5 mmol). The resulting solution was stirred for 11 hours under a nitrogen atmosphere at 80° C. The resulting reaction solution was concentrated under reduced pressure. To the residue was added ethyl acetate and washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=80:1), to thereby yield 5.2 g of the title compound.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:15](=[O:29])[N:16]([CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=3)[N:17]=2)[CH:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[OH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]2[N:6]=[CH:5][N:4]3[C:15](=[O:29])[N:16]([CH2:18][C:19]4[CH:20]=[N:21][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:23][CH:24]=4)[N:17]=[C:3]3[C:2]=2[C:35]2[CH:36]=[CH:37][C:32]([CH2:31][OH:30])=[CH:33][CH:34]=2)=[CH:13][CH:12]=1
Reactant: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2c(Br)c(-c3ccc(Cl)cc3)ncn12
Reactant: OCc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2c(-c3ccc(CO)cc3)c(-c3ccc(Cl)cc3)ncn12
Temperature: 100 °C
Yield: 13.1 %

Procedure:
A suspension of 8-bromo-7-(4-chlorophenyl)-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (48 mg, 0.10 mmol), 4-(hydroxymethyl)phenylboronic acid (46 mg, 0.30 mmol), K3PO4 (63 mg, 0.30 mmol), and Pd(dppf)Cl2.CH2Cl2 (20 mg, 0.025 mmol) in THF (1 mL) at room temperature was degassed by bubbling with argon for 1 min. This was then stirred and heated at 100° C. in a sealed vessel for 3 h. Analysis by HPLC/MS indicated that starting material had been consumed. After the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography eluted with ethyl acetate-hexanes. This provided the title compound (6.7 mg) as a light yellow solid. HPLC/MS (methanol-water with 10 mM NH4OAc): retention time=3.53 min, [M+H]30 =512.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([C:18]2[N:22]=[C:21]([C@H:23]([CH2:32][CH2:33][CH2:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[CH2:24][C:25]([O:27][C:28](C)(C)C)=[O:26])[O:20][N:19]=2)[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)Cl>[NH:14]1[CH2:17][CH:16]([C:18]2[N:22]=[C:21]([C@H:23]([CH2:32][CH2:33][CH2:34][CH:35]3[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]3)[CH2:24][C:25]([O:27][CH3:28])=[O:26])[O:20][N:19]=2)[CH2:15]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C2CN(C(c3ccccc3)c3ccccc3)C2)no1
Solvent: ClCCl
Product: COC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C2CNC2)no1
Yield: 73.3 %

Procedure:
A solution of tert-butyl(3R)-3-[3-(1-benzhydryl-3-azetidinyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoate (preparation 36) (1.99 g, 3.66 mmol) in DCM (15 ml) was treated with ACE-CI (530 μl, 4.90 mmol) and heated at reflux for 4 hours. The solvent was removed under reduced pressure. The residue was dissolved in MeOH (15 ml) and heated at reflux for 1.5 hours. The solvent was removed under reduced pressure. The oil was dissolved in EtOAc (150 ml) and washed with sat. NaHCO3 solution (50 ml) and brine (40 ml). The aqueous extracts were combined and extracted with EtOAc. All of the organic extracts were combined, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure to afford the title compound as a colourless oil (900 mg).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[NH:10][CH:9]=2)[CH2:4][CH2:3]1.C=O.[C:21](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(#N)C>[CH3:21][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[NH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=c1[nH]cc(C2CCNCC2)c2ccccc12
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: CN1CCC(c2c[nH]c(=O)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.2 %

Procedure:
4-(Piperidin-4-yl)-2H-isoquinolin-1-one hydrochloride (0.5 g) obtained in Example 31 and 35% aqueous formalin solution (0.33 g) were dissolved in acetonitrile (20 mL), and sodium triacetoxyborohydride (0.81 g) was added under ice-cooling, and the mixture was stirred at room temperature for 3 hrs. After the completion of the reaction, diluted hydrochloric acid was added to the reaction mixture. The mixture was once heated under reflux, and the solvent was evaporated. Aqueous potassium carbonate solution was added to the obtained residue, and the mixture was extracted with chloroform, and purified by silica gel column chromatography (chloroform:methanol=4:1+triethylamine 2%) to give 4-(1-methylpiperidin-4-yl)-2H-isoquinolin-1-one (88 mg) as white crystals.
Reaction SMILES: [H-].[Na+].CI.[CH2:5]([OH:12])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[CH:11].[CH3:13]COCC>CN(C=O)C.O>[CH3:13][O:12][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[CH:11]
Reactant: C#CCCCCCO
Reactant: CCOCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: C#CCCCCCOC
Yield: 61.7 %

Procedure:
To a slurry of sodium hydride (7.86 g, 197 mmol) in DMF (100 mL) was added methyl iodide (12.29 mL, 197 mmol) followed by a solution of hept-6-yn-1-ol (24.5 g, 197 mmol) in DMF (50 mL). Following the addition the reaction was monitored by TLC. After 2 h additional methyl iodide (6 mL, 50 mmol) was added followed by sodium hydride (1 g, 25 mmol) portions. At 1 h intervals additional sodium hydride (1 g, 25 mmol) portions was added until no alcohol remained as indicated by TLC. Et2O (50 mL) and water (100 mL) was added to the reaction mixture and the layers were separated. The organic layer was washed with brine, dried using Na2SO4, filtered and distilled (145-155° C.) to provide 7-methoxyhept-1-yne (18 g, 121 mmol, 61.7% yield) as a colorless oil.