Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[OH:23].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Cl[CH2:36][C:37](Cl)=[O:38]>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[C:37](=[O:38])[CH2:36][O:23][C:15]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]1=2
Reactant: COc1cc(C(F)(F)F)ccc1Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C(F)(F)F)ccc1N1C(=O)COc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Yield: 106.9 %

Procedure:
To a flask charged with 2-((2-methoxy-4-(trifluoromethyl)phenyl)amino)-5-nitrophenol (1.75 g, 5.33 mmol) and cesium carbonate (8.69 g, 26.7 mmol) was added DMF (21.33 ml) followed by chloroacetyl chloride (0.854 ml, 10.66 mmol), dropwise over 5 min. The resulting solution was maintained at rt for 1 h. Quenched reaction with saturated ammonium chloride (25 mL) and diluted with EtOAc (25 mL). Separated layers, and extracted aqueous layer with EtOAc (3×25 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated via rotary evaporation to provide 4-(2-methoxy-4-(trifluoromethyl)phenyl)-7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (2.10 g, 5.70 mmol, 107% yield) as a yellow solid. The crude product was used in the next step without further purification.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[C:10]1([P:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O.C1(C)C=CC=CC=1>[Cl-:2].[C:23]1([P+:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:3][C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: ClCc1cccnc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: [Cl-]
Product: c1ccc([P+](Cc2cccnc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C

Procedure:
To an ice-cooled 2-phase mixture of 55.8 g (195 mmol) Na2CO3·10 H2O in 200 ml water and 100 ml toluene, 21.3 g (133 mmol) 3-chloromethylpyridine hydrochloride is added in portions. The mixture is stirred at 0° C. until a clear solution is obtained, the aqueous phase separated off, and the mixture extracted twice with 50 ml toluene. The toluene phases are dried (Na2SO4) and evaporated in the RE (10 mbar, 30° C.) to about half its original volume. To the yellowish solution, 68.1 g (259 mmol) triphenylphosphine is added and the mixture stirred for several days under a N2 atmosphere at 70° C. The title compound is precipitated off in the process. It is filtered off and washed with toluene and hexane; 1H-NMR (DMSO-d6) 8.47 (m, 1HPy), 8.18 (sb, 1HPy), 7.91 (m, 3H), 7.72 (m, 12H), 7.37 (m, 1HPy), 7.26 (m, 1HPy), 5.33 (d, J=15 Hz, H2C); FAB-MS (M−Cl)+=354; an. calc. (C24H21NClP·0.17 H2O) C, 73.36%; H, 5.47%; N, 3.56%; Cl, 9.02%; P, 7.88%; H2O, 0.78%; meas. C, 73.11%; H, 5.43%; N, 3.82%; Cl, 9.49%; P, 7.98%; H2O, 0.77%.
Reaction SMILES: C[Si]([I:5])(C)C.F[B-](F)(F)F.[F:11][S:12]([F:24])([F:23])([F:22])([F:21])[C:13]1[CH:18]=[CH:17][C:16]([N+]#N)=[CH:15][CH:14]=1>>[I:5][C:16]1[CH:17]=[CH:18][C:13]([S:12]([F:24])([F:23])([F:22])([F:21])[F:11])=[CH:14][CH:15]=1
Reactant: C[Si](C)(C)I
Reactant: N#[N+]c1ccc(S(F)(F)(F)(F)F)cc1
Agent: F[B-](F)(F)F
Product: FS(F)(F)(F)(F)c1ccc(I)cc1
Reaction time: 0.08 h
Yield: 40.3 %

Procedure:
(Bowden, et al., Tetrahedron 2000, 56, 3393-3408) Trimethylsilyl iodide (15.0 mg, 0.0750 mmol) was added to a solution of 1 (11.0 mg, 0.0346 mmol) in [BMIM][BF4] (67.6 mg). After stifling for 5 min the mixture was extracted with hexane (0.5 mL×3) and the combined extracts was evaporated to give pure 25b as a colorless oil (4.6 mg, 40%): MS (GC, EI): m/z=330 [M+], 311 [M+ F], 222, 96. 1H NMR (500 MHz, CDCl3): δ=7.82 (d, J=8.8 Hz, 2H), 7.48 (d, J=8.8 Hz, 2H) ppm. 13C NMR (125 MHz, CDCl3): δ=137.9 (2CH), 127.5 (2CH), 98.2 (C) ppm. 19F NMR (470 MHz, CDCl3): δ=83.5 (quint, J=151 Hz, 1 F), 62.8 (d, J=151 Hz, 4 F) ppm.
Reaction SMILES: N1C=CC=C(CN)C=1.[CH3:9][C:10]1[O:14][N:13]=[C:12]([CH2:15][NH2:16])[CH:11]=1.[F:17][C:18]1[CH:40]=[CH:39][C:21]([CH2:22][N:23]2[C@@H:27]([CH3:28])[CH2:26][N:25]([C:29]3[S:30][C:31]([C:35](O)=[O:36])=[C:32]([CH3:34])[N:33]=3)[C:24]2=[O:38])=[CH:20][CH:19]=1.FC1C=CC(CN2[C@H](C)CN(C3SC(C(O)=O)=C(C)N=3)C2=O)=CC=1>>[F:17][C:18]1[CH:40]=[CH:39][C:21]([CH2:22][N:23]2[C@H:27]([CH3:28])[CH2:26][N:25]([C:29]3[S:30][C:31]([C:35]([NH:16][CH2:15][C:12]4[CH:11]=[C:10]([CH3:9])[O:14][N:13]=4)=[O:36])=[C:32]([CH3:34])[N:33]=3)[C:24]2=[O:38])=[CH:20][CH:19]=1
Reactant: Cc1cc(CN)no1
Reactant: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2C[C@@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1cc(CNC(=O)c2sc(N3C[C@@H](C)N(Cc4ccc(F)cc4)C3=O)nc2C)no1

Procedure:
Following the procedure as described in Example 2, making variations as required to replace pyridin-3-ylmethanamine with (5-methylisoxazol-3-yl)methanamine and replace (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with (R)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid the title compound was obtained as a white solid: mp 139-140° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ 8.51 (t, J=5.8 Hz, 1H), 7.40-7.35 (m, 2H), 7.21-7.15 (m, 2H), 6.14 (d, J=0.4 Hz, 1H), 4.60 (d, J=15.6 Hz, 1H), 4.37-4.16 (m, 4H), 3.78-3.71 (m, 1H), 3.55 (dd, J=10.2, 6.8 Hz, 1H), 2.47 (s, 3H), 2.37 (s, 3H), 1.22 (d, J=6.2 Hz, 3H); MS (ES+) m/z 443.9 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:47]1[CH:52]=[CH:51][C:50]([CH2:53]Br)=[CH:49][CH:48]=1>CN(C=O)C>[C:50]1([CH2:53][N:25]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:24][CH2:23][CH2:22][N:21]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:12]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:11][CH2:10][CH2:9][N:8]([CH2:53][C:50]2[CH:51]=[CH:52][CH:47]=[CH:48][CH:49]=2)[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:51]=[CH:52][CH:47]=[CH:48][CH:49]=1
Reactant: CC(C)(C)OC(=O)NCCCN(CCCCCCCCN(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCCCCCCCN(CCCN(Cc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CCCN(Cc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 49.3 %

Procedure:
Dissolve 20.0 gm (0.03 mol) of the product from Step C in 30 ml DMF and treat with 7.5 gm (0.067 mol) KtBuO and 7.96 ml (0.067 mol) BnBr, with stirring for 18 hours. Evaporate the volatiles (0.5 mm and 45° C.) and take up the resulting residue in 1400 ml of EtOAc and water-wash (2×, 500 ml). The organic layer is then dried (MgSO4) and the solvent is evaporated (in vacuo). Flash chromatography on silica gel eluted with 20% EtOAc/hexane yields 12.4 gm (50%) of desired product as a clear viscous oil. Rf is 0.42 (silica gel plates eluted with 25% EtOAc/hexane).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:27][CH2:26][C:25]2[C:24]3[C:19](=[CH:20][C:21]([N:28]4[CH:33]=[CH:32][C:31]([C:34]5[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=5[O:41][CH3:42])=[CH:30][C:29]4=[O:43])=[CH:22][CH:23]=3)[N:18]([CH3:44])[C:17]=2[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[ClH:40].[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([C:31]2[CH:32]=[CH:33][N:28]([C:21]3[CH:20]=[C:19]4[C:24]([C:25]5[CH2:26][CH2:27][NH:15][CH2:16][C:17]=5[N:18]4[CH3:44])=[CH:23][CH:22]=3)[C:29](=[O:43])[CH:30]=2)=[C:35]([O:41][CH3:42])[CH:36]=1
Reactant: COc1cc(Cl)ccc1-c1ccn(-c2ccc3c4c(n(C)c3c2)CN(C(=O)OC(C)(C)C)CC4)c(=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(Cl)ccc1-c1ccn(-c2ccc3c4c(n(C)c3c2)CNCC4)c(=O)c1
Product: Cl
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (1.0 mL) was added to a solution of tert-butyl-7-(4-(4-chloro-2-methoxyphenyl)-2-oxopyridin-1(2H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (0.23 g, 0.44 mmol) in CH2Cl2 (2 mL) under argon and stirred for 1 h. The mixture was concentrated under reduced pressure, and the residue was partitioned between CH2Cl2 and saturated NaHCO3 solution. The organic phase was removed, and the aqueous phase was extracted with CH2Cl2 (10×25 mL). The combined organic extracts were washed with brine (25 mL), dried over Na2SO4, and concentrated under reduced pressure. Flash column chromatography (12 g ISCO CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 2 column volumes to 0:100 over 20 column volumes and hold for 10 column volumes) provided the free base of the title compound. The free base was converted to the HCl salt using 2 N HCl in Et2O as of Example 129 (step b), providing the title compound (0.13 g, 33%) as a yellow solid: mp 294-300° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.43 (br s, 2H), 7.65 (d, J=7.0 Hz, 1H), 7.61 (d, J=1.5 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.44 (d, J=8.5 Hz, 1H), 7.26 (d, J=2.0 Hz, 1H), 7.13 (dd, J=8.5, 2.0 Hz, 1H), 7.09 (dd, J=8.0, 2.0 Hz, 1H), 6.56 (d, J=2.0 Hz, 1H), 6.47 (dd, J=7.0, 1.5 Hz, 1H), 4.49-4.47 (m, 2H), 3.87 (m, 3H), 3.69 (s, 3H), 3.47-3.43 (m, 2H), 3.00-2.97 (m, 2H); ESI MS m/z 420 [M+H]+; HPLC (Method A) 96.7% (AUC), tR=15.5 min.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)[CH:7]=[CH:6][C:5]=1[Cl:16].[OH-].[Na+]>C(O)(C)(C)C>[Cl:16][C:5]1[CH:6]=[CH:7][C:8]([C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:9][C:4]=1[C:3]([OH:17])=[O:2]
Reactant: COC(=O)c1cc(-c2csc(C)n2)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: Cc1nc(-c2ccc(Cl)c(C(=O)O)c2)cs1
Temperature: 25 °C
Reaction time: 72 h
Yield: 69 %

Procedure:
A mixture of 2-chloro-5-(2-methyl-thiazol-4-yl)-benzoic acid methyl ester (10 mg, 0.04 mmol) and sodium hydroxide (80 μL, 1M aqueous, 0.08 mmol) in tert-butanol (1 mL) was stirred at room temperature for 3 d. The mixture was concentrated to dryness in vacuo, dissolved in water (5 mL), acidified to pH6 (1M HCl) and extracted with ethyl acetate. The combined organic layers were washed with water, and brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (7 mg).
Reaction SMILES: ClC1C=CC(C2C3C=C(OC)C=CC=3N3C(C)=NN=C3[C@H](CC(O)=O)N=2)=CC=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[C:42]3[CH:43]=[C:44]([O:47][CH3:48])[CH:45]=[CH:46][C:41]=3[N:40]3[C:49]([CH3:52])=[N:50][N:51]=[C:39]3[C@H:38]([CH2:53][C:54]([NH:56][CH2:57][CH3:58])=[O:55])[N:37]=2)=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.NC[CH2:94][CH2:95][CH2:96][NH:97][C:98](=[O:104])[O:99][C:100]([CH3:103])([CH3:102])[CH3:101]>>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]2[C:42]3[CH:43]=[C:44]([O:47][CH3:48])[CH:45]=[CH:46][C:41]=3[N:40]3[C:49]([CH3:52])=[N:50][N:51]=[C:39]3[C@H:38]([CH2:53][C:54]([NH:56][CH2:57][CH2:58][CH2:94][CH2:95][CH2:96][NH:97][C:98](=[O:104])[O:99][C:100]([CH3:103])([CH3:102])[CH3:101])=[O:55])[N:37]=2)=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OC)ccc2-n2c(C)nnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COc1ccc2c(c1)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)O)c1nnc(C)n1-2
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)NCCCCCNC(=O)OC(C)(C)C)c1nnc(C)n1-2
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
A mixture of [(4S)-6-(4-chlorophenyl)-1-methyl-8-(methyloxy)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]acetic acid (for a preparation see Reference compound H) (1.0 g, 2.5 mmol), HATU (1.9 g, 5 mmol) and DIPEA (0.88 ml, 5 mmol) was stirred for 80 minutes at room temperature, to this was added 1,1-dimethylethyl (4-aminobutyl)carbamate (1.05 ml, 5.0 mmol, available from Aldrich). The reaction mixture was stirred at room temperature for 2 h before it was concentrated. The residue was taken up in dichloromethane and washed with 1N HCl. The aqueous layer was extracted with dichloromethane twice. Organic layer was washed with 1N sodium hydroxide, followed by a saturated solution of sodium chloride, dried over sodium sulphate and concentrated. The residue was purified by flash-chromatography on silica using dichloromethane/methanol 95/5 to give the title compound as a yellow solid (1.2 g). LC/MS (Method A): rt=3.04 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:23])([F:22])[S:20]Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][NH:11][C:12]=2[S:20][C:19]([F:23])([F:22])[F:18])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c[nH]cc1-c1ccc(Cl)cc1
Reactant: FC(F)(F)SCl
Solvent: ClCCl
Product: CCOC(=O)c1c[nH]c(SC(F)(F)F)c1-c1ccc(Cl)cc1
Temperature: -30 °C
Reaction time: 0.75 h
Yield: 95.3 %

Procedure:
A solution of ethyl 4-(p-chlorophenyl)-pyrrole-3-carboxylate (9.0 g, 0,036 mol) in methylene chloride (180 mL) is treated with trifluoromethylsulfenyl chloride (4.9 g, 0.036 mol) with stirring for 45 minutes at -30° C. The reaction mixture is warmed to room temperature and stirred for several hours. Since a TLC shows some starting material present, the reaction mixture is cooled to -30° C., treated with additional trifluoromethylsulfenyl chloride (1.3 g, 0.0095 mol), warmed to room temperature overnight with stirring, washed with water, saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title product as an off-white solid (12.0 g, mp 161.5°-164.0° C.) which is identified by 1HNMR, 19FNMR and 13CNMR spectral analyses.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]([OH:8])[C:5]2[CH:9]=[CH:10][O:11][C:4]=2[CH2:3]1.[Cl:12][C:13]1[CH:18]=[C:17](F)[CH:16]=[CH:15][C:14]=1[CH3:20]>>[ClH:12].[Cl:12][C:13]1[CH:18]=[C:17]([O:8][CH:6]2[CH2:7][N:2]([CH3:1])[CH2:3][C:4]3[O:11][CH:10]=[CH:9][C:5]2=3)[CH:16]=[CH:15][C:14]=1[CH3:20]
Reactant: CN1Cc2occc2C(O)C1
Reactant: Cc1ccc(F)cc1Cl
Product: Cc1ccc(OC2CN(C)Cc3occc32)cc1Cl
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 6-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 1) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2-chloro-4-fluoro-1-methylbenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:7][O:6][C:5]([CH3:8])=[N:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:37][C:38]1[CH:39]=[C:40]([CH2:46][CH2:47]O)[CH:41]=[CH:42][C:43]=1[O:44][CH3:45].C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>C1COCC1>[F:37][C:38]1[CH:39]=[C:40]([CH2:46][CH2:47][O:17][C:14]2[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][C:3]3([CH2:2][OH:1])[CH2:7][O:6][C:5]([CH3:8])=[N:4]3)=[CH:16][CH:15]=2)[CH:41]=[CH:42][C:43]=1[O:44][CH3:45]
Reactant: CC1=NC(CO)(CCc2ccc(O)cc2)CO1
Reactant: COc1ccc(CCO)cc1F
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CCOc2ccc(CCC3(CO)COC(C)=N3)cc2)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[2-(4-hydroxymethyl-2-methyl-4,5-dihydro-oxazol-4-yl)-ethyl]-phenol (300 mg, 1.27 mmol) in dry THF (6 ml) is added under inert atmosphere polystyrene supported triphenylphosphine (loading 3 mmol·g−1, 1.27 g, 3.81 mmol, 3 eq.), 2-(3-fluoro-4-methoxyphenyl)-ethanol (647.7 mg, 3.81 mmol, 3 eq.) and DBAD (877.3 mg, 3.81 mmol, 3 eq.). The reaction mixture was stirred under inert atmosphere at room temperature overnight. Polystyrene supported triphenylphosphine was then filtered through frit and washed with ethyl acetate and methanol. The reaction mixture was then concentrated to dryness following by addition of 4M HCl in dioxane (3 ml), the reaction was stirred at room temperature for 3 hours. The reaction mixture was quenched by addition of saturated solution of NaHCO3 (10 ml) and ethyl acetate (40 ml). The organic layer is separated and the aqueous phase is extracted with ethyl acetate (3×40 ml). The combined organic extracts are washed with brine, dried over MgSO4, and evaporated to dryness. Purification using Flashmaster (chexane/ethyl acetate (1/9), ethyl acetate and ethyl acetate/methanol (98/2)) affords [4-(2-{4-[2-(3-fluoro-4-methoxy-phenyl)-ethoxy]-phenyl}ethyl)-2-methyl-4,5-dihydro-oxazol-4-yl]-methanol as colorless oil. MS (ESI+): 364.2 (MH+)
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[O:12]=[C:13]([O:31][C@@H:32]1[CH:37]2[CH2:38][CH2:39][N:34]([CH2:35][CH2:36]2)[CH2:33]1)[CH:14]([NH:21][C:22]1[CH:26]=[CH:25][S:24][C:23]=1[C:27]([O:29][CH3:30])=[O:28])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCOC(C)=O>[Br-:1].[CH3:30][O:29][C:27]([C:23]1[S:24][CH:25]=[CH:26][C:22]=1[NH:21][CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:13]([O:31][C@@H:32]1[CH:37]2[CH2:36][CH2:35][N+:34]([CH2:2][CH2:3][CH2:4][O:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)([CH2:39][CH2:38]2)[CH2:33]1)=[O:12])=[O:28]
Reactant: BrCCCOc1ccccc1
Reactant: COC(=O)c1sccc1NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1sccc1NC(C(=O)O[C@H]1C[N+]2(CCCOc3ccccc3)CCC1CC2)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.2 %

Procedure:
(3-Bromopropoxy)benzene (19.7 μl, 0.12 mmol) was added to a solution of methyl 3-(2-oxo-1-phenyl-2-((R)-quinuclidin-3-yloxy)ethylamino)thiophene-2-carboxylate (C11) (50 mg, 0.12 mmol) in EtOAc (2 ml). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was triturated with Et2O and then purified by preparative HPLC (Eluent: CH3CN/H2O) to obtain (3R)-3-(2-(2-(methoxycarbonyl)thiophen-3-ylamino)-2-phenylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (25.3 mg, 32.9% yield).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.C(N(CC)CC)C.Cl.[CH2:23]([O:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([NH2:32])=[NH:31])[CH:24]([CH3:26])[CH3:25]>C(#N)C>[CH3:14][S:13][C:4]1[N:3]=[C:2]2[N:31]=[C:30]([C:29]3[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=3[O:27][CH2:23][CH:24]([CH3:26])[CH3:25])[NH:32][C:8](=[O:10])[C:7]2=[CH:6][N:5]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: CC(C)COc1ccccc1C(=N)N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CSc1ncc2c(=O)[nH]c(-c3ccccc3OCC(C)C)nc2n1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 21.5 %

Procedure:
Ethyl 4-chloro-2-methylthio-5-pyrimidine carboxylate (1.50 g) followed by triethylamine (0.65 g) was added to a stirred mixture of 2-isobutoxybenzamidine hydrochloride (1.46 g) and triethylamine (0.65 g) in acetonitrile (150 ml). The reaction mixture was stirred at 5° C. for 15 minutes and then at ambient temperature for 3 days. A solid (0.55 g) was collected by filtration and the filtrate was reduced in volume to yield a second crop of solid (0.47 g). The solids were combined and recrystallised from ethanol to yield the title compound, 0.57 g, m.p. 185°-186° C.
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH2:9][CH3:10])[C:3]([O:5]CC)=O.[CH3:11][O-].[Na+].CO.[CH3:16][NH:17][CH3:18].P(=O)(O)(O)O>>[OH:1][CH:2]([CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([N:17]([CH3:18])[CH3:16])=[O:5]
Reactant: C[O-]
Reactant: CNC
Reactant: CCCC(O)C(=O)OCC
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: CO
Product: CCCCC(O)C(=O)N(C)C
Yield: 80 %

Procedure:
In a three-neck flask, at 20° C. and under an inert atmosphere, are mixed ethyl 2-hydroxyvalerate (31 g; 210 mmol) and sodium methylate in solution in methanol (25% w/w) (2.2 g; 10 mmol). To this mixture, is added dimethylamine in solution in methanol (50% w/w) (37.1 g; 411 mmol) within 30 minutes. The temperature of this mixture is brought to 40° C. and maintained for 3 hours. After return of the temperature of this reaction mixture to 20° C., orthophosphoric acid is added until a pH of 5 is obtained. The salts formed are removed by filtration and the solvents are removed under reduced pressure. 2-hydroxy-N,N-dimethylhexanamide is then obtained with a purity<98% i.e. a yield of 80%.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[N:11]1([C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[Si](C#N)(C)(C)C.[N:31]1([C:36](N2C=CN=C2)=[O:37])C=CN=[CH:32]1>[Pd]>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:20]([C:19]4[CH:22]=[CH:23][CH:24]=[C:17]([N:11]5[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]5)[CH:18]=4)[CH2:32][NH:31][C:36]3=[O:37])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Nc1ccc2[nH]cnc2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=Cc1cccc(N2CCCCC2)c1
Agent: [Pd]
Agent: C[Si](C)(C)C#N
Product: O=C1NCC(c2cccc(N3CCCCC3)c2)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from 1H-benzo[d]imidazol-5-amine (0.400 g, 3 mmol), 3-(piperidin-1-yl)benzaldehyde (0.570 g, 3 mmol), TMSCN (0.375 mL, 3 mmol), Pd/C (10%, 0.02 g), TEA 1.05 mL, 7.5 mmol), di-(imidazol-1-yl)methanone (0.730 g, 4.5 mmol) as described in method 2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15](OS(C(F)(F)F)(=O)=O)=[CH:16][CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]1([CH2:33][C:34]#[CH:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([C:35]#[C:34][CH2:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:16][CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(OS(=O)(=O)C(F)(F)F)c2CC1
Product: CC(C)(C)OC(=O)N1CCc2cccc(C#CCc3ccccc3)c2CC1
Yield: 73.8 %

Procedure:
Use a method similar to the General Procedure 3 to couple 3-tert-butoxycarbonyl-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.6 g, 1.5 mmol) with 3-phenyl-1-propyne (0.38 mL, 3 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 40:1 and 20:1) to give 3-tert-butoxycarbonyl-6-(3-phenyl-prop-1-ynyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an orange oil (400 mg, 74%).