Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[CH:11]=[C:10]3[N:19]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:20](=O)[CH2:21][O:22][C:9]3=[CH:8][C:7]=2[N:6]=1)([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>C1(C)C=CC=CC=1>[CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[CH:11]=[C:10]3[N:19]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:20](=[S:38])[CH2:21][O:22][C:9]3=[CH:8][C:7]=2[N:6]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)Oc1cc(C(F)(F)F)c2cc3c(cc2n1)OCC(=O)N3CC(F)(F)F
Solvent: Cc1ccccc1
Product: CC(C)Oc1cc(C(F)(F)F)c2cc3c(cc2n1)OCC(=S)N3CC(F)(F)F
Yield: 81.2 %

Procedure:
A mixture of 7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinolin-2(3H)-one (EXAMPLE 22) (48.4 mg, 0.119 mmol) and Lawesson's reagent (0.144 g, 0.356 mmol) in 2.4 mL toluene was heated at reflux for 6 h, whereupon the mixture was partitioned between EtOAc (40 mL) and water (20 mL). The aqueous layer was extracted with EtOAc (20 mL), and the combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered, and concentrated. Flash chromatography (9:1 hexanes:EtOAc) afforded 41 mg of 7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinolin-2(3H)-thione, a yellow oil. Data for 7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinolin-2 (3H)-thione: Rf 0.36 (9:1 hexanes:EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.72 (broad s, 1H), 7.48 (s, 1H), 7.13 (s, 1H), 5.54 (hept, 1H, J=6.2), 5.32-5.42 (m, 2H), 5.05 (s, 2H), 1.41 (d, 6H, J=6.2).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[CH:4][N:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][N:37]([C:40](=[O:42])[CH3:41])[CH2:36][CH2:35]2)=[CH:30][CH:29]=1>CN(C=O)C.CCOC(C)=O>[CH2:12]([CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:27][C:28]1[CH:29]=[CH:30][C:31]([N:34]3[CH2:35][CH2:36][N:37]([C:40](=[O:42])[CH3:41])[CH2:38][CH2:39]3)=[CH:32][CH:33]=1)=[N:3][CH:4]=2)[CH2:14][CH3:15])[CH3:13]
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: CCC(CC)n1cnc2cnc(Cl)nc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(CC)n1cnc2cnc(Nc3ccc(N4CCN(C(C)=O)CC4)cc3)nc21
Temperature: 140 °C
Yield: 24.5 %

Procedure:
To a mixture of 2-chloro-9-(1-ethyl-propyl)-9H-purine (90 mg, 0.4 mmol) and TsOH (1.6 mL, 0.2 M in 1,4-dioxane) in DMF (0.25 mL) is added 1-[4-(4-amino-phenyl)-piperazin-1-yl]-ethanone (105 mg, 0.5 mmol). The reaction mixture is sealed in a microwave reactor and heated at 140° C. for 30 min. The mixture is diluted with EtOAc and washed with NaHCO3 aqueous solution and brine. The organics are dried over Na2SO4, filtered and concentrated. The crude product is purified by preparative HPLC to give 40 mg of 1-(4-{4-[9-(1-ethyl-propyl)-9H-purin-2-ylamino]-phenyl}-piperazin-1-yl)-ethanone.
Reaction SMILES: [NH2:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)([O-:15])=[O:14]>C1(C)C=CC=C(C)C=1>[OH:12][C:11]1[C:2]([NH:1][C:20](=[O:21])[C:19]2[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:24][CH:23]=2)=[C:3]([CH:8]=[CH:9][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1cccc(O)c1N
Solvent: Cc1cccc(C)c1
Product: COC(=O)c1cccc(O)c1NC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Methyl 2-amino-3-hydroxybenzoate (0.5 g; 2.99 mmol) was dissolved in m-xylene (40 ml) with warming to 60° C. 4-Nitrobenzoyl chloride (0.556 ml; 2.99 mmol) was added dropwise, and this was left to stir for 4 hours. The solution was cooled to ambient temperature and the m-xylene removed under reduced pressure. The solid was dissolved in water (100 ml) and the organics extracted into ethyl acetate (3×50 ml). The organic fractions were pooled, dried over magnesium sulphate, filtered and the solvent removed under reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[C@H:10]([CH3:11])[O:9][C@@H:8]([CH3:12])[CH2:7][N:6]1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:4].I[CH2:24][C:25]#[C:26][C:27]([CH3:30])([OH:29])[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)C>[CH3:1][O:2][C:3]([C@H:5]1[C@H:10]([CH3:11])[O:9][C@@H:8]([CH3:12])[CH2:7][N:6]1[S:13]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:24][C:25]#[C:26][C:27]([OH:29])([CH3:30])[CH3:28])=[CH:20][CH:21]=1)(=[O:15])=[O:14])=[O:4]
Reactant: COC(=O)[C@H]1[C@H](C)O[C@@H](C)CN1S(=O)(=O)c1ccc(O)cc1
Reactant: CC(C)(O)C#CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1[C@H](C)O[C@@H](C)CN1S(=O)(=O)c1ccc(OCC#CC(C)(C)O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(2S,3R,6S)-4-(4-Hydroxy-benzenesulfonyl)-2,6-dimethyl-morpholine-3-carboxylic acid methyl ester, (200 mg, 0.607 mmol) (prepared according to the methods described in U.S. patent application Ser. No. 60/096256, filed Aug. 12, 1998) was dissolved in dimethyl formamide (6 mL). 5-Iodo-2-methyl-pent-3-yn-2-ol (272 mg, 1.214 mmol) and cesium carbonate (593 mg, 1.821 mmol) were added and the reaction stirred at room temperature for 4 hours. The reaction was diluted with diethyl ether (100 mL) and washed with water (5 times 10 mL) and brine (30 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo to yield the title compound. The crude material was used directly in the preparation of Example 1 without further purification. 1HNMR (400 MHz, CDCl3): δ=7.70 (d, J=8.9 Hz, 2H), 7.0 (d, J=8.9 Hz, 2H), 4.74 (bs, 2H), 4.50 (q, J=6.6 Hz, 1H), 4.26 (s, 1H), 3.92 (m, 1H), 3.54 (s, 3H), 3.50 (m, 1H), 2.93 (dd, J=12.3 and 11.0 Hz, 1H), 1.48(s, 6H), 1.44 (d, J=5.4 Hz, 3H), 1.01(d, J=6.0, 3H). MS: Calculated for C20H27NO7S (M−OH): 408.15. Found: 408.1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([CH:12]([CH2:14][N:15]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)CC2C=CC=CC=2)[OH:13])=[CH:4][C:3]=1[Cl:37].Cl.C(O)C>C(O)C.[Pd]=O>[NH2:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:5]([CH:12]([CH2:14][NH:15][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[OH:13])=[CH:4][C:3]=1[Cl:37]
Reactant: Nc1c(Cl)cc(C(O)CN(CCCCCOCCc2ccccc2)Cc2ccccc2)cc1C(F)(F)F
Agent: O=[Pd]
Agent: Cl
Solvent: CCO
Product: Nc1c(Cl)cc(C(O)CNCCCCCOCCc2ccccc2)cc1C(F)(F)F
Yield: 63 %

Procedure:
A solution of 4-amino-3-chloro-α-[[[5-(2-phenylethoxy) pentyl](phenylmethyl)amino]methyl]-5-(trifluoromethyl)benzenemethanol (0.42 g) and conc. hydrochloric acid/ethanol (1:9 v/v, 0.71 ml) was hydrogenated over pre-reduced 10% palladium oxide on charcoal (80 mg, 50% aqueous paste) in absolute ethanol (5 ml). The mixture was filtered through hyflo and evaporated in vacuo to give an oil which was purified by FCC eluting with toluene-ethanol-triethylamine (95:5:1) to give the title compound as a white solid (0.22 g) m.p. 70°-71.5°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[CH3:2].C(N(CC)CC)C.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([CH:5]1[CH2:6][CH2:7][N:8]([S:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:27])=[O:26])[CH2:9][CH2:10]1)=[O:11])[CH3:2]
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(S(=O)(=O)c2ccccc2)CC1
Reaction time: 0.17 h

Procedure:
To isonipecotic acid ethyl ester (1.08 mL) dissolved in tetrahydrofuran (10 mL), triethylamine (1.40 mL) was added, and benzenesulfonyl chloride (1.02 mL) was added thereto at 0° C. The resultant mixture was stirred at room temerature for 21 hours. Ice was added to the mixture, followed by stirring for 10 minutes. Ethyl acetate and 0.5N hydrochloric acid were added thereto to thereby give two layers. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride. The resultant mixture was dried over sodium sulfate anhydrate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→2:1), to thereby give the title compound (1.66 g) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:12][CH2:13][CH2:14][Cl:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:15][CH2:14][CH2:13][CH2:12][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: ClCCCBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(OCCCCl)cc1
Yield: 93.7 %

Procedure:
A mixture of 7.0 g (0.05 mole) of 4-nitrophenol, 15.7 g (0.1 mole) of 1-bromo-3-chloropropane and 20.7 g (0.15 mole) of anhydrous potassium carbonate in 350 ml of acetone was heated at reflux for 17 hr. The mixture was cooled, filtered, and the filtrate was concentrated to give an oil which crystallized. The solid was collected by filtration, washed with petroleum ether, and dried to yield 10.1 g (94%) of the title compound. An analytical sample was prepared from ethyl ether-petroleum ether, m.p. 37°-39° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:15][CH2:16][C:17](Cl)=[O:18]>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:17](=[O:18])[CH2:16][Cl:15])=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(Br)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CCl)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
4-bromoaniline (1.72 g, 10 mmol) was dissolved in 50 mL dichloromethane. Pyridine (cat.) was added and then 2-chloroacetyl chloride (800 uL, 10 mmol) was added dropwise. The reaction was stirred at room temperature for 1 hr. The reaction was quenched with water and the aqueous layer was extracted with dichloromethane (2×25 mL). The combined organic layer was washed with water, then brine, and dried over Na2SO4. The solvent was evaporated to give the intermediate 7a (1.03 g, 4 mmol, 42% yield). 1H NMR (400 MHz, Chloroform-d) δ 8.24 (broad s, 1H), 7.54-7.44 (m, 4H), 4.21 (s, 2H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:37])[CH2:25][O:26][Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])[CH:22]=1)[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)=[O:12].Br[C:39]1[CH:40]=[CH:41][C:42]2[S:46][CH:45]=[CH:44][C:43]=2[CH:47]=1>CC(N(C)C)=O>[S:46]1[C:42]2[CH:41]=[CH:40][C:39]([O:7][C:8]3[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:37])[CH2:25][O:26][Si:27]([CH:34]([CH3:36])[CH3:35])([CH:28]([CH3:29])[CH3:30])[CH:31]([CH3:33])[CH3:32])[CH:22]=3)[C:11]([NH:13][C:14]3[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=3)=[O:12])=[CH:47][C:43]=2[CH:44]=[CH:45]1
Reactant: CC(C)[Si](OC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1)(C(C)C)C(C)C
Reactant: Brc1ccc2sccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(C)[Si](OC[C@H](C)Oc1cc(Oc2ccc3sccc3c2)cc(C(=O)Nc2ccn(C)n2)c1)(C(C)C)C(C)C
Temperature: 200 °C
Yield: 34.5 %

Procedure:
Cesium carbonate (163 mg, 0.05 mmol) was added to a solution of 3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-{(1S)-1-methyl-2-[(triisopropylsilyl)oxy]ethoxy}benzamide (225 mg, 0.5 mmol), bromotris(triphenylphosphine)copper1 (93 mg, 0.1 mmol) and 5-bromobenzothiophene (107 mg, 0.5 mmol) in dimethylacetamide (2.5 mL) and the stirred mixture heated at 200° C. in a “Biotage Initiator” microwave for 4 hours. The mixture was cooled to ambient temperature and pressure, poured onto water (40 mL) and extracted with ethyl acetate (3×15 mL), the combined organic layers washed with brine, dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with 40% ethyl acetate in isohexane, to give the desired compound (100 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:9]=1)[C:5]#[N:6].Br[C:20]1[CH:37]=[C:36]2[C:23]([CH2:24][CH2:25][C:26]3([C:29]42[N:33]=[C:32]([NH2:34])[C:31]([CH3:35])=[N:30]4)[CH2:28][CH2:27]3)=[CH:22][CH:21]=1>>[NH2:34][C:32]1[C:31]([CH3:35])=[N:30][C:29]2([C:36]3[C:23](=[CH:22][CH:21]=[C:20]([C:8]4[CH:7]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:9]=4)[C:5]#[N:6])[CH:37]=3)[CH2:24][CH2:25][C:26]32[CH2:27][CH2:28]3)[N:33]=1
Reactant: CC1=NC2(N=C1N)c1cc(Br)ccc1CCC21CC1
Reactant: CC1(C)OB(c2cc(Cl)cc(C#N)c2)OC1(C)C
Product: CC1=NC2(N=C1N)c1cc(-c3cc(Cl)cc(C#N)c3)ccc1CCC21CC1
Yield: 23.7 %

Procedure:
The title compound was prepared following the procedure described for Example 2, starting from 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (Intermediate 4, 71 mg, 0.27 mmol) and 7′-bromo-5″-methyl-3′,4′-dihydrodispiro[cyclopropane-1,2′-naphthalene-1′,2″-imidazol]-4″-amine (Example 1, 86 mg, 0.27 mmol). The product was purified by preparative HPLC to give the title compound (24 mg, 24% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.08 (td, 1 H), 0.10-0.16 (m, 1 H), 0.24 (ddd, 1 H), 0.49-0.62 (m, 1 H), 1.49 (dt, 1 H), 2.18 (s, 3 H), 2.32-2.44 (m, 1 H), 2.94-3.07 (m, 2 H), 6.53 (br. s, 2 H), 6.73 (d, 1 H), 7.29 (d, 1 H), 7.52 (dd, 1 H), 7.79 (t, 1 H), 7.88 (s, 1 H), 7.98 (t, 1 H); MS (ES+) m/z 375 [M+H]+.
Reaction SMILES: [NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:2]([C:20](O)=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].CCN(C(C)C)C(C)C.[NH2:39][CH2:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:2]([C:20]([NH:39][CH2:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: NCC(=O)OCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a suspension of Boc-(D)-Arg(Tos)-OH (1 g, 2.34 mmol) in CH2Cl2 (10 mL) was added DIEA (1 mL) at 0° C. To the clear solution was added Gly-OBn.eHCl (0.52 g, 2.58 mmol) and BOP (1.2 g, 2.8 mmol). The solution was stirred for 4 h at 0° C. Solvents were evaporated and residue was dissolved in a mixture of EtOAc (100 mL) and water (20 mL). The organic layer was washed with sat. NaHCO3 (10 mL), water (10 mL), 1N HCl (10 mL) and sat. NaCl (3×10 mL), dried with MgSO4, filtered and evaporated. The solid residue was purified by column chromatography on silica gel (EtOAc) to give 1.12 g of the title compound as a powder. ES-MS (M+H)+=576.3
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10](I)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:16][N:17]([CH3:30])[CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[C:23]([O:28][CH3:29])[CH:22]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH:27][C:24]2[CH:25]=[CH:26][C:21]([O:20][CH2:19][CH2:18][N:17]([CH3:16])[CH3:30])=[CH:22][C:23]=2[O:28][CH3:29])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COc1cc(OCCN(C)C)ccc1N
Reactant: COC(=O)c1cccc(I)c1C(=O)OC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1cccc(Nc2ccc(OCCN(C)C)cc2OC)c1C(=O)OC
Yield: 60 %

Procedure:
A mixture of 3-iodophthalic acid dimethyl ester (1.0 g, 3.1 mmol), 4-(2-dimethylaminoethoxy)-2-methoxyphenylamine (0.65 g, 3.1 mmol), Pd2(dba)3 (0.13 g, 0.14 mmol), rac-BINAP (0.058 g, 0.093 mmol), and cesium carbonate (1.4 g, 4.3 mmol), in 6 mL toluene was heated to reflux under nitrogen for 24 hours. The reaction mixture was cooled, diluted with CH2Cl2 (10 mL), and filtered through Celite, and the filter was washed with additional CH2Cl2 (30 mL). The filtrate was evaporated, and the residue was chromatographed using a methylene chloride-methanol gradient, eluting 0.75 g of the product at 96:4 methylene chloride-methanol, in 60% yield: 1H NMR (CDCl3) δ 2.35 (s, 6H), 2.73 (t, J=5.7 Hz, 2H), 3.80 (s, 3H), 3.87 (s, 3H), 3.88 (s, 3H), 4.06 (t, J=5.7 Hz, 2H), 6.46 (dd, J=8.6 Hz, J=2.7 Hz, 1H), 6.59 (d, J=2.7 Hz, 1H), 6.98 (dd, J=7.3 Hz, J=1.0 Hz, 1H), 7.08-7.16 (m, 2H), 7.22 (t, J=7.5 Hz, 1H), 7.93 (br, 1H).
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]O)=[CH:3][CH:2]=1.[S:23](Cl)([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24].N1C=CC=CC=1>O>[CH3:30][C:29]1[CH:31]=[CH:32][C:26]([S:23]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][C:4]2[CH:5]=[CH:6][C:1]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:2][CH:3]=2)(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: OCCCCCCCCOc1ccc(-c2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)CCCCCCCCOc2ccc(-c3ccccc3)cc2)cc1

Procedure:
A mixture of 33.26 g of 8-([1,1'-biphenyl]-4-yl-oxy)-1-octanol, 23.37 g of tosyl chloride and 200 ml of pyridine was allowed to stand in a refrigerator overnight. Then water was added, the solid collected, washed with water and dissolved in chloroform. This solution was washed with dilute hydrochloric acid then saturated aqueous sodium bicarbonate, dried and the solvent removed, giving the desired compound as a white solid.
Reaction SMILES: CCN(OC(C1C=CC=CC=1)=O)[C:4]([C:6]1[C:11](OC)=[C:10]([Cl:14])[CH:9]=[CH:8][C:7]=1OC)=O.CC1C=CC(/[N:33]=[CH:34]/[N:35]([CH3:46])/[CH:36]=N/C2C=CC(C)=CC=2C)=C(C)C=1>>[CH3:4][C:6]1[CH:11]=[C:10]([Cl:14])[CH:9]=[CH:8][C:7]=1/[N:33]=[CH:34]/[N:35]([CH3:46])[CH3:36]
Reactant: Cc1ccc(/N=C/N(C)/C=N/c2ccc(C)cc2C)c(C)c1
Reactant: CCN(OC(=O)c1ccccc1)C(=O)c1c(OC)ccc(Cl)c1OC
Product: Cc1cc(Cl)ccc1/N=C/N(C)C

Procedure:
benzomate and amitraz.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH3:13])=[C:7]([CH3:14])[C:4]=1[CH:5]=O.C([O-])(=O)C.[NH4+].[N+:20]([CH2:23][CH3:24])([O-:22])=[O:21]>C(OC(C)C)(C)C>[CH3:13][O:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:3]([O:2][CH3:1])=[C:4]([CH:5]=[C:23]([N+:20]([O-:22])=[O:21])[CH3:24])[C:7]=1[CH3:14]
Reactant: COc1cc(C)c(OC)c(C=O)c1C
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(C)OC(C)C
Product: COc1cc(C)c(OC)c(C=C(C)[N+](=O)[O-])c1C
Yield: 99 %

Procedure:
A mixture of 2,5-dimethoxy-3,6-dimethyl-benzaldehyde (4.0 g, 20 mmol), ammonium acetate (1 g, 13 mmol) and nitroethane (25 ml) was heated under reflux for 4 hours. The reaction mixture was diluted with diisopropyl ether, washed with water and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:isopropyl ether=95:5) and then recrystallized from methanol to obtain 5.1 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10]Br.[CH3:12][C@H:13]1[CH2:18][O:17][CH2:16][CH2:15][NH:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][N:14]1[CH2:15][CH2:16][O:17][CH2:18][C@@H:13]1[CH3:12]
Reactant: C[C@H]1COCCN1
Reactant: N#Cc1ccc(Br)c(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@H]1COCCN1Cc1cc(C#N)ccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-3-(bromomethyl)benzonitrile (0.9 g, 3.27 mmol) in DMF (13.09 ml) was added (S)-3-methylmorpholine (0.541 g, 3.93 mmol) and potassium carbonate (0.995 g, 7.20 mmol). The reaction mixture was allowed to stir at RT overnight. The reaction mixture was poured onto water and extracted with EtOAc (×2). The organic extractions were combined, washed with brine (×3), dried (MgSO4) and evaporated to give the sub-title compound as a yellow oil. Yield: 0.75 g
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9](/[CH:12]=[N:13]/[S@@:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[O:15])=[N:10][CH:11]=2)[CH2:3][CH2:2]1.[CH3:20][Mg]Br.[Cl-].[NH4+]>ClCCl>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]([C@H:12]([NH:13][S@@:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[O:15])[CH3:20])=[N:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)[S@@](=O)/N=C/c1ccc(OCC2CC2)cn1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: C[C@@H](N[S@](=O)C(C)(C)C)c1ccc(OCC2CC2)cn1
Temperature: -78 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
A solution of (R,E)-N-((5-(cyclopropylmethoxy)pyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (6.2 g, 22 mmol) was dissolved into dichloromethane (110 ml). Methyl magnesium bromide (44 ml, 44 mmol, 1.0M in THF) was added to the mixture at −78° C. dropwise. The mixture was stirred for 1 h at −78° C. The mixture was poured into saturated ammonium chloride aqueous solution, and the aqueous phase was extracted with ethyl acetate (twice). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (1:1 (v/v)) to give 3.2 g (49% yield) of the title compound as a white solid:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH:20]3[N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[NH:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[C:27]([N:15]1[CH:16]2[CH:21]([CH:20]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:19][CH2:18][CH2:17]2)[N:12]([C:10](=[O:11])[CH2:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:13][CH2:14]1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNC2CCCC(N3CCCC3)C21
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCN(C(=O)Cc2ccc(Cl)c(Cl)c2)C2C(N3CCCC3)CCCC21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under N2, 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)-perhydroquinoxalin-1-yl]-ethan-1-one (111 mg, 0.28 mmol) was dissolved in absolute CH2Cl2 (14 ml) and benzoyl chloride (47 mg, 0.35 mmol) was added dropwise. The mixture was stirred at room temperature overnight and then evaporated in vacuo. The residue was purified by flash chromatography (Ø 2 cm, CH2Cl2/MeOH/NH3 9.5:0.5:0.05, l=15 cm, V=5 ml) and was obtained as a yellowish resin.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12]CC)=[CH:9][CH:10]=2)[N:5]([CH2:15][CH3:16])[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([CH:26]2[CH2:28][CH2:27]2)=[O:25])=[CH:19][CH:18]=1)#[N:2].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[N:5]([CH2:15][CH3:16])[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([CH:26]2[CH2:28][CH2:27]2)=[O:25])=[CH:19][CH:18]=1)#[N:2]
Reactant: CCOc1ccc2c(C#N)c(-c3ccc(NC(=O)C4CC4)cc3)n(CC)c2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCn1c(-c2ccc(NC(=O)C3CC3)cc2)c(C#N)c2ccc(O)cc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To a solution of cyclopropanecarboxylic acid [4-(3-cyano-6-ethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-amide (4.4 g, 11.8 mmol) in 60 mL of DCM is added BBr3 (6.65 mL, 70 mmol) at −10° C. After the addition, the mixture is stirred for 3 h at 0° C. Then aqueous NaHCO3 is added to the mixture carefully until it became basic. The crude solid is collected by filtration to give 91% of cyclopropanecarboxylic acid [4-(3-cyano-1-ethyl-6-hydroxy-1H-indol-2-yl)-phenyl]-amide and is used for the next step without further purification.