Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:10]=1.[F:35][C:36]1[C:46]([F:47])=[CH:45][C:44](I)=[CH:43][C:37]=1[C:38]([N:40]([CH3:42])[CH3:41])=[O:39].C(=O)([O-])[O-].[Na+].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(#N)C>[F:35][C:36]1[C:46]([F:47])=[CH:45][C:44]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[N:10][N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:32])[CH3:33])[C:12]3=[N:13][CH:14]=2)=[CH:43][C:37]=1[C:38]([N:40]([CH3:42])[CH3:41])=[O:39]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: CN(C)C(=O)c1cc(I)cc(F)c1F
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cc(F)c(F)c(C(=O)N(C)C)c3)cc12
Yield: 68 %

Procedure:
A mixture of 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (3.1 g, 6.43 mmol), 2,3-difluoro-5-iodo-N,N-dimethyl-benzamide (2 g, 6.43 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)-dichloride dichlormethane adduct (262 mg, 0.32 mmol) in acetonitrile (14 mL) and aqueous solution of sodium carbonate (2M, 6.5 mL) was irradiated in a Personal Chemistry Optimizer at 100° C. for 15 min. Sodium sulfate was added to the crude reaction mixture and the solids were filtered over Celite. The solids were washed with acetonitrile and the combined filtrate was concentrated. Purification by flash silica gel chromatography using a gradient of ethyl acetate and hexanes afforded 1.23 g (4.37 mmol, 68%) of 2,3-difluoro-5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-benzamide as a colorless solid. 1H NMR (500 MHz, DMSO-d6) δ 8.95 (d, J=2.5 Hz, 1H), 8.46 (d, J=2 Hz, 1H), 8.02 (ddd, J=12 Hz, J2=10 Hz, J3=2.5 Hz, 1H), 7.67 (m, 1H), 7.61 (dd, J1=8 Hz, J2=1.5 Hz, 1H), 7.49 (m, 1H), 7.23 (d, J=8 Hz, 1H), 7.10 (td, J=8 Hz, J2=1 Hz, 1H), 5.84 (s, 2H), 3.81 (s, 3H), 3.68 (t, J=8 Hz, 2H), 3.02 (s, 3H), 2.91 (s, 3H), 0.85 (t, J=8 Hz, 2H), −0.09 (s, 9H). MS: m/z 539 [MH+]
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8](O)=[C:5]([O:6][CH3:7])[CH:4]=1.[CH3:12][N:13]([CH3:18])[S:14](Cl)(=[O:16])=[O:15].CCOC(C)=O.CCCCCC>CN(C1CCCCC1)C.CCOC(C)=O.CCCCCC>[CH3:12][N:13]([CH3:18])[S:14]([C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7])(=[O:16])=[O:15]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: COc1cc(C=O)ccc1O
Solvent: CCOC(C)=O
Solvent: CN(C)C1CCCCC1
Solvent: CCCCCC
Product: COc1cc(C=O)ccc1S(=O)(=O)N(C)C
Reaction time: 4 h

Procedure:
To a solution of vanillin (4.56 g, 30 mmol) in N,N-dimethylcyclohexylamine (30 mL) at 80-90° C., was added N,N-dimethylsulfamoyl chloride (3.79 mL, 35.27 mmol). The mixture was stirred at this temperature for 4 h, transferred to a separating funnel and diluted with EtOAc (100 mL). The organic layer was washed with water (2×200 mL), 6M HCl (aq.) (200 mL), brine (2×200 mL), dried (Na2SO4) and filtered. Concentration in vacuo of the combined filtrates gave a golden-yellow oil which solidified on standing. The product was stirred in n-hexane, filtered and air-dried to give OBS02011 as yellow plates (6.92 g, 89%). TLC [SiO2, EtOAc-n-hexane (1:1)] Rf=0.65; 1H-NMR (270 MHz, CDCl3)=2.98 (6H, s), 3.93 (3H, s), 7.44 (1H, d, J=1.6), 7.48 (1H, dd, J=1.6, 8.1), 7.53 (1H, d, J=8.1), 9.92 (1H, s).
Reaction SMILES: [C:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][C:4]=1[CH3:15])#[N:2].F[B-](F)(F)F.[CH3:21][O+](C)C.[OH-].[Na+]>C(Cl)Cl>[C:1]([C:3]1[C:4]([CH3:15])=[CH:5][C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:7][C:8]=1[O:9][CH3:21])#[N:2]
Reactant: C[O+](C)C
Reactant: CCOC(=O)c1cc(C)c(C#N)c(=O)[nH]1
Agent: F[B-](F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)c1cc(C)c(C#N)c(OC)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52.9 %

Procedure:
To a stirred suspension of ethyl 5-cyano-4-methyl-6-oxo-1,6-dihydropyridine-2-carboxylate (2.0 g, 9.70 mmol) in CH2Cl2 (25 mL) was added trimethyloxonium tetrafluoroborate (2.0 g, 13.52 mmol). The reaction was rinsed down with CH2Cl2 and stirred at RT for 24 hr. (The reaction eventually cleared up.) To the reaction was added 1N NaOH (75 mL). After stirring for 10 minutes the mixture was poured into a separatory funnel. The CH2Cl2 phase was removed, dried (Na2SO4), filtered and concentrated under vacuum. Purification by silica gel chromatography (Analogix SF25-40 g, 50 to 100% CH2Cl2 in hexanes) gave the product ethyl 5-cyano-6-methoxy-4-methylpicolinate (1.13 g, 5.13 mmol, 52.9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 1H), 4.37 (q, J=7.1 Hz, 2H), 4.03 (s, 3H), 2.55 (s, 3H), 1.33 (t, J=7.2 Hz, 3H). MS (ES)+m/e 221.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.F[C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[O:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cu]>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=[O:13])=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1F
Reactant: Oc1ccc(Cl)nc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccccc1Oc1ccc(Cl)nc1
Yield: 93.6 %

Procedure:
A mixture of 6-chloro-pyridin-3-ol (418 mg, 3.2 mmol), 2-fluorobenzaldehyde (522 mg, 4.21 mmol), potassium carbonate (442 mg, 3.2 mmol) and copper powder (201 mg, 3.2 mmol) was heated in DMF (6.4 mL) at 120° C. for 6 hours. The reaction was then cooled, and concentrated to an oil. The residue was purified by flash chromatography (eluting with 20% ethyl acetate/hexane) to give the title compound as a brown solid (700 mg, 93%).
Reaction SMILES: [NH2:1][C:2]1([CH3:15])[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.CO.O.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25]([OH:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1>CC(O)C>[CH3:29][C:19]1[CH:20]=[CH:21][C:22]([S:25]([OH:28])(=[O:27])=[O:26])=[CH:23][CH:24]=1.[CH3:29][C:19]1[CH:20]=[CH:21][C:22]([S:25]([OH:28])(=[O:27])=[O:26])=[CH:23][CH:24]=1.[CH3:15][C:2]1([NH2:1])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: CC1(N)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CC(C)O
Solvent: O
Product: CC1(N)CCNCC1
Temperature: 60 °C

Procedure:
A solution of tert-butyl 4-amino-4-methylpiperidine-1-carboxylate (1.96 g, 9.15 mmol) in MeOH (15.2 mmol) was added dropwise over 30 minutes to a solution of p-toluenesulfonic acid monohydrate (4.00 g, 21.0 mmol) in 2-propanol (7.9 mL) at 60° C. The reaction mixture was then heated to 60° C. for 16 h. After cooling to 0° C. the precipitate was filtered off and washed with 2-propanol and dried to give the title compound (3.91 g, 93%) as a white solid.
Reaction SMILES: [CH3:1][C:2]([S:5](/[N:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:11][N:10]=1)=O)([CH3:4])[CH3:3].[CH:21]([Mg]Br)=[CH2:22]>O1CCCC1>[C:2]([S:5][NH:7][C@@H:8]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:11][N:10]=1)[CH:21]=[CH2:22])([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)S(=O)/N=C/c1ccc(OCC(F)(F)F)cn1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=C[C@@H](NSC(C)(C)C)c1ccc(OCC(F)(F)F)cn1
Temperature: -78 °C
Yield: 73.5 %

Procedure:
To a mixture of 2-methyl-N-{(1E)-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylidene}propane-2-sulfinamide (10.0 g, 32.4 mmol) and tetrahydrofuran (150 ml) at −78° C. was added dropwise 1.0M vinylmagnesium bromide in tetrahydrofuran (58.4 ml, 58.4 mmol), maintaining temperature during addition below −70° C. Reaction was stirred at −78° C. for an hour. To complete reaction, an additional amount of 1.0M vinylmagnesium bromide (19.4 ml, 19.4 mmol) was required. The reaction was then quenched by pouring mixture into a cold solution of saturated NH4Cl (800 ml) and ethyl acetate (600 ml) with vigorous stirring at 0° C. Layers were separated and organic extracts were combined, dried over Na2SO4, filtered and concentrated in vacuum. The resulting brown oil was purified by flash chromatography (Si2O, 25-100% ethyl acetate in hexanes, gradient) to give 2-{(1R)-1-[(tert-butylthio)amino]prop-2-enyl}-5-(2,2,2-trifluoroethoxy)pyridine as a white solid (8.10 g, 73.5%). 1H NMR (400 MHz, CDCl3) 8.30 (d, J=2.8 Hz, 1H), 7.28 (m, 2H), 5.92-5.83 (m, 1H), 5.34 (dd, J=16 Hz and 33 Hz, 2H), 5.01 (m, 1H), 4.99 (bs, 1H), 4.39 (q, J=8.0 Hz, 2H), 1.28 (s, 9H); MS(Electrospray): m/z 337.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=[CH:10][N+:9]=2[O-])=[CH:4][CH:3]=1.C(=O)([O-])[O-:20].[K+].[K+]>C(OC(=O)C)(=O)C.CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=[C:10]([OH:20])[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc[n+]([O-])c1-c1ccc(F)cc1
Agent: [K+]
Solvent: CO
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COC(=O)c1ccc(O)nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
A solution of 2-(4-fluorophenyl)-3-(methoxycarbonyl)pyridine-1-oxide (10.5 g.) in acetic anhydride (500 ml.) was stirred at reflux for 17 hr., cooled, evaporated to dryness and the residue partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organic layer was separated, dried and evaporated to dryness. The gum obtained was dissolved in methanol (400 ml.), treated with a solution of potassium carbonate (11.7 g.) in water (100 ml) and stirred at ambient temperature for 2 hours. The methanol was evaporated off, the aqueous residue diluted with more water (200 ml.) and the mixture filtered to give methyl 2-(4-fluorophenyl)-6-hydroxypyridin-3-carboxylate (8.0 g.) as a brown solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:16]2[O:15][CH2:14][CH2:13][C:12]([C:17]([O:19]CC)=O)=[CH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)=O)C.[ClH:22].[NH2:23][C:24]([NH2:26])=[NH:25].C[O-].[Na+]>CN(C)C=O.CO>[ClH:22].[ClH:22].[NH:25]([C:4]([C:6]1[C:16]2[O:15][CH2:14][CH2:13][C:12]([C:17]([NH:25][C:24]([NH2:26])=[NH:23])=[O:19])=[CH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:3])[C:24]([NH2:26])=[NH:23]
Reactant: N=C(N)N
Reactant: CCOC(=O)C1=Cc2cccc(C(=O)OCC)c2OCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: N=C(N)NC(=O)C1=Cc2cccc(C(=O)NC(=N)N)c2OCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.3 %

Procedure:
To a mixture of ethyl 2,3-dihydro-9-ethoxycarbonyl-1-benzoxepin-4-carboxylate (0.10 g) and guanidine hydrochloride (0.33 g) in N,N-dimethylformamide (2 ml) was added 28% sodium methoxide in methanol (0.66 ml) at room temperature. After the mixture was stirred at room temperature overnight, it was purified by column chromatography on silica gel using a mixture of chloroform and methanol (30:1 to 4:1). The fractions containing objective compound was collected and evaporated in vacuo. The residue was treated with methanol and 4N hydrogen chloride in 1,4-dioxane, and the solvent was evaporated in vacuo. The residue was triturated with ethanol to give (2,3-dihydro-9-guanidinocarbonyl-1-benzoxepin-4-carbonyl)guanidine dihydrochloride (46 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:29])[C:10]([C:12]1[S:21][C:20]2[C:19]3[CH:22]=[C:23]([C:26]([OH:28])=O)[CH:24]=[CH:25][C:18]=3[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=1)=[O:11].[CH2:30]([CH2:32][NH2:33])[OH:31]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:29])[C:10]([C:12]1[S:21][C:20]2[C:19]3[CH:22]=[C:23]([C:26]([NH:33][CH2:32][CH2:30][OH:31])=[O:28])[CH:24]=[CH:25][C:18]=3[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=1)=[O:11]
Reactant: NCCO
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)O)ccc1OCC2)c1ccc(Cl)cc1Cl
Product: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)NCCO)ccc1OCC2)c1ccc(Cl)cc1Cl

Procedure:
2-[(2,4-Dichloro-phenyl)-methyl-carbamoyl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid and ethanolamine were reacted by General Procedure B to give 361. NMR: (CDCl3): 2.70-2.73 (1 H, m, OH), 3.04-3.07 (2 H, m), 3.38 (3 H, s, Me), 3.66-3.70 (2 H, m), 3.89-3.91 (2 H, m), 4.26-4.29 (2 H, m), 6.48-6.51 (1 H, m, NH), 6.73 (1 H, s, Ar), 7.02 (1 H, d, J 8.4, Ar), 7.32 (1 H, d, 8.4, Ar), 7.38 (1 H, dd, J 8.4 and 2.2, Ar), 7.56-7.61 (2 H, m, Ar) and 7.94 (1 H, s, Ar). MS: (ESI+) MH+=532.08
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(N(CC)CC)C.[Cl:16][CH2:17][C:18](Cl)=[O:19]>C(OCC)(=O)C>[Cl:16][CH2:17][C:18]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])=[O:19]
Reactant: Nc1ccccc1O
Reactant: O=C(Cl)CCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1ccccc1O
Temperature: 0 °C
Reaction time: 1.67 h

Procedure:
To a mixture of 8.90 g (81.5 mmol) of 2-aminophenol and 11.4 ml (81.5 mmol) of triethylamine in 250 ml of ethyl acetate cooled at 0° C. were added over several minutes 6.5 ml (81.5 mmol) of chloroacetyl chloride. The reaction mixture was stirred at 0° C. for 100 min and then washed with saline, aqueous sodium bicarbonate, and saline. The organic layers were dried over magnesium sulfate and concentrated. Dichloromethane was added to the residue and the resulted solid collected and dried to give the title compound, mp 133°-134°; NMR (CDCl3) 4.27, 6.93, 7.02, 7.17, 7.25, 7.80 and 8.53 δ.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].[CH3:9][C:10]([CH3:12])=O>>[CH2:1]([O:3][C:4](=[O:8])[C:5](=[C:10]([CH3:12])[CH3:9])[C:6]#[N:7])[CH3:2]
Reactant: CC(C)=O
Reactant: CCOC(=O)CC#N
Product: CCOC(=O)C(C#N)=C(C)C

Procedure:
reacting ethylcyanoacetate with acetone to yield ethylisopropylidenecyanoacetate;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14]O)[N:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][C@H:9]1[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[NH:36]1[CH:40]=[CH:39][CH:38]=[N:37]1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:36]2[CH:40]=[CH:39][CH:38]=[N:37]2)[N:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][C@H:9]1[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1cn[nH]c1
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](CO)CN1C(=O)OC(C)(C)C
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](Cn2cccn2)CN1C(=O)OC(C)(C)C
Temperature: 10 °C
Reaction time: 0.05 h
Yield: 21.6 %

Procedure:
To a stirred solution of (2R,5R)-4-benzyl-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.96 g, 3 mmol) in DCM (10 mL) externally cooled in an ice-methanol bath was added triethylamine (0.91 g, 1.25 mL, 9 mmol) followed, dropwise over 0.05 h, methylsulfonyl chloride (0.38 g, 0.26 mL, 3.3 mmol). The mixture was stirred at 0-20° C. for 2 h, then pyrazole (0.27 g, 4 mmol) was added in one portion and stirring continued at 20° C. for 7 days. Mixture was poured into saturated aqueous NaHCO3 and extracted with DCM (3×20 mL). Combined organic extracts were dried (Na2SO4) then evaporated in vacuo to give an oil. Chromatography (SiO2, 0-100% Et2O in petrol) gave the title compound (0.24 g). MS: [M+H]+=371.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([CH:26]=O)=[CH:22][NH:23]2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21](/[CH:26]=[CH:14]/[C:13]([C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:15])=[CH:22][NH:23]2)=[CH:19][CH:18]=1
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: O=Cc1c[nH]c2cc(Cl)ccc12
Product: COc1cc(C(=O)/C=C/c2c[nH]c3cc(Cl)ccc23)cc(OC)c1OC
Yield: 69.2 %

Procedure:
Substantially the same procedure as in Example 1 was repeated using 3',4',5'-trimethoxyacetophenone (2.1 g) and 6-chloroindole-3-carboxaldehyde (1.8 g) except that the obtained product was recrystallized from ethyl acetate, to give Compound 42 (2.57 g).
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=2)[C:12]#[N:13])[S:4][N:3]=1.[CH2:19]([C:21]1[C:26](/[CH:27]=[CH:28]/[O:29][CH3:30])=[CH:25][CH:24]=[CH:23][C:22]=1B1OC(C)(C)C(C)(C)O1)[CH3:20].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:19]([C:21]1[C:26](/[CH:27]=[CH:28]/[O:29][CH3:30])=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=2)[C:12]#[N:13])[S:4][N:3]=1)[CH3:20]
Reactant: CCc1c(/C=C/OC)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)Oc1ccc(-c2nc(Br)ns2)cc1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(/C=C/OC)cccc1-c1nsc(-c2ccc(OC(C)C)c(C#N)c2)n1
Temperature: 120 °C
Yield: 85 %

Procedure:
To a solution of 5-(3-bromo-1,2,4-thiadiazol-5-yl)-2-[(1-methylethyl)oxy]benzonitrile (D44) (630 mg), 2-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (560 mg) and tripotassium phosphate (1237 mg) in N,N-dimethylformamide (DMF) (5 mL) and water (1.25 mL) stirred under nitrogen was added Pd(Ph3P)4 (225 mg). The mixture was sealed and heated under microwave at 120° C. for 15 min. After cooling the reaction, the mixture was concentrated and purified by column chromatography to give 5-(3-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,2,4-thiadiazol-5-yl)-2-[(1-methylethyl)oxy]benzonitrile (D54) (670 mg) as a colorless oil. MS (ES): C23H23N3O2S requires 405. found 406.2 (M+H+).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[H][H]>S(=O)(=O)(O)O.[Pd].C(O)C>[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:11][CH2:10]1
Reactant: O=C1CCCCC1
Reactant: CN1CCNCC1
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CN1CCN(C2CCCCC2)CC1
Reaction time: 96 h
Yield: 51.9 %

Procedure:
A 100 mL flask was charged with 3.02 g of cyclohexanone, 3.19 g of 1-methylpiperazine, 25 mL of ethanol, 3 drops of concentrated sulfuric acid and a catalytic amount of Pd/C, typically 5 mol %. A balloon filled with hydrogen gas was attached. After stirring for 4 days the reaction mixture was filtered through Celite and concentrated to give 2.91 g of 1-methyl-4-cyclohexylpiperazine.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][CH:34]=1)[NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]3[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=3)[CH:15]=2)[CH2:9][CH2:8]1.[Cl:35][CH2:36][C:37]1[C:38]([C:43]2[CH:48]=[C:47]([O:49][CH3:50])[C:46]([O:51][CH3:52])=[C:45]([O:53][CH3:54])[CH:44]=2)=[N:39][CH:40]=[CH:41][CH:42]=1>>[ClH:35].[ClH:35].[ClH:35].[CH3:1][S:2][C:3]1[CH:4]=[C:5]([N:6]([CH:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]4[CH:21]=[C:22]([O:30][CH3:31])[C:23]([O:28][CH3:29])=[C:24]([O:26][CH3:27])[CH:25]=4)[CH:15]=3)[CH2:11][CH2:12]2)[CH2:36][C:37]2[C:38]([C:43]3[CH:48]=[C:47]([O:49][CH3:50])[C:46]([O:51][CH3:52])=[C:45]([O:53][CH3:54])[CH:44]=3)=[N:39][CH:40]=[CH:41][CH:42]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: COc1cc(-c2ncccc2CCl)cc(OC)c1OC
Reactant: COc1cc(-c2cc(CN3CCC(Nc4cccc(SC)c4)CC3)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCC(N(Cc4cccnc4-c4cc(OC)c(OC)c(OC)c4)c4cccc(SC)c4)CC3)ccn2)cc(OC)c1OC
Product: Cl

Procedure:
4-(3-Methylthioanilino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (143 mg) and 3-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as yellow powder after converting a free base to a trihydrochloride.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([NH:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl:28][C:29]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:30]=1[CH2:31]Br>C1COCC1>[C:13]([NH:21][CH:22]([CH2:31][C:30]1[C:29]([Cl:28])=[CH:36][CH:35]=[CH:34][C:33]=1[Cl:37])[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)CNC(=O)c1ccccc1
Reactant: Clc1cccc(Cl)c1CBr
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1c(Cl)cccc1Cl)NC(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution comprised of N,N-diisopropylamine (3.97 mL, 22.8 mmol) in dry THF (57 mL) was cooled to −78° C. under nitrogen and then solutions of n-butyl lithium in hexanes (14.25 mL, 22.8 mmol) and ethyl benzoylaminoacetate (2.37 g, 11.4 mmol) in dry THF (23 mL) were added dropwise sequentially. The mixture was stirred for 1 hour and then a solution comprised of 2,6-dichlorobenzyl bromide (1.87 g, 11.4 mmol) in dry THF (2 mL) was added dropwise. The mixture was stirred for 1 hour at −78° C. and then for 30 minutes while allowing to warm. The mixture then was quenched with water (8 mL) and extracted with ethyl acetate (2×54 mL). The combined extracts were washed with 1M hydrochloric acid (1×27 mL) and saturated sodium chloride solution (1×27 mL), dried (Na2SO4) and concentrated on a rotary evaporator. Product was purified from the residue by flash column (silica gel, 10:90 to 50:50 v/v EtOAc-hexane) to provide crude ethyl 2-benzoylamino-3-(2,6-dichlorophenyl)propionate. The propionate ester was treated with lithium hydroxide (118.8 mg, 4.96 mmol) in ethanol (12 mL) and water (50 mL) for 15 hours. The mixture was then diluted with 1M hydrochloric acid (12 mL) and ethyl acetate (24 mL). The aqueous layer was separated and extracted with ethyl acetate (2×4 mL). The combined organic layers were washed with saturated sodium chloride solution (25 mL), dried (Na2SO4), filtered and concentrated on a rotary evaporator to provide 2-benzoylamino-3-(2,6-dichlorophenyl)propionic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C:11]([OH:13])=O)=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.OC(C(F)(F)F)=O.[C:43]([C:47]1[N:51]([CH2:52][CH2:53][CH2:54][O:55][CH3:56])[C:50]([C:57]2([OH:63])[CH2:62][CH2:61][CH2:60][NH:59][CH2:58]2)=[N:49][CH:48]=1)([CH3:46])([CH3:45])[CH3:44]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@@H:9]([NH:14][C:15](=[O:16])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:10][C:11]([N:59]2[CH2:60][CH2:61][CH2:62][C:57]([C:50]3[N:51]([CH2:52][CH2:53][CH2:54][O:55][CH3:56])[C:47]([C:43]([CH3:46])([CH3:44])[CH3:45])=[CH:48][N:49]=3)([OH:63])[CH2:58]2)=[O:13])=[CH:6][CH:7]=1
Reactant: COCCCn1c(C(C)(C)C)cnc1C1(O)CCCNC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc(Br)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COCCCn1c(C(C)(C)C)cnc1C1(O)CCCN(C(=O)C[C@@H](Cc2ccc(Br)cc2)NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
(R)-4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoic acid (45 mg, 81 gmol), EDC (24 mg, 125 μmol), HOBt (17 mg, 125 μmol) and 3-(5-tert-butyl-1-(3-methoxypropyl)-1H-imidazol-2-yl)piperidin-3-ol TFA salt (133C) (34 mg, 83 μmol) were added to a 10 mL round bottomed flask. DMF (420 μL) was added and the reaction was stirred overnight at room temperature. The solvent was removed and the residue was purified by preparatory LC/MS (35-50% CH3CN in H2O) to give the product tert-butyl (2R)-1-(4-bromophenyl)-4-(3-(5-tert-butyl-1-(3-methoxypropyl)-1H-imidazol-2-yl)-3-hydroxypiperidin-1-yl)-4-oxobutan-2-ylcarbamate (133D) (29 mg, 55% yield). ESI-MS:m/z 635.4 (M+H)+.