Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10]Br)=[CH:6][CH:5]=1>CC#N>[F:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][NH:2][CH3:1])=[CH:6][CH:5]=1
Reactant: Fc1ccc(CBr)cn1
Reactant: CN
Solvent: CC#N
Product: CNCc1ccc(F)nc1
Reaction time: 8 h
Yield: 61 %

Procedure:
To a mixture of 2.5 g of 40% aqueous methylamine solution and 30 ml of CH3CN was added dropwise 3.0 g of crude (6-fluoro-3-pyridyl)methyl bromide with constant stirring. The mixture was allowed to stand at room temperature overnight and concentrated under reduced pressure. The residue was extracted with AcOEt and the extract was dried over MgSO4 and concentrated. The procedure gave 1.35 g of the title compound as a crude orange-colored oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][OH:7].[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CC=CC=1>C(Cl)Cl>[C:14]([Si:11]([CH3:13])([CH3:12])[O:1][C:2]1[CH:3]=[C:4]([CH2:5][CH2:6][OH:7])[CH:8]=[CH:9][CH:10]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCc1cccc(O)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc(CCO)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a solution of 3-hydroxyphenethyl alcohol (6.0 g, 43.4 mmol) in 275 mL of CH2Cl2 was added 6.55 g (43.4 mmol) of TBDMS-Cl (tert-butyldimethylsilyl chloride), cooled to 0° C., then added 7.0 mL (86.8 mmol) of pyridine. The reaction mixture was stirred at ambient temperature overnight. Upon concentration, the crude mixture was purified by silica gel flash chromatography (eluted with hexane then 5% EtOAc/hexane) to provide 8.9 g of a clear oil: 1H NMR (300 MHz, DMSO-d6) δ 9.17 (s, 1H), 7.04 (m, 1H), 6.60 (m, 3H), 3.73 (t, J=6.9 Hz, 2H), 2,65 (t, J=6.9 Hz, 2H), 0.83 (s, 9H), −0.03 (s, 6H).
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:36]=[C:10]3[C:11]([C:15]4[CH:35]=[CH:34][C:18]([CH2:19][N:20]5[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][C@H:21]5[CH3:33])=[CH:17][CH:16]=4)=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)=[O:5])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:33][C@@H:21]1[CH2:22][NH:23][CH2:24][CH2:25][N:20]1[CH2:19][C:18]1[CH:17]=[CH:16][C:15]([C:11]2[C:10]3[N:9]([N:8]=[C:7]([NH:6][C:4]([CH:1]4[CH2:3][CH2:2]4)=[O:5])[CH:36]=3)[CH:14]=[CH:13][CH:12]=2)=[CH:35][CH:34]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1Cc1ccc(-c2cccn3nc(NC(=O)C4CC4)cc23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CNCCN1Cc1ccc(-c2cccn3nc(NC(=O)C4CC4)cc23)cc1

Procedure:
(R)-tert-Butyl 4-(4-(2-(cyclopropanecarboxamido)pyrazolo[1,5-a]pyridin-4-yl)benzyl)-3-methylpiperazine-1-carboxylate (162 mg, 0.33 mmol) was stirred in DCM (2 mL) and TFA (0.3 mL) at room temperature for 2 h. The reaction mixture was concentrated in vacuo and loaded onto an SCX column in DCM. MeOH (20 mL) was passed through the column and the compound was eluted with (7 N NH3 in MeOH in MeOH) (1:5) (50 mL). The filtrate was concentrated in vacuo to give (R)—N-(4-(4-((2-methylpiperazin-1-yl)methyl)phenyl)pyrazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[CH3:7][O:8][CH:9](OC)[C:10]1[N:11]=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[O:13][CH:14]=1.B(F)(F)F.CCOCC>>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:12]2[O:13][CH:14]=[C:10]([CH:9]([O:8][CH3:7])[C:5]#[N:6])[N:11]=2)=[CH:20][CH:19]=1
Reactant: COC(OC)c1coc(-c2ccc(F)cc2)n1
Reactant: C[Si](C)(C)C#N
Agent: FB(F)F
Solvent: CCOCC
Product: COC(C#N)c1coc(-c2ccc(F)cc2)n1
Reaction time: 0.33 h
Yield: 25.5 %

Procedure:
Trimethylsilyl cyanide (4.13 g, 41.76 mmol) was added to a solution of 4-(dimethoxymethyl)-2-(4-fluorophenyl)oxazole (400 mg, 1.69 mmol) at room temperature, followed by boron trifluoride diethyl etherate (37 mg, 0.26 mmol). The reaction mixture was stirred for 20 min, quenched with saturated aqueous NaHCO3 solution, and extracted with EtOAc. The combined extracts were washed with H2O and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 8-10% EtOAc in petroleum ether) to afford 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methoxyacetonitrile (100 mg, yield 16%) as a light yellow liquid. 1H NMR (400 MHz, CDCl3) δ 8.08-8.06 (m, 2H), 7.90 (d, J=0.9 Hz, 1H), 7.19-7.15 (m, 2H), 5.29 (d, J=0.9 Hz, 1H), 3.62 (s, 3H). MS (ESI) m/z: Calculated for C12H9FN2O2: 232.21. found: 232.9 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][N:8]=[CH:7][C:6]=2[CH:5]=[CH:4][C:3]=1I.[CH3:12][N:13](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[Br:1][C:2]1[C:10]2[S:9][N:8]=[CH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:12]#[N:13]
Reactant: Brc1c(I)ccc2cnsc12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2cnsc2c1Br
Temperature: 80 °C
Yield: 50 %

Procedure:
A suspension of 7-bromo-6-iodo-1,2-benzothiazole (43.2 mg, 0.127 mmol), zinc cyanide (13.6 mg, 0.116 mmol), and Pd(PPh3)4 (15.9 mg, 0.0138 mmol) in DMF (1.6 mL) was heated to 80° C. in a microwave for 15 min. The reaction mixture was concentrated in vacuo. Purification of the residue by ISCO chromatography (20 to 100% dichloromethane:heptane) to afford 16.4 mg (50%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 9.25 (s, 1H), 7.77 (d, J=7.58 Hz, 1H), 7.69 (d, J=8.08 Hz, 1H); MS (ESI): 237.15, 239.14 [M−H]+; HPLC tR=0.90 min (HPLC: nonpolar—2 min).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH3:12])=[O:10].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([NH2:21])=[N:18][C:19]=1[CH3:20]>C(#N)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH3:12])=[O:10])=[C:2]([NH:21][C:17]2[CH:16]=[CH:15][C:14]([Cl:13])=[C:19]([CH3:20])[N:18]=2)[CH:7]=1
Reactant: Cc1nc(N)ccc1Cl
Reactant: COC(=O)c1nnc(Cl)cc1Cl
Solvent: CC#N
Product: COC(=O)c1nnc(Cl)cc1Nc1ccc(Cl)c(C)n1
Temperature: 130 °C
Reaction time: 36 h
Yield: 20.4 %

Procedure:
A pressure tube was charged with methyl 4,6-dichloropyridazine-3-carboxylate (2 g, 9.66 mmol) and 5-chloro-6-methylpyridin-2-amine (2.76 g, 19.3 mmol). To the mixture was added acetonitrile (12 mL) and the reaction mixture heated with stirring at 130° C. for 1.5 days. After cooling to room temperature, the acetonitrile was removed in vacuo. The residue obtained was purified by chromatography (silica, 80 g, 50 μm from Analogix, 0% to 5% acetone in dichloromethane over 20 min., holding at 5% for 5 min, then increasing the gradient from 5% to 10% over the next 20 min) to give methyl 6-chloro-4-(5-chloro-6-methylpyridin-2-ylamino)pyridazine-3-carboxylate (618 mg, 20%) as an orange solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.70 (br. s., 1H), 9.18 (s, 1H), 7.63 (d, J=8.34 Hz, 1H), 6.78 (d, J=8.34 Hz, 1H), 4.12 (s, 3H), 2.66 (s, 3H), 1.58 (br. s., 1H); LC-MS 313 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:18][C:19]#[CH:20])[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=O>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CCC>[CH:7](=[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH:9]([CH2:18][C:19]#[CH:20])[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[CH2:2][CH2:3][CH3:4]
Reactant: C#CCC(C(=O)c1cccnc1)c1ccc(Cl)cc1Cl
Agent: CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: C#CCC(C(=CCCC)c1cccnc1)c1ccc(Cl)cc1Cl

Procedure:
starting from 2-(2,4-dichlorophenyl)-1-(3-pyridyl)-4-pentyn-1-one and butyltriphenylphosphonium bromide 1 there is obtained 3-[α-butylidene-2,4-dichloro-β-(2-propynyl)-phenethyl]-pyridine
Reaction SMILES: [CH:1]1([CH:7]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=2)[C:8]2[O:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=2)[C:8]2[O:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3cccnc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)NCCC(=O)O)cc2)C2CCCCC2)oc2cccnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
To a mixture of ethyl 3-{[(4-{[cyclohexyl(3-methylfuro[3,2-b]pyridin-2-yl)methyl]amino}phenyl)carbonyl]amino}propanoate (383 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred overnight at room temperature, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (315 mg, 88%) as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[C:22][C:23]3[CH:46]=[CH:45][C:26]([O:27][CH2:28][CH2:29][N:30]([CH3:44])[CH:31]4[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]4)=[CH:25][CH:24]=3)=[N:19][CH:20]=2)=[CH:11][CH:10]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[C:22][C:23]3[CH:24]=[CH:25][C:26]([O:27][CH2:28][CH2:29][N:30]([CH3:44])[CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[CH:45][CH:46]=3)=[N:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: CN(CCOc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(CCOc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
60 μL (0.8 mmol) trifluoroacetic acid are added to a solution of 22 mg (0.04 mmol) tert-butyl 4-[(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-methyl-amino]-piperidin-1-carboxylate in 5 mL DCM and the reaction mixture is stirred for 24 h at RT. The mixture is evaporated down i. vac. and the residue is stirred with diethyl ether. The precipitate is suction filtered, washed with diethyl ether and dried.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:21]=[CH:20][C:12]3[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=3[CH:10]=2)O1.Cl[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([S:30]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[N:25]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>CS(C)=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>[F:39][C:36]1[CH:35]=[CH:34][C:33]([S:30]([C:26]2[N:25]=[C:24]([C:9]3[CH:21]=[CH:20][C:12]4[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=4[CH:10]=3)[CH:29]=[CH:28][CH:27]=2)(=[O:32])=[O:31])=[CH:38][CH:37]=1
Reactant: O=S(=O)(c1ccc(F)cc1)c1cccc(Cl)n1
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: CC(=O)Nc1nc2ccc(-c3cccc(S(=O)(=O)c4ccc(F)cc4)n3)cc2s1
Temperature: 95 °C
Reaction time: 2.5 h

Procedure:
A RBF was charged with N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (0.3 g, 1 mmol), 2-chloro-6-(4-fluorophenylsulfonyl)pyridine (0.230 g, 0.8 mmol), 2M Na2CO3 (0.8 mL, 2 mmol), tetrakis(triphenylphosphine)palladium(0) (0.1 g, 0.1 mmol), and dioxane (6 mL). The flask was heated in a pre-heated (95° C.) bath and allowed to stir under an inert atmosphere for 2.5 hours. The mixture was allowed to cool to ambient temperature and diluted with DMSO and filtered. The crude material was purified by reverse-phase HPLC to give N-(6-(6-(4-fluorophenylsulfonyl)pyridin-2-yl)benzo[d]thiazol-2-yl)acetamide as an off-white solid. MS (ESI pos. ion) m/z: 428 (MH+). Calculated exact mass for C20H14FN3O3S2: 427. 1H NMR (400 MHz, DMSO-d6): 8.06-8.27 (m, 5H), 7.97-7.99 (m, 1H), 7.82-7.84 (m, 1H), 7.52-7.54 (m, 2H), 7.37-7.40 (m, 1H), 1.96 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[C:4]([N+:10]([O-:12])=[O:11])[C:5](N)=[N:6][C:7]=1[CH3:8].N([O-])=[O:15].[Na+]>FC(F)(F)C(O)=O.O>[Br:1][C:2]1[C:3]([CH3:13])=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([OH:15])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(N)c([N+](=O)[O-])c(C)c1Br
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(O)c([N+](=O)[O-])c(C)c1Br
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-4,6-dimethyl-3-nitro-2-pyridinylamine (Heitsch, H.; et al. Bioorg. Med. Chem. 1997, 5, 673., 2.0 g, 8.1 mmol) in trifluoroacetic acid/water (v/v, 2:1, 30 mL) was added sodium nitrite (1.1 g, 16 mmol) in small portions at room temperature, and then the reaction mixture was stirred overnight. The resulting precipitates were collected by filtration, washed with water, and dried under reduced pressure to give 2.2 g (quant.) of the title compound: 1H-NMR (CDCl3) δ 2.53 (3H, s), 2.38 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][CH2:14][CH2:15][CH:16]=O)[O:10][N:9]=2)=[CH:4][CH:3]=1.[C:18]1([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH:24]([N:25]1[CH2:30][CH2:29][N:28]([CH2:16][CH2:15][CH2:14][CH2:13][CH:11]2[O:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:12]2)[CH2:27][CH2:26]1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=CCCCC1CC(c2ccc(F)cc2)=NO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1ccc(C2=NOC(CCCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)C2)cc1
Yield: 65.2 %

Procedure:
4-[3-(4-Fluorophenyl)-4,5-dihydroisoxazol-5-yl]butanal (27.0 mg, 0.114 mmol), 1-(diphenylmethyl)piperazine (26.3 mg, 0.104 mmol), molecular sieve (5 beads) and NaBH(OAc)3 (66.3 mg, 0.313 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 32.0 mg (65.1%) of the target compound was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[C:13](B(O)O)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:21][C:22]1[CH:30]=[CH:29][C:25]2[N:26]=[CH:27][S:28][C:24]=2[CH:23]=1>>[C:1]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[C:13]([NH:21][C:22]2[CH:30]=[CH:29][C:25]3[N:26]=[CH:27][S:28][C:24]=3[CH:23]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc2ncsc2c1
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1B(O)O
Product: CC(C)(C)c1ccccc1Oc1ncccc1Nc1ccc2ncsc2c1

Procedure:
According to the experimental procedure of Example 234, Example 235 was obtained by reacting 234b with 6-aminobenzothiazole. tR=7.344 min (Shimadzu Phenomenex S5 ODS 4.6×50 mm Luna 4.6×50 mm; flow rate 2.5 mL/mn; detection at 220 nM; Gradient elution 0% to 100% B over 8 min; (A=10% MeOH, 90% H2O, 0.2% H3PO4 & B=90% MeOH, 10% H2O, 0.2% H3PO4). HRMS (ESI) m/z calcd for C22H22N3OS [M+H]+. found 376.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C([Li])CCC.CCCCCC.[C:42]([NH:45][C:46]([CH2:57][CH2:58][CH2:59][CH2:60]C=O)([C:52]([O:54][CH2:55][CH3:56])=[O:53])[C:47]([O:49][CH2:50][CH3:51])=[O:48])(=[O:44])[CH3:43].C(O)(C)(C)C>O1CCCC1.CCOCC>[C:42]([NH:45][C:46]([CH2:57][CH2:58][CH2:59][CH:60]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])([C:52]([O:54][CH2:55][CH3:56])=[O:53])[C:47]([O:49][CH2:50][CH3:51])=[O:48])(=[O:44])[CH3:43]
Reactant: CCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(CCCCC=O)(NC(C)=O)C(=O)OCC
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: CCCCCCCCCC=CCCCC(NC(C)=O)(C(=O)OCC)C(=O)OCC
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Decyltriphenylphosphonium bromide (10.85 g) was dissolved in 100 ml of dry tetrahydrofuran. Under an argon atmosphere, 13 ml of a 1.6 M n-butyl lithium/hexane solution was dropwise added thereto and the mixture was stirred for 15 minutes. The mixture was cooled to -78° C. and a solution of diethyl 2-acetamido-2-(4-formylbutyl)malonate (4.17 g)/dry tetrahydrofuran (50 ml) was dropwise added thereto and the mixture was stirred at 78° C. for 40 minutes under an argon atmosphere. Under the same conditions, a solution of t-butanol (3.3 ml)/tetrahydrofuran (15 ml) was dropwise added thereto and the mixture was stirred at room temperature under an argon atmosphere for 1.5 hours. The reaction mixture was diluted with ether and washed with water. The organic layer was dried and concentrated. The concentrate was purified by silica gel column chromatography using hexane-acetic acid (5:1→5:2) as an eluent to give 2.1 g of colorless, oily diethyl 2-acetamido-2-(4-tetradecenyl)malonate.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH:3]=[CH2:4].COCCOC.[Cl:13][C:14]([Cl:19])(Cl)[C:15](Cl)=[O:16]>C(OCC)C.[Zn]>[C:2]([CH:3]1[CH2:4][C:15](=[O:16])[C:14]1([Cl:19])[Cl:13])([CH3:6])([CH3:5])[CH3:1]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: C=CC(C)(C)C
Agent: [Zn]
Solvent: CCOCC
Solvent: COCCOC
Product: CC(C)(C)C1CC(=O)C1(Cl)Cl
Temperature: 25 °C

Procedure:
Suspend 3,3-dimethyl-1-butene (10 mL, 80.8 mmol), ethylene glycol dimethyl ether (11.5 mL, 106 mmol), and freshly activated zinc (13.8 g, 211 mmol) in dry diethyl ether (100 mL) under a nitrogen atmosphere. Add to this suspension a solution of trichloroacetyl chloride (11.5 mL, 103 mmol) in dry diethyl ether (50 mL) dropwise over 20 minutes. Heat to reflux for 24 hours. Cool to room temperature and filter off the residual solid materials. Concentrate the filtrate and triturate the residue with hexanes. Filter the mixture to remove solid materials. Wash the filtrate solution with saturated aqueous sodium bicarbonate solution (3×), saturated aqueous sodium chloride solution, dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 0:100 to 10:90 ethyl acetate:hexanes) to give the pure fractions and concentrate. Isolate the desired compound by vacuum distillation to give a clear liquid (7.59 g, 48%).
Reaction SMILES: C([O:8][C:9]([C:11]1([N:17]([CH:35]=[CH:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1.[H][H]>C(O)C.O>[CH2:40]([O:39][C:37]([CH2:36][CH2:35][N:17]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)=[CH:23][CH:22]=1)(=[O:20])=[O:19])[C:11]1([C:9]([OH:10])=[O:8])[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)=[O:38])[CH3:41]
Reactant: CCOC(=O)C=CN(C1(C(=O)OCc2ccccc2)CCOCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: [H][H]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCN(C1(C(=O)O)CCOCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1

Procedure:
A solution of (4.4 mmol) of the product of step D in 25 mL of ethanol is treated with 2.5 g of 50% water wet 10% palladium on carbon catalyst and shaken under 53 psi of hydrogen for 21 hours. The catalyst is removed by filtration and washed with ethanol (4×25 mL). The filtrate and washings are combined and concentrated under vacuum to crude product.
Reaction SMILES: CS(O)(=O)=O.[CH2:6]1[O:24][C:9]2([CH2:14][CH2:13][C:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([CH2:15]O)[CH2:11][CH2:10]2)[O:8][CH2:7]1.[C-]#[N:26].[K+]>CN(C)P(N(C)C)(N(C)C)=O>[CH2:6]1[O:24][C:9]2([CH2:14][CH2:13][C:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:15]#[N:26])[CH2:11][CH2:10]2)[O:8][CH2:7]1
Reactant: OCC1(Cc2ccccc2)CCC2(CC1)OCCO2
Reactant: [C-]#N
Agent: CS(=O)(=O)O
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: N#CC1(Cc2ccccc2)CCC2(CC1)OCCO2

Procedure:
A mixture of 18.6 g. (0.055 M) of 4-benzyl-4-hydroxymethylcyclohexan-1-one ethylene ketal methanesulfonate (2) (prepared as in Example 2C) and 18 g. of potassium cyanide in 180 ml. of hexamethylphosphoramide is heated for about 17 hours in an oil bath at about 145° C. The resulting gel is allowed to cool, diluted to 800 ml. with water and extracted with benzene. The organic layer is washed with water and brine and evaporated to dryness. The residue is chromatographed on 1 l. of silica gel and eluted with 25% ethyl acetate in Skellysolve B and the fractions found similar to TLC pooled to give 4-benzyl-4-cyanocyclohexan-1-one ethylene ketal (3).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N-:5]=[N+:6]=[N-:7].[Na+].[CH2:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N:18]=[C:19]=[O:20])[C:13]=1[CH3:21])[CH3:10].N([O-])=O.[Na+].Cl>O.CN(C)C=O>[CH3:21][C:13]1[C:12]([O:11][CH2:9][CH3:10])=[CH:17][CH:16]=[CH:15][C:14]=1[N:18]1[C:19](=[O:20])[NH:7][N:6]=[N:5]1
Reactant: CCOc1cccc(N=C=O)c1C
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Al+3]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cccc(-n2nn[nH]c2=O)c1C
Temperature: 75 °C
Reaction time: 1 h

Procedure:
Under ice-cooling, to a mixture of N,N-dimethylformamide 350 mL and anhydrous aluminum chloride 33.6 g was added sodium azide 15 g, and the resulting mixtures were stirred for one hour. Thereto was thereafter added 1-ethoxy-3-isocyanato-2-methylbenzene described in Reference Preparation example 2737.2 g and the resulting mixtures were heated to 75° C. and were stirred for five hours. The mixtures were cooled and under ice-cooling, to the reaction mixtures was added ice water 100 mL, followed by addition of a mixture of sodium nitrite 23 g and water 150 mL, and the mixtures were acidified with concentrated hydrochloric acid to pH about 4. The mixtures were extracted with ethyl acetate and the organic layers were washed with water and saturated saline, and were dried over anhydrous magnesium sulfate and were then concentrated under reduced pressure. The resulting residues were subjected to a silica gel column chromatography to give 1-(2-methyl-3-ethoxyphenyl)-1,4-dihydrotetrazole-5-one 39.0 g.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([C:30]3[CH:31]=[C:32]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:33]=[CH:34][CH:35]=3)[CH2:26][CH2:25]2)=[CH:14][CH:13]=1>>[C:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH:18]([C:15]1[CH:14]=[CH:13][C:12]([F:11])=[CH:17][CH:16]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:25][CH2:26][CH:27]([C:30]2[CH:31]=[C:32]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:33]=[CH:34][CH:35]=2)[CH2:28][CH2:29]1)(=[O:10])[CH3:9]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccc(F)cc3)CC2)c1
Reactant: CC(=O)c1cccc(O)c1
Product: CC(=O)c1cccc(OC(CCCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc(F)cc2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 1-(3-hydroxyphenyl)ethanone and N-(3-{1-[6-(4-fluorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 559.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([CH2:11][Br:12])[CH:8]=[C:7]([CH2:13]Br)[CH:6]=1)[CH3:2].[C:16]1([OH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:6]=[C:7]([CH2:13][O:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:8]=[C:9]([CH2:11][Br:12])[CH:10]=1)[CH3:2]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)c1cc(CBr)cc(CBr)c1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(CBr)cc(COc2ccccc2)c1

Procedure:
The subtitle compound was prepared from 3,5-bis[bromomethyl]benzoic acid ethyl ester (5.18 g) and phenol (1.45 g) in dimethylformamide (10 ml) by the method of example 7 step (i). Yield after chromatography, eluting with 10% ethyl acetate in isohexane, 2.13 g of a mixture containing 15% product and 85% diphenoxy compound.