Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[C:5](=[O:6])[N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[O:16][CH3:17])[C@H:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]1[O:28][CH2:27][CH2:26][O:25]1.C(N(CC)CC)C.[O:36]([CH2:43][C:44](Cl)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(OCC)(=O)C>[CH3:17][O:16][C:9]1[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:8]=1[CH2:7][N:4]1[C:5](=[O:6])[C@H:2]([NH:1][C:44](=[O:45])[CH2:43][O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@@H:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]1[O:28][CH2:27][CH2:26][O:25]1
Reactant: O=C(Cl)COc1ccccc1
Reactant: COc1ccc(CN2C(=O)[C@H](N)[C@@H]2c2ccccc2C2OCCO2)c(OC)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(CN2C(=O)[C@H](NC(=O)COc3ccccc3)[C@@H]2c2ccccc2C2OCCO2)c(OC)c1
Reaction time: 0.75 h

Procedure:
The amino compound from Example 3 (4.22 g, 11 mmol) was dissolved in ethyl acetate (60 ml) and cooled in an ice-alcohol bath. Triethylamine (1.67 g, 16.5 mmol) was added, followed by the dropwise addition of phenoxyacetyl chloride (2.06 g, 12.1 mmol) over a period of 5 minutes. The reaction was stirred for 45 minutes with cooling and then filtered. The filtrate was washed with 5% NaHCO3 and brine. The dried filtrate was evaporated to give the title product; 2.0 g. The product was recrystallized from ethyl acetate-ether; 1.02 g, mp 137-138°. The solid which was filtered from the reaction solution was stirred with hot ethyl acetate (100 ml) and filtered. The filtrate was treated with ether (200 ml) and cooled to give additional product; 3.91 g, mp 138-139°.
Reaction SMILES: C([O:8][C:9]1[CH:45]=[CH:44][C:12]([O:13][C:14]2[CH:43]=[CH:42][C:17]([C:18]([NH:20][CH2:21][C:22](=[O:41])[N:23]3[CH2:28][CH2:27][N:26]([C:29](=[O:40])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]([F:39])([F:38])[F:37])[CH2:25][CH2:24]3)=[O:19])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.CCCCCC>[Pd].CO>[OH:8][C:9]1[CH:45]=[CH:44][C:12]([O:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:20][CH2:21][C:22](=[O:41])[N:23]3[CH2:24][CH2:25][N:26]([C:29](=[O:40])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]([F:39])([F:38])[F:37])[CH2:27][CH2:28]3)=[O:19])=[CH:42][CH:43]=2)=[CH:11][CH:10]=1
Reactant: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(Oc2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCCCCC
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(Oc2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.1 %

Procedure:
Pd/C (20 mg in 3 drops of water) was added to 4-(4-benzyloxy-phenoxy)-N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-benzamide (80 mg, 0.13 mmol) in MeOH (10 mL). The resulting reaction mixture was stirred at room temperature under an atmosphere of hydrogen for 3 hours. The reaction mixture was then filtered through a bed of celite. The methanol was removed to afford 80 mg of crude product. Purification by column chromatography (using silica gel of mesh size of 60-120 and 80/20 EtOAc:Hexane as the eluent) afforded 33 mg (48% yield) of 4-(4-hydroxy-phenoxy)-N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-benzamide LC-MS purity: 93%. 1H NMR (DMSO-D6): δ 9.4 (s, 1H), 8.5 (t, 1H), 7.9-7.5 (m, 6H), 6.8-7 (m, 5H), 4.2 (d, 2H), 3.5 (m, 6H), 3.1 (m, 2H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:14]([CH2:15][OH:16])=[C:13]([CH3:17])[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1.Cl[C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][N:20]=1.[Cl-].[Na+]>C1COCC1>[CH3:26][O:25][C:23](=[O:24])[C:22]1[CH:27]=[CH:28][C:19]([O:16][CH2:15][C:14]2[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=3)=[N:11][O:12][C:13]=2[CH3:17])=[N:20][CH:21]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: Cc1onc(-c2cccc(Cl)c2)c1CO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2c(-c3cccc(Cl)c3)noc2C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a suspension of sodium hydride (55% dispersion in mineral oil, 852 mg, 20 mmol) in THF (27 mL) was added a solution of [3-(3-chloro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (18 mmol) in THF (54 mL) at 0° C. and the reaction mixture warmed to room temperature over 30 min. Then a solution of methyl 6-chloronicotinate (3.35 g, 20 mmol) in THF (1.5 mL) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=7:3) afforded 6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (52%) which was obtained as an off-white solid. MS: m/e=359.4 [M+H]+. To a solution of 6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (1.1 mmol) in THF (5 mL) was added a solution of lithium hydroxide monohydrate (94 mg, 2.2 mmol) in water (5 mL) and methanol (1 mL) added and the resulting mixture stirred at room temperature overnight. The mixture was acidified to pH 4 with HCl (25%, 3 drops) and methanol (2 drops) added. A gum began to form and the mixture was cooled at 0° C. for 1.5 h and then the aqueous layer decanted off. Trituration with diethylether and hexane afforded the title compound (84%) which was obtained as a white solid. MS: m/e=343.4 [M−H]−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:44]=[CH:45][CH:46]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:21]([O:32][CH3:33])=[N:22][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:24][CH:25]=4)[CH:18]=3)[N:13]([S:34]([C:37]3[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:12]=2)[CH:8]=[N:7]1.[CH3:47][C@H:48]1[CH2:50][O:49]1.CCN(C(C)C)C(C)C>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:44]=[CH:45][CH:46]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][N:29]([CH2:47][C@@H:48]([OH:49])[CH3:50])[CH2:28][CH2:27]5)=[N:22][C:21]=4[O:32][CH3:33])[CH:18]=3)[N:13]([S:34]([C:37]3[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:12]=2)[CH:8]=[N:7]1
Reactant: C[C@H]1CO1
Reactant: COc1nc(N2CCNCC2)ccc1-c1cnc2c(c1)c(-c1cnn(Cc3cccc(F)c3)c1)cn2S(=O)(=O)c1ccc(C)cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1nc(N2CCN(C[C@H](C)O)CC2)ccc1-c1cnc2c(c1)c(-c1cnn(Cc3cccc(F)c3)c1)cn2S(=O)(=O)c1ccc(C)cc1
Yield: 108.2 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(2-methoxy-6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (52 mg. 0.081 mmol) was alkylated using (S)-2-methyloxirane (8 mg, 0.137 mmol), DIPEA (18 mg, 0.137 mmol) and ethanol (5 mL) to get 61 mg (95.3%) of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[C:20]([C:22]4[O:23][C:24]([CH3:27])=[N:25][N:26]=4)[CH:19]=[CH:18][C:17]=3[CH3:28])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH:31]1([CH2:34]Br)[CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:34][CH:31]2[CH2:33][CH2:32]2)[C:8]([C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[C:20]([C:22]4[O:23][C:24]([CH3:27])=[N:25][N:26]=4)[CH:19]=[CH:18][C:17]=3[CH3:28])=[CH:14][CH:15]=2)=[O:9])=[CH:29][CH:30]=1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccc(Cl)cc4)cc3)c2)o1
Reactant: BrCC1CC1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)N(Cc4ccc(Cl)cc4)CC4CC4)cc3)c2)o1

Procedure:
N-(4-Chlorobenzyl)-N-(cyclopropylmethyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from N-(4-chlorobenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide and cyclopropylmethyl-bromide using method L. LCMS; retention time 3.89 min, MH+ 472/474.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([C:12]1[N:13]=[CH:14][NH:15][C:16]=1[CH3:17])(=[O:11])[CH3:10]>CCOCC.O1CCCC1>[CH3:17][C:16]1[N:15]=[CH:14][NH:13][C:12]=1[C:9]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([OH:11])[CH3:10]
Reactant: Br[Mg]c1ccccc1
Reactant: CC(=O)c1nc[nH]c1C
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1nc[nH]c1C(C)(O)c1ccccc1

Procedure:
A 3.0 M solution of phenyl-magnesium bromide (1.3 ml, 4 mmol) in ether was added to a solution of 0.25 g (2.0 mmol) 4-acetyl-5-methyl-imidazole in 20 ml dry tetrahydrofuran at ambient temperature. The mixture was refluxed for 2 h. The solvents are evaporated and the organics are extracted twice with ethyl acetate. The combined organic extracts are concentrated and the residue was purified by flash chromatography (silica gel, dichloromethane/methanol 95:5) to yield a product mainly containing 1-(5-methyl-3H-imidazol-4-yl)-1-phenyl-ethanol. This product was dissolved in 20 ml ethanol/ethyl acetate (1:1) and 0.5 ml of 10M hydrochloric acid was added. The mixture was hydrogenated (5% Pd/C, 0.07 g; 4 bar H2, 50° C.) for 4 h. Then the mixture was filtered through Celite®, and the solvent was evaporated. The residue was partitioned between an aqueous solution of potassium carbonate and ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated to yield a yellow oil that was purified by flash chromatography (silica gel, dichloromethane/methanol 95:5). To the amine an equimolar amount of hydrochloric acid in ethanol (5M) was added. By dilution with ether 4-methyl-5-(1-phenyl-ethyl)-1H-imidazole hydrochloride precipitated as a colourless solid that was filtered off (45 mg, 12%); MS (EI): 186.1 (M+.), 171.1 (((M-CH3)+.), 100%).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:6][C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[N:10]2[N:27]=[CH:28][C:29]([CH:30]([CH3:32])[CH3:31])=[C:9]2[N:8]=1)[CH2:4]C.NC(CO)C[OH:36]>>[OH:36][CH2:4][CH:3]([NH:6][C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:19][CH:20]=2)[N:10]2[N:27]=[CH:28][C:29]([CH:30]([CH3:31])[CH3:32])=[C:9]2[N:8]=1)[CH2:2][OH:1]
Reactant: NC(CO)CO
Reactant: CC[C@H](CO)Nc1nc(NCc2ccc(-c3ccccn3)cc2)n2ncc(C(C)C)c2n1
Product: CC(C)c1cnn2c(NCc3ccc(-c4ccccn4)cc3)nc(NC(CO)CO)nc12
Yield: 30 %

Procedure:
According to the same conditions resulting in the preparation of the compound 2, the compound 17 is prepared from IIa.2 by oxidation reaction of the sulfur atom and then introduction of serinol. Yield=30%. Oil. 1H NMR (300 MHz, CDCl2): δ 8.68 (d, 1H, J=4.4 Hz, Harom), 7.96 (d, 2H, J=8.3 Hz, Harom), 7.79-7.69 (m, 2H, Harom) 7.64 (s, 1H, Harom) 7.45 (d, 2H, J=8.3 Hz, Harom) 7.26-7.21 (m, 1H, Harom), 6.80 (bs, 1H, NH), 5.71 (bs, 1H, NH), 4.77 (d, 2H, J=5.9 Hz, CH2), 4.08-4.95 (m, 1H, CH), 3.92-3.80 (m, 4H, 2 CH2), 3.02 (hept, 1H, J=7.0 Hz, CH), 1.28 (d, 6H, J=7.0 Hz, 2 CH3). MS (ESI): m/z 434 (MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH2:34][CH2:35][NH:36][CH2:37][CH:38]=2)=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:35][CH:34]=2)=[CH:29][CH:28]=1
Reactant: Fc1ccc(C2=CCNCC2)cc1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CC=C(c2ccc(F)cc2)CC1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (100 g), triethylamine (50 cc) and 4-(4-fluorophenyl) 1,2,3,6-tetrahydropyridine (77.9 in toluene (950 cc). The mixture is heated for 7 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is continued for 8 hours at this temperature. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, 2-{3-[4-(4-fluorophenyl)-1,2,3,6-tetrahydro-l-pyridyl]propyl}-naphtho[1,8-cd]isothiazole 1,1-dioxide (105.4 g) is obtained in the form of a brown oil [Rf=0.8; thin-layer chromatography on silica gel; eluant: ethyl acetate]. This oil is converted to the hydrochloride, m.p. 224° C.
Reaction SMILES: C(C1C=CC2[NH:7][C:8](=O)[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[CH:11]([OH:12])C=2C=1)#N.NCCC1CCCN1CC>>[C:11]1(=[O:12])[C:10]2[C:9](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][NH:7]1
Reactant: N#Cc1ccc2c(c1)C(O)c1ccccc1C(=O)N2
Agent: CCN1CCCC1CCN
Product: O=C1NCc2ccccc21

Procedure:
The same procedures as in Example 29 were repeated except for using 5.01 g of 2-cyano-11-hydroxy-5, 11-dihydro-6H-dibenz[b,e]-azepin-6-one and 12.82 g of 2-(aminoethyl)-1-ethylpyrrolidine as the starting materials. Thus, 0.93 g of 3-(2-amino-5-cyanophenyl)-2-[1-ethylpyrrolidin-2-yl) methyl]isoindolin-1-one (Compound 35) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.Br[CH2:11][CH2:12][O:13][CH2:14]CBr.C([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([O:8][CH2:11][CH2:12][O:13][CH3:14])[CH:7]=1
Reactant: BrCCOCCBr
Reactant: Oc1cc(Br)ccc1F
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOc1cc(Br)ccc1F
Reaction time: 6 h

Procedure:
5-Bromo-2-fluoro-phenol (5.0 g, 26.2 mmol), 2-bromoethylether (2.71 ml, 28.8 mmol) and K2CO3 (4.4 g, 31.4 mmol) are mixed in 50 ml DMF and stirred at 50 C for 6 hours. Addition of aqueous NaHCO3 solution and extraction into ethyl acetate yields the title compound as viscous oil. 1H-NMR (400 MHz; DMSO-d6): 7.40 (d, 1H), 7.21 (dd, 1H), 7.08-7.14 (m, 1H), 4.21 (t, 2H), 3.66 (t, 2H), 3.30 (s, 3H). LC-MS (m/z, ES+): 248 (MH+), retention time: 3.02 mins (LC-MS method 3)
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[F:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]([CH2:15][CH:16]=[CH2:17])[C:12](Cl)=[O:13])=[CH:7][CH:6]=1>C(Cl)Cl>[CH2:1]([NH:3][C:12](=[O:13])[C@H:11]([C:8]1[CH:7]=[CH:6][C:5]([F:4])=[CH:10][CH:9]=1)[CH2:15][CH:16]=[CH2:17])[CH3:2]
Reactant: C=CC[C@H](C(=O)Cl)c1ccc(F)cc1
Reactant: CCN
Solvent: ClCCl
Product: C=CC[C@H](C(=O)NCC)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
A stream of ethylamine was introduced to ice-cooled CH2Cl2 (5 mL) until 350 mg gas had been consumed. A solution of (2S)-2-(4-fluorophenyl)pent-4-enoyl chloride (0.24 g in 5 mL of CH2Cl2, 1.1 mmol) was added dropwise. The mixture was stirred at room temperature for 1 h and then diluted with CH2Cl2 (10 mL). The solution was washed with aqueous solutions of KHSO4 (8 mL, 1M), NaOH (8 mL, 1M) and then brine. The organic solution was dried over Na2SO4 and then the solvent was evaporated. There was obtained 0.15 g (59%) of (2S)-N-ethyl-2-(4-fluorophenyl)pent-4-enamide. 1H NMR (500 MHz, CDCl3): 1.1 (t, 3H), 2.5 (m, 1H), 2.8-3.0 (m, 2H), 3.2-3.4 (m, 3H), 5.0-5.1 (m, 2H), 5.6-5.8 (m, 1H), 7.0 (t, 2H), 7.3 (m, 2H).
Reaction SMILES: [C:1]([OH:11])(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CC(O)COC(CO)C>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]/[C:2](/[CH:1]=[O:11])=[CH:3]\[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)C=Cc1ccccc1
Agent: CC(O)COC(C)CO
Product: CCCCCC/C(C=O)=C\c1ccccc1

Procedure:
Solid at 10°-23° C. At higher temperature, yellowish, oily liquid which has a high tendency to oxidation (cinnamic acid). Dissolves readily in diethyl phthalates and dipropylene glycol, floral, fruity note.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]([CH3:19])([N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:10]=[CH:9]1)[CH3:7].[BH4-].[Na+]>C(O)C>[CH3:19][C:6]([N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:10]=[CH:9]1)([CH3:7])[CH2:5][CH2:4][CH2:3][OH:2]
Reactant: COC(=O)CCC(C)(C)n1cnc(-c2cccnc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(CCCO)n1cnc(-c2cccnc2)c1
Temperature: 50 °C
Yield: 68 %

Procedure:
To a solution of 4-methyl-4-(4-pyridin-3-yl-imidazol-1-yl)pentanoic acid methyl ester (1 eq) in ethanol was added sodium borohydride (4 eq) at room temperature. The reaction mixture was heated in a 50° C. oil bath for 60 minutes and then quenched by addition of H2O. Once the reaction solvent was removed in vacuo, a solution of the residue in dichloromethane was washed with NaCl (sat.), dried over sodium sulfate, filtered and concentrated to give 4-methyl-4-(4-pyridin-3-yl-imidazol-1-yl)-pentan-1-ol (68%). MH+(246)
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:22]([C:24]2[N:28](COCC[Si](C)(C)C)[C:27]3[CH:37]=[CH:38][C:39]([C:41]#[N:42])=[CH:40][C:26]=3[N:25]=2)[CH3:23])=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7](S(C1C=CC(C)=CC=1)(=O)=O)[CH:6]=[CH:5]2.CC1C(C(C2N(COCC[Si](C)(C)C)C3C=C(C#N)C=CC=3N=2)C)=C2C(=C(C)C=1)N(S(C1C=CC(C)=CC=1)(=O)=O)C=C2>>[CH3:1][C:2]1[C:3]([CH:22]([C:24]2[NH:28][C:27]3[CH:37]=[CH:38][C:39]([C:41]#[N:42])=[CH:40][C:26]=3[N:25]=2)[CH3:23])=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C(C)c4nc5cc(C#N)ccc5n4COCC[Si](C)(C)C)c(C)cc(C)c32)cc1
Agent: Cc1ccc(S(=O)(=O)n2ccc3c(C(C)c4nc5ccc(C#N)cc5n4COCC[Si](C)(C)C)c(C)cc(C)c32)cc1
Product: Cc1cc(C)c2[nH]ccc2c1C(C)c1nc2cc(C#N)ccc2[nH]1

Procedure:
The title compound was synthesized from a mixture of (±)-2-(1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile as described in Example 64-B and 64-C. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.22 (br. s., 1H) 10.86 (br. s., 1H) 8.13 (m) 7.69-7.84 (m) 7.36-7.54 (m) 7.05 (t, J=2.78 Hz, 1H) 6.76 (s, 1H) 5.83-5.96 (m, 1H) 4.72-4.90 (m, 1H) 2.39 (s, 3H) 2.37 (s, 3H) 1.76 (d, J=7.07 Hz, 3H). HRMS calcd. for C20H18N4 (M+H)+ 315.1610. found 315.1610.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.CO[C:14](OC)([CH3:16])[CH3:15].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1.FC(F)(F)C(O)=O.N1C=CC=CC=1.CCOC(C)=O.CCCCCC>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:14]([CH3:16])[CH3:15])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: COC(C)(C)OC
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1ccc(F)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 56.5 %

Procedure:
4-fluoro-2-nitroaniline (15.6 g; 0.1 mole), 2,2-dimethoxypropane (24.6 ml; 0.2 mole) and trifluoroacetic acid [TFA] (23.1 ml; 0.005 moles) were dissolved in toluene (500 ml) and stirred for 1 hr. BH3 * pyridine (10.0 ml; 0.1 moles) was added in 1.0 ml increments. The reaction was exothermic, and the reaction progress was monitored by tlc 40% EtOAc/Hexane. Additional TFA, BH3 * pyridine and 2,2-dimethoxypropane were added until the tlc indicated that the 4-fluoro-2-nitroaniline was consumed. The reaction mixture was placed on a bed of silica and eluted with 10% methyl-t-butylether/hexane. The product was the first major component to elute, which produced 11.2 g (58%) of a yellow oil.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Cl-].[Cl-].[Ta+5].C([Mg]Br)(C)C.C(C1([Li])C=CC=C1)CC.C(C1CC=CC=1)CC.C([Li])CCC.Cl[Ta:35](Cl)([C:44]1([CH2:49][CH2:50][CH3:51])[CH:48]=[CH:47][CH:46]=[CH:45]1)[C:36]1([CH2:41][CH2:42][CH3:43])[CH:40]=[CH:39][CH:38]=[CH:37]1.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>CCOCC.C1COCC1.O.C1(C)C=CC=CC=1>[CH2:49]([C:44]1([TaH3:35][C:36]2([CH2:41][CH2:42][CH3:43])[CH:40]=[CH:39][CH:38]=[CH:37]2)[CH:48]=[CH:47][CH:46]=[CH:45]1)[CH2:50][CH3:51]
Reactant: CCCC1([Ta](Cl)(Cl)C2(CCC)C=CC=C2)C=CC=C1
Agent: [Ta+5]
Agent: CC(C)[Mg]Br
Agent: CCCC1=CC=CC1
Solvent: O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCC1([TaH3]C2(CCC)C=CC=C2)C=CC=C1
Temperature: -70 °C
Reaction time: 19.5 h
Yield: 12.8 %

Procedure:
80.0 g (223 mmol) of tantalum pentachloride was suspended in 1,340 ml of ether, and 324 ml (220 mmol) of isopropyl magnesium bromide (0.68M THF solution) was added thereto. A solution of 50.2 g (440 mmol) of propylcyclopentadienyl lithium prepared from propylcylopentadiene and butyl lithium in THF (380 ml) was added, followed by refluxing for 1 hour. The solvent was distilled away, and the residue was dried at 80° C. in vacuo for 8 hours to obtain a brownish-red solid containing dichlorobis(propylcyclopentadienyl)tantalum (Ta (PrCp)2Cl2). 2,100 ml of toluene was added to this brownish-red solid, and the resulting mixture was ice-cooled. 198 ml (660 mmol) of a toluene solution (65 wt %) of sodium bis(2-methoxyethoxy)aluminum hydride was added dropwise to the mixture, and temperature was returned to room temperature, followed by stirring for 19.5 hours. 106 ml of water was added to the mixture, followed by stirring until foaming does not occur. Insoluble contents were filtered out, and the solvent was distilled away from the filtrate. 2,000 ml of hexane was added to the residue, the insoluble contents were filtered out, and the filtrate was concentrated to about 800 ml. When the concentrated liquid was cooled to −70° C., a white solid was formed. A supernatant was removed, and the solid was washed with 40 ml of cold pentane two times to obtain 11.2 g (yield: 12.8%) of a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:16]1[CH:17]=[CH:18][N:19]=[C:20]2[C:25]=1[N:24]=[CH:23][C:22]([O:26][CH3:27])=[CH:21]2.O>CN(C=O)C>[CH3:27][O:26][C:22]1[CH:21]=[C:20]2[C:25]([C:16]([O:8][C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=3)=[CH:17][CH:18]=[N:19]2)=[N:24][CH:23]=1
Reactant: Nc1ccc(O)cc1
Reactant: COc1cnc2c(Cl)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cnc2c(Oc3ccc(N)cc3)ccnc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Five 20 mL microwave vials were each charged with 4-aminophenol (0.700 mg, 33 mmol) and 3 equivalents of cesium carbonate in 6.0 ml of DMF. The mixture was stirred at RT for 10 minutes. Following addition of 8-chloro-3-methoxy-1,5-naphthyridine (1 g, 26 mmol), the reaction vessels were capped and irradiated at 150° C. for 15 min in the microwave, at which time the reaction was determined complete by LCMS. The mixture was allowed to cool to ambient temperature and material from the five vessels was combined. A deep brown solid crashed out with addition of water. Filtered solids, washed with water and dried overnight in the vacuum oven to afford 4-(7-methoxy-1,5-naphthyridin-4-yloxy)benzenamine as a brown solid.