Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][CH2:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][N:12]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=3[CH3:26])[C:20]([OH:22])=O)[C:13]2=[O:16])=[CH:8][CH:7]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[NH2:39][C:40]1[CH:44]=[CH:43][O:42][N:41]=1>C(Cl)Cl.CO>[CH3:27][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][N:12]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=3[CH3:26])[C:20]([NH:39][C:40]3[CH:44]=[CH:43][O:42][N:41]=3)=[O:22])[C:13]2=[O:16])=[CH:8][CH:7]=1
Reactant: Nc1ccon1
Reactant: Cc1ccc(C(=O)O)cc1-n1ccc2ccc(CCCN(C)C)cc2c1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2ccon2)cc1-n1ccc2ccc(CCCN(C)C)cc2c1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of 3-[7-[3-(dimethylamino)propyl]-1-oxoisoquinolin-2(1H)-yl]-4-methylbenzoic acid (151 mg) in methylene chloride (3 ml) was cooled to 0° C. and oxalyl chloride (72 μl) was added. After the addition of DMF (25 μl), the reaction mixture was stirred at room temperature for 2 hours, 3-aminoisoxazole (153 μl) was added and stirring continued at room temperature for 2.5 hours. The reaction mixture was dissolved in methanol and water and purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution yielded an orange oil. The oil was triturated with water resulted in a solid which was collected by filtration washed with diethyl ether and air dried to give 3-[7-[3-(dimethylamino)propyl]-1-oxoisoquinolin-2(1H)-yl]-N-isoxazol-3-yl-4-methylbenzamide as a tan solid (124 mg); NMR Spectrum: (DMSOd6) 0.57 (m, 2H), 0.71 (m, 2H), 1.35 (s, 3H), 2.09 (s, 3H), 6.64 (d, 1H), 7.10 (d, 1H), 7.23 (m, 1H), 7.45 (d, 1H), 7.59 (m, 3H), 7.72 (s, 1H), 7.83 (d, 1H), 8.63 (s, 1H), 9.98 (s, 1H); Mass Spectrum: M+H+ 349.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:12]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[C:13]([C:15]([OH:17])=O)[N:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.[NH2:30][C:31]1[S:32][CH2:33][CH2:34][N:35]=1>>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[NH:11][C:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)=[N:14][C:13]=2[C:15]([NH:30][C:31]2[S:32][CH2:33][CH2:34][N:35]=2)=[O:17])=[CH:23][CH:22]=1
Reactant: COc1ccc(-c2[nH]c(-c3ccc([N+](=O)[O-])cc3)nc2C(=O)O)cc1
Reactant: NC1=NCCS1
Solvent: O=S(Cl)Cl
Product: COc1ccc(-c2[nH]c(-c3ccc([N+](=O)[O-])cc3)nc2C(=O)NC2=NCCS2)cc1

Procedure:
2-(4-Nitrophenyl)-5-(4-methoxyphenyl)imidazole-4-carboxylic acid, 1 M hydrochloric acid—ether solution, thionyl chloride and 2-aminothiazoline were reacted and treated in the same manner as in Example 1 to give 5-(4-methoxyphenyl)-2-(4-nitrophenyl)-N-(2-thiazolinyl)imidazole-4-carboxamide.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27](OC)=[O:28])=[CH:21][CH:20]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CO.Cl>O1CCCC1>[O:7]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][OH:28])=[CH:21][CH:20]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)CCc1ccc(OCCCCOc2ccccc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CO
Solvent: C1CCOC1
Product: OCCCc1ccc(OCCCCOc2ccccc2)cc1
Yield: 99.3 %

Procedure:
20.1 ml of a 1 molar solution of lithium aluminium hydride in tetrahydrofuran is introduced. While stirring, a solution of 12.0 g of methyl 3-[4-(4-phenoxybutoxy)-phenyl]propanoate in 40 ml of THF is added dropwise in such a way that the mixture just starts to boil. The mixture is stirred at room temperature for 30 minutes. 1 ml of methanol is cautiously added to the suspension in order to hydrolyze excess lithium aluminium hydride. The mixture is then added to 1 molar hydrochloric acid and extracted with ethyl acetate. The organic phase is separated off, washed with saturated sodium chloride solution and dried over anhydrous sodium sulphate. Filtration and evaporation result in 10.9 g of product.
Reaction SMILES: [OH:1][CH:2]([CH:8]([N:15]([CH3:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3](OCC)=[O:4].[NH3:23]>>[OH:1][CH:2]([CH:8]([N:15]([CH3:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([NH2:23])=[O:4]
Reactant: CCOC(=O)C(O)C(c1ccccc1)N(C)c1ccccc1
Reactant: N
Product: CN(c1ccccc1)C(c1ccccc1)C(O)C(N)=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 54 %

Procedure:
A mixture of ethyl (2RS,3RS)-2-hydroxy-3-[methyl(phenyl)amino]-3-phenylpropanoate (1.20 g, 4.00 mmol) and methanolic ammonia solution (7 N, 20 mL) was stirred at 100° C. in a sealed tube for 5 hours. After cooling, all volatiles were removed under reduced pressure. The resulting yellow oil was purified via silica gel chromatography (15-30% isopropanol/hexane) and recrystallized (warm ethyl acetate/hexane/−25° C.) to yield 582 mg (54%) of (2RS,3RS)-2-hydroxy-3-[methyl(phenyl)amino]-3-phenylpropanamide as white needles. MS (ESI) m/z 268.9 ([M−H]−); HRMS: calculated for C16H18N2O2+H, 271.1447; found (ESI, [M+H]+), 271.1458.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([OH:12])=O)=[N:7][CH:8]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.Cl.[CH3:27][C:28]1[CH:29]=[N:30][N:31]([C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[C@H:38]([N:42]2[CH2:45][C:44]4([CH2:50][CH2:49][NH:48][CH2:47][CH2:46]4)[CH2:43]2)[CH2:37][CH2:36]3)[CH:32]=1.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([N:48]2[CH2:49][CH2:50][C:44]3([CH2:43][N:42]([C@H:38]4[C:39]5[C:35](=[CH:34][C:33]([N:31]6[CH:32]=[C:28]([CH3:27])[CH:29]=[N:30]6)=[CH:41][CH:40]=5)[CH2:36][CH2:37]4)[CH2:45]3)[CH2:46][CH2:47]2)=[O:12])=[N:7][CH:8]=1
Reactant: COc1ccc(CC(=O)O)nc1
Reactant: Cc1cnn(-c2ccc3c(c2)CC[C@H]3N2CC3(CCNCC3)C2)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CC(=O)N2CCC3(CC2)CN([C@@H]2CCc4cc(-n5cc(C)cn5)ccc42)C3)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.8 %

Procedure:
To a mixture of (5-methoxypyridin-2-yl)acetic acid (SM-1aa, 25.9 mg, 0.16 mmol) in dichloromethane (5 mL) was added 1,1′-carbonyldiimidazole (25.9 mg, 0.16 mmol) and the reaction was stirred overnight at room temperature. In a separate flask, to a mixture of 2-((R)-5-(4-methyl-1H-pyrazol-1-yl)-2,3-dihydro-1H-inden-1-yl)-2,7-diazaspiro[3.5]nonane dihydrochloride (8-1b, 60.0 mg, 0.15 mmol) in dichloromethane (10 mL) was added triethylamine (0.31 mL, 0.23 mmol). The activated acid was then added to the amine solution and the resulting mixture was stirred at room temperature for 2 hours. The reaction was concentrated and purified on an ISCO (Teledyne Isco Inc., Lincoln Nebr.) 12 g silica column eluting with 50-100% MeOH in ethyl acetate gradient to give 26 mg (36%) of the title compound (8A) as a gum. MS (ES+) 472.9 (M+H)+. 1H NMR (CD3OD) δ 1.62-1.75 (m, 4H), 1.85-1.97 (m, 1H), 2.13 (s, 3H), 2.17-2.31 (m, 1H), 2.80-2.92 (m, 1H), 3.03-3.15 (m, 1H), 3.20-3.27 (m, 2H), 3.32 (d, 2H), 3.48-3.56 (m, 4H), 3.84 (s, 3H), 3.85 (s, 2H), 4.03 (dd, 1H), 7.22-7.28 (m, 1H), 7.35 (dd, 1H), 7.38-7.44 (m, 1H), 7.44-7.51 (m, 2H), 7.55 (s, 1H), 7.94 (s, 1H), 8.13 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16][N:17]1C(=O)C3C(=CC=CC=3)C1=O)=[C:5]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O.NN>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16][NH2:17])=[C:5]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1CN
Yield: 71.7 %

Procedure:
To a solution of 2-[(6-bromo-2-isobutyl-4-phenylquinolin-3-yl)methyl]-1H-isoindole-1,3(2H)-dione (1.7 g, 3.4 mmol) in ethanol (150 ml), being heated under reflux, was added hydrazine monohydrate (5 ml, 103 mmol), and the mixture was heated under reflux for 2 hrs. The reaction mixture was partitioned between ethyl acetate (100 ml) and saturated aqueous sodium hydrogen carbonate (250 ml). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (100 ml) and then saturated brine (100 ml), and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography, and crystallized from n-hexane-diisopropyl ether to give the title compound (0.90 g, yield 72%) as colorless crystals.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:19]#[CH:20])[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[C:22]1[S:23][CH:24]=[C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:26]=1>>[C:1]12([C:11]3[CH:12]=[C:13]([C:19]#[C:20][C:22]4[S:23][CH:24]=[C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:26]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CCOC(=O)c1csc(Br)c1
Reactant: C#Cc1ccc(OC)c(C23CC4CC(CC(C4)C2)C3)c1
Product: CCOC(=O)c1csc(C#Cc2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)c1

Procedure:
In a manner analogous to Example 1(b) above, by reaction of 3.2 g (12 mmol) of 3-(1-adamantyl)-4-methoxyphenylacetylene with 2.8 g (12 mmol) of ethyl 2-bromo-4-thiophenecarboxylate, there were obtained, after chromatography on a silica column eluted with a mixture of hexane and ethyl acetate, 2.4 g (48%) of the expected ethyl ester with the melting point 88°-90° C.
Reaction SMILES: [Li]CCCC.CC1(C)CCCC(C)(C)N1.[Br:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH3:28])[CH:23]=2)[N:18]=1.[B:29](OC)([O:32]C)[O:30]C.[OH-].[Na+]>C1COCC1.CCOCC.O>[Br:16][C:17]1[C:26]([B:29]([OH:32])[OH:30])=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH3:28])[CH:23]=2)[N:18]=1
Reactant: COB(OC)OC
Reactant: COc1ccc2nc(Br)ccc2c1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2nc(Br)c(B(O)O)cc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
n-BuLi (1.6 N in hexanes, 14.4 mL, 23.0 mmol) was added at −78° C. to a solution of 2,2,6,6-tetramethylpiperidine (3.11 g, 22.05 mmol) in anhydrous THF (59 mL), and the mixture was then warmed to 0° C. for 0.5 h. The mixture was cooled back to −78° C. and treated with a solution of 2-bromo-6-methoxyquinoline (4.57 g, 19.17 mmol) in THF (14 mL). After stirring for 1 h, a solution of trimethyl borate (2.46 mL, 22.05 mmol) in THF (14 mL) was added, and the mixture was maintained at −78° C. for a further 2 h. A mixture of THF (14 mL) and H2O (3.5 mL), were added then the solution was warmed to −10° C. and treated with water (70 mL) and Et2O (70 mL). Aqueous NaOH (1 N, 75 mL) was added, and the aqueous layer was separated and acidified to pH 4 with aqueous HCl (3 N). The aqueous phase was extracted with Et2O, and the combined extracts were washed with brine and dried over Na2SO4. Filtration and removal of the volatiles afforded the title compound (4.64 g, 86% yield) as an oily solid that was used directly in the subsequent step. LCMS (ES+) m/z 282, 284 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[C:10](Cl)(=O)[CH2:11][CH:12]([CH3:14])[CH3:13]>CCCCCCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH2:11][CH:12]([CH3:14])[CH3:13])=[N:9][N:8]=2)[CH:7]=1
Reactant: CC(C)CC(=O)Cl
Reactant: NNc1ccc(Br)cn1
Solvent: CCCCCCC
Product: CC(C)Cc1nnc2ccc(Br)cn12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.7 %

Procedure:
A mixture of 5-bromo-2-hydrazinopyridine (1.00 g, 5.00 mmol; Frontier) and isovaleryl chloride (5.50 mL, 45.1 mmol) was heated at reflux for about 3 h. The reaction was cooled to ambient temperature then heptane (5 mL) was added and the reaction was stirred for about 15 min. The mixture was filtered, washing with additional heptane, and suspended in water/DCM (1:1, 20 mL) then added 1N NaOH (3.5 mL). This mixture was stirred for about 15 min. The layers were separated and the aqueous layer was extracted with DCM (2×10 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to give the title compound (0.86 g, 65%): LC/MS (Table 1, Method b) Rt, =1.87 min; MS m/z: 254.0 (M+H)+.
Reaction SMILES: C(C1C=CC([C@@H](NCCC2(O)CCC3(OCC(C)(C)CO3)CC2)C)=CC=1)(C)(C)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[C:42]([C:46]1[CH:51]=[CH:50][C:49]([C@@H:52]([N:54]2[CH2:59][CH2:58][C:57]3([CH2:71][CH2:70][C:62]4(OCC(C)(C)C[O:63]4)[CH2:61][CH2:60]3)[O:56][C:55]2=[O:72])[CH3:53])=[CH:48][CH:47]=1)([CH3:45])([CH3:44])[CH3:43]>>[C:42]([C:46]1[CH:51]=[CH:50][C:49]([C@@H:52]([N:54]2[CH2:59][CH2:58][C:57]3([CH2:60][CH2:61][C:62](=[O:63])[CH2:70][CH2:71]3)[O:56][C:55]2=[O:72])[CH3:53])=[CH:48][CH:47]=1)([CH3:43])([CH3:44])[CH3:45]
Reactant: C[C@@H](c1ccc(C(C)(C)C)cc1)N1CCC2(CCC3(CC2)OCC(C)(C)CO3)OC1=O
Agent: C[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccc(C(C)(C)C)cc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: C[C@@H](c1ccc(C(C)(C)C)cc1)N1CCC2(CCC(=O)CC2)OC1=O

Procedure:
The title compound is prepared from 9-{2-[(S)-1-(4-tert-butyl-phenyl)-ethylamino]-ethyl}-3,3-dimethyl-1,5-dioxa-spiro[5.5]undecan-9-ol and triphosgene following a procedure analogous to that described in Step 4 of Intermediate 2; the crude product, a mixture of the title compound and 3-[(S)-1-(4-tert-butyl-phenyl)-ethyl]-12,12-dimethyl-1,10,14-trioxa-3-aza-dispiro[5.2.5.2]hexadecan-2-one, obtained after that is treated as described in Step 10 of Intermediate 2 to convert the intermediate to the title compound as well. Yield: 65% of theory; LC (method 6): tR=1.51 min; Mass spectrum (ESI+): m/z=344 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]([OH:15])[C:9]2[O:10][CH2:11][O:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[CH2:24][CH2:25]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]([O:15][CH2:25][CH2:24][C:18]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:17]=2[Cl:16])[C:9]2[O:10][CH2:11][O:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: OCCc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)c1cc(O)c2c(c1)OCO2
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(OCCc2ccc(Cl)cc2Cl)c2c(c1)OCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
410 mg (1.95 mmol) of 7-Hydroxy-benzo[1,3]dioxole-5-carboxylic acid ethyl ester was dissolved in 20 ml of anhydrous tetrahydrofuran. To this solution was added 410 mg (2.15 mmol) of 2-(2,4-Dichlorophenyl)-ethanol, 1.9 g (equivalent to 5.85 mmol PPh3) of triphenylphosphine derivatized polystyrene and 1.0 g (5.85 mmol) of DEAD. The solution was shaken for 16 h at RT. The polymer was filtered off and washed with ethyl acetate. The solvent was removed under reduced pressure. The residue was taken-up in ethyl acetate and the solution was washed three times with water and twice with saturated aqueous sodium chloride. The organic phase was dried with magnesium sulphate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with ethyl acetate/n-heptane (1/5).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([CH2:21][OH:22])=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:29])[CH:17]=4)[C:12]3=[O:30])=[CH:9][C:4]=2[O:3][CH2:2]1.[N:31]1[CH:36]=[CH:35][C:34]([CH2:37]O)=[CH:33][CH:32]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([CH2:21][O:22][CH2:37][C:34]4[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=4)=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:29])[CH:17]=4)[C:12]3=[O:30])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=c1c2ccc(Br)cc2c(-c2ccccc2)c(CO)n1Cc1ccc2c(c1)OCO2
Reactant: OCc1ccncc1
Product: O=c1c2ccc(Br)cc2c(-c2ccccc2)c(COCc2ccncc2)n1Cc1ccc2c(c1)OCO2

Procedure:
The present compound was synthesized by a method similar to that in Example 240 and using 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-3-hydroxymethyl-4-phenyl-2H-isoquinolin-1-one (250 mg) and pyridin-4-ylmethanol. Colorless crystals (59 mg).
Reaction SMILES: [CH2:1]([C:5]1([C:18](OC)=[O:19])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[CH2:2][CH:3]=[CH2:4].[H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.O>C1COCC1.[OH-].[Na+]>[CH2:1]([C:5]1([CH2:18][OH:19])[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH2:9][CH2:10]1)[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCC1(C(=O)OC)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCC1(CO)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of 1-tert-butyl 4-methyl 4-(but-3-en-1-yl)piperidine-1,4-dicarboxylate (21.2 g, 71.3 mmol) in THF (300 mL) at 0° C. was added 2M LAH/THF (35.6 mL, 71.3 mmol) and the resulting mixture was stirred at 0° C. for 1 h and then stirred at room temp for 2 h. The mixture was then recooled to 0° C. and water (2.7 mL), IN NaOH (2.7 mL) and water (8.2 mL) were added successively and the mixture was stirred for 5 min. The solids were filtered off and the cake was washed with ethyl acetate. The filterate was washed with water (2×50 mL), brine (100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to give tert-butyl 4-(but-3-en-1-yl)-4-(hydroxymethyl)piperidine-1-carboxylate (16.5 g, 61.3 mmol, 86% yield) as yellow oil. 1H NMR (500 MHz, CDCl3) δ 5.90-5.78 (m, 1H), 5.13-5.01 (m, 1H), 5.01-4.86 (m, 1H), 3.57-3.42 (m, 4H), 3.39-3.28 (m, 2H), 2.46-2.33 (m, 1H), 2.06-1.99 (m, 2H), 1.54-1.38 (m, 14H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([CH2:11][NH2:12])=[N:6][C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Si:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][C:15]=1[F:24].[C:26](OC(=O)C)(=[O:28])C>C(O)=O>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([CH2:11][NH:12][CH:26]=[O:28])=[N:6][C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Si:20]([CH3:21])([CH3:23])[CH3:22])=[CH:16][C:15]=1[F:24]
Reactant: COC(=O)c1cc(F)c(CN)nc1Nc1ccc([Si](C)(C)C)cc1F
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: COC(=O)c1cc(F)c(CNC=O)nc1Nc1ccc([Si](C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 6-aminomethyl-5-fluoro-2-(2-fluoro-4-trimethylsilanyl-phenylamino)-nicotinic acid methyl ester (2.0 g, 5.5 mmol) in formic acid (30 mL) at 0° C. was added acetic anhydride (6 mL). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated in vacuo and the resultant residue azeotroped with toluene, then dissolved in dichloromethane. This organic layer was washed with a saturated aqueous solution of sodium bicarbonate, followed by brine, dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound as a dark brown solid (2.1 g, 100%). LCMS (method B): RT=4.36 min, [M+H]+=394.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]3[C:13](=[C:14]([C:15]4[CH:20]=[C:19]([CH3:21])[C:18]([OH:22])=[C:17]([CH3:23])[CH:16]=4)[C:4]=2[C:3]=1[CH3:24])[CH:12]=[CH:11][CH:10]=[CH:9]3.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]3[C:13](=[C:14]([C:15]4[CH:20]=[C:19]([CH3:21])[C:18]([O:22][C:25](=[O:27])[CH3:26])=[C:17]([CH3:23])[CH:16]=4)[C:4]=2[C:3]=1[CH3:24])[CH:12]=[CH:11][CH:10]=[CH:9]3
Reactant: Cc1cc(-c2c3ccccc3cc3sc(C)c(C)c23)cc(C)c1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C)cc(-c2c3ccccc3cc3sc(C)c(C)c23)cc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.8 %

Procedure:
To a solution of 4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenol (24.0 g, 72.2 mmol) in pyridine (200 mL) at 0C under nitrogen was added dropwise acetic anhydride (8.9 mL, 93.9 mmol) over a period of 10 min. After 45 min at 0C, the reaction mixture was placed in the freezer for 18 h, then removed and stirred for 2 h in an ice bath that was allowed to warm to room temperature. The reaction mixture was poured onto water (1 L) and acidified with 10% hydrochloric acid to a pH of 1. The resulting mixture was extracted with diethyl ether (1 L), which was washed with 10% hydrochloric acid (1 L), twice with water (1 L), brine (700 mL), and dried (MgSO4). Concentration under reduced pressure and chromatography with petroleum ether:ethyl acetate (97:3) gave the title compound as a cream solid (22.4 g, 79%): NMR (CDCl3): δ 8.26 (s, 1H), 7.87 (d, 1H), 7.58 (d, 1H), 7.44-7.40 (m, 1H), 7.33-7.29 (m, 1H), 7.07 (s, 2H), 2.42 (s, 3H), 2.41 (s, 3H), 2.23 (s, 6H), 1.67 (s, 3H); MS(EI): [M+] 374; Anal. Calc. for C24H22O2S: C, 76.97, H, 5.92, N, 0.00. Found: C, 76.17, H, 5.75, N, 0.22.
Reaction SMILES: Br.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[O:19][C:18]([NH2:20])=[N:17][N:16]=3)=[CH:11][CH:10]=2)[CH:3]=1.[F:21][C:22]([F:34])([F:33])[O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>N1C=CC=CC=1.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[O:19][C:18]([NH:20][C:27](=[O:28])[C:26]4[CH:30]=[CH:31][CH:32]=[C:24]([O:23][C:22]([F:21])([F:33])[F:34])[CH:25]=4)=[N:17][N:16]=3)=[CH:13][CH:14]=2)[CH:3]=1
Reactant: Nc1nnc(-c2ccc(Oc3cccnc3)cc2)o1
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1
Agent: Br
Solvent: c1ccncc1
Solvent: CO
Product: O=C(Nc1nnc(-c2ccc(Oc3cccnc3)cc2)o1)c1cccc(OC(F)(F)F)c1
Reaction time: 3 h
Yield: 17.5 %

Procedure:
5-[4-(Pyridin-3-yloxy)phenyl]-1,3,4-oxadiazol-2-amine hydrobromide salt (167.5 mg, 0.5 mmol) was suspended in 2 mL of anhydrous pyridine. Neat 3-trifluoromethoxybenzoyl chloride (117 uL) was added directly into the solution. The reaction mixture formed an orange-red solution with a small amount of white precipitate. It was left to stir for 3 hours. Then it was diluted with ca. 1 mL of MeOH, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetonitrile/water mixture containing 0.01% of TFA. Fractions, containing the product, were combined and partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated aqueous NaHCO3. The EtOAc layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title product as a yellow solid (38.8 mg). Yield 17.5%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:9]2[N:14]=[C:13]([C:15]#[N:16])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:28][CH2:29][Mg+].[Br-].O>C1COCC1.C(Cl)Cl>[NH2:16][C:15]1([C:13]2[N:14]=[C:9]([N:8]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:27][CH:26]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:29][CH2:28]1
Reactant: CC[Mg+]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cccc(C#N)n2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cccc(C3(N)CC3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.2 %

Procedure:
To a solution of 6-[bis-(4-methoxy-benzyl)-amino]-pyridine-2-carbonitrile (1.83 g, 5.09 mmol) in anhydrous THF (64 mL) was added Ti(Oi-Pr)4 (1.79 mL, 6.11 mmol) in one portion followed by EtMgBr (3.0 M solution in THF, 4.07 mL, 12.2 mmol) slowly over 5 min. The reaction was stirred at room temperature overnight. Additional Ti(Oi-Pr)4 (0.5 mL, 1.7 mmol) and EtMgBr (1.2 mL, 3.60 mmol) were added and stirring was continued for 2 h. Additional Ti(Oi-Pr)4 (1.8 mL, 6.1 mmol) and EtMgBr (3 M, 4.1 mL, 12 mmol) were added and stirring was continued for 3 h. Water (12 mL) was added to the reaction mixture causing the formation of a precipitate. The mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated in vacuo to give an orange/red oil. The concentrate was re-dissolved in CH2Cl2, causing precipitation of a white solid. After filtration, the filtrate was concentrated in vacuo and purified via iterative flash chromatography on silica gel (1→10% MeOH/CH2Cl2) to give 381 mg of the title compound as a light orange viscous oil, m/z 391.08 [M+2]+.