Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Product: CCOC(=O)n1c(C(=O)c2ccc(OC)cc2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 2-bromo-4′-methoxyacetophenone.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22])[CH:2]=[CH2:3].IC.[C:25]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:25])=[CH:7][C:6]=1[N:12]1[C:13](=[O:22])[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]1=[O:21])[CH:2]=[CH2:3]
Reactant: O=C([O-])[O-]
Reactant: C=CCOc1ccc(O)cc1N1C(=O)c2ccccc2C1=O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: C=CCOc1ccc(OC)cc1N1C(=O)c2ccccc2C1=O

Procedure:
A mixture of Example 84A (0.69 g, 2.34 mmol), iodomethane (0.58 mL, 9.34 mmol) and K2CO3 (1.61 g, 11.68 mmol) in acetone (20 mL) was stirred, and refluxed for 3 hours, cooled. The solution was filtered, dried with silica gel powder (10 g). 30% Ethyl acetate in hexanes (2 L) was used to run flash chromatography. The title compound was obtained (377 mg, 52%). MS (APCI) m/z 310 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19].Cl>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:15][CH:16]=2)=[N:4][C:3]=1[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:19])=[O:20]
Reactant: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccccc3)c(C)o2)cc1
Agent: Cl
Product: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)c1ccccc1
Yield: 99.7 %

Procedure:
Reaction of benzoate 16 (290 mg, 0.78 mmol) and 6 M HCl (5 mL) gave acid 17 (278 mg, 100%) as a white solid: mp (H2O) 284-287° C.; 1H NMR δ 12.68 (br s, 1H, CO2H), 8.04 (br d, J=8.4 Hz, 2H, H-2, H-6), 7.90 (br d, J=8.4 Hz, 2H, H-3, H-5), 7.80 (br ddd, J=8.1, 1.9, 1.2 Hz, 2H, H-2′, H-6′), 7.75 (tt, J=7.5, 1.2 Hz, 1H, H-4′), 7.62 (br dd, J=8.1, 7.4 Hz, 2H, H-3′, H-5′), 4.68 (s, 2H, CH2SO2), 2.13 (s, 3H, CH3); MS m/z 358.8 (MH+, 100%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1.C(N(C(C)C)C(C)C)C.[C:25]1([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[OH:13][CH2:12][CH2:11][NH:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([N:34]2[CH2:35][CH2:36][CH:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:32][CH2:33]2)[N:3]=[C:4]([S:14][CH3:15])[N:5]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CSc1nc(Cl)c(C#N)c(NCCO)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSc1nc(NCCO)c(C#N)c(N2CCC(c3ccccc3)CC2)n1
Reaction time: 7 h
Yield: 70 %

Procedure:
A solution of 0.47 g (1.9 mmol) of 4-chloro-6-(2-hydroxy-ethylamino)-2-methylsulfanyl-pyrimidine-5-carbonitrile (Timkevicius, S., Chemija 1997, 1, 58-61) and 0.33 ml (1.9 mmol) of N-ethyl-diisopropylamine in 5 ml of dichloromethane was treated at 30° C. with 310 mg (1.9 mmol) of 4-phenyl-piperidine and stirred during 7 hours. For the working-up, the reaction mixture was evaporated under reduced pressure, and the residue obtained was directly chromatographed on silica gel using a 99:1 mixture of dichloromethane and methanol as the eluent yielding 490 mg (1.33 mmol, 70% of theory) of the 4-(2-hydroxy-ethylamino)-2-methylsulfanyl-6-(4-phenyl-piperidin-1-yl)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=370.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:10][N:11]=[C:4]2[CH:3]=1.[CH:19]1([NH:22][C:23](=[O:40])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:25]=2)[CH2:21][CH2:20]1.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:9]1[N:5]2[C:6]([CH3:8])=[CH:7][C:2]([C:26]3[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=3[CH3:30])[C:23]([NH:22][CH:19]3[CH2:20][CH2:21]3)=[O:40])=[CH:3][C:4]2=[N:11][N:10]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1cc(Cl)cc2nnc(-c3ccccc3Cl)n12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1cc(C)n2c(-c3ccccc3Cl)nnc2c1
Temperature: 140 °C
Yield: 239.9 %

Procedure:
In a microwave tube was placed 7-chloro-3-(2-chlorophenyl)-5-methyl-[1,2,4]triazolo[4,3-a]pyridine (0.061 g, 0.22 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.086 g, 0.29 mmol), trans-dichlorobis(triphenylphosphine)palladium (II) (0.013 g, 0.018 mmol) and sodium carbonate monohydrate (0.16 g, 1.3 mmol) in 1 mL of DME and 0.4 mL of water. The mixture was heated in the microwave at 140° C. for 15 min. Water was then added and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 220 mg of a brown oil. The crude material was purified by silica gel chromatography (0-5% MeOH in DCM) to afford the title compound as an off-white solid. MS (ESI, pos. ion) m/z: 417.2 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[S:10][CH:9]=[N:8][CH:7]=1.[CH3:11][N:12]=[C:13]=[S:14]>C(O)C>[CH3:11][NH:12][C:13]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[S:10][CH:9]=[N:8][CH:7]=1)=[S:14]
Reactant: NCCSCc1cncs1
Reactant: CN=C=S
Solvent: CCO
Product: CNC(=S)NCCSCc1cncs1

Procedure:
The reaction of 5-[(2-aminoethyl)thiomethyl]thiazole (2.24 g.) with methyl isothiocyanate (0.94 g.) in ethanol (10 ml.) gave a thiourea which was purified by chromatography on a column of silica gel with ethyl acetate as eluant. Recrystallisation from isopropyl acetate-methyl ethyl ketone-ether gave N-methyl-N'-]2-(5-thiazolylmethylthio)ethyl]thiourea (2.1 g.), m.p. 86°-88°. (Found: C, 38.6; H, 5.4; N, 16.9; S, 38.6. C8H13N3S3 requires: C, 38.8; H, 5.3; N, 17.0; S, 38.9).
Reaction SMILES: [C:1]1(=O)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[C:2]1=O.[CH2:15]([C:18]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[C:21]([NH2:22])=[C:20]([CH:28]([CH3:30])[CH3:29])[CH:19]=1)[CH:16]=[CH2:17]>C(O)(=O)C>[CH2:15]([C:18]1[CH:19]=[C:20]([CH:28]([CH3:30])[CH3:29])[C:21]([N:22]=[C:1]2[C:11]3[C:12]4[C:7]([CH:8]=[CH:9][CH:10]=3)=[CH:6][CH:5]=[CH:4][C:3]=4[C:2]2=[N:22][C:21]2[C:23]([CH:25]([CH3:26])[CH3:27])=[CH:24][C:18]([CH2:15][CH:16]=[CH2:17])=[CH:19][C:20]=2[CH:28]([CH3:30])[CH3:29])=[C:23]([CH:25]([CH3:26])[CH3:27])[CH:24]=1)[CH:16]=[CH2:17]
Reactant: O=C1C(=O)c2cccc3cccc1c23
Reactant: C=CCc1cc(C(C)C)c(N)c(C(C)C)c1
Solvent: CC(=O)O
Product: C=CCc1cc(C(C)C)c(N=C2C(=Nc3c(C(C)C)cc(CC=C)cc3C(C)C)c3cccc4cccc2c34)c(C(C)C)c1
Temperature: 25 °C
Yield: 82 %

Procedure:
A mixture of 1.00 g of acenaphthoquinone (5.5 mmol) and 4-allyl-2,6-diisopropylaniline (2.49 g, 11.1 mmol) in acetic acid (10 mL) was heated to reflux. After 1 h the mixture was cooled to room temperature, and the solid was filtered. The product was washed with acetic acid (5 mL), hexane (4×10 mL) and dried in vacuum, yielding 2.59 g as a yellow-golden solid (82%). 1H-NMR (400 MHz, CDCl3): δ 7.86 (d, 2H, Ho-Ace-C═N), 7.37 (t, 2H, Hm-Ace-C═N), 7.07 (s, 4H, H—Ar—N═C), 6.65 (d, 2H, Hp-Ace-C═N), 6.15 (m, 2H, CH═C), 5.15 (m, 4H, C═C—H), 3.50 (d, 4H, CH2—C═C), 3.00 (m, 4H, CH(Me)2),1.22 (d,12H, C(CH3)2), 0.96 (d, 12H, C(CH3)2). Anal. Calcd for C42H48N2: C, 86.86; H, 8.32; N, 4.82. Found: C, 87.75; H, 7.35; N, 4.82.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([N:10]2[CH2:17][CH:16]3[CH:12]([CH2:13][NH:14][CH2:15]3)[CH2:11]2)[N:3]=1.[F:18][C:19]1[C:20]([N:28]2[N:32]=[CH:31][CH:30]=[N:29]2)=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](O)=[O:23]>>[F:18][C:19]1[C:20]([N:28]2[N:32]=[CH:31][CH:30]=[N:29]2)=[C:21]([C:22]([N:14]2[CH2:13][CH:12]3[CH:16]([CH2:17][N:10]([C:4]4[N:5]=[C:6]([CH3:9])[C:7]([CH3:8])=[C:2]([CH3:1])[N:3]=4)[CH2:11]3)[CH2:15]2)=[O:23])[CH:25]=[CH:26][CH:27]=1
Reactant: Cc1nc(N2CC3CNCC3C2)nc(C)c1C
Reactant: O=C(O)c1cccc(F)c1-n1nccn1
Product: Cc1nc(N2CC3CN(C(=O)c4cccc(F)c4-n4nccn4)CC3C2)nc(C)c1C

Procedure:
The title compound was prepared in a manner analogous to Example 15, utilizing Intermediate 42 and 3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI): mass calculated for C22H24FN7O, 421.20; m/z found 422.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.82-7.77 (m, 2H), 7.51-7.44 (m, 1H), 7.31 (ddd, J=9.8, 8.4, 1.3, 1H), 7.25-7.20 (m, 1H), 3.86-3.60 (m, 3H), 3.59-3.42 (m, 4H), 3.14 (dd, J=10.9, 5.3, 1H), 2.94 (dd, J=10.9, 7.1, 2H), 2.38-2.27 (m, 6H), 2.07 (d, J=7.2, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.Br[C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([O:36][CH:37]([CH3:39])[CH3:38])[CH:32]=2)[CH:27]=1>>[C:21]([C:18]1[CH:17]=[CH:16][C:15]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:26]2[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([O:36][CH:37]([CH3:39])[CH3:38])[CH:32]=4)[CH:27]=2)[C:6]([C:4]([OH:5])=[O:3])=[CH:14]3)=[CH:20][CH:19]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)Oc1ccc2cc(Br)ccc2c1
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2[nH]1
Product: CC(C)Oc1ccc2cc(-n3c(C(=O)O)cc4cc(-c5ccc(C(C)(C)C)cc5)ccc43)ccc2c1

Procedure:
The title compound was prepared in accordance with Example 1 using 5-(4-tert-butylphenyl)indole-2-carboxylic acid ethyl ester and 2-bromo-6-isopropoxynaphthalene.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=1.C([Li])CCC.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>O1CCCC1>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C:31]([C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]2[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=2)([OH:34])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC1(C)COC(c2cc(Cl)ccc2Br)=N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)COC(c2cc(Cl)ccc2C2(O)CCN(C(=O)OC(C)(C)C)CC2)=N1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a cold (−78° C.) solution of the product of step 1 (1.09 g, 4.63 mmol) in anhydrous tetrahydrofuran (10 mL) was added a solution of n-butyllithium (1.6 M in hexanes, 2.89 mL, 4.63 mmol) and the contents of the reaction were allowed to react for 0.5 h. A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (922 mg, 4.63 mmol) in tetrahydrofuran (10 mL) was added and the combined contents stirred for 2 h at −78° C. Reaction was quenched by the addition of saturated aqueous ammonium chloride (30 mL), followed by warming to rt. The biphasic mixture was extracted with ethyl acetate (150 mL); washed with water and brine; dried over magnesium sulfate; filtered and concentrated. 4-[4-Chloro-2-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-phenyl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester was isolated (412 mg, 22%) following silica gel chromatography (80% hexanes/20% ethyl acetate).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14]/[N:15]=[C:16](\[CH3:24])/[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:4](OC)=[O:5].[CH3:25][NH2:26]>CO>[CH3:1][O:2][CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14]/[N:15]=[C:16](\[CH3:24])/[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:4]([NH:26][CH3:25])=[O:5]
Reactant: COC(=O)C(OC)c1ccccc1O/N=C(\C)c1ccc(Cl)cc1
Reactant: CN
Solvent: CO
Product: CNC(=O)C(OC)c1ccccc1O/N=C(\C)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 86 %

Procedure:
A solution of methyl (E)-α-methoxy-2-(α-methyl-4-chlorobenzylideneaminooxy)phenylacetate (0.48 g, 1.3 mmol) and 40% monomethylamine--methanol solution (10 ml) was stirred in a sealed tube at 80° C. for 15 hours. The mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. Water was added, the mixture was adjusted to pH 1 with 1N hydrochloric acid, extracted with methylene chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=3/2) to give the desired compound (E)-α-methoxy-N-methyl-2-(α-methyl-4-chlorobenzylideneaminooxy)phenylacetamide (0.41 g, 86%) as an oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:10]=1)=[O:5])C.C>O1CCOCC1.[OH-].[Na+]>[F:17][C:14]1[CH:13]=[CH:12][C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[CH:8]2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1cn(-c2ccc(F)cc2)cn1

Procedure:
Crude 1-(4-fluoro-phenyl)-1H-imidazole-4-carboxylic acid ethyl ester is dissolved in dioxane and sodium hydroxide solution. The reaction mixture is refluxed for about 2 h. Charcoal is added and reflux is continued. The desired compound 1-(4-fluoro-phenyl)-1H-imidazole-4-carboxylic acid is obtained.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11](=[O:13])[CH3:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:14]1([Mg]Br)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCOCC>C1COCC1>[Si:1]([O:8][CH2:9][CH2:10][C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([OH:13])[CH3:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(=O)CCO[Si](C)(C)C(C)(C)C
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)(CCO[Si](C)(C)C(C)(C)C)c1ccccc1
Reaction time: 1 h

Procedure:
The product of Example 457A (2.0 g, 9.88 mmol) in anhydrous THF (50ml) under at 0 C under nitrogen was reacted with phenylmagnesium bromide as a 3.0M solution in ether (5.0 ml, 15 mmol) dropwise via syringe then stirred for one hour. The reaction was quenched by the drop wise addition of a saturated solution of ammonium chloride and the reaction was partitioned with ether and water. The combined organics were dried over magnesium sulfate and concentrated in vacuo to give the desired compound as a clear oil (2.71 g, quantitative).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([CH:18]=[O:19])[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[CH2:20]([Mg]Cl)[CH3:21]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([CH:18]([OH:19])[CH2:20][CH3:21])[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Reactant: CC[Mg]Cl
Solvent: ClCCl
Product: CCC(O)c1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-7-carbaldehyde (25 mg, 0.093 mmol) was dissolved in 4 mL of hot dichloromethane. The solution was cooled to room temperature and ethylmagnesium chloride (0.047 mL of 2.0 M in THF, 0.093 mmol) was added. The reaction was stirred at room temperature for 1.5 hours at which point it was quenched via the addition of saturated aqueous ammonium chloride. The mixture was extracted three times with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered, concentrated in vacuo, and purified via flash chromatography (silica, 5-60% ethyl acetate/hexanes) to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 8.80 (d, 1H); 8.52 (d, 1H); 8.21 (d, 1H); 7.73 (dd, 1H); 7.60 (d, 1H); 7.32 (d, 1H); 7.27 (d, 1H); 4.79 (t, 1H); 1.99 (s, 1H); 1.89-1.79 (m, 2H); 0.94 (t, 3H). LRMS (APCI) calc'd for (C17H15ClNO2) [M+H]+, 300.1; found 300.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[NH:15][C:14](=[O:16])[C:13]([CH:17]([NH:20][C:21]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=O)[CH2:18][CH3:19])=[N:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>ClC(Cl)C>[CH:23]1([C:21]2[N:12]3[C:13]([C:14](=[O:16])[NH:15][C:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)=[N:11]3)=[C:17]([CH2:18][CH3:19])[N:20]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CCC(NC(=O)C1CCCC1)c1nnc(-c2cccc([N+](=O)[O-])c2)[nH]c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nc(C2CCCC2)n2nc(-c3cccc([N+](=O)[O-])c3)[nH]c(=O)c12
Temperature: 0 °C

Procedure:
3.5 g (9.4 mmol) N-{1-[3-(3-nitrophenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}-cyclopentanecarboxamide (Example 19A) are suspended in 60 ml dichloroethane, and 1.45 g (9.4 mmol) phosphoroxychloride are added. The mixture is stirred at reflux for 3 hour. After cooling down to 0° C., 10 ml saturated NaHCO3 (aq) is added dropwise. The mixture is stirred for about 20 min at room temperature and then evaporated to dryness in vacuo. The product is purified by chromatography (flash or column chromatography).
Reaction SMILES: [NH3:1].[CH2:2]([O:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([OH:25])[CH2:19][C:20](OCC)=[O:21])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO>[CH2:2]([O:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([OH:25])[CH2:19][C:20]([NH2:1])=[O:21])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC(O)CCCCCNC(=O)OCc1ccccc1
Reactant: N
Solvent: CO
Product: NC(=O)CC(O)CCCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.5 %

Procedure:
Into 40 ml of methanol saturated with gaseous ammonia was dissolved 1.69 g (5 mmoles) of ethyl 8-benzyloxycarbonylamino-3-hydroxyoctanoate. The solution was stirred for 3 days at room temperature, and the reaction mixture was evaporated to dryness. The residue was crystallized from ethanol to yield 1.18 g (72.5% yield) of 8-benzyloxycarbonylamino-3-hydroxyoctanamide having a melting point of 100°-101° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=2[S:9][C:10]=1[NH:11][C:12]([CH:14]1[CH2:16][CH2:15]1)=O)=O)C.[NH3:21]>>[CH:14]1([C:12]2[N:21]=[C:4]([OH:3])[C:6]3[C:7]4[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=4[S:9][C:10]=3[N:11]=2)[CH2:16][CH2:15]1
Reactant: CCOC(=O)c1c(NC(=O)C2CC2)sc2ccccc12
Reactant: N
Product: Oc1nc(C2CC2)nc2sc3ccccc3c12
Temperature: 90 °C
Reaction time: 24 h

Procedure:
A suspension of 10 millimol VII in 10 milliliter 25% aqueous NH3 was stirred at 90° C. for 24 hours in closed vial. The reaction mixture was cooled down to room temperature, and poured onto crushed ice with continuous stirring then collected by filtration. The product was washed with water and n-hexane, then dried.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:30]=[C:31]([Cl:33])[CH:32]=1)[NH2:29].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[Cl:19][C:18]1[C:4]2[N:3]=[C:2]([NH:29][C:28]3[CH:27]=[C:26]([Cl:25])[CH:32]=[C:31]([Cl:33])[CH:30]=3)[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]=2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)CCCn1c(Nc2cc(Cl)cc(Cl)c2)nc2c(Cl)ccc(C(CC)CC)c21
Yield: 40.1 %

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 33; 500 mg, 1.35 mmol), 3,5-dichloroaniline (655 mg, 4.04 mmol) and p-toluenesulfonic acid monohydrate (257 mg, 1.35 mmol) in 1-methyl-2-pyrrolidinone (4 mL) was irradiated by microwave at 180° C. for 15 min. After cooling, aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. Organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 5-20% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give a residue, which was purified by preparative HPLC to give the title compound (270 mg, 0.542 mmol, 40%) as a colorless amorphous.
Reaction SMILES: C(N[C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([C:23]#[N:24])[N:6]=1)C=C.[OH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[OH:25][CH:26]1[CH2:31][CH2:30][N:29]([C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=3)[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:7]([C:23]#[N:24])[N:6]=2)[CH2:28][CH2:27]1
Reactant: C=CCNc1nc(C#N)c(-c2ccccc2)c2cc(OC)ccc12
Reactant: OC1CCNCC1
Product: COc1ccc2c(N3CCC(O)CC3)nc(C#N)c(-c3ccccc3)c2c1

Procedure:
Following the procedure for 1-(allylamino)-6-methoxy-4-phenylisoquinoline-3-carbonitrile, using 4-hydroxypiperidine in place of allylamine, the title compound was synthesized.
Reaction SMILES: [CH:1]12[CH2:10][C:5]3([C:11](OC)=[O:12])[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[N:2]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:8]2.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:12][CH2:11][C:5]12[CH2:4][CH:3]3[CH2:9][CH:7]([CH2:8][CH:1]([N:2]3[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)[CH2:6]2
Reactant: COC(=O)C12CC3CC(C1)N(C(=O)OC(C)(C)C)C(C3)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C2CC3CC1CC(CO)(C3)C2
Temperature: 0 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A 50 mL RB flask fitted with magnetic stirrer was charged with 5 mL of THF, 2-tert-butyl 5-methyl 2-azatricyclo[3.3.1.13,7]decane-2,5-dicarboxylate, Intermediate-9 (0.15 g, 0.5 mmol) and cooled to 0° C. Under N2 atm, LAH was added portion wise (30 mg, 0.8 mmol) and stirred for 2 hr. After completion of the reaction (reaction was monitored by TLC), reaction mixture was quenched with ethyl acetate and washed with water followed by 1N HCl solution. The organic layer was washed with brine solution. Finally the organic layer was dried over anhydrous sodium sulfate and concentrated to give crude Intermediate-15, as an oily mass (0.12 g, yield=88%).