Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N2C(=O)C3SC=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)C=CC=CC=1.[NH2:23][C:24]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])=[CH:27][S:26][C:25]=1[C:36]([O:38]C)=O.C(OCC)(OCC)OCC.C1(N)CCCCCCC1>C(O)(=O)C>[CH:10]1([N:9]2[C:36](=[O:38])[C:25]3[S:26][CH:27]=[C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[F:35])[C:24]=3[N:23]=[CH:8]2)[CH2:16][CH2:17][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COC(=O)c1scc(-c2ccccc2F)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: NC1CCCCCCC1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: O=c1c2scc(-c3ccccc3F)c2ncn1C1CCCCCCC1
Yield: 63.4 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(2-fluorophenyl)thiophene-2-carboxylate (100 mg, 0.40 mmol), triethyl orthoformate (1.0 ml), cyclooctylamine (0.128 ml, 0.92 mmol), and acetic acid (0.1 ml) were used to give 90.4 mg (0.25 mmol, 63.4% yield) of the title compound.
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([OH:16])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([O:16][CH:2]([CH3:4])[CH3:3])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: CC(C)I
Reactant: COC(=O)c1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(Cl)ccc1OC(C)C
Temperature: 25 °C
Yield: 49 %

Procedure:
A mixture of 2-iodo-propane (2.2 ml, 22 mmol), methyl 5-chloro-2-hydroxy-benzoate (2.0 g, 10.7 mmol), potassium carbonate (3.0 g, 10.9 mmol), and acetonitrile (40 ml) was heated under reflux for 3 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (100 ml) and saturated aqueous sodium chloride solution (100 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with dichloromethane-hexane (1:3 followed by 1:2 followed by 1:1) to provide methyl 5-chloro-2-isopropoxy-benzoate (1.2 g, 49% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[Li]CCCC.[O:14]=[C:15]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1>O1CCCC1.C(OCC)C.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:15]2([OH:14])[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:18]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: Brc1ccc(I)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CC(O)(c2ccc(Br)cc2)C1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 27.6 %

Procedure:
Into a 1-L 3-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 1-bromo-4-iodobenzene (25.0 g, 88.4 mmol) in tetrahydrofuran/diethyl ether (400/200 mL). The solution was cooled to −78° C. then n-BuLi (2.5 M, 37.1 mL, 92.8 mmol) was added drop-wise over 10 min. To the resulting mixture was added tert-butyl 3-oxoazetidine-1-carboxylate (16.6 g, 97.0 mmol) in THF (100 mL) drop-wise at −78° C. The resulting mixture was stirred for 1.5 h at −78° C., then carefully quenched with water (300 mL). The aqueous phase was extracted with ethyl acetate (200 mL) and the combined organic layers were washed with brine (2×100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:20-1:5) as the eluent followed by re-crystallized from ethyl acetate:PE in the ratio of 1:100 to yield 8.0 g (28%) of the title compound as a white solid.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([NH:11][NH2:12])[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[CH2:13]([O:15][C:16](=[O:24])[CH:17]([C:21](=O)[CH3:22])[C:18](=O)[CH3:19])[CH3:14].N1C=CC=CC=1>C(O)C>[CH2:13]([O:15][C:16]([C:17]1[C:18]([CH3:19])=[N:12][N:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=2)[C:21]=1[CH3:22])=[O:24])[CH3:14]
Reactant: NNc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)c1c(C)nn(-c2cccc([N+](=O)[O-])c2)c1C

Procedure:
Similar to Example 1, m-nitrophenylhydrazine hydrochloride (10 mmol, 1.9 g) and 2-acetyl-3-oxo-butyric acid ethyl ester (10 mmol, 1.7 g) were mixed in a 50% solution of pyridine in ethanol. A precipitate was formed in the-reaction medium, and was collected by filtration. Analysis confirmed synthesis of the named product, m.p., 107.7° C.-109.2° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C[O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1>>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([O:21][C:18]2[CH:19]=[CH:20][C:15]([C:14]([OH:22])=[O:13])=[CH:16][CH:17]=2)=[CH:3][CH:4]=1
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccc(O)cc1
Product: O=C(O)c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Yield: 84 %

Procedure:
4-(4-Trifluoromethyl-phenoxy)benzoic acid (474 mg, 80%) was prepared from 1-fluoro-4-trifluoromethyl benzene (328 mg, 2.0 mmol) and 4-hydroxy benzoic acid methyl ester (304 mg, 2.0 mmol) following general procedure B, then hydrolyzed following general procedure C to give the corresponding acid (450 mg, 80%). 3-(4′-Trifluoromethyl-biphenyl-4-yl)-(2S)-[4-(4-trifluoromethyl-phenoxy)-benzoylamino]-propionic acid methyl ester (121 mg, 82%) was prepared starting from the above acid (70 mg, 0.25 mmol) and 2-amino-3-(4′-trifluoromethyl-biphenyl-4-yl)-(2S)-propionic acid methyl ester (108 mg, 0.30 mmol) according to general procedure A. The ester was hydrolyzed following general procedure C to give the title compound (105 mg, 89%)
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]3[CH2:23][C:13]4([C:21]5[C:16](=[N:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12][C:7]=3[CH:8]=2)[N:3]=1.[CH3:24][O:25][C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)=[O:27].C(=O)([O-])[O-].[K+].[K+].O>COCCOC.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>[O:22]=[C:14]1[NH:15][C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:21]2[C:13]21[CH2:12][C:7]1[CH:8]=[C:9]3[C:4](=[CH:5][C:6]=1[CH2:23]2)[N:3]=[C:2]([C:32]1[CH:33]=[C:28]([CH:29]=[CH:30][CH:31]=1)[C:26]([O:25][CH3:24])=[O:27])[CH:11]=[CH:10]3
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: O=C1Nc2ncccc2C12Cc1cc3ccc(Cl)nc3cc1C2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cccc(-c2ccc3cc4c(cc3n2)CC2(C4)C(=O)Nc3ncccc32)c1

Procedure:
A stirred mixture of (±)-2-chloro-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (204 mg, 0.634 mmol, described in Intermediate 20), 3-methoxycarbonylphenylboronic acid (229 mg, 1.27 mmol), PdCl2(PPh3)2 (44 mg, 0.063 mmol), and potassium carbonate (290 mg, 2.10 mmol), in 1,2-dimethoxyethane (3 mL) and H2O (1 mL) was heated at 80° C. for 18 h. The cooled mixture was partitioned between H2O (40 mL) and EtOAc (40 mL). The organic layer was removed and the aqueous phase was extracted further with EtOAc (40 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The product-containing fractions were combined and concentrated to give the title compound. MS: m/z=422 (M+1). HRMS: m/z=422.1504; calculated m/z=422.1499 for C26H20N3O3.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].CC(C)([O-])C.[K+].[CH3:12][C:13]([C:16]1[CH:17]=[C:18]([CH:27]=[C:28]2[S:32][C:31](SC)=[N:30][C:29]2=[O:35])[CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[OH:22])([CH3:15])[CH3:14]>C(O)C>[CH3:15][C:13]([C:16]1[CH:17]=[C:18]([CH:27]=[C:28]2[S:32][C:31](=[N:1][CH2:2][C:3]([OH:5])=[O:4])[NH:30][C:29]2=[O:35])[CH:19]=[C:20]([C:23]([CH3:24])([CH3:25])[CH3:26])[C:21]=1[OH:22])([CH3:12])[CH3:14]
Reactant: CSC1=NC(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)S1
Reactant: NCC(=O)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)c1cc(C=C2SC(=NCC(=O)O)NC2=O)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.2 %

Procedure:
A mixture of glycine (2.25 g, 0.03 mole), potassium-t-butoxide (2.81 g, 0.025 mole), and ethanol (700 mL) is stirred at room temperature for 15 minutes. 5-[(3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl)methylene]-2-(methylthio)-4(5H)-thiazolone (7.27 g, 0.02 mole) is added to it and the mixture is refluxed with stirring for 20 hours. The mixture is then filtered and the solvent removed at 40° C. under reduced pressure. The residue is treated with ice-water, acidified with 1N aqueous hydrochloric acid and extracted with ether. The organic layer is washed with water, dried, and the solvent removed to give 7.75 g of a solid. The crude solid is recrystallized from tetrahydrofuran-ether to give 2.95 g (38%) of pure N-[5-[3,5-[bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-4-oxo-2-thiazolidinylidene]glycine, (Z)-, mp 260° C. (dec). Anal. for C20H26N2O4S.0.25C4H8O: Calcd: C, 61.74; H, 6.91; N, 6.86; S, 7.85. Found: C, 61.82; H, 7.08; N, 6.50; S, 7.55.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@H:10]([OH:14])[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:23]1[C:27]2C=CC=C[C:26]=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N)C>CN(C=O)C.CCOC(C)=O>[CH3:4][C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:10]([OH:14])[C:11]([NH:23][CH2:27][CH3:26])=[O:13])([CH3:2])[CH3:3]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)O
Agent: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCNC(=O)C(O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 85.7 %

Procedure:
(5)(3S)-3-(tert-Butoxycarbonylamino)-2-hydroxy-4-phenylbutanoic acid (6.3 g, 21 mmol) and 1-hydroxybenzotriazole (HOBt) (3.0 g, 22.4 mmol) were dissolved in DMF (45 mL) and cooled in an ice bath. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (4.6 g, 24 mmol) was added, followed by aqueous ethylamine solution (3.0 mL). The solution was stirred for 18 hours. The solution was diluted into EtOAc (200 mL) and washed with 1M HCl, saturated aqueous NaHCO3, and saturated aqueous NaCl. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo to yield ((1S)-1-benzyl-3-ethylamino-2-hydroxy-3-oxo-propyl)carbamic acid 1,1-dimethylethyl ester (5.8 g, 84%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[C:22]1([S:28]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(OS(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 1-tert-butoxycarbonylpiperidin-4-ol, triethylamine, benzenesulfonyl chloride, and methylene chloride was stirred at ambient temperature for 2 days to yield 1-tert-butoxycarbonylpiperidin-4-yl benzenesulfonate. A mixture of 1-tert-butoxycarbonylpiperidin-4-yl benzenesulfonate obtained, diethyl malonate, 20% NaOEt-EtOH, and EtOH was heated under reflux with stirring for 22 hours to yield diethyl[1-(tert-butoxycarbonyl)piperidin-4-yl]malonate. A mixture of diethyl [1-(tert-butoxycarbonyl)piperidin-4-yl]malonate obtained, lithium borohydride, toluene, and THF was stirred at 60° C. for 18 hours to yield 2-(1-tert-butoxycarbonylpiperidin-4-yl)propane-1,3-diol, which was stirred together with 4M HCl-dioxane solution in MeOH at ambient temperature for 1 hour to yield 2-piperidin-4-ylpropane-1,3-diol hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[C:9](=[O:20])[N:10]([CH3:19])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)[CH:7]=1.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][NH:30][CH3:31])=[CH:27][CH:26]=1.C1CCN2C(=NCCC2)CC1>CN1C(=O)CCC1>[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][N:30]([CH3:31])[C:13]2[CH:12]=[C:11]3[C:16]([CH:17]=[C:8]([C:6]4[CH:7]=[C:2]([NH2:1])[C:3]([F:22])=[CH:4][C:5]=4[CH3:21])[C:9](=[O:20])[N:10]3[CH3:19])=[CH:15][N:14]=2)=[CH:27][CH:26]=1
Reactant: Cc1cc(F)c(N)cc1-c1cc2cnc(Cl)cc2n(C)c1=O
Reactant: CNCc1ccc(OC)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN1CCCC1=O
Product: COc1ccc(CN(C)c2cc3c(cn2)cc(-c2cc(N)c(F)cc2C)c(=O)n3C)cc1
Temperature: 180 °C
Yield: 100.5 %

Procedure:
3-(5-amino-4-fluoro-2-methylphenyl)-7-chloro-1-methyl-1,6-naphthyridin-2(1H)-one (1.36 g, 4.28 mmol, 1.00 eq), 4-methoxy-N-methylbenzylamine (0.971 g, 6.42 mmol, 1.50 eq) and DBU (0.960 mL, 6.42 mmol, 1.50 eq) were combined in NMP (20 mL) and heated at 180° C. under Ar overnight. The mixture was cooled to RT and poured onto H2O (200 mL). The resulting solids were collected by filtration, rinsed very well with H2O, dried on the filter to dampness and then dissolved in EtOAc. The solution was dried (MgSO4), filtered and evaporated to afford 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-4-fluoro-2-methylphenyl)-1-methyl-1,6-naphthyridin-2(1H)-one (1.86 g, 100% yield) as a brittle brown foam which was used as is in the next reaction. 1H NMR (400 MHz, DMSO-d6): δ 8.45 (s, 1H), 7.63 (s, 1H), 7.16 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 6.86-6.82 (m, 1H), 6.57 (d, J=9.6 Hz, 1H), 6.29 (s, 1H), 4.88 (br s, 2H), 4.85 (s, 2H), 3.69 (s, 3H), 3.52 (s, 3H), 3.07 (s, 3H), 1.94 (s, 3H); MS (ESI) m/z: 433.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]([NH:16][CH:17]([CH3:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[N:7][C:8]3[C:9](I)=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1.C1([Mg]Cl)C=CC=CC=1.C([Mg]Cl)(C)C.[CH:38]1([CH:41]=[O:42])[CH2:40][CH2:39]1>C1COCC1>[Br:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]([NH:16][CH:17]([CH3:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[N:7][C:8]3[C:9]([CH:41]([CH:38]4[CH2:40][CH2:39]4)[OH:42])=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1
Reactant: O=CC1CC1
Reactant: CC(Nc1nc2c(I)c[nH]c(=O)c2c2cc(Br)ccc12)C(C)(C)C
Agent: CC(C)[Mg]Cl
Agent: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CC(Nc1nc2c(C(O)C3CC3)c[nH]c(=O)c2c2cc(Br)ccc12)C(C)(C)C
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
9-bromo-4-iodo-6-[(1,2,2-trimethylpropyl)amino]benzo[c]-1,6-naphthyridin-1(2H)-one (50 mg, 0.100 mmol) was dissolved in THF and cooled to −30° C. Phenylmagnesium chloride (2M in THF) (105 μl, 0.210 mmol) was added dropwise, then stirred for 30 minutes before allowing to warm to room temperature by removing cooling baths and stirring an additional 30 minutes. Then, isopropylmagnesium chloride (2M in ether) (60.0 μl, 0.120 mmol) was added dropwise and stirred for 1 h. Then, cyclopropanecarboxaldehyde (29.9 μl, 0.400 mmol) was added and the reaction mixture was stirred for 30 minutes before quenching with saturated NH4Cl (10 mL). The reaction was then diluted with brine and extracted with ethyl acetate. The organic extract was then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Then, the residue was purified by preparative HPLC reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA, to give the title compound as a pale yellow solid as an approximate 1:1 mixture of diastereomers. LRMS (ESI) calc'd for (C22H27BrN3O2) [M+H]+ 444.1; found 444.1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][N:4]=1)#[CH:2].[C:10]([OH:14])([CH3:13])([CH3:12])[CH3:11].CC(C)([O-])C.[K+]>>[C:10]([O:14]/[CH:2]=[CH:1]\[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][N:4]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)O
Reactant: C#Cc1ccc(C)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: Cc1ccc(/C=C\OC(C)(C)C)nc1

Procedure:
To the solution of 2-ethynyl-5-methylpyridine (12-2) (1.38 g, 11.8 mmol) in tert-butyl alcohol (4.734 g, 63.9 mmol) was added potassium tert-butoxide (531 mg, 4.7 mmol) under nitrogen. The solution was heated to reflux for overnight. The solvent was removed under reduced pressure. The residue was purified by silca gel chromatography with the gradient eluent (PE/EA/NEt3=10/1/1%; 5/1/1%). The product (Z)-2-(2-tert-butoxyvinyl)-5-methylpyridine (12-3) was obtained as yellow oil (1.40 g, 62%) and by product was (E)-2-(2-tert-butoxyvinyl)-5-methylpyridine (0.3 g, 13%).
Reaction SMILES: [C:1]1([CH3:13])[C:2]([S:7]([N:10]=[C:11]=[O:12])(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH3:14][C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([CH3:29])[C:21]=1[S:22]([CH2:25][N+:26]([O-:28])=[O:27])(=[O:24])=[O:23])[NH2:18]>C(Cl)Cl>[CH3:29][C:20]1[CH:19]=[C:17]([NH:18][C:11]([NH:10][S:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:13])(=[O:9])=[O:8])=[O:12])[CH:16]=[C:15]([CH3:14])[C:21]=1[S:22]([CH2:25][N+:26]([O-:28])=[O:27])(=[O:24])=[O:23]
Reactant: Cc1cc(N)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Reactant: Cc1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCl
Product: Cc1ccccc1S(=O)(=O)NC(=O)Nc1cc(C)c(S(=O)(=O)C[N+](=O)[O-])c(C)c1
Reaction time: 1 h
Yield: 84.6 %

Procedure:
A solution of 0.77 ml (5.09 mmol) of o-toluenesulphonyl isocyanate in 7.7 ml of anhydrous methylene chloride is added dropwise to a suspension, maintained under a nitrogen atmosphere, of 1.3 g (5.32 mmol) of 3,5-dimethyl-4-[(nitromethyl)sulphonyl]aniline in 25.6 ml of anhydrous methylene chloride. The temperature of the reaction medium rises spontaneously by 7° C. A precipitate forms in the solution initially obtained. Stirring is continued for 1 hour at room temperature and the solid is then isolated by filtration and washed with hexane to give 1.9 g (yield=86%) of 1-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]-3-[(2-methylphenyl)sulphonyl]urea.
Reaction SMILES: Cl.[C:2]1([NH:8][S:9]([C:12]2[CH:21]=[C:20]3[C:15]([CH2:16][CH2:17][NH:18][CH2:19]3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:24][C:25](=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29]Br)C>>[C:2]1([NH:8][S:9]([C:12]2[CH:21]=[C:20]3[C:15]([CH2:16][CH2:17][N:18]([CH2:29][CH2:28][CH2:27][CH2:26][C:25]([OH:31])=[O:24])[CH2:19]3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Nc1ccccc1)c1ccc2c(c1)CNCC2
Reactant: CCOC(=O)CCCCBr
Agent: Cl
Product: O=C(O)CCCCN1CCc2ccc(S(=O)(=O)Nc3ccccc3)cc2C1

Procedure:
7-(Phenylsulphamoyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride was reacted with ethyl-5-bromovalerate under conditions analogous to those described in Example 5 and the resulting ethyl ester was hydrolysed according to the method described in Example 2(b) to give 5-(7-phenylsulphamoyl-1,2,3,4-tetrahydroisoquinolin-2-yl)valeric acid as a colourless microcrystalline solid. mpt. 176°-176.5° C. (acetonitrile/ethanol).
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([O:13][CH2:14][C@@H:15]2[CH2:19][CH2:18][CH2:17][N:16]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].CN1C(=O)CCC1.[NH:34]([C:36](OCC)=[O:37])[NH2:35]>CCOC(C)=O>[O:37]=[C:36]1[NH:34][N:35]=[C:1]([C:3]2[N:4]=[C:5]([O:13][CH2:14][C@@H:15]3[CH2:19][CH2:18][CH2:17][N:16]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:2]1
Reactant: CCOC(=O)NN
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1nc(C#N)cc2ccccc12
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1nc(-c2n[nH]c(=O)[nH]2)cc2ccccc12
Temperature: 175 °C

Procedure:
To a crude reaction mixture containing (S)-tert-butyl 2-(((3-cyanoisoquinolin-1-yl)oxy)methyl)pyrrolidine-1-carboxylate (0.562 g) was added NMP (2 mL) followed by ethyl hydrazinecarboxylate (0.663 g, 6.36 mmol). The reaction mixture was heated at 175° C. overnight and was subsequently cooled, diluted with EtOAc, and washed with brine. The organic layer was separated, dried over Na2SO4, and concentrated to give the title compound, which was used directly in the next step.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]([CH2:12][CH3:13])[N:10]=[C:9]([CH3:14])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[NH2:15][CH2:16][CH2:17][OH:18].C(N(CC)CC)C>C(Cl)Cl>[CH2:12]([N:11]1[C:3]2[C:2]([NH:15][CH2:16][CH2:17][OH:18])=[N:7][C:6]([CH3:8])=[N:5][C:4]=2[C:9]([CH3:14])=[N:10]1)[CH3:13]
Reactant: CCn1nc(C)c2nc(C)nc(Cl)c21
Reactant: NCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCn1nc(C)c2nc(C)nc(NCCO)c21
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.7 %

Procedure:
A solution of 12 g (0.057 mol) of 7-chloro-3,5-dimethyl-1-ethyl-1H-pyrazolo[4,3-d]pyrimidine in 150 ml of methylene dichloride is treated with 12 g (0.2 mol) of 2-aminoethanol and 8 ml of triethyamine and stirred at room temperature 48 hours. The mixture is filtered to give 7.6 g (56%) of 2-[1-ethyl-3,5-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl]aminoethanol, mp 181°-183° C. from ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18].Cl>O.C1(C)C=CC=CC=1>[N:1]1([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH2:14][CH2:15][CH2:16][C:17]1=[O:18]
Reactant: O=C(Cl)CCCCl
Reactant: Nc1ccc(C(=O)O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(N2CCCC2=O)cc1
Temperature: 17.5 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
4-Aminobenzoic acid (100 g, 0.73 mol) is suspended in water (400 mL) and toluene (200 mL), and thereto is added dropwise 30% aqueous sodium hydroxide solution (97 g, 0.73 mol) under ice-cooling. After confirming that pH is basic enough, 4-chlorobutyric chloride (103 g, 0.73 mol) and 30% aqueous sodium hydroxide solution (290 g, 2.2 mol) are added dropwise simultaneously while maintaining the pH range of 9-12 and temperature range of 15-20° C. over 1 hour. After stirring at room temperature for 1 hour, sodium hydroxide (88 g, 2.2 mol) is added to the mixture under ice-cooling. To the reaction solution is added conc. hydrochloric acid (370 g) at 30° C. or below and precipitated crystals are collected by filtration. The resulting crystals are washed with water and air-dried at 40° C. to give 4-(2-pyrrolidon-1-yl)benzoic acid (144 g, yield: 96.0%, purity: 98.3%). The purity was determined by HPLC analysis.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:34])=[C:4]([O:35][CH3:36])[CH:3]=1.C1COCC1.[N:42]1[CH:47]=[CH:46][CH:45]=[N:44][C:43]=1[NH2:48].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>Cl.CCOC(C)=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:48][C:43]4[N:44]=[CH:45][CH:46]=[CH:47][N:42]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:34])=[C:4]([O:35][CH3:36])[CH:3]=1
Reactant: Nc1ncccn1
Reactant: COc1cc(Br)c(C)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(Br)c(C)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ncccn3)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
A RBF was charged with perfluorophenyl 1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (5.00 g, 8.47 mmol), and THF (85 ml). To this, was added pyrimidin-2-amine (1.208 g, 12.71 mmol) and the reaction was cooled to 0° C. Lithium bis(trimethylsilyl)amide, 1.0 M solution in tetrahydrofuran (18.63 ml, 18.63 mmol) was added dropwise and allowed to stir at 0° C. After 1 hour, the mixture was diluted with 1N aq. HCl (10 mL) and EtOAc. The layers were separated, and the aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (40 g Redi-Sep Gold column, 10-50% of a 3:1 EtOAc/EtOH solution in heptane) to give 1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (3.54 g, 7.06 mmol, 83% yield) as an off white solid. m/z (ESI) 502.8 (M+H)+.