Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[Li+].COC([C:7]1([CH2:31][CH:32]=[CH2:33])[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[CH2:12][C:11]2[C:22]([C:26]([F:29])([F:28])[F:27])=[CH:23][CH:24]=[CH:25][C:10]=2[NH:9][C:8]1=[O:30])=O>N1C=CC=CC=1.O>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:13]1[CH2:12][C:11]2[C:22]([C:26]([F:27])([F:28])[F:29])=[CH:23][CH:24]=[CH:25][C:10]=2[NH:9][C:8](=[O:30])[CH:7]1[CH2:31][CH:32]=[CH2:33]
Reactant: C=CCC1(C(=O)OC)C(=O)Nc2cccc(C(F)(F)F)c2CC1c1ccccc1OC
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Solvent: O
Product: C=CCC1C(=O)Nc2cccc(C(F)(F)F)c2CC1c1ccccc1OC
Reaction time: 11 h
Yield: 69.9 %

Procedure:
Lithium iodide (11.98 g; 89.44 mmole) was added to 1,3,4,5-tetrahydro-3-(methoxycarbonyl)-4-(methoxyphenyl)-3-(2-propenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-one (9.69 g; 22.36 mmole) in pyridine (40 ml) and water (a few drops). The mixture was refluxed with stirring for 11 hours. The pyridine was vacuum distilled off and the residue was dissolved into methanol and washed with 1N hydrochloric acid (three times), and saturated sodium chloride, and dried (magnesium sulfate). The concentrated residue was black indicating some decomposition occurred. The 9.67 g of this black residue was flash chromatographed (silica gel/3:1-hexane:ethyl acetate, followed by 1:1-hexane/ethyl acetate). Appropriate fractions were combined and concentrated giving 5.87 g of the title compound as a solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:45])[C@@H:20]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[N:28]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:27]=2)=[O:25])[CH2:21][NH2:22])[CH2:15][CH2:14]1)=[O:12])[CH3:9].Cl[C:47]([O:49][CH3:50])=[O:48]>C(Cl)Cl.C(N(CC)CC)C>[CH2:8]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:45])[C@@H:20]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[N:28]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:27]=2)=[O:25])[CH2:21][NH:22][C:47]([O:49][CH3:50])=[O:48])[CH2:15][CH2:14]1)=[O:12])[CH3:9]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CN)NC(=O)c2cc(OCC(=O)C(C)(C)C)n(-c3ccccc3)n2)CC1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)[C@H](CNC(=O)OC)NC(=O)c2cc(OCC(=O)C(C)(C)C)n(-c3ccccc3)n2)CC1
Reaction time: 4 h

Procedure:
To a solution of 100 mg of 4-((S)-3-Amino-2-{[5-(3,3-dimethyl-2-oxo-butoxy)-1-phenyl-1H-pyrazole-3-carbonyl]-amino}-propionyl)-piperazine-1-carboxylic acid ethyl ester trifluoroacetate in 2 ml DCM and 0.1 ml triethylamine, 20 mg methyl chloroformate was added at RT. After stirring for 4 h, the reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. Yield: 19 mg
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:34]1([CH2:40][C:41](Cl)=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:41](=[O:42])[CH2:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(Cc1ccccc1)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 54.7 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.65 g, 4.26 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.60 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, phenylacetyl chloride (0.35 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 mL). The CH2Cl2 solution was washed with 1N HCl (30 mL), H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2: EtOAc 6:4) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}-2-phenylacetamide (0.41 g, 55%) as a white solid: mp 128-130° C.; 1H NMR (DMSO-d6) δ 11.14 (s, 1H), 8.67 (t, J=5.5 Hz, 1H), 7.80-7.61 (m, 3H), 7.29 (s, 5H), 5.19-5.12 (dd, J=5.1 and 12.4 Hz, 1H), 4.71 (d, J=5.5 Hz, 2H), 3.53 (s, 2H), 2.96-2.83 (m, 1H), 2.63-2.50 (m, 2H), 2.08-2.03 (m, 1H); 13HNMR (DMSO-d6) δ 172.77, 170.65, 169.82, 167.45, 166.93, 139.19, 136.15, 134.68, 133.18, 131.53, 129.05, 128.25, 127.13, 126.43, 121.90, 48.85, 42.24, 37.85, 30.93, 21.98; Anal. Calcd. For C22H19N3O5: C, 65.18; H, 4.72; N, 10.36. Found: C, 65.16; H, 4.75; N, 10.11.
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18]([OH:20])=O)[CH2:10][CH2:9]1)=O)(C)C.[NH2:24][CH2:25][C:26]1[CH:27]=[C:28]([C:32]2[N:37]=[C:36]([CH2:38][N:39]3[CH2:44][CH2:43][N:42](C(OC(C)(C)C)=O)[C@@H:41]([CH3:52])[CH2:40]3)[CH:35]=[CH:34][CH:33]=2)[CH:29]=[CH:30][CH:31]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C([O-])([O-])=O.[Na+].[Na+].C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[CH3:52][C@@H:41]1[NH:42][CH2:43][CH2:44][N:39]([CH2:38][C:36]2[N:37]=[C:32]([C:28]3[CH:27]=[C:26]([CH2:25][NH:24][C:18](=[O:20])[C:17]4[CH:21]=[CH:22][CH:23]=[C:15]([CH2:14][CH:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)[CH:16]=4)[CH:31]=[CH:30][CH:29]=3)[CH:33]=[CH:34][CH:35]=2)[CH2:40]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(C(=O)O)c2)CC1
Reactant: C[C@H]1CN(Cc2cccc(-c3cccc(CN)c3)n2)CCN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CN(Cc2cccc(-c3cccc(CNC(=O)c4cccc(CC5CCNCC5)c4)c3)n2)CCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
To a solution of the commercially available 3-[(1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinyl)methyl]benzoic acid (40 mg, 0.13 mmol) in CHCl3 (2.0 mL) was added 1,1-dimethylethyl (2S)-4-({6-[3-(aminomethyl)phenyl]-2-pyridinyl}methyl)-2-methyl-1-piperazinecarboxylate (50 mg, 0.13 mmol), TEA (0.04 ml, 0.3 mmol), EDC (36 mg, 0.19 mmol) and HOBt (18 mg, 0.14 mmol). The reaction mixture was stirred at room temperature for 2 h, followed by addition of 0.5 mL of saturated Na2CO3. The organic layer was isolated via a hydrophobic frit followed by addition of 0.5 mL of TFA, and stirred at room temperature for 1 h. After removal of the solvent, the residue was purified by Gilson reverse phase HPLC, eluting with acetonitrile/water/0.1% TFA (10/90 to 70/30, v/v, over 12 in), to give the title compound (23 mg, 19%). LC/MS: m/z, 499 (M+H), 1.19 min.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][C:11]=2[C:17]([OH:19])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:20][C:21]1[CH:22]=[C:23]([CH:32]=[CH:33][CH:34]=1)[O:24][CH2:25][C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[CH2:1]([C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][C:11]=2[C:17]([NH:20][C:21]1[CH:22]=[C:23]([CH:32]=[CH:33][CH:34]=1)[O:24][CH2:25][C:26]([O:28][CH:29]([CH3:30])[CH3:31])=[O:27])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(C)OC(=O)COc1cccc(N)c1
Reactant: CCCCCCc1cnc2c(C(=O)O)cccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCCCCCc1cnc2c(C(=O)Nc3cccc(OCC(=O)OC(C)C)c3)cccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.5 %

Procedure:
To a solution of 3-hexylquinoline-8-carboxylic acid (170 mg, 0.66 mmol), isopropyl 2-(3-aminophenoxy)acetate (207 mg, 0.99 mmol) and N-methylmorpholine (0.18 mL, 1.65 mmol) in DMF (2.0 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (380 mg, 1.0 mmol) and the solution was stirred at room temperature for 16 h. The DMF was removed in vacuo and the residue was partitioned between EtOAc and water. The organic phase was washed with saturated aqueous NaHCO3 (2×) then dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified on 12 g silica gel eluting (17:3 hexanes/EtOAc) to afford 259 mg (87%) of isopropyl 2-(3-(3-hexylquinoline-8-carboxamido)phenoxy)acetate.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][C@@H:8]([NH2:38])[C:9]([O:11][C@H:12]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[C:25]([O:33][CH2:34][CH:35]2[CH2:37][CH2:36]2)[CH:24]=1)[CH2:13][C:14]1[C:19]([Cl:20])=[CH:18][N+:17]([O-:21])=[CH:16][C:15]=1[Cl:22])=[O:10])(=[O:3])[CH3:2].N1C=CC=CC=1.[CH3:45][O:46][C:47]1[CH:48]=[C:49]([S:55](Cl)(=[O:57])=[O:56])[CH:50]=[CH:51][C:52]=1[O:53][CH3:54]>C(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][CH2:7][C@@H:8]([NH:38][S:55]([C:49]1[CH:50]=[CH:51][C:52]([O:53][CH3:54])=[C:47]([O:46][CH3:45])[CH:48]=1)(=[O:57])=[O:56])[C:9]([O:11][C@H:12]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:31])[F:32])=[C:25]([O:33][CH2:34][CH:35]2[CH2:37][CH2:36]2)[CH:24]=1)[CH2:13][C:14]1[C:15]([Cl:22])=[CH:16][N+:17]([O-:21])=[CH:18][C:19]=1[Cl:20])=[O:10])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCC[C@@H](N)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N[C@H](CCCOC(C)=O)C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 103.2 %

Procedure:
To a solution of 4-((S)-2-((R)-5-acetoxy-2-aminopentanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (205 mg, 0.354 mmol) dissolved in DCM (2.5 mL), pyridine (58 μl, 0.710 mmol) and 3,4-dimethoxybenzene-1-sulfonyl chloride (168 mg, 0.710 mmol) were added. The mixture was stirred at RT for 48 hours. The mixture was then diluted with DCM and washed with NaHCO3 sat. sol., HCl 0.1M and brine. The organic phase was dried over Na2SO4, and the solvent was evaporated, to yield 284 mg of a yellow solid which was purified by preparative reverse-phase HPLC to yield 42 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:15][CH:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[CH:17]([OH:21])[C:18](O)=[O:19].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.CN1CCOCC1.[Cl-].[Na+]>CN(C)C=O>[OH:21][C@H:17]1[C:18](=[O:19])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:4][C:3]=2[S:15][C@H:16]1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1
Reactant: COc1ccc(C(Sc2cc(Oc3ccccc3)ccc2N)C(O)C(=O)O)cc1
Agent: [Cl-]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1ccc([C@@H]2Sc3cc(Oc4ccccc4)ccc3NC(=O)[C@@H]2O)cc1
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
2.2 g of 3-(2-amino-5-phenoxyphenyl)thio-2-hydroxy-3-(4-methoxyphenyl)propionic acid [prepared as described in step (b) above] were dissolved in 11 ml of dimethylformamide, and 1.38 ml of diphenylphosphorylazide was added, whilst ice-cooling, the mixture was then stirred for 30 minutes. At the end to this time, 1.38 ml of N-methylmorpholine was added to the mixture, which was then stirred at the same temperature for 30 minutes, and then at room temperature for 2 hours. After this, an aqueous solution of sodium chloride was added and the mixture was extracted twice with ethyl acetate. The extracts were combined, washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was triturated in diethyl ether, filtered and washed with diethyl ether, to give 1.13 g of the title compound.
Reaction SMILES: [N:1]1([CH:16]2[CH2:22][CH:21]3[N:23]([C:24]([O:26][C@@H:27]4[CH2:31][CH2:30][O:29][CH2:28]4)=[O:25])[CH:18]([CH2:19][CH2:20]3)[CH2:17]2)[CH2:6][CH2:5][C:4]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][NH:8][CH2:7]2)[CH2:3][CH2:2]1.[CH3:32][N:33]([CH3:37])[C:34](Cl)=[O:35].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:32][N:33]([CH3:37])[C:34]([N:8]1[CH2:7][C:4]2([CH2:3][CH2:2][N:1]([CH:16]3[CH2:22][CH:21]4[N:23]([C:24]([O:26][C@@H:27]5[CH2:31][CH2:30][O:29][CH2:28]5)=[O:25])[CH:18]([CH2:19][CH2:20]4)[CH2:17]3)[CH2:6][CH2:5]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:35]
Reactant: CN(C)C(=O)Cl
Reactant: O=C(O[C@@H]1CCOC1)N1C2CCC1CC(N1CCC3(CC1)CNCc1ccccc13)C2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)C(=O)N1Cc2ccccc2C2(CCN(C3CC4CCC(C3)N4C(=O)O[C@@H]3CCOC3)CC2)C1
Reaction time: 0.17 h

Procedure:
(R)-tetrahydrofuran-3-yl 3-(2,3-dihydro-1H-spiro[isoquinoline-4,4-piperidine]-1′-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (20 mg, 0.047 mmol) was dissolved in CH2Cl2 (1 mL) and treated with a solution of dimethylcarbamic chloride (20 mg, 0.13 mmol) in CH2Cl2 (100 μL). A solution of diisopropyl ethylamine (20 μL, 14.8 mg, 0.11 mmol) was added. The resulting mixture was allowed to stand at room temperature for 10 min and was then purified by LC/MS (10-99% CH3CN—H2O, with 0.03% TFA, 9 min) to provide (R)-tetrahydrofuran-3-yl 3-(2-(dimethylcarbamoyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate. LC/MS m/z [M+H]+ 497.4, retention time 2.15 min (10-99% CH3CN—H2O gradient, with 0.05% TFA, 5 min).
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=1)[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:28](I)[CH2:29][CH3:30]>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[C:3]([O:7][C:8]([N:10]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH2:29][CH3:30])[CH:22]=1)[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N(CCc1cccc(Cl)c1)Cc1cccc(O)c1
Reactant: CCCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCOc1cccc(CN(CCc2cccc(Cl)c2)C(=O)OC(C)(C)C)c1

Procedure:
Add a solution of 50% sodium hydroxide in water (0.8 mL) to a solution of N-t-butoxycarbonyl-N-2-(3-chlorophenyl)ethyl-3-hydroxybenzylamine (46.7 mg, 0.129 mmol), n-propyl iodide (0.17 gm. 1.00 mmol), and tetrabutylammonium bromide (18 mg, 0.057 mmol) in toluene (1 mL). Stir the mixture at 1200 rpm and heat at 50–54° C. After 64.5 hour pour the mixture into 5 mL of water, separate the phases and extract the aqueous phase twice with dichloromethane. Combine the organic phases and wash with saturated sodium bicarbonate solution, and then saturated brine, dry (MgSO4), and concentrate to give a residue. Chromatograph the residue on silica gel to give the title compound: MS (ES+): m/e (M+1) 404. TLC (20% EtOAc in hexanes, Rf 0.54).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]3[N:15]=[C:16]([CH3:18])[CH:17]=[C:13]3[NH:12][C:11](=O)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].N1C=CC=CC=1.O=P(Cl)(Cl)[Cl:28]>>[Cl:28][C:11]1[CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[N:14]2[N:15]=[C:16]([CH3:18])[CH:17]=[C:13]2[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc2[nH]c(=O)cc(-c3ccc(F)c(F)c3)n2n1
Solvent: c1ccncc1
Product: Cc1cc2nc(Cl)cc(-c3ccc(F)c(F)c3)n2n1
Temperature: 25 °C

Procedure:
7-(3,4-Difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidin-5(4H)-one (821 mg) is dissolved in POCl3 (15 mL) and pyridine (0.2 mL) and stirred overnight while heating. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with 1 M NaHCO3 aqueous solution and brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and the target compound (301 mg) is yielded by column chromatography. 1H NMR (CDCl3, 300 MHz) δ 8.08 (m, 1H), 7.78 (m, 1H), 7.36 (q, J=8.7 Hz, 1H), 6.73 (s, 1H), 6.40 (s, 1H), 2.51 (s, 3H).
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[CH2:11]([O:13][C:14](=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1)[CH3:12]>>[O:4]=[C:2]([CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1)[C:14]([O:13][CH2:11][CH3:12])=[O:23])[C:1]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOC(=O)Cc1cccc(Cl)c1
Product: CCOC(=O)C(=O)C(C(=O)OCC)c1cccc(Cl)c1

Procedure:
The title compound is prepared according to the method of Klioze and Ehrgott (U.S. Pat. No. 4,216,218) from diethyl oxalate and ethyl(3-chlorophenyl)acetate.
Reaction SMILES: O.[OH-].[Li+].[CH:4]1([C:8]2[S:9][CH:10]=[C:11]([C:13]([O:15]CC)=[O:14])[N:12]=2)[CH2:7][CH2:6][CH2:5]1.Cl>C1COCC1.O>[CH:4]1([C:8]2[S:9][CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N:12]=2)[CH2:5][CH2:6][CH2:7]1
Reactant: CCOC(=O)c1csc(C2CCC2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1csc(C2CCC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lithium hydroxide monohydrate (0.38 g) was added to a solution of ethyl 2-cyclobutylthiazole-4-carboxylate (example 58, step b) (0.48 g) in a mixture of THF (8 mL) and water (2 mL). The resulting suspension was stirred overnight at RT. The reaction was acidified with aqueous HCl solution (2M, 5 mL) and evaporated to dryness. The residue was partitioned between brine (5 mL) and ethyl acetate (20 mL). The layers were separated and the aqueous phase extracted with ethyl acetate (2×20 mL). The combined organic solutions were dried over sodium sulphate, filtered and evaporated to give the subtitled compound as a white solid. Yield 0.38 g.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[CH3:10][CH:11]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:12][CH2:13]Br.[OH-].[Na+].C1(C)C=CC=CC=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:10][CH:11]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:12][CH2:13][O:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: CC(C)CCCC(C)CCBr
Reactant: Cc1ccc(C)c(O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C)c(OCCC(C)CCCC(C)C)c1
Temperature: 95 °C
Yield: 70 %

Procedure:
Into a 500 ml four-necked flask was placed 36.7 g (0.3 mol) of 2,5-dimethylphenol, then, 73.0 g (0.33 mol) of 3,7-dimethyloctyl bromide was added, further, 150 g of water and 2.0 g (6.2 mmol) of tetrabutylammonium bromide were charged into the flask, and sufficient nitrogen purge was conducted by bubbling nitrogen through the mixture while stirring. Into this mixed solution was added an aqueous solution of sodium hydroxide (a solution prepared by dissolving 14.4 g (0.36 mol) of sodium hydroxide in 22 g of water) dropwise over 10 minutes while stirring. The mixture was heated to 95° C. and reacted for 30 minutes. Then, the mixture was kept at 100° C. and stirred for 4 hours to complete the reaction. The mixture was cooled to room temperature, and 200 ml of toluene was added before liquid separation. The intended substance was extracted into the organic layer which was washed with 200 ml of a 5% sodium hydroxide aqueous solution. The organic layer was dried over sodium sulfate, then, the solvent was distilled off by an evaporator. The intended 1-(3,7-dimethyloctyloxy)-2,5-dimethylbenzene was obtained from the condensed solution by distillation isolation (101 to 108° C./0.01 mmHg). The yield amount was 54.8 g (0.21 mol) and the yield was 70%.
Reaction SMILES: [Na].O=[C:3]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:15][C:16]1[CH:27]=[CH:26][C:19]2[C:20](=O)[O:21]C(=O)[NH:23][C:18]=2[CH:17]=1>CN(C)C=O>[Br:15][C:16]1[CH:17]=[C:18]2[C:19]([C:20]([OH:21])=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N:23]2)=[CH:26][CH:27]=1
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Reactant: O=c1[nH]c2cc(Br)ccc2c(=O)o1
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2cc(Br)ccc2c(O)c1C(=O)OCC
Temperature: 130 °C
Yield: 23.7 %

Procedure:
To a stirred mixture of diethyl oxosuccinate sodium salt (1.31 g, 6.23 mM) in dimethylformamide (DMF, 15 mL) under a nitrogen atmosphere was added a solution of 7-bromo-2H-3,1-benzoxazine-2,4(1H)-dione (1.50 g, 6.20 mM) in DMF (15 mL). The resulting reaction mixture was heated to 130° C. over 2.5 hr and then refluxed for 5 hr. After cooling to room temperature, the reaction mixture was concentrated and the residue was chromatographed over silica gel (eluant: ethyl acetate/methylene chloride; 5/95). The fractions containing the desired material were combined and concentrated. The solid residue was recrystallized from ethanol/ether to provide (0.54 g, 24%) the title compound as a tan solid, mp 233.5°-234.5° C.; MS(CI): 368, 369 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([Cl:15])[CH:14]=1)[NH:11][CH:10]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=1)[C:9]([CH3:24])([CH3:23])[CH:8]2O)=[O:4].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([Cl:15])[CH:14]=1)[NH:11][CH:10]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=1)[C:9]([CH3:24])([CH3:23])[CH2:8]2)=[O:4]
Reactant: COC(=O)c1cc(Cl)c2c(c1)C(O)C(C)(C)C(c1cccc(Br)c1)N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Cl)c2c(c1)CC(C)(C)C(c1cccc(Br)c1)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.9 %

Procedure:
To a stirred mixture solution of 2-(3-bromo-phenyl)-8-chloro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (48 g, 113.2 mmol) and triethylsilane (60 mL) at 25° C. was added trifluoroacetic acid (30 mL) dropwise. The resulting mixture solution was stirred at 25° C. for 3 hours. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with saturated aqueous sodium bicarbonate solution (4×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was triturated with methanol. The resulting precipitate was collected, dried in vacuo to afford 2-(3-bromo-phenyl)-8-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (23.1 g, 50%) as a white solid: LC/MS m/e calcd for C19H19BrClNO2 (M+H)+: 409.73, observed: 407.9 & 409.9.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[N:4]=[CH:3]1.C([Li])CCC.[CH2:13]=[O:14]>>[CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[N:4]=[C:3]1[CH2:13][OH:14]
Reactant: Cc1cn(C)cn1
Reactant: C=O
Agent: [Li]CCCC
Product: Cc1cn(C)c(CO)n1

Procedure:
The reaction of 1,4-dimethylimidazole (5.65 g.) with n-butyl lithium followed by treatment with formaldehyde according to the method described for the preparation of 3-hydroxymethyl-5,6,7,8-tetrahydroimidazo[1,5-alpyridine (used for Example 224) gave 1,4-dimethyl-2-hydroxymethylimidazole (2.71 g.), m.p. 125°-126° (ethyl acetate-petroleum ether).