Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]1[CH:7](Cl)[N:6]([CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([O:12][CH3:13])=[O:11])[C:5]1=[O:20])=[N+:2]=[N-:3].C(=O)([O-])[O-].[K+].[K+].[CH3:27][C:28]1[S:32][C:31]([SH:33])=[N:30][N:29]=1>C(Cl)Cl>[N:1]([CH:4]1[CH:7]([S:33][C:31]2[S:32][C:28]([CH3:27])=[N:29][N:30]=2)[N:6]([CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([O:12][CH3:13])=[O:11])[C:5]1=[O:20])=[N+:2]=[N-:3]
Reactant: Cc1nnc(S)s1
Reactant: COC(=O)C(c1ccccc1)N1C(=O)C(N=[N+]=[N-])C1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)C(c1ccccc1)N1C(=O)C(N=[N+]=[N-])C1Sc1nnc(C)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
Methyl 2-(3-azido-4-chloro-2-oxo-1-azetidinyl)-2-phenylacetate (two trans and two cis isomers) (4.0 g.) was dissolved in dried methylene chloride (50 ml.), and to the solution were added anhydrous potassium carbonate (1.13 g.) and 5-methyl-1,3,4-thiadiazole-2-thiol (2.10 g.). The mixture was stirred at room temperature for 8 hrs, poured into icewater and then extracted with ether. The extract was washed with 1% aqueous potassium carbonate and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off from the solution under reduced pressure, and the residue (4.05 g.) was subjected to column chromatography on silica gel (160 g.). The elution was conducted with chloroform and the fractions containing the object compound were collected. The solvent was distilled off from the solution under reduced pressure to give methyl 2-[3-azido-4-(5-methyl-1,3,4-thiadiazol-2-ylthio)-2-oxo-1-azetidinyl]-2-phenylacetate (two trans and two cis isomers) (2.81 g.).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:11][C@H:12]([CH2:18][NH:19][CH3:20])[CH2:13][C:14](OC)=[O:15])[CH:6]=[CH:7][C:8]=1[C:9]#[N:10].C([O-])([O-])=O.[K+].[K+]>CC#N.CO>[Cl:2][C:3]1[CH:4]=[C:5]([NH:11][C@H:12]2[CH2:13][C:14](=[O:15])[N:19]([CH3:20])[CH2:18]2)[CH:6]=[CH:7][C:8]=1[C:9]#[N:10]
Reactant: CNC[C@H](CC(=O)OC)Nc1ccc(C#N)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: CN1C[C@@H](Nc2ccc(C#N)c(Cl)c2)CC1=O
Temperature: 68 °C
Reaction time: 0.33 h
Yield: 81.2 %

Procedure:
A mixture of methyl (3S)-3-[(3-chloro-4-cyanophenyl)amino]-4-(methylamino)butanoate, hydrochloride (15.6 g., 49 mmole) and K2CO3 (325 mesh, 15.0 g, 110 mmole) in MeCN (120 mL) and MeOH (30 mL) was heated with stirring at 68° C. for 20 min. The solvents were evaporated, and the residue partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (2×), the combined EtOAc extracts were washed with H2O and brine, dried (MgSO4) and the solvent evaporated. The crude product (10.3 g) was triturated with Et2O, chilled and the solid filtered to give the titled compound (9.93 g, 81%). LC-MS (ES) m/e 250 (M+H)+.
Reaction SMILES: CO[C:3]1[CH:27]=[CH:26][C:25](C)=[CH:24][C:4]=1[C:5]([NH:7][C@H:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[NH:13][C:14]1[CH:19]=[N:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=1)=[O:6].Cl.FC(F)(F)C1N=CC(N[C@H]2CCC[C@@H]2N)=NC=1.[CH3:47][C:48]1[O:52][C:51](C2C=CC=CC=2C(O)=O)=[N:50][N:49]=1>>[CH3:47][C:48]1[O:52][C:51]([C:3]2[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=2[C:5]([NH:7][C@H:8]2[CH2:12][CH2:11][CH2:10][C@@H:9]2[NH:13][C:14]2[CH:19]=[N:18][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:16][N:15]=2)=[O:6])=[N:50][N:49]=1
Reactant: COc1ccc(C)cc1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reactant: Cc1nnc(-c2ccccc2C(=O)O)o1
Agent: Cl
Agent: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Product: Cc1nnc(-c2ccccc2C(=O)N[C@H]2CCC[C@@H]2Nc2cnc(C(F)(F)F)cn2)o1

Procedure:
Prepared according to the procedure for 2-methoxy-5-methyl-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 37) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 75 mg, 0.27 mmol) and 2-(5-methyl-1,3,4-oxadiazol-2-yl)benzoic acid (CAS number 898289-64-0; 75 mg, 0.37 mmol) except this was purified by column chromatography (silica, 40-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH:23]=[CH2:24])[C:17]=4O)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:26][CH3:27])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)[OH:29]>C(O)(=O)C>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[CH:20][C:19]5[O:29][CH:23]([CH3:24])[CH2:22][C:18]=5[CH:17]=4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:26][CH3:27])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(O)O
Reactant: C=CCc1cccc(-c2nc3n(C4CCCC4)[nH]c(CC)c-3c(=O)n2)c1O
Solvent: CC(=O)O
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccc4c(c3)CC(C)O4)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 1-cyclopentyl-3-ethyl-6-[2-hydroxy-3-(2-propenyl)phenyl]pyrazolo[3,4-d]pyrimidin-4-one (1.0 g) in acetic acid (15 ml) was added sulfuric acid (15 ml) while cooling in an ice bath. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was poured into ice/water, a precipitate formed which was collected by filtration and washed with water. The product was purified by recrystallization from ether, followed by column chromatography on silica gel eluting with 25% EtOAc/hexane to afford 0.5 g of 1-cyclopentyl-3-ethyl-6-[2-methyl-2,3-dihydrobenzo[b]furan-5-yl]pyrazolo[3,4-d]pyrimidin-4-one, m.p. 164°-165° C.
Reaction SMILES: Cl[C:2]1[CH:24]=[C:23](Cl)[CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[C:9](=[O:20])[NH:10][N:11]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:13]=1)=[O:7].O=C1C(C(O)=O)=CC(C2C=CN=CC=2)=NN1.C(Cl)(=O)C(Cl)=O.C(N)C1C=CC=CC=1>C(N(CC)CC)C.CN(C)C=O.ClCCl>[CH2:4]([NH:5][C:6]([C:8]1[C:9](=[O:20])[NH:10][N:11]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:13]=1)=[O:7])[C:3]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:2]=1
Reactant: O=C(NCc1ccc(Cl)cc1Cl)c1cc(-c2ccncc2)n[nH]c1=O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)c1cc(-c2ccncc2)n[nH]c1=O
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: NCc1ccccc1
Product: O=C(NCc1ccccc1)c1cc(-c2ccncc2)n[nH]c1=O

Procedure:
Working as in example 2 for the preparation of N-(2,4-dichlorobenzyl)-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxamide, but starting with 0.3 g of 3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxylic acid, 10 cm3 of dichloromethane, 0.02 cm3 of dimethylformamide, 0.12 cm3 of oxalyl chloride, 0.17 cm3 of benzylamine and 0.19 cm3 of triethylamine, 0.22 g of N-benzyl-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxamide was obtained in the form of a cream-colored solid melting at 258° C.
Reaction SMILES: CO[C:3](=O)[NH:4][CH2:5][CH2:6][CH:7]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[CH:17]2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH:19]1[C:20]2[C:16](=[CH:15][C:14]([CH:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:6][CH2:5][NH:4][CH3:3])=[CH:22][CH:21]=2)[CH:17]=[CH:18]1
Reactant: COC(=O)NCCC(c1ccccc1)c1ccc2[nH]ccc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCCC(c1ccccc1)c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of [3-(1H-indol-5-yl)-3-phenyl-propyl]-carbamic acid methylester X (0.52 g, 1.7 mmol) in THF (35 ml), LiAlH4 (321 mg, 8.4 mmol) was slowly added. The mixture was refluxed for 1.5 hours, cooled to room temperature, and quenched by slow addition of freshly ground Na2SO4.10H2O. The mixture was stirred at room temperature for 1 hour, filtered through celite with EtOAc. The filtrate was evaporated and purified via flash chromatography (DCM/MeOH/NH4OH) affording [3-(1H-indol-5-yl)-3-phenyl-propyl]-methyl-amine (XI) as an off-white foam (408 mg, 91% yield). The amine compound was dissolved in a Et2O/THF mixture and HCl (2 M in Et2O, 0.772 ml) was added. The precipitate was filtered, washed with Et2O, and dried affording [3-(1H-indol-5-yl)-3-phenyl-propyl]-methyl-amine hydrochloride salt (371 mg, 80% yield). MS (M+H)=265.
Reaction SMILES: N=O.[CH3:3][CH:4]([OH:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[O-]Cl.[Na+]>C1(C)C=CC=CC=1>[CH3:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC(C)O
Agent: N=O
Agent: [Na+]
Agent: [O-]Cl
Solvent: Cc1ccccc1
Product: CCCCCCC(C)=O
Reaction time: 2 h
Yield: 100 %

Procedure:
In a flask 0.072 g (0.05 mmol) of the product from example 1, 2.5 g (19.2 mmol) of 2-octanol, 10 ml of toluene and 2.8 gr of KHCO3 (20% sol.) were added; the heterogeneous mixture was cooled to 10–15° C. then were added 13.2 g of an aqueous solution of NaOCl (10.5%). After 2 hours the crude organic layer was analyzed using GC and 1H-13C-NMR and 100% of 2-octanone was obtained as desired product. The catalyst was recovered by filtration of the crude reaction mixture.
Reaction SMILES: [Li]C(C)(C)C.[CH3:6][Si:7]([CH3:20])([CH3:19])[CH2:8][CH2:9][O:10][CH2:11][O:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.Cl[Si:22]([CH3:25])([CH3:24])[CH3:23].O>CCOCC>[CH3:23][Si:22]([CH3:25])([CH3:24])[C:18]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[O:12][CH2:11][O:10][CH2:9][CH2:8][Si:7]([CH3:20])([CH3:19])[CH3:6]
Reactant: C[Si](C)(C)CCOCOc1cccnc1
Reactant: C[Si](C)(C)Cl
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCOCC
Product: C[Si](C)(C)CCOCOc1cnccc1[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
Add t-BuLi dropwise to a −78° C. solution of 3-(2-trimethylsilanyl-ethoxymethoxy)-pyridine (1.98 g, 8,8 mmol) in Et2O (25 mL, freshly distilled over Na0). After 1 hour, add chlorotrimethylsilane (1.33 mL, 10.5 mmol) dropwise and allow reaction to warm slowly to RT. After 1.5 hours, add water (5 mL) dropwise to quench. Wash with saturated NaHCO3 solution and brine. Dry the combined organic layers over MgSO4 and concentrate. Purify the residue by flash chromatography on silica gel eluting with 0-30% EtOAc/hexanes to afford the title compound (1.57 g, 60%) as yellow oil. MS(IS) 298 (M+1). TLC: Rf=0.38 (35% EtOAc/hexanes).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:32])[C@:4]1([OH:31])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C@@H:19]([OH:23])[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:24])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[O:25][CH2:26][C:27]1(C)[CH2:29][O:28]1.I(O)(=O)(=O)=O>O1CCCC1.O>[Cl:1][CH2:2][C:3](=[O:32])[C@:4]1([OH:31])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C@@H:19]([OH:23])[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:24])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[O:25][CH2:26][C:27](=[O:28])[CH3:29]
Reactant: CC1(CO[C@@H]2C[C@H]3[C@@H]4CCC5=CC(=O)C=C[C@]5(C)[C@H]4[C@@H](O)C[C@]3(C)[C@@]2(O)C(=O)CCl)CO1
Agent: [O-][I+3]([O-])([O-])O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)CO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CCl

Procedure:
A solution of 21-chloro-11β,17-dihydroxy-16α-[(2-methyloxiranyl)methoxy]pregna-1,4-diene-3,20-dione (12 mmoles) in 200 ml of tetrahydrofuran is stirred with a solution of 10 g of periodic acid in 20 ml of water for 3 hours. The slurry is diluted with water and extracted with chloroform. The chloroform solution is dried and evaporated in vacuo to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([Si:13]([CH3:16])([CH3:15])[CH3:14])[Si:9]([CH3:12])([CH3:11])[CH3:10])=[C:4]([Cl:17])[CH:3]=1.C([Li])(C)(C)C.[C:23]([O:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C:31]1([CH2:37][CH2:38][CH2:39][CH3:40])[CH:35]=[O:36])=[O:29])([CH3:26])([CH3:25])[CH3:24]>CCOCC>[C:23]([O:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C:31]1([CH2:37][CH2:38][CH2:39][CH3:40])[CH:35]([C:2]1[CH:7]=[CH:6][C:5]([N:8]([Si:13]([CH3:16])([CH3:15])[CH3:14])[Si:9]([CH3:12])([CH3:11])[CH3:10])=[C:4]([Cl:17])[CH:3]=1)[OH:36])=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CCCCC1(C=O)CCCN1C(=O)OC(C)(C)C
Reactant: C[Si](C)(C)N(c1ccc(Br)cc1Cl)[Si](C)(C)C
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CCCCC1(C(O)c2ccc(N([Si](C)(C)C)[Si](C)(C)C)c(Cl)c2)CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 49.1 %

Procedure:
To a stirred solution of 2-(4-bromo-2-chloro-phenyl)-1,1,1,3,3,3-hexamethyl-disilazane (0.484 g, 1.38 mmol) in ether (14 mL) at −78° C. and under nitrogen was added tert-butyllithium (2.03 mL, 1.43 M solution in pentanes, 2.91 mmol) dropwise. After 90 minutes, a solution of 2-butyl-2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.353 g, 1.38 mmol) in ether (3 mL) was added to the reaction mixture dropwise. After one hour, the reaction mixture was warmed to ambient temperature and stirred at ambient temperature for 30 minutes. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl (10 mL) and extracted with EtOAc. The combined extracts were washed with brine, then dried (MgSO4), filtered, and concentrated in vacuo to an oil (0.75 g). Purification by chromatography (silica, 5-20% EtOAc in hexanes) gave 2-butyl-2-{[3-chloro-4-(1,1,1,3,3,3-hexamethyl-disilazan-2-yl)-phenyl]-hydroxy-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.357 g, 0.678 mmol, 49%) as a colourless oil.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][C:26]([CH:29]([CH3:33])[C:30]([OH:32])=O)=[CH:25][CH:24]=4)=[CH:22][C:17]=3[N:16]=[CH:15]2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[O:36]1[CH:40]=[CH:39][CH:38]=[C:37]1[CH2:41][NH2:42]>>[O:36]1[CH2:40][CH2:39][CH2:38][CH:37]1[CH2:41][NH:42][C:30](=[O:32])[CH:29]([C:26]1[CH:27]=[CH:28][C:23]([C:21]2[CH:20]=[CH:19][C:18]3[N:14]([C:10]4[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:1])([F:35])[F:34])=[O:6])[CH:9]=4)[CH:15]=[N:16][C:17]=3[CH:22]=2)=[CH:24][CH:25]=1)[CH3:33]
Reactant: CC(C(=O)O)c1ccc(-c2ccc3c(c2)ncn3-c2cccc(NC(=O)NCC(F)(F)F)c2)cc1
Reactant: NCc1ccco1
Product: CC(C(=O)NCC1CCCO1)c1ccc(-c2ccc3c(c2)ncn3-c2cccc(NC(=O)NCC(F)(F)F)c2)cc1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 14 starting from 2-(4-{1-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]-1H-benzimidazol-5-yl}phenyl)propanoic acid and 2-furanmethanamine, tetrahydro- (Aldrich, Cat. No. 131911). LCMS (M+H)+: m/z=566.2.
Reaction SMILES: CC([O:4][CH2:5][C@H:6]1[O:11][C@H:10]([O:12][C:13]([CH3:15])=O)[C@H:9]([O:16]C(C)=O)[C@@H:8]([O:20]C(C)=O)[C@@H:7]1[O:24][C@@H:25]1[O:30][C@H:29]([CH2:31][O:32]C(C)=O)[C@@H:28]([O:36]C(C)=O)[C@H:27]([O:40]C(C)=O)[C@H:26]1[O:44]C(C)=O)=O.[CH2:48](O)C=C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C[O-].[Na+]>C(Cl)Cl.O>[C@@H:25]1([O:24][C@@H:7]2[C@@H:6]([CH2:5][OH:4])[O:11][CH:10]([O:12][CH2:13][CH:15]=[CH2:48])[C@H:9]([OH:16])[C@H:8]2[OH:20])[O:30][C@H:29]([CH2:31][OH:32])[C@@H:28]([OH:36])[C@H:27]([OH:40])[C@H:26]1[OH:44]
Reactant: CC(=O)OC[C@H]1O[C@@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C=CCO
Agent: C[O-]
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C=CCOC1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.6 %

Procedure:
α-D-cellobiose octaacetate (48.59 g, 71.6 mmol) was dissolved in methylene chloride (600 mL), and allyl alcohol (29 ml, 0.43 mol) and trimethylsilyl trifluoromethanesulfonate (16 mL, 86.0 mmol) were added thereto under ice-cooling, followed by stirring of the mixture at room temperature for 1.5 hours. Water (200 mL) was added to the reaction mixture and the mixture was extracted with methylene chloride (200 mL). The extract was washed with a saturated aqueous NaCl solution (100 mL) and after it was dried with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in methanol (300 mL) and sodium methoxide (28 mL, 0.14 mol) was added thereto under ice-cooling, followed by stirring of the mixture at room temperature for 2 hours. Dowex 50w×8 was added to the reaction mixture until the reaction mixture became neutral and after it was filtered, the solvent was distilled off under reduced pressure. The residue was purified using silica gel flash column chromatography (ethyl acetate:methanol:water, 8:2:1, V/V) to obtain the desired title compound (24.8 g, yield: 91%) as a pale yellow amorphous substance.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][NH:6]1)=[O:4].[C:20](OC(C)(C)C)(=[O:25])[CH2:21][C:22]([CH3:24])=[O:23]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:11])=[O:12])[CH2:7][N:6]1[C:20](=[O:25])[CH2:21][C:22](=[O:23])[CH3:24])=[O:4]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)CC(C)=O

Procedure:
In analogy to the procedure described in example 192f, (2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with tert-butyl acetoacetate to give the title compound as yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8](=[O:26])[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[C:10]([CH3:17])[NH:11]2.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].I[CH:40]([CH3:42])[CH3:41]>O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:26][CH:40]([CH3:42])[CH3:41])=[C:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[C:10]([CH3:17])=[N:11]2
Reactant: COC(=O)COc1ccc(Cl)c2[nH]c(C)c(Cc3ccc(F)cc3)c(=O)c12
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(Cl)c2nc(C)c(Cc3ccc(F)cc3)c(OC(C)C)c12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of [8-chloro-3-(4-fluorobenzyl)-2-methyl-4-oxo-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester (0.020 g), N,N-dimethylformamide (1.0 mL), potassium carbonate (0.020 g) and 2-iodopropane (0.050 g) was stirred at room temperature for 2 days. The mixture was diluted with water, extracted with ethyl acetate and the combined extracts washed with water and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1:9 by volume) to afford title compound as a light brown oil, 0.024 g.
Reaction SMILES: [CH:1]1[C:17]2[CH2:16][C@H:15]3[N:18]([CH2:20][CH2:21][C@@:7]45[C@H:14]3[CH:13]=[CH:12][C@H:10]([OH:11])[C@@H:8]4[O:9][C:5]([C:6]=25)=[C:3]([OH:4])[CH:2]=1)[CH3:19].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-].[Na+]>C1COCC1.C(Cl)Cl>[CH2:22]([C:3]1([OH:4])[C:5]2[O:9][C@@H:8]3[C@@:7]45[CH2:21][CH2:20][N:18]([CH3:19])[C@@H:15]([C@@H:14]4[CH:13]=[CH:12][C@@H:10]3[OH:11])[CH2:16][C:17]([C:6]5=2)=[CH:1][CH2:2]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN1CC[C@]23C4=C5O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1CC4=CCC5(O)Cc1ccccc1
Reaction time: 8 h
Yield: 59.6 %

Procedure:
To a suspension of morphine (10.0 g, 35.1 mmol) in THF (200 ml), was added benzyl bromide (5.5 ml, 98%, 45.3 mmol) and sodium hydroxide (1.48 g, 37.0 mmol) at 0° C. The reaction mixture was stirred overnight. The reaction temperature rose gradually to rt. during the process. THF in the reaction mixture was removed on a rotary evaporator. The residue was dissolved in CH2Cl2 (150 ml) and water (50 ml). The organic layer was separated. The aqueous layer was extracted with CH2Cl2 (3×50 ml). The combined organic layer was dried over anhydrous sodium sulfate, evaporated in vacuo to obtain a crude product (13 g), which was dissolved in CH2Cl2 and loaded onto a silica gel column (3×30 cm). The column was first eluted with 3% methanol in CH2Cl2, followed by 5% methanol in CH2Cl2. Pure fractions were combined to obtain 3-benzylmorphine (7.9 g, 60% yield). IR (KBr)(ν, cm-1): 3540 (m, sharp, --OH), 3020 (m, sharp), 2900 (s, sharp), 1600 (m, sharp); NMR (δH)(CDCl3): 7.50-7.20 (5, m, --C6H5), 6.70 (1, d, J, 8.1, 2-H), 6.51 (1, dd, J, 8.1 & 0.9, 1-H), 5.65 (1, dm, J, 9.9, 7-H), 5.26 (1, dt, J, 9.9 & 2.5, 8-H), 5.12 (2, AB, OCH2Ph), 4.85 (1, dd, J, 6.6 & 1.2, 5-H), 4.22-4.05 (1, m, 6-H), 3.32 (1, dd, J, 6.2 & 3.3, 9-H), 3.02 (1, d, J, 18.6, 10-Hβ), 2.75-2.65 (1, m, 14-H), 2.75-2.65 (1, b, --OH), 2.58 (1, dm, J, 12.0, 16-He), 2.5-2.3 (1, m, 16-Ha), 2.42 (3, s, N--CH3), 2.27 (1, dd, J, 18.6 & 6.6, 10-Hα), 2.05 (1, td, J, 12.1 & 5.3, 15-Ha), 1.85 (1, dm, J, 12.5, 15-He).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[C:4]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.P(Br)(Br)[Br:19].[OH-].[Na+]>C1C=CC=CC=1>[Br:19][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrP(Br)Br
Reactant: Cc1ccc(CO)c(OCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: Cc1ccc(CBr)c(OCc2ccccc2)c1
Reaction time: 0.17 h
Yield: 92.9 %

Procedure:
A solution of crude 4-methyl-2-phenylmethoxy-benzenemethanol (20 g, 87.6 mmol) in dry benzene (100 ml) was treated with 9.1 ml (96 mmol) PBr3 at room temperature and after being stirred for 10 min the mixture was treated with 50 ml 2N NaOH solution. The organic layer was separated and dried (Na2SO4) to give 1-bromomethyl-4-methyl-2-phenylmethoxybenzene (23.7 g, 93% crude yield) as an oil.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:8][O:9][C:10]2[C:11]3[N:12]([C:16]([C:20]([O:22]CC)=[O:21])=[C:17]([CH3:19])[N:18]=3)[CH:13]=[CH:14][CH:15]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[Li+].[ClH:27]>C1COCC1.CO>[ClH:27].[F:1][C:2]1[C:3]([CH2:8][O:9][C:10]2[C:11]3[N:12]([C:16]([C:20]([OH:22])=[O:21])=[C:17]([CH3:19])[N:18]=3)[CH:13]=[CH:14][CH:15]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3ncccc3F)cccn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc2c(OCc3ncccc3F)cccn2c1C(=O)O
Temperature: 40 °C
Reaction time: 8 h

Procedure:
4.66 g of ethyl 8-[(3-fluoropyridin-2-yl)methoxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate (Example 116A, 14.2 mmol) were dissolved in 304 ml of THF/MeOH (5/1), 70.8 ml of 1 N aqueous lithium hydroxide solution (70.8 mmol) were added and the mixture was stirred at 40° C. overnight. The reaction mixture was acidified (pH about 3-4) using 1 N aqueous hydrochloric acid, and the solution was concentrated. The precipitate formed was cooled with ice-water and then filtered off with suction and dried under reduced pressure. This gave 3.97 g of the product (83% of theory).
Reaction SMILES: FC1C=C(CN)C=NC=1.[O:10]1[CH:14]=[CH:13][N:12]=[C:11]1[CH2:15][NH2:16].[CH:17]1([CH2:20][N:21]2[CH2:25][CH2:24][N:23]([C:26]3[S:27][C:28]([C:32](O)=[O:33])=[C:29]([CH3:31])[N:30]=3)[C:22]2=[O:35])[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][N:21]2[CH2:25][CH2:24][N:23]([C:26]3[S:27][C:28]([C:32]([NH:16][CH2:15][C:11]4[O:10][CH:14]=[CH:13][N:12]=4)=[O:33])=[C:29]([CH3:31])[N:30]=3)[C:22]2=[O:35])[CH2:18][CH2:19]1
Reactant: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)O
Reactant: NCc1ncco1
Agent: NCc1cncc(F)c1
Product: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)NCc1ncco1
Yield: 25 %

Procedure:
Following the procedure as describe in Example 12, making variations as required to replace (5-fluoropyridin-3-yl)methanamine with oxazol-2-ylmethanamine to react with 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 25% yield: mp 172-174° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CD3OD) δ 7.86 (s, 1H), 7.14-7.10 (m, 1H), 4.61 (s, 2H), 4.12-4.07 (m, 2H), 3.78-3.72 (m, 2H), 3.18 (d, J=7.1 Hz, 2H), 2.53 (s, 3H), 1.03-0.98 (m, 1H), 0.60-0.54 (m, 2H), 0.29-0.24 (m, 2H); MS (ES+) m/z 362.1 (M+1).