Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[Si](C)(C)C.[F:6][C:7]1[C:8]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:16]=2)=[CH:9][C:10]([O:13]C)=[N:11][CH:12]=1.CO.C([O-])(O)=O.[Na+]>C(#N)C>[F:6][C:7]1[C:8]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:16]=2)=[CH:9][C:10](=[O:13])[NH:11][CH:12]=1
Reactant: COc1cc(-c2ccnc(NC3CCOCC3)n2)c(F)cn1
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: O=c1cc(-c2ccnc(NC3CCOCC3)n2)c(F)c[nH]1
Temperature: 80 °C
Yield: 31 %

Procedure:
Iodotrimethylsilane (0.186 mL, 1.30 mmol) was added dropwise to a solution of 4-(5-fluoro-2-methoxypyridin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine (0.0992 g, 0.3260 mmol) in acetonitrile (6 mL) in a vial at room temperature. The sealed vial was heated at 80° C. overnight. The reaction mixture was treated with MeOH (about 2 mL) and some saturated aqueous NaHCO3. The mixture was concentrated, and the aqueous residue was treated dropwise with 1M HCl until a tan precipitate formed (pH 2). This was extracted with 2 portions 10% isopropyl alcohol (“IPA”) in DCM. The combined organics were dried over MgSO4, filtered, and evaporated to yield 5-fluoro-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.0293 g, 0.1009 mmol, 30.96% yield) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[C:6]([CH:9]=1)[CH:7]=O.[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([CH2:21][C:22](=[O:26])[NH:23]2)=[CH:19][CH:18]=1.N1CCCC1>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[C:6]([CH:9]=1)/[CH:7]=[C:21]1\[C:22](=[O:26])[NH:23][C:24]2[C:20]\1=[CH:19][CH:18]=[C:17]([Cl:16])[CH:25]=2
Reactant: O=Cc1cc(Br)ccc1OCC(F)(F)F
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: C1CCNC1
Solvent: CO
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1cc(Br)ccc1OCC(F)(F)F
Temperature: 70 °C
Yield: 69.3 %

Procedure:
5-Bromo-2-(2,2,2-trifluoro-ethoxy)-benzaldehyde prepared in Example 232a (11 g, 39 mmol) and 6-chlorooxindole (5.4 g, 32 mmol) were mixed in anhydrous methanol (50 mL) at room temperature. Then pyrrolidine (2.7 g, 39 mmol) was added dropwise. The mixture was then heated at 70° C. for 3 h. After cooled to 4° C., the mixture was filtered and resulting precipitate was collected, dried to give E/Z-3-[5-Bromo-2-(2,2,2-trifluoro-ethoxy)-benzylidene]-6-chloro-1,3-dihydro-indol-2-one as yellow solid (9.6 g).
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[C:7](Cl)(=O)[C:8]([CH3:11])([CH3:10])[CH3:9]>ClCCl.C(N(CC)CC)C>[CH3:9][C:8]([C:7]1[N:2]([CH3:1])[C:3](=[S:6])[NH:4][N:5]=1)([CH3:11])[CH3:10]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CNC(=S)NN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(C(C)(C)C)n[nH]c1=S
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-methyl-3-thiosemicarbazide (0.53 g) in dichloromethane (10 mL) and triethylamine (0.73 mL) was added slowly via syringe pivaloyl chloride (5 mmol). Formation of a precipitate was observed. The mixture was kept overnight. Volatiles were evaporated in vacuo, the residue heated to 80° C. in aqueous NaOH (1 M, 25 mL) for 3 h. Aqueous HCl (2 M) was then added at 25° C. until pH ca. 6. The mixture was concentrated to dryness, water (10 mL) was added and the product collected by filtration, washing with saturated aqueous NaHCO3 (2.5 mL) and then water (10 mL) to give, after drying, the title compound (0.23 g) of ca. 90% purity by NMR as a colourless solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[C@H:10]([CH:12]([CH3:14])[CH3:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](Cl)(=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20]>>[CH2:1]([O:8][C:9](=[O:15])[C@H:10]([CH:12]([CH3:13])[CH3:14])[NH:11][C:16](=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC(=O)Cl
Reactant: CC(C)[C@H](N)C(=O)OCc1ccccc1
Product: CCCCC(=O)N[C@H](C(=O)OCc1ccccc1)C(C)C

Procedure:
According to EP 1714963 4-Bromomethyl-2′-cyanobiphenyl is condensed with L-valinebenzylester tosylate to give (S)-N-[(2′-cyanobiphenyl-4-yl]methyl]-(L)-valine benzylester hydrochloride. (S)-N-cyanobiphenyl-4-yl]methyl]-(L)-valine benzylester on reaction with valerylchloride yields (S)-N-cyanobiphenyl-4-yl]methyl]-N-valeryl-(L)-valine benzylester further by the reaction of tributyltin chloride and sodiumazide gives benzyl valsartan and debenzylation with Pd/C to give valsartan. Also discloses the process for the recovery of benzyl valsartan substantially free of organo tin impurity.
Reaction SMILES: [Na+].[Na+].C([O:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]([C:10]([O-:12])=[O:11])[C:8]=1[C:16]([O-:18])=[O:17])C.[Mn]([O-])(=O)(=O)=[O:20].[K+]>O>[C:6]([OH:5])(=[O:20])[C:7]1[CH:15]=[CH:14][CH:13]=[C:9]([C:10]([OH:12])=[O:11])[C:8]=1[C:16]([OH:18])=[O:17]
Reactant: CCOCc1cccc(C(=O)[O-])c1C(=O)[O-]
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cccc(C(=O)O)c1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 42 %

Procedure:
3-(Ethoxymethyl)phthalic acid disodium salt (3.7 mmol) from Example 2 was dissolved in water (40 ml). Potassium permanganate (7.5 mmol) was added and the resulting solution was stirred for 18 h at room temperature. The precipitate formed was filtered off and washed three times with hot water. The combined aqueous phase was evaporated under reduced pressure to approximately one third of the initial volume and cooled in an ice-bath. Concentrated HCl was added carefully for neutralization. The precipitated hemimellitic acid was collected on a glass filter, washed with water and dried (yield: 42%).
Reaction SMILES: C(C1[O:5]C1)Cl.[C:6]1([O:16][CH3:17])[C:7](=[CH:9][CH:10]=[C:11]([CH:15]=1)[CH:12]=[CH:13][CH3:14])[OH:8].[OH-].[Na+]>C(O)C>[O:5]1[C:12](=[CH:13][CH3:14])[C:11]2[CH:15]=[C:6]([O:16][CH3:17])[C:7]([OH:8])=[CH:9][C:10]1=2
Reactant: ClCC1CO1
Reactant: CC=Cc1ccc(O)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC=C1Oc2cc(O)c(OC)cc21

Procedure:
Epichlorohydrin 100 ml was mixed with isoeugenol 20 ml and NaOH 10 g dissolved in ethanol 10 ml, boiled to reflux for 4 hours. Obtained mixture was removed the included ethanol and passed through silica gel column chromatography, eluated with n-hexane and ethyl acetate (9:1), dryed with reduced pressure and obtained 4-epoxy isoeugenol (63 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:18]1([CH3:27])[C:19]([N:24]=[C:25]=[O:26])=[CH:20][CH:21]=[CH:22][CH:23]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:25]([NH:24][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH3:27])=[O:26])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccccc1N=C=O
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Solvent: ClCCl
Product: Cc1ccccc1NC(=O)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
7-Chloro-4-(piperazin-1-yl)quinoline (62 mg, 0.25 mmol) and o-tolyl isocyanate (31 μL, 0.25 mmol) in CH2Cl2 (5 mL) are reacted according to method C yielding the title product as colorless solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:12]3([CH2:16][C:15](=[O:17])[NH:14][C:13]3=[O:18])[C:11](=[O:19])[NH:10][C:7]2=[CH:8][CH:9]=1.Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>CN(C)C=O.[Cl-].[NH4+]>[C:25]([O:24][C:22](=[O:23])[CH2:21][N:10]1[C:7]2[C:6](=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)[C:12]2([CH2:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])[C:11]1=[O:19])([CH3:28])([CH3:27])[CH3:26]
Reactant: O=C1CC2(C(=O)N1)C(=O)Nc1ccc(Cl)cc12
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)C2(CC(=O)NC2=O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A stirred suspension of sodium hydride (60% dispersion in mineral oil, 1.68 g, 42 mmol) in anhydrous N,N-dimethylformamide (140 ml) was treated with the crude 5-chloro-1H-spiro[indole-3,3′-pyrrolidine]-2,2′,5′-trione, intermediate 9 (5.0 g, 19.96 mmol). After stirring at ambient temperature for 40 min, the dark orange solution was cooled in an ice-bath and treated, over 30 min., with a solution of t-butyl bromoacetate (3.24 g, 2.26 ml, 18.96 mmol) in anhydrous N,N-dimethylformamide (46 ml). The resultant dark yellow mixture was allowed to come to ambient temperature and stirred for 4 hours. The resultant mixture was diluted with saturated aqueous ammonium chloride (500 ml) and extracted with ethyl acetate (3×200 ml). The combined extracts were dried (MgSO4) and the solvent removed to give the crude (5-Chloro-2,2′,5′-trioxo-spiro[indole-3,3′-pyrrolidin]-1-yl)acetic acid tert-butyl ester which was purified by flash chromatography (silica) eluting with petroleum ether (40-60) containing an increasing amount (0 to 80%) of ethyl acetate. This gave 4.76 g (95%) of a yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[N:22]2[C:30]3[CH2:29][CH2:28][CH2:27][NH:26][C:25]=3[N:24]=[N:23]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:31](O)=O>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[N:22]2[C:30]3[CH2:29][CH2:28][CH2:27][N:26]([CH3:31])[C:25]=3[N:24]=[N:23]2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=CO
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2nnc3c2CCCN3)cc1
Product: CN1CCCc2c1nnn2-c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 100 °C

Procedure:
A 4 mL scintillation vial was charged with 4-tert-butyl-N-[4-chloro-2-(4,5,6,7-tetrahydro-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-phenyl]-benzenesulfonamide (synthesized according to general procedure M, 11 mg, 0.025 mmol), H2CO (37% in H2O, 3 mg, 0.037 mmol), and HCO2H (100 μL). The vial was sealed and heated to 100° C. for 1 hour. The solvent was subsequently removed in vacuo and the residue purified by preparative TLC to afford 4-tert-butyl-N-[4-chloro-2-(4-methyl-4,5,6,7-tetrahydro-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-phenyl]-benzenesulfonamide: MS (ES) M+H expected 460.2, found 460.0.
Reaction SMILES: C(O[CH2:5][C:6]1[NH:10][C:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:8]([CH3:21])[C:7]=1[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(=O)C.[CH2:28]([C:30]1[C:34]([CH2:35][CH3:36])=[CH:33][NH:32][CH:31]=1)[CH3:29]>>[CH2:14]([O:13][C:11]([C:9]1[NH:10][C:6]([CH2:5][C:31]2[NH:32][C:33]([CH2:5][C:6]3[NH:10][C:9]([C:11]([O:13][CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[O:12])=[C:8]([CH3:21])[C:7]=3[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:34]([CH2:35][CH3:36])[C:30]=2[CH2:28][CH3:29])=[C:7]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:8]=1[CH3:21])=[O:12])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)Cc1c(COC(C)=O)[nH]c(C(=O)OCc2ccccc2)c1C
Reactant: CCc1c[nH]cc1CC
Product: CCOC(=O)Cc1c(Cc2[nH]c(Cc3[nH]c(C(=O)OCc4ccccc4)c(C)c3CC(=O)OCC)c(CC)c2CC)[nH]c(C(=O)OCc2ccccc2)c1C

Procedure:
condensing two molecular equivalents of benzyl 5-(acetoxymethyl)-4-ethoxycarbonylmethyl-3-methylpyrrole-2-carboxylate with 3,4-diethyl pyrrole under acidic conditions to produce 2,5-bis(5-benzyloxycarbonyl-3-ethoxycarbonylmethyl-4-methylpyrrol-2-ylmethyl)-3,4-diethylpyrrole;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH3:12][O:13][CH2:14]Br.O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:12][O:13][CH3:14])[CH:4]=1
Reactant: COCBr
Reactant: COc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCOc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a solution of 3-(methyloxy)phenol (10.38 g, 84 mmol) in tetrahydrofurane (100 ml, SCRC) was added NaH (60% wt., 1.824 g, 76 mmol, Aldrich) portionwise under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour and bromomethyl methyl ether (9.5 g, 76 mmol, SCRC) was then added. The resulting mixture was stirred at room temperature for 2 hours and water (50 ml) was added. The reaction mixture was extracted with ethyl acetate (2 times 50 ml, SCRC) and the combined organic layers were dried over sodium sulphate, evaporated. The residue was purified by column chromatography on silica gel (EtOAc: PE=1:100) to afford the title compound (10.2 g) as a colorless liquid.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[C:8]([C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]([CH3:40])[CH:32]=2)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([N:22]3[CH2:26][CH2:25][C@@H:24]([N:27]([CH3:29])[CH3:28])[CH2:23]3)=[C:16]([NH2:30])[CH:15]=2)=[N:11][CH:12]=1.CCN(C(C)C)C(C)C>C1COCC1.O.C(Cl)Cl.C(OCC)C>[Cl:6][C:7]1[C:8]([C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]([CH3:40])[CH:32]=2)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([N:22]3[CH2:26][CH2:25][C@@H:24]([N:27]([CH3:29])[CH3:28])[CH2:23]3)=[C:16]([NH:30][C:1](=[O:4])[CH:2]=[CH2:3])[CH:15]=2)=[N:11][CH:12]=1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CC[C@@H](N(C)C)C2)c(N)cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cc(Nc2ncc(Cl)c(-c3cn(C)c4ccccc34)n2)c(OC)cc1N1CC[C@@H](N(C)C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
Acryloyl chloride (0.459 mL, 1M in THF, 0.46 mmol) was added dropwise to a mixture of N-[5-chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]-4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-6-methoxybenzene-1,3-diamine (Intermediate 85, 226 mg, 0.46 mmol) and DIPEA (0.088 mL, 0.51 mmol) in THF (15 mL) at 0° C. under N2. The resulting suspension was stirred at 0° C. for 1 h, then allowed to warm to r.t. The mixture was then diluted with water (15 mL) and concentrated in vacuo. The resulting material was dissolved in a mixture of CH2Cl2 (20 mL) and CH3OH (5 mL). The resulting solution was washed with water and sat. brine. The organic solution was dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 1-8% 7M methanolic ammonia in CH2Cl2 gave a yellow dry film after concentration of appropriate fractions in vacuo. This material was dissolved in CH2Cl2 and the resulting solution was diluted with diethyl ether. This resulted in a yellow gelatinous solid precipitating from the solution. The mixture was concentrated in vacuo and dried to give the title compound (142 mg, 57%) as a yellow solid; 1H NMR: 1.68-1.81 (1H, m), 2.04-2.14 (1H, m), 2.18 (6H, s), 2.64-2.75 (1H, m), 3.22 (3H, dd), 3.32-3.44 (1H, m), 3.78 (3H, s), 3.90 (3H, s), 5.66 (1H, dd), 6.16 (1H, dd), 6.49 (1H, dd), 6.54 (1H, s), 7.08 (1H, t), 7.23 (1H, t), 7.49 (1H, d), 7.54 (1H, s), 8.29-8.39 (3H, m), 8.53 (1H, s), 9.35 (1H, s); m/z: ES+ MH+ 546.57.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:7]([C:16]2[S:17][C:18](Br)=[CH:19][CH:20]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3].O.CO.C(O)=O.[CH3:28][N:29](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:7]([C:16]2[S:17][C:18]([C:28]#[N:29])=[CH:19][CH:20]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cn1cc(-c2ccncc2)c(-c2ccc(Br)s2)n1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O=CO
Solvent: CO
Solvent: O
Product: CC(C)Cn1cc(-c2ccncc2)c(-c2ccc(C#N)s2)n1
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 49 %

Procedure:
To a solution of 4-[1-isobutyl-3-(5-bromo-2-thienyl)-1H-pyrazol-4-yl]pyridine (1 eq, 0.28 mmol) in N,N-dimethylformamide (1 mL) were added zinc cyanide (0.5 eq, 0.14 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.2 eq, 0.055 mmol). The resulting mixture was stirred at 120° C. in the microwave for 10 min. Water was added and the aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by preparative HPLC (SunFire 50×150 mm 5 μm, eau/methanol/formic acid) to afford 44 mg of 4-[1-isobutyl-3-(5-cyano-2-thienyl)-1H-pyrazol-4-yl]pyridine (49% yield).
Reaction SMILES: [NH2:1][C@@H:2]1[C:25](=[O:26])[N:4]2[C:5]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[O:14])=[C:6]([CH2:9][N:10]=[N+:11]=[N-:12])[CH2:7]S[C@H:3]12.OO.[S:29]([O-:32])([O-])=[O:30].[Na+].[Na+]>C(OCC)(=O)C.O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[NH2:1][C@@H:2]1[C:25](=[O:26])[N:4]2[C:5]([C:13]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)=[O:14])=[C:6]([CH2:9][N:10]=[N+:11]=[N-:12])[CH2:7][S:29](=[O:32])(=[O:30])[C@H:3]12
Reactant: COc1ccc(COC(=O)C2=C(CN=[N+]=[N-])CS[C@@H]3[C@H](N)C(=O)N23)cc1
Reactant: O=S([O-])[O-]
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(COC(=O)C2=C(CN=[N+]=[N-])CS(=O)(=O)[C@@H]3[C@H](N)C(=O)N23)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
p-Methoxybenzyl 7β-amino-3-azidomethyl-3-cephem-4-carboxylate (17.15 g, 0.046 mol) in ethyl acetate was cooled to 15° C., sodium tungstate dihydrate (1.52 g, 0.0046 mol) was added followed by hydrogen peroxide (30%, 20.73 ml) in one portion and the stirring was continued at room temperature. After two hours an additional portion of hydrogen peroxide (5.18 ml) was added and the reaction mixture was stirred at room temperature for a total period of 18 h; the mixture was cooled to 10° C. and a solution of sodium sulphite (10%, 600 ml) was added while stirring. Organic layer was separated out, washed with aq. sodium bicarbonate solution, brine and dried (Na2SO4). Evaporation of the solvent in vacuo gave a foam (12 g) which was purified over a silica column using hexane-ethyl acetate (1:3) as eluant to give the pure product as a white foam (6.8 g, 36.5%). IR (Nujol) ν max 2083 cm-1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH:7]([NH:25][C:26]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27])[CH2:8][S:9](=[O:24])(=[O:23])[CH2:10][CH2:11][NH:12]C(OCC1C=CC=CC=1)=O)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:33])[CH:7]([NH:25][C:26]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27])[CH2:8][S:9](=[O:23])(=[O:24])[CH2:10][CH2:11][NH2:12])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCCOC(=O)NC(CS(=O)(=O)CCNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CCCCOC(=O)NC(CS(=O)(=O)CCN)C(=O)OC(C)(C)C
Yield: 82.1 %

Procedure:
To a solution of 2-(butyloxycarbonylamino)-6-(benzyloxycarbonylamino)-4,4-dioxo-4-thiahexanoic acid tert-butyl ester (200 mg) in methanol (5 ml) was added Pd/C (50%) (Degussa type) (200 mg) and the mixture hydrogenated at room temperature until no further change was observed. The reaction mixture was then filtered through a pad of Hyflo and the residue washed with fresh methanol (2×2 ml). The combined filtrates were evaporated to dryness to give 119 mg of the title compound as an almost colourless glass.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[N:9]=[N:10][O:11][CH:12]=2)=[CH:5][CH:4]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C[N:28]1C(=O)CCC1>C(Cl)Cl>[NH2:28][CH2:1][C:3]1[S:7][C:6]([C:8]2[N:9]=[N:10][O:11][CH:12]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(-c2conn2)s1
Reactant: CN1CCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: NCc1ccc(-c2conn2)s1
Reaction time: 2 h

Procedure:
To a solution of the 5-formyl-thiophen-2-yl-oxadiazol derivative (1 eq., usual scale 0.02-0.25 mmol) and the appropriate amine (2-40 eq.) in DCM (24 mL/mmol) and NMP (6 mL/mmol), sodium triacetoxy borohydride (NaBH(OAc)3) (3 eq.) is added. The mixture is stirred for 2 h before another portion of NaBH(OAc)3 (3 eq.) is added. Stirring of the suspension is continued for another 2 h and a third portion of NaBH(OAc)3 (3 eq.) is added. The mixture is stirred for 16 h before the DCM is evaporated. The remaining residue is diluted with water (4 mL/mmol) and formic acid (4 mL/mmol) and the resulting solution is separated by prep. HPLC (XBridge Prep C18, 19×50 mm, 5 μm, 10% to 95% acetonitrile in water containing 0.5% formic acid) to give the desired 5-aminomethyl-thiophen-2-yl-oxadiazol derivative as a colourless to pale yellow resin.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][OH:6].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:21]([O:25][C:26]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[O:44][CH3:45])=[CH:35][CH:36]=2)[C:31]([CH:46](OS(C)(=O)=O)[CH3:47])=[CH:30][C:29]1([CH3:54])[CH3:53])=[O:27])([CH3:24])([CH3:23])[CH3:22]>CS(C)=O>[C:21]([O:25][C:26]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[O:44][CH3:45])=[CH:35][CH:36]=2)[C:31]([CH:46]([O:6][CH2:5][CH2:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[Br:1])[CH3:47])=[CH:30][C:29]1([CH3:53])[CH3:54])=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: COc1ccccc1-c1ccc2c(c1)C(C(C)OS(C)(=O)=O)=CC(C)(C)N2C(=O)OC(C)(C)C
Reactant: OCCc1ccccc1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccccc1-c1ccc2c(c1)C(C(C)OCCc1ccccc1Br)=CC(C)(C)N2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.037 mL of 2-bromophenethyl alcohol and 1 mL of DMSO was treated with 0.277 mL of 1.0 M sodium bis(trimethylsilyl)amide, then 86 mg of 4-(1-methanesulfonyloxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylic acid tert-butyl ester in 1 mL DMSO was added at room temperature. The reaction mixture was allowed to stir at room temperature overnight. TLC showed starting material was consumed. The reaction was quenched with water and the product was extracted with EtOAc three times. The organic layers were combined, washed sequentially with saturated aqueous ammonium chloride solution, saturated aqueous sodium bicarbonate solution, water, and brine, dried over magnesium sulfate, and the solvent evaporated in vacuo. The residue was purified by flash chromatography to yield 37 mg of 4-{1-[2-(2-bromophenyl)ethoxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[C:8]([OH:13])=[C:7]([CH:14]([OH:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:6]([CH3:21])=[CH:5]2.[Cl:22]C1C=CC(CC(=O)C)=CC=1>>[Cl:22][C:11]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([CH3:21])[C:7]([CH:14]([OH:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:8]2[OH:13])=[CH:3][CH:2]=1
Reactant: CC(=O)Cc1ccc(Cl)cc1
Reactant: CCOC(=O)C(O)c1c(C)cc2cc(Cl)c(F)cc2c1O
Product: CCOC(=O)C(O)c1c(C)cc2ccc(Cl)cc2c1O

Procedure:
Prepared in a manner similar to ethyl 2-(6-chloro-7-fluoro-1-hydroxy-3-methylnaphthalen-2-yl)-2-hydroxyacetate of Example 99 except using 1-(4-chlorophenyl)propan-2-one. 1H-NMR: (400 MHz, CDCl3): δ 8.42 (s, broad, 1H), 8.18 (d, J=2.0 Hz, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.38 (dd, J=8.6, 2.0 Hz, 1H), 7.18 (s, 1H), 5.68 (s, 1H), 4.33-4.10 (m, 2H), 2.53 (s, 3H), 1.20 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:16][CH2:17][CH:18]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:22]=[C:23]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:24]=[CH:25][C:26]=1[Cl:27].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:16][CH2:17][CH2:18][N:31]2[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][C:26]([Cl:27])=[C:21]([Cl:20])[CH:22]=3)[CH2:33][CH2:32]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)n1nc(CCCN2CCN(c3ccc(Cl)c(Cl)c3)CC2)cc1-c1ccccc1

Procedure:
74 mg (47%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propanal (80 mg, 0.312 mmol), 1-(3,4-dichlorophenyl)piperazine (72 mg, 0.312 mmol), DIPEA (82 mL, 0.468 mmol) and NaBH(OAc)3 (198 mg, 0.936 mmol).