Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[N:5][C:6]([CH3:16])=[C:7]([CH3:15])[N:8]=2)[N:3]=1.[C:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([N:30]=[C:31]=[O:32])(=[O:29])=[O:28])([O:19][CH3:20])=[O:18].C(OC(C)C)(C)C>C(#N)C>[CH3:13][N:12]([CH3:14])[C:10]1[C:9]2[C:4](=[N:5][C:6]([CH3:16])=[C:7]([CH3:15])[N:8]=2)[N:3]=[C:2]([NH:1][C:31]([NH:30][S:27]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:17]([O:19][CH3:20])=[O:18])(=[O:29])=[O:28])=[O:32])[N:11]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: Cc1nc2nc(N)nc(N(C)C)c2nc1C
Solvent: CC(C)OC(C)C
Solvent: CC#N
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(N(C)C)c2nc(C)c(C)nc2n1
Yield: 80.8 %

Procedure:
A mixture of 1 g of 2-amino-4-dimethylamino-6,7-dimethylpteridine and 1.3 g of 2-carbomethoxyphenylsulfonyl isocyanate was stirred in 10 ml of acetonitrile for 30 minutes at room temperature and then the mixture was heated to reflux for 3 to 4 minutes. After cooling diisopropyl ether was added thereto and the mixture was vacuum filtered to obtain 1.7 g (81% of theory) of N-(4-dimethylamino-6,7-dimethylpteridin-2-yl)-N'-(2-carbomethoxyphenylsulfonyl)-urea melting at 196° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[F:30])([CH3:22])[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)O)[CH3:2].B(F)(F)F.CCOCC.C([SiH](CC)CC)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[F:30])([CH3:22])[CH2:6][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Oc1ccccc1F)C(O)c1ccc(OCc2ccccc2)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C(C)(Cc1ccc(OCc2ccccc2)cc1)Oc1ccccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(4-Benzyloxyphenyl)-3-hydroxy-2-(2-fluorophenoxy)-2-methylpropionic acid ethyl ester (9.5 mmol) in anhydrous CH2Cl2 (30 mL) was cooled to 0° C. and treated with BF3-Et2O (1.16 mL, 9.5 mmol) and triethylsilane (1.51 mL, 9.5 mmol). The mixture was stirred for 2 h and gradually warmed to ambient temperature. Saturated aqueous Na2CO3 (15 mL) was added and the mixture was stirred vigorously. The solution was partitioned and the organic layer was washed twice with water and brine, dried over Na2SO4, and concentrated in vacuo to produce 3-(4-benzyloxyphenyl)-2-(2-fluorophenoxy)-2-methylpropionic acid ethyl ester as an oil.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([CH3:3])[CH3:2].[Br:16][CH2:17][CH2:18]O.S(=O)(=O)(O)O>O>[Br:16][CH2:17][CH2:18][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: OCCBr
Reactant: CC(C)c1cc([N+](=O)[O-])ccc1C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)c1cc([N+](=O)[O-])ccc1C(=O)OCCBr
Temperature: 80 °C
Yield: 69 %

Procedure:
A mixture of 2-isopropyl-4-nitro-benzoic acid (0.23 g, 1.10 mmol), 2-bromoethanol (1.0 mL, 14.1 mmol) and conc. sulfuric acid (0.2 mL) was heated at 80° C. overnight. The mixture was cooled to r.t., diluted with water and extracted twice with ethyl acetate. The organic phase was washed with sat. sodium bicarbonate solution, water and brine then dried over sodium sulfate and concentrated. The crude product was purified by column chromatography on silica (60-120 mesh), eluting with 7% ethyl acetate/petroleum ether, to afford 2-isopropyl-4-nitro-benzoic acid 2-bromo-ethyl ester (0.24 g, 69%) as a colourless oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25]#[N:26].CN(C)C=O.[N-:32]=[N+:33]=[N-:34].[Na+].[Cl-].[NH4+]>O>[CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[N:4][N:3]1[C:25]1[NH:34][N:33]=[N:32][N:26]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C#N)OCO3
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1c1nnn[nH]1)OCO3
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 101.7 %

Procedure:
A mixture of 0.60 g (1.70 mmol) of the starting material XXIII, 3 ml of dimethylformamide, 0.12 g (1.87 mmol) of sodium azide and 0.10 g (1.87 mmol) of ammonium chloride was stirred at 140° C. for 30 min. The cooled reaction mixture was diluted with water and the precipitated crystals were filtered off. The so obtained product was purified by column chromatography using silica gel (MN Kieselgel 60) as adsorbent and a mixture of chloroform-methanol (99:1) as eluent to yield 0.68 g (54%) of the title compound; Mp.: 263-264° C.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].Cl.[CH2:8]([NH:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26])[CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.COCCOC>[Br:2][CH2:3][CH2:4][CH2:5][NH:6][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=1[NH:22][CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCC=CCCCNc1ccccc1C(=O)Cl
Reactant: NCCCBr
Agent: Br
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CCCCCCCCCC=CCCCNc1ccccc1C(=O)NCCCBr

Procedure:
To a slurry of 21.80 g. of 3-bromopropylamine hydrobromide in 200 ml. of glyme at 3° C. is added a solution of 23.9 g. of 2-(4-tetradecenylamino)benzoyl chloride hydrochloride in 65 ml. of glyme, concurrently with 26 ml. of triethylamine diluted to 39 ml. with 1,2-dimethoxyethane. The solution is warmed to reflux and 0.2 g. of 4-dimethylaminopyridine is added. The solution is heated for four hours and cooled overnight. The solid is removed and the mother liquor diluted with 200 ml. of water to yield a solid which is crystallized from cyclohexane and recrystallized from acetonitrile to yield the product.
Reaction SMILES: C(C1CC(SCC(F)(F)F)CC1[C:14]1[N:18]2[C:19]3[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:20]=3[N:21]=[CH:22][C:17]2=[N:16][N:15]=1)C.C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[CH3:31][Si:30]([CH3:33])([CH3:32])[CH2:29][CH2:28][O:27][CH2:26][N:23]1[C:20]2[N:21]=[CH:22][C:17]3[N:18]([CH:14]=[N:15][N:16]=3)[C:19]=2[CH:25]=[CH:24]1
Reactant: CCC1CC(SCC(F)(F)F)CC1c1nnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2c1ncc1nncn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 164.1 %

Procedure:
To a mixture of 1-(2-ethyl-4-(2,2,2-trifluoroethylthio)cyclopentyl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.100 g, 0.200 mmol, Preparation #MMM.1) in DCM (0.667 mL) was added m-CPBA (0.090 g, 0.400 mmol). The reaction stirred at ambient temperature for about 0.5 h. The reaction mixture was quenched by the addition of saturated aqueous NaHCO3 (5 mL). The aqueous portion was extracted with DCM (2×10 mL). The combined organic layers were separated, dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-60% EtOAc in DCM to afford 1-2-ethyl-4-(2,2,2-trifluoroethylsulfonyl)cyclopentyl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.095 g, 89%, 93% purity) as a clear oil: LC/MS (Table 1, Method a) Rt=2.63 min; MS m/z: 532 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13]CC)=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:16]1[CH2:21][CH2:20][CH2:19][S:18](=[O:23])(=[O:22])[CH2:17]1.CO.[OH-].[Na+]>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:16]1[CH2:21][CH2:20][CH2:19][S:18](=[O:22])(=[O:23])[CH2:17]1
Reactant: CCOC(=O)c1cc(Br)cc2c(C3CCCS(=O)(=O)C3)c[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(Br)cc2c(C3CCCS(=O)(=O)C3)c[nH]c12
Temperature: 85 °C
Yield: 92 %

Procedure:
Ethyl 5-bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-1H-indole-7-carboxylate (0.380 g, 0.949 mmol), was stirred in a methanol (5 mL)/water (3 mL) solution. 6M NaOH (1.5 mL, 0.900 mol, 10 eq) was added and the reaction was heated to 85° C. for 1.5 hours. The methanol was concentrated and the aqueous solution was acidified with 6M HCl. The resulting white solid was filtered and dried under vacuum to give 0.325 g (92%) of the title compound.
Reaction SMILES: C(Cl)CCl.Cl.[NH2:6][C:7]1[CH:17]=[CH:16][C:10]([CH:11]=[CH:12][C:13]([OH:15])=O)=[CH:9][CH:8]=1.[CH3:18][N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]1[CH2:28][NH:29][CH3:30].C1C=CC2N(O)N=NC=2C=1.O.C(N(CC)CC)C>CN(C=O)C>[NH2:6][C:7]1[CH:8]=[CH:9][C:10](/[CH:11]=[CH:12]/[C:13]([N:29]([CH3:30])[CH2:28][C:20]2[N:19]([CH3:18])[C:27]3[C:22]([CH:21]=2)=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:15])=[CH:16][CH:17]=1
Reactant: CNCc1cc2ccccc2n1C
Reactant: Nc1ccc(C=CC(=O)O)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1ccc(N)cc1
Reaction time: 8 h
Yield: 19.4 %

Procedure:
EDC (218 mg, 1.14 mmole) was added to a solution of 4-aminocinnamic acid hydrochloride (220 mg, 1.10 mmole), 1-methyl-2-(methylaminomethyl)-1H-indole (0.20 g, 1.15 mmole), HOBt.H2O (154 mg, 1.14 mmole), and triethylamine (0.20 mL, 1.43 mmole) in DMF (20 mL) at RT. The reaction was stirred overnight, then was concentrated in vacuo. The residue was diluted with 5% NaHCO3 and extracted with CH2Cl2. The combined organic extracts were washed with brine (2×30 mL) and dried over MgSO4. Flash chromatography on silica gel (3% MeOH/CH2Cl2) gave the title compound (68 mg, 19%) as a yellow foam: 1H NMR (360 MHz, DMSO-d6, 330K) δ 7.46 (d, J=7.8 Hz, 1H), 7.42 (d, J=15.3 Hz, 1H), 7.37 (d, J=8.3 Hz, 1H), 7.32 (d, J=8.5 Hz, 2H), 7.06-7.15 (m, 1H), 6.94-7.03 (m, 1H), 6.81 (d, J=15.3 Hz, 1H), 6.58 (d, J=8.5 Hz, 2H), 6.33 (s, 1H), 5.25 (br s, 2H), 4.85 (s, 2H), 3.70 (s, 3H), 3.02 (s, 3H); MS (ES) m/e 320 (M+H)+. Anal. Calcd for C20H21N3O.0.20H2O: C, 74.37; H, 6.68; N, 13.01. Found: C, 74.21; H, 6.60; N, 12.80.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([N:9]2[C:21]3[CH:20]=[CH:19][C:18]([Br:22])=[CH:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[CH:6]=[CH:7][CH:8]=1.C([Li])CCC.Cl[Si:30]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[Cl-].[NH4+]>C1COCC1>[Br:22][C:18]1[CH:19]=[CH:20][C:21]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:5]3[C:6]([C:16]=2[CH:17]=1)=[CH:7][C:8]([Si:30]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[CH:3][CH:4]=3
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cccc(-n2c3ccc(Br)cc3c3cc(Br)ccc32)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)c1cc([Si](c3ccccc3)(c3ccccc3)c3ccccc3)ccc1n2-c1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
A solution of 9-(3-methoxyphenyl)-3,6-dibromo-9H-carbazole (26 g, 1 eq) in dry THF (700 ml) is admixed slowly at −78° C. under argon with n-butyllithium (1.6 M in hexane, 41 ml, 1 eq) and stirred at −78° C. for 2 h. After a solution of chlorotriphenylsilane (30 g, 1.5 eq) in dry THF (150 ml) had been added at −78° C., the mixture was warmed to room temperature overnight with stirring. Excess butyllithium is hydrolyzed with saturated ammonium chloride solution. The precipitated reaction product is filtered off and washed thoroughly with methylene chloride. The combined methylene chloride filtrates are extracted with water and concentrated to dryness. The residue is stirred with acetone and filtered off. Yield 74%.
Reaction SMILES: [O:1]1[CH2:12][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH3:13][CH:14]([NH2:23])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:13][CH:14]([NH:23][CH2:12][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Oc1ccc(OCC2CO2)cc1
Reactant: CC(N)COc1ccccc1
Product: CC(COc1ccccc1)NCC(O)COc1ccc(O)cc1

Procedure:
A mixture of 1.66 g. (10 mmole) of 4-(2,3-epoxy-1-propoxy)-phenol and 4.5 g. (30 mmole) of 1-methyl-2-phenoxyethylamine was heated at 90° C. for 3 hours. The residue was triturated with ether and filtered. Recrystallization from ethyl acetate to which a little methanol was added gave 1-(1-methyl-2-phenoxyethylamino)-3-(4-hydroxyphenoxy)-2-propanol; mp 173°-175° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[N:23]([C:30]5[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=5[Cl:37])[N:24]=[N:25][C:26]=4[CH:27]4[CH2:29][CH2:28]4)=[CH:16][C:15]=3[CH3:38])=[CH:11][CH:12]=2)[N:7]([CH:39]([CH3:41])[CH3:40])[N:6]=1)=[O:4].C1COCC1.[Li+].[OH-].Cl>O.CO>[CH:27]1([C:26]2[N:25]=[N:24][N:23]([C:30]3[C:31]([Cl:37])=[CH:32][CH:33]=[CH:34][C:35]=3[Cl:36])[C:22]=2[CH2:21][O:20][C:17]2[CH:18]=[CH:19][C:14]([C:10]3[CH:9]=[C:8]4[C:13]([C:5]([C:3]([OH:4])=[O:2])=[N:6][N:7]4[CH:39]([CH3:41])[CH3:40])=[CH:12][CH:11]=3)=[C:15]([CH3:38])[CH:16]=2)[CH2:28][CH2:29]1
Reactant: COC(=O)c1nn(C(C)C)c2cc(-c3ccc(OCc4c(C5CC5)nnn4-c4c(Cl)cccc4Cl)cc3C)ccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCc2c(C3CC3)nnn2-c2c(Cl)cccc2Cl)ccc1-c1ccc2c(C(=O)O)nn(C(C)C)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.4 %

Procedure:
To a solution of 6-{4-[5-cyclopropyl-3-(2,6-dichloro-phenyl)-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-1-isopropyl-1H-indazole-3-carboxylic acid methyl ester (0.18 g, 0.30 mmol) in a 1:1:1 mixture of THF, methanol, water (6.0 mL) is added LiOH (0.13 g, 3.0 mmol). The reaction is stirred for 18 h at room temperature. The reaction is adjusted to pH 3 with 1N HCl and extracted with EtOAc to yield the title compound (0.12 g, 70%). LC-ES/MS m/e 576.0 (M+1).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([CH3:17])=[C:14]([OH:16])[CH:15]=1.[H-].[Na+].Br[CH2:21][O:22][CH2:23]Br>C1COCC1>[CH3:21][O:22][CH2:23][O:16][C:14]1[CH:15]=[C:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH:11]=[CH:12][C:13]=1[CH3:17]
Reactant: Cc1ccc(-c2nc3ccccc3o2)cc1O
Reactant: BrCOCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1cc(-c2nc3ccccc3o2)ccc1C
Temperature: 25 °C

Procedure:
A solution of 5-(1,3-benzoxazol-2-yl)-2-methylphenol (200 mg, 0.89 mmol) in THF (6 mL) was cooled to −78° C. under Argon and sodium hydride (24 mg, 1.0 mmol) was added. After 30 min at this temperature, bromomethyl ether (225 mg, 1.8 mmol) was added via syringe. The reaction was warmed to rt for 1 h. The reaction mixture was concentrated and the residue was purified by flash column (silica gel, hexanes:EtOAc 4:1) to afford 2-[3-(methoxymethoxy)-4-methylphenyl]-1,3-benzoxazole. MS (ESI) 270 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[N:16][NH:17][CH:18]=3)=[CH:11][CH:12]=2)[N:7]([C:19]([O:21][CH:22]2[CH2:25][CH2:24][CH2:23]2)=[O:20])[CH2:6][C@@H:5]1[CH3:26])(=[O:3])[CH3:2].CN(C)C=O.Br[CH:33]1[CH2:38][CH2:37][S:36](=[O:40])(=[O:39])[CH2:35][CH2:34]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[N:16][N:17]([CH:34]4[CH2:33][CH2:38][CH2:37][S:36](=[O:40])(=[O:39])[CH2:35]4)[CH:18]=3)=[CH:11][CH:12]=2)[N:7]([C:19]([O:21][CH:22]2[CH2:25][CH2:24][CH2:23]2)=[O:20])[CH2:6][C@@H:5]1[CH3:26])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3cn[nH]c3)cc2N(C(=O)OC2CCC2)C[C@@H]1C
Reactant: O=S1(=O)CCC(Br)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3cnn(C4CCCS(=O)(=O)C4)c3)cc2N(C(=O)OC2CCC2)C[C@@H]1C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A 100-mL round-bottom flask was charged with cyclobutyl (35)-4-acetyl-3-methyl-7-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxylate (1.67 g, 4.71 mmol), N,N-dimethylformamide (10 mL), 4-bromo-1λ6-thiane-1,1-dione (1.0 g, 4.7 mmol), and cesium carbonate (3.08 g, 9.45 mmol). The resulting mixture was stirred overnight at 100° C. After cooling to room temperature, the resulting solution was diluted with water (20 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified via column chromatography on silica gel (eluting with 1:1, ethyl acetate/petroleum ether). The material was further purified by Prep-HPLC with the following conditions (Waters III): Column, Xbridge RP18 Sum, 19×150 mm; mobile phase, water (0.05% ammonium bicarbonate) and acetonitrile (50% acetonitrile up to 100% in 10 min); Detector, UV 220&254 nm. This afforded cyclobutyl (3S)-4-acetyl-7-[1-(1,1-dioxo-1λ6-thian-3-yl)-1H-pyrazol-4-yl]-3-methyl-1,2,3,4-tetrahydroquinoxaline-1-carboxylate (1.01 g, 44%) as a white solid. 1H NMR (300 MHz, CD3OD) δ ppm 1.09 (d, J=6.60 Hz, 3H), 1.62-1.74 (m, 1H), 1.75-1.92 (m, 1H), 2.03-2.35 (m, 9H), 2.36-2.45 (m, 2H), 3.06-3.18 (m, 2H), 3.38-3.56 (m, 2H), 3.67 (t, J=13.20 Hz, 1H), 4.07-4.18 (m, 1H), 4.75-4.83 (m, 1H), 4.97-5.07 (m, 2H), 7.37 (s, 2H), 7.88 (s, 1H), 8.03 (s, 1H), 8.11 (s, 1H). MS (ESI, pos. ion) m/z 487 [M+H]
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=[O:6])[CH3:2].[NH2:8][C:9]1[C:10]([Cl:26])=[N:11][C:12]([CH3:25])=[C:13]([CH3:24])[C:14]=1[NH:15][CH2:16][C:17]1([OH:23])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>ClCCl>[Cl:26][C:10]1[C:9]([NH:8][C:5](=[O:6])[CH2:4][O:3][CH2:1][CH3:2])=[C:14]([NH:15][CH2:16][C:17]2([OH:23])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:13]([CH3:24])=[C:12]([CH3:25])[N:11]=1
Reactant: CCOCC(=O)Cl
Reactant: Cc1nc(Cl)c(N)c(NCC2(O)CCOCC2)c1C
Solvent: ClCCl
Product: CCOCC(=O)Nc1c(Cl)nc(C)c(C)c1NCC1(O)CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere ethoxyacetyl chloride (2.26 g, 16.6 mmol) was added dropwise to a chilled (0° C.) suspension of 4-{[(3-amino-2-chloro-5,6-dimethylpyridin-4-yl)amino]methyl}tetrahydro-2H-pyran-4-ol (3.96 g) in dichloromethane (140 mL). The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was cooled to 0° C., more ethoxyacetyl chloride (0.3 mL) was added, and the reaction mixture was stirred at ambient temperature for an additional 4 hours. The reaction mixture was concentrated under reduced pressure to provide crude N-(2-chloro-4-{[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]amino}-5,6-dimethylpyridin-3-yl)-2-ethoxyacetamide.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11]2([CH2:18][CH2:17][N:16](CC3C=CC=CC=3)[CH2:15][CH2:14]2)[N:10]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCCl.ClC(OC(Cl)C)=O>CO>[CH2:1]([N:8]1[C:12](=[O:13])[C:11]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[N:10]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1N(Cc2ccccc2)C(=O)C2(CCN(Cc3ccccc3)CC2)N1c1ccc(F)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Solvent: CO
Product: O=C1N(Cc2ccccc2)C(=O)C2(CCNCC2)N1c1ccc(F)cc1
Temperature: 25 °C

Procedure:
Combine 3,8-dibenzyl-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione (10 mmol) and 1,2-dichloroethane (70 mL). Cool using an ice bath. Add in dropwise fashion, 1-chloroethyl chloroformate (48.6 mmol). Warm to ambient temperature and maintain for 1 h. Extract using saturated NaHCO3 (120 mL). Extract the aqueous phase using dichloromethane (120 mL). Combine the organic layers, extract with saturated NaCl, dry over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Add anhydrous methanol (70 mL) and heat at reflux for 1 h. Concentrate in vacuo to obtain a residue and purify to obtain the title compound.
Reaction SMILES: C([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[CH:25]=[C:26]([S:28][C:29]1[S:33][C:32]([CH3:34])=[N:31][N:30]=1)[CH3:27])[CH:20]([NH:35][C:36](=[O:66])[C:37](=[N:63][O:64][CH3:65])[C:38]1[N:39]=[C:40]([NH:43]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[S:41][CH:42]=1)[C:19]2=[O:67])=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1>C(O)=O>[NH2:43][C:40]1[S:41][CH:42]=[C:38]([C:37](=[N:63][O:64][CH3:65])[C:36]([NH:35][CH:20]2[C:19](=[O:67])[N:18]3[CH:21]2[S:22][CH2:23][C:24]([CH:25]=[C:26]([S:28][C:29]2[S:33][C:32]([CH3:34])=[N:31][N:30]=2)[CH3:27])=[C:17]3[C:15]([OH:16])=[O:14])=[O:66])[N:39]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=C(C)Sc3nnc(C)s3)CSC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C=C(C)Sc3nnc(C)s3)CSC12)c1csc(N)n1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 13.7 %

Procedure:
The Z form of the syn isomer of 2-benzhydryloxycarbonyl-3-{2-[(2-methyl-1,3,4-thiadiazol-5-yl)-thio]-prop-1-en-1-yl}-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.76 g) is dissolved in formic acid (8 cc). The solution is heated to 50° C. and distilled water (4 cc) is added dropwise in the course of 10 minutes. The mixture is stirred for 30 minutes at 50° C., distilled water (4 cc) is then added, the mixture is cooled and filtered and the solution is concentrated to dryness under reduced pressure (1 mm Hg; 0.13 kPa) at 40° C. Ethanol (40 cc) is added and evaporated off under reduced pressure (1 mm Hg; 0.13 kPa) at 30° C., and this operation is repeated a further 2 times. The residue is taken up in ethanol (10 cc), the solution is filtered, the cake is washed with diethyl ether (20 cc), the filtrate is dried over sodium sulphate and the solvent is evaporated off under reduced pressure (1 mm Hg; 0.13 kPa) at 20° C. The Z form of the syn isomer of 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-2-carboxy-3-{2-[(2-methyl-1,3,4-thiadiazol-5-yl)-thio]-prop-1-en-1-yl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (60 mg) is thus isolated in the form of a yellow powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](=[CH2:21])[CH:19]=[O:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25](=[O:29])[CH2:26][N+:27]#[C-:28])[CH3:23]>C1(C)C=CC=CC=1.[Cu-]=O>[CH2:22]([O:24][C:25]([CH:26]1[CH:19]([C:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])=[CH2:21])[O:20][CH:28]=[N:27]1)=[O:29])[CH3:23]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: C=C(C=O)CCCCCCNC(=O)OCc1ccccc1
Agent: O=[Cu-]
Solvent: Cc1ccccc1
Product: C=C(CCCCCCNC(=O)OCc1ccccc1)C1OC=NC1C(=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38.3 %

Procedure:
15.30 g (52.9 mmol) of 8-(N-benzyloxycarbonylamino)-2-methyleneoctanal and 7.37 ml (67.4 mmol) of isocyanoacetic acid ethyl ester are dissolved in 78 ml of toluene and added dropwise under argon, within a period of 75 minutes, to a suspension of 0.30 g of copper(I) oxide in 76 ml of toluene. The mixture is then stirred for 90 minutes at 30°, cooled to room temperature and filtered, and the clear, bright red filtrate is introduced into a column filled with 250 g of silica gel (particle size 0.04-0.063 mm) and eluted with hexane/ethyl acetate (2:1). Concentration of the suitable fractions by evaporation yields 8.15 g of 5-[8-(N-benzyloxycarbonylamino)oct-1-en-2-yl]-oxazoline-4-carboxylic acid ethyl ester in the form of a colourless honey.