Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[Li][CH3:13].CI.O>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10]#[N:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(CC#N)cc1
Reactant: [Li]C
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(C)C#N)cc1
Reaction time: 3 h
Yield: 112.8 %

Procedure:
To a mixture of 4-methoxyphenylacetonitrile (17 g, 0.11 mol) and MeLi (1M; 100 ml, 0.11 mol) in THF (200 ml) was added MeI (32 g, 0.22 mol) at -78° C. After the mixture was stirred for 3 hours, the mixture was poured into H2O (100 ml), and extracted with AcOEt. The combined extracts were dried (Na2SO4), and concentrated to give a yellow oil (20 g), which was purified by a column chromatography on silica gel to give Compound 13 as a colorless oil (11 g, 62%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[F:13])[C:7]([OH:9])=[O:8])([O-:3])=[O:2].S(Cl)(Cl)=O.[CH3:18]O>>[F:13][C:12]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH3:18])=[O:8])=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
3-Nitro-4-fluorobenzoic acid (25.6 g, 138 mmol) was dissolved in methanol (300 mL), added thionyl chloride (18.4 mL, 258 mmol) under −78° C. The mixture was stirred at −78° C. for 10 minutes, and then stirred at room temperature overnight. The reaction solution was concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate). The title compound (29.6 g (yield >99%)) was obtained as a white crystal.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.O>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][C:9](=[O:11])[CH3:10]
Reactant: NCc1ccccn1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)NCc1ccccn1

Procedure:
A mixture of 5.0 g 2-(aminomethyl)pyridine, 5.02 ml acetic anhydride, 0.847 g 4-dimethylaminopyridine and 35 ml of pyridine is heated at reflux temperature for 23.5 hours. The cooled solution is poured into water and extracted with methylene chloride. The organic layer is washed with saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel:5% methyl alcohol/ethyl acetate) to give 3.3 g of desired product as a light yellow oil.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([F:15])[CH:6]=1)=O.[NH2:16][C:17]([NH2:19])=[S:18]>CO>[BrH:1].[F:15][C:7]1[CH:6]=[C:5]([C:3]2[N:16]=[C:17]([NH2:19])[S:18][CH:2]=2)[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=1
Reactant: NC(N)=S
Reactant: O=C(CBr)c1cc(F)cc(C(F)(F)F)c1
Solvent: CO
Product: Br
Product: Nc1nc(-c2cc(F)cc(C(F)(F)F)c2)cs1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 7.2 g of 2-bromo-1-(3-fluoro-5-trifluoromethyl-phenyl)-ethanone in 60 ml of methanol was treated at room temperature with 2.7 g of thiourea and boiled for 1 hour. 5.2 g of 4-(3-fluoro-5-trifluoromethyl-phenyl)-thiazol-2-ylamine hydrobromide separated as colorless crystals upon cooling to 0° C. and after the addition of 15 ml of diethyl ether.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=O)[C:5]2=[O:12].FC1C=[C:18]2[C:19](O[C:22](=[O:24])[NH:23][C:17]2=[CH:16][CH:15]=1)=O.FC1C=C2[NH:35]C(=O)OC(=O)C2=CC=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]1[C:5](=[O:12])[C:16]3[C:17]([N:23]1[C:22]2=[O:24])=[CH:18][CH:19]=[N:35][CH:15]=3
Reactant: O=C1Nc2ccc(F)cc2C1=O
Reactant: O=c1[nH]c2ccc(F)cc2c(=O)o1
Reactant: O=c1[nH]c2cc(F)ccc2c(=O)o1
Product: O=C1c2cnccc2-n2c1nc1ccc(F)cc1c2=O

Procedure:
Using the procedure in Example 36 and substituting 5-azaisatin (Example 8) for 5-fluoroisatin and 5-fluoroisatoic anhydride for 4-fluoroisatoic anhydride gives the title compound.
Reaction SMILES: [CH:1]1([O:7][C:8]2[C:9]([NH:14][C:15]3[S:16][CH:17]=[C:18]([CH3:20])[N:19]=3)=[N:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.CC1C=CC(S(NN)(=O)=O)=CC=1.CC([O-])=O.[Na+]>C(COC)OC.O>[CH:1]1([O:7][C:8]2[C:9]([NH:14][C:15]3[S:16][CH:17]=[C:18]([CH3:20])[N:19]=3)=[N:10][CH:11]=[CH:12][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1csc(Nc2ncccc2OC2C=CCCC2)n1
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1csc(Nc2ncccc2OC2CCCCC2)n1
Yield: 55.3 %

Procedure:
3-(Cyclohex-2-enyloxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine (0.115 g, 0.400 mmol) and 4-methylbenzenesulfonohydrazide (1.12 g, 6.00 mmol) were placed in dimethoxyethane (5 mL). NaOAc (0.492 g, 6.00 mmol) was dissolved in water (2 mL) and added to the above solution and refluxed. Additional 4-methylbenzenesulfonohydrazide (1.12 g, 6.00 mmol) was added and the reaction mixture was refluxed overnight. An aqueous work up was done and the crude material was purified by silica gel chromatography to provide 3-(cyclohexyloxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine (0.064 g, 55.3%) after HCl salt formation. 1H NMR (d6-DMSO) δ 7.79 (d, 1H), 7.57 (d, 1H), 7.09 (m, 1H), 6.83 (s, 1H), 4.54 (m, 1H), 2.32 (s, 3H), 1.97 (m, 2H), 1.79, (m, 2H), 1.57 (m, 3H), 1.36 (m, 3H); Mass spectrum (apci) m/z=291.1 (M+H—HCl).
Reaction SMILES: [N+]([C:4]1[C:5]([N+:11]([O-:13])=[O:12])=[C:6](C)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[C:14]1(C)C=CC=C(N)C=1N.S(=O)(=O)(O)O.[N+]([O-])(O)=O>C1(C)C=CC=CC=1>[N+:11]([C:5]1[CH:4]=[CH:9][C:8]([CH3:14])=[CH:7][CH:6]=1)([O-:13])=[O:12]
Reactant: Cc1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Reactant: Cc1cccc(N)c1N
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])O
Solvent: Cc1ccccc1
Product: Cc1ccc([N+](=O)[O-])cc1

Procedure:
Nitroaromatics, particularly dinitrotoluene, are widely used as intermediates in the manufacture of aromatic amines, e.g. toluene diamine which then can be converted to isocyanates for polyurethane manufacture. Commercially, dinitrotoluene, for example, is produced by the mixed acid nitration of toluene, the mixed acid being a mixture of concentrated sulfuric acid and nitric acid. In this process mononitrotoluene is formed in a first nitration stage and then separated from the aqueous phase. The crude mononitrotoluene is then dinitrated with fresh acid in a second nitration stage and the aqeuous phase is recycled to the mononitration stage. The dinitrotoluene then is recovered from the dinitration stage and the impurities removed.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[C:9]([CH3:20])[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([Cl:18])=[CH:13][C:12]=3[CH3:19])=[C:6]2[N:5]=[C:4]([CH3:21])[CH:3]=1.C([O-])(O)=O.[Na+].O=P(Cl)(Cl)[Cl:29]>C(Cl)Cl>[Cl:29][C:2]1[N:7]2[N:8]=[C:9]([CH3:20])[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([Cl:18])=[CH:13][C:12]=3[CH3:19])=[C:6]2[N:5]=[C:4]([CH3:21])[CH:3]=1
Reactant: Cc1cc(O)n2nc(C)c(-c3c(C)cc(Cl)cc3C)c2n1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Cl)n2nc(C)c(-c3c(C)cc(Cl)cc3C)c2n1
Reaction time: 2 h

Procedure:
Slurry 7-hydroxy-2,5-dimethyl-3-(4-chloro-2,6-dimethylphenyl)-pyrazolo[1,5-a] pyrimidine in 10 mL POCl3 and reflux at 130° C. under N2. After 2 hours, monitoring by TLC (alcohol Rf=0.5, chloride Rf=1.0; EtOAc as eluent), quench the reaction carefully at ambient temperature by diluting with 50 mL CH2Cl2 and pouring slowly into non-stirring saturated NaHCO3. Adjust stirring speed to control rate of quenching of residual POCl3 and stir until gas evolution ceases. Separate the layers and extract the aqueous layer with CH2Cl2 (2×50 mL). Pool the organic layers and dry over Na2SO4. Filter and evaporate to yellow oil, which is used directly without further purification.
Reaction SMILES: [NH:1]1[C:6]2C=N[O:9][CH2:10][C:5]=2[C:4](=O)[CH2:3][C:2]1=O.C[NH2:14].[C:15](=O)([O-])[NH2:16].C(=O)=O>O1CCOCC1.C(O)C>[CH3:15][NH:16][C:10](=[O:9])[C:5]1[CH:4]=[CH:3][CH:2]=[N:1][C:6]=1[NH2:14]
Reactant: O=C1CC(=O)C2=C(C=NOC2)N1
Reactant: CN
Reactant: NC(=O)[O-]
Agent: O=C=O
Solvent: CCO
Solvent: C1COCCO1
Product: CNC(=O)c1cccnc1N
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
14.96 g (0.09 mol) of 1H-Pyrido[2,3-d]oxazin-2,4-dione was suspended in 138 ml dioxane. The mixture is heated to 40° C. and 17 ml of a 33% solution of methyl amine in ethanol is added dropwise directly into the reaction mixture, to avoid carbamate formation with the evolving CO2. The reaction is allowed to continue for 90 minutes. After cooling down to room temperature, the formed precipitate is removed by filtration and the filtrate is concentrated to dryness. 13.2 g (97%) of 2-aminonicotinic acid methyl amide was isolated (m.p. 140-2° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([N+:12]([O-])=O)=[CH:5][C:4]=1[O:15][CH3:16]>CO>[CH3:16][O:15][C:4]1[CH:5]=[C:6]([NH2:12])[C:7]([NH2:9])=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1OC
Solvent: CO
Product: COc1cc(N)c(N)cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1,2-dimethoxy-4,5-dinitrobenzene (500 mg, 2.19 mmol) in MeOH (10 mL) was degassed and put under N2 atmosphere. A catalytic amount of Pd on charcoal (10%) was quenched with MeOH (1 mL) and transferred in one shot as a suspension in MeOH into the solution. Acetic acid (1.5 mL) was added and the black mixture was put under H2 atmosphere (1 atm), stirred at rt for 16 h. The mixture was filtered through a celite pad and rinsed with MeOH. The filtrate was concentrated in vacuo at 80° C. to afford the title compound 182 (residual acetic acid could not be removed from the product). 1H NMR: (DMSO-d6) δ (ppm): 6.23 (s, 2H), 3.56 (s, 6H). m/z: 169.3. (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.CN.C(Cl)CCl.C[CH2:22][N:23](C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:23][CH3:22])=[O:5]
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: ClCCCl
Product: CNC(=O)c1cccc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.5 %

Procedure:
2-Amino-3-nitro-benzoic acid (1.8 g, 9.9 mmol) and methylamine hydrochloride (1.33 g, 19.8 mmol), were stirred in dry CH2Cl2 (30 ml)/DMF (5 mL) at 0° C. EDC (2.83 g, 14.8 mmol) and DIEA (4.92 mL, 27.7 mmol) were added, and the solution stirred 3 h while warming to r.t. The reaction was concentrated in vacuo and purified by silica gel chromatography (8% MeOH/CHCl3) to give 1.42 g (74%) of 2-amino-N-methyl-3-nitro-benzamide as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.58 (br s, 1H), 8.23 (br s, 2H), 8.15 (dd, 1H, J=8.1, 1.8 Hz), 7.82 (dd, 1H, J=8.1, 1.8 Hz), 6.68 (t, 1H, J=8.1 Hz), 2.76 (d, 3H, J=4.5 Hz). 2,3-Diamino-N-methyl-benzamide. 2-Amino-N-methyl-3-nitro-benzamide (1.4 g, 7.2 mmol) was reduced by hydrogenation using 50 psi of H2 with 10% Pd—C, (250 mg) in EtOAc (25 mL) for 5 h. After filtering through Celite, solvent was removed in vacuo. Purification by silica gel chromatography (10% MeOH/CHCl3) gave 1.08 mg (91%) of 2,3-diamino-N-methyl-benzamide as a faintly yellow solid. 1H NMR (300 MHz, CDCl3) δ6.87 (dd, 1H, J=7.8, 1.5 Hz), 6.76 (dd, 1H, J=7.8, 1.5 Hz), 6.59 (t, 1H, J=7.8 Hz), 6.14 (br s, 1H), 4.28 (br s, 4H), 2.95 (d, 3H, J=5.1 Hz).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([N:33]3[C:37](=[O:38])[CH:36]([CH3:39])[NH:35][C:34]3=[O:40])[CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([N:33]3[C:37](=[O:38])[CH:36]([CH3:39])[NH:35][C:34]3=[O:40])[CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2ccc(N3C(=O)NC(C)C3=O)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2ccc(N3C(=O)NC(C)C3=O)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-propyl-6-(5-methyl-imidazolidin-2,4-dion-3-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24]C)[C:19]=1[O:26][CH3:27].[Cl-].[Al+3].[Cl-].[Cl-].COC1C=CC(OC)=CC=1C(C1C=C(OC)C=C(OC)C=1)=O>C(Cl)Cl>[OH:24][C:20]1[C:19]([O:26][CH3:27])=[C:18]([O:17][CH3:16])[CH:23]=[CH:22][C:21]=1[C:6]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=1)=[O:7]
Reactant: COc1cccc(OC)c1OC
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: COc1cc(OC)cc(C(=O)c2cc(OC)ccc2OC)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(C(=O)c2ccc(OC)c(OC)c2O)cc(OC)c1OC
Yield: 56.5 %

Procedure:
3,4,5-Trimethoxybenzoyl chloride (11.07 g, 48.0 mmol), 1,2,3-trimethoxybenzene (8.07 g, 48.0 mmol) in anhydrous methylene chloride (60 ml), and aluminum chloride (7.04 g, 52.8 mmol) were treated in the same manner as described above for the synthesis of (2,5-dimethoxy-phenyl)-(3,5-dimethoxy-phenyl)methanone. The crude material was purified via flash column chromatography (25% EtOAc in hexane) to give (2-hydroxy-3,4-dimethoxy-phenyl)-(3,4,5-trimethoxy-phenyl)-methanone as a yellow solid (9.44 g, 54%); mp, 135-137° C.: 1HNMR (DMSO-d6) δ 11.39 (s, 1H, OH), 7.35 (d, J=8 Hz, 1H, Ar), 6.97 (s, 2H, Ar), 6.70 (d, J=9 Hz, 1H, Ar), 3.89 (s, 3H, OCH3), 3.81 (s, 6H, 2OCH3), 3.76 (s, 3H, OCH3), 3.74 (s, 3H, OCH3); 13C NMR (DMSO-d6) δ 197.5, 157.6, 154.6, 152.5, 140.8, 136.0, 132.9, 128.7, 115.8, 106.7, 103.6, 60.1, 60.0, 56.0; Anal. Calcd. For C18H20O7: C, 62.06; H, 5.79. Found: C, 62.05; H, 5.55. The product was carried over to the next step.
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1C=O.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[C:23]([CH2:25][CH:26]([CH3:30])[C:27]([OH:29])=O)=[O:24].[NH:31]1[CH2:38][CH2:37][CH2:36][C@H:32]1[C:33]([OH:35])=[O:34].[C:39]([O-:42])(=[S:41])[CH3:40].[Na+]>C(#N)C>[C:39]([S:41][CH:25]([C:23]([C:14]1[CH:15]=[CH:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=1)=[O:24])[CH:26]([CH3:30])[C:27]([N:31]1[CH2:38][CH2:37][CH2:36][C@H:32]1[C:33]([OH:35])=[O:34])=[O:29])(=[O:42])[CH3:40]
Reactant: CC(CC(=O)c1ccc2ccccc2c1)C(=O)O
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC([O-])=S
Agent: O=Cc1ccc2ccccc2c1
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)SC(C(=O)c1ccc2ccccc2c1)C(C)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
As for Example 48, 2-naphthaldehyde is converted to 3-(2-naphthoyl)-2-methylpropionic acid and coupled to L-proline. The 1-[3-(2-naphthoyl)-2-methylpropionyl]-L-proline is separated into isomers A and B. Isomer A, (S)-1-[3-(2-naphthoyl)-2-methylpropionyl]-L-proline is reacted with bromine in acetic acid and the product reacted with sodium thioacetate in acetonitrile as for Example 72 to give the product of the example as a glass (mixture of diastereomers).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3nccs3)cc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3nccs3)cc2)S(C)(=O)=O)c1

Procedure:
A solution of ({3-[(4-thiazol-2-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester (0.045 g, 0.109 mmol), triethylamine (16.8 mL, 0.120 mmol) and methanesulfonyl chloride (8.6 ml, 0.11 mmol) in 2 mL CH2Cl2 was stirred at room temperature for 2 hours. The reaction was quenched with water. The aqueous solution was washed with CH2Cl2 and the organic solution was dried over Na2SO4, filtered, and concentrated. The product was purified via flash chromatography on silica gel (1/1 EtOAc/Hexanes) to afford the title compound of Step B as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.97 (d, 2H), 7.85 (s, 1H), 7.35 (m, 3H), 7.32 (m, 1H), 6.80–6.90 (m, 3H), 4.48 (s, 2H), 4.36 (s, 2H), 4.29 (s, 2H), 2.79 (s, 3H), 1.47 (s, 9H); MS 489 (M+1).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][CH2:23][C:24]([NH:26][NH2:27])=[O:25].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:27][NH:26][C:24](=[O:25])[CH2:23][O:22][CH3:21])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCC(=O)NN
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COCC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (15.0 mL) were added 2-methoxyacetohydrazide 218 (0.141 g, 1.358 mmol), 1-hydroxybenzotriazole (0.186 g, 1.358 mmol) and 1-ethyl-(3-dimethylamino propyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue, which was subjected to chromatography to give 219 (0.27 g, 82%) as a white foam.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[C:6]([NH:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH:17](O)[CH3:18])([CH3:9])([CH3:8])[CH3:7]>C1(C)C=CC=CC=1>[C:1]([NH:5][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][NH:10][C:6]([CH3:7])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: CC(O)OCCOCCNC(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)NCCOCCOCCNC(C)(C)C
Temperature: 200 °C
Yield: 68.2 %

Procedure:
To a 300 ml stainless steel, stirred autoclave there was added 21 g of tertiarybutylamine, 20 g of tertiarybutylaminoethoxyethoxyethanol, 0.6 g of Ni-Al2O3 -SiO2 catalyst (Harshaw NI-5132P), and 50 ml of toluene. The autoclave containing the reactants was heated to 200° C. under autogenous pressure (180 psi) for 6 hours. The contents were cooled, removed and filtered. The autoclave and filtercake were washed with additional toluene. G.C. analysis revealed that the product was comprised of about 91 wt. % 1,2-bis-(tertiarybutylaminoethoxy) ethane and less than about 5 wt. % tertiarybutylaminoethoxyethoxyethanol. Vacuum distillation gave 17.3 g of 1,2-bis-(tertiarybutylaminoethoxy) ethane, having a boiling point of 125°-128° C./3 mm.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C:11]3[C:16]4[O:17][CH2:18][CH2:19][NH:20][C:15]=4[CH:14]=[CH:13][CH:12]=3)[NH:8][C:7]=2[CH:21]=1.Cl[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=1.ClC1C(Cl)=CC=CN=1>>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([N:20]2[C:15]3[CH:14]=[CH:13][CH:12]=[C:11]([C:9]4[NH:8][C:7]5[CH:21]=[C:3]([C:2]([F:22])([F:1])[F:23])[CH:4]=[CH:5][C:6]=5[N:10]=4)[C:16]=3[O:17][CH2:18][CH2:19]2)=[N:26][CH:27]=1
Reactant: FC(F)(F)c1ccc2nc(-c3cccc4c3OCCN4)[nH]c2c1
Reactant: Clc1ccc(Cl)nc1
Agent: Clc1cccnc1Cl
Product: FC(F)(F)c1ccc2nc(-c3cccc4c3OCCN4c3ccc(Cl)cn3)[nH]c2c1
Yield: 92 %

Procedure:
The procedure of Example 6 was repeated except for using 8-(6-(trifloromethyl)-1H-benzo[d]imidazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine and 2,5-dichloropyridine instead of 4-(5-tert-butyl-1H-benzo[d]imidazol-2-yl)benzenamine and 2,3-dichloropyridine in Example 6 respectively to obtain the title compound (4.0 g, yield: 92%).
Reaction SMILES: CO[C:3]([C:5]1[S:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4].[CH2:25]([CH2:27][NH2:28])[OH:26]>>[CH:13]([NH2:14])([CH3:18])[CH3:12].[OH:26][CH2:25][CH2:27][NH:28][C:3]([C:5]1[S:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4]
Reactant: NCCO
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cn3)noc2C)ns1
Product: CC(C)N
Product: Cc1onc(-c2ccc(F)cn2)c1COc1cc(C(=O)NCCO)sn1
Yield: 141.5 %

Procedure:
As described for example 38b, 3-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-isothiazole-5-carboxylic acid methyl ester (120 mg, 0.34 mmol), was converted, using ethanolamine (25 mg, 0.41 mmol), instead of isopropyl amine, to the title compound (91 mg, 70%) which was obtained as a white solid after purification by chromatography (silica, dichloromethane:methanol=97.5:2.5 to 9:1). MS: m/e=379.3 [M+H]+.
Reaction SMILES: C[OH:2].C(N)CCC.[S:8]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[C:26](=O)[C:25]3C(=CC=CC=3)C2=O)[S:9]1.[O:29]1CCOC[CH2:30]1>C1(C)C=CC=CC=1>[S:8]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][CH2:26][C:25]([O:29][CH3:30])=[O:2])[S:9]1
Reactant: CO
Reactant: O=C1c2ccccc2C(=O)N1CCCCCC1CCSS1
Reactant: C1COCCO1
Solvent: Cc1ccccc1
Solvent: CCCCN
Product: COC(=O)CNCCCCCC1CCSS1
Reaction time: 8 h

Procedure:
2 ml of methanol and 2 ml of butylamine were added to a solution of 1.6 mmol of 2-[5-(1,2-dithiolan-3-yl)pentyl]isoindole-1,3-dione in 3 ml of toluene. The resulting mixture was allowed to stand overnight at room temperature. The solvent was then removed from the reaction mixture by distillation under reduced pressure. Water was added to the resulting residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. 4 ml of anhydrous tetrahydrofuran were added to the residue, and then 0.33 ml of triethylamine and 0.17 ml of methyl bromoacetate were added dropwise, whilst ice-cooling. The resulting mixture was stirred for one hour, whilst ice-cooling and then for 5 hours at room temperature. The reaction mixture was then allowes to stand at room temperature for 2 days. At the end of this time, the solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 1:0 and 20:1 by volume mixtures of ethyl acetate and methanol as eluent. The solvent was removed from the eluate so obtained by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilised, to give 195 mg of the title compound as a yellow oil having an Rf value of 0.55 (silica gel thin layer chromatography; using a 4:1 by volume mixture of ethyl acetate and methanol as the developing solvent.