Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:4][CH:3]=1.[Br:19]Br>>[Br:19][C:8]1[N:7]2[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]([C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:12])[C:6]2=[N:10][CH:9]=1
Reactant: BrBr
Reactant: O=C(c1ccccc1)c1ccc(Cl)n2ccnc12
Product: O=C(c1ccccc1)c1ccc(Cl)n2c(Br)cnc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 100.4 %

Procedure:
100 mg (0.39 mmol) of (5-Chloroimidazo[1,2-a]pyridin-8-yl)(phenyl)methanone (example L, step 3) are dissolved in 5 ml glacial acid. 30 mg (0.19 mmol) of bromine are added dropwise to the solution. The mixture is stirred for 20 h at rt. The solvent is evaporated under vacuum and the crude is purified over preparative HPLC (RP 18-Column, eluent: acetonitrile-water-gradient) to yield 64 mg (49.0% of th.) (3-Bromo-5-chloroimidazo[1,2-a]pyridin-8-yl)(phenyl)methanone.
Reaction SMILES: [I:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH:11]([CH3:14])[CH2:12][OH:13])[CH:3]=1.N1C=CN=C1.[CH3:20][C:21]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])[CH3:22].O>C(Cl)Cl>[Si:24]([O:13][CH2:12][CH:11]([N:4]1[C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[C:2]([I:1])=[CH:3]1)[CH3:14])([C:21]([CH3:23])([CH3:22])[CH3:20])([CH3:26])[CH3:25]
Reactant: CC(CO)n1cc(I)c2cnccc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(CO[Si](C)(C)C(C)(C)C)n1cc(I)c2cnccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.6 %

Procedure:
To a solution of 2-(3-iodo-1H-pyrrolo[3,2-c]pyridin-1-yl)propan-1-ol (Preparation 56, 11.5 g, 38.1 mmol) and imidazole (6.48 g, 95.2 mmol) in DCM (300 mL) was added a solution of TBDMSCl (6.95 g, 45.7 mmol) in DCM (50 mL) dropwise at 0° C. The reaction was allowed to warm to room temperature and stirred for 1.5 hours. To the reaction was added water (500 mL) and DCM (200 mL), the organic layer collected, dried over MgSO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-10% MeOH in DCM to afford the title compound (15 g, 100%).
Reaction SMILES: [Cl:1][CH2:2][O:3]S(Cl)(=O)=O.[N+:8]([C:11]1[CH:34]=[CH:33][C:14]([CH2:15][O:16][C:17]([NH:19][CH2:20][C:21]([NH:23][C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=2)=[O:22])=[O:18])=[CH:13][CH:12]=1)([O-:10])=[O:9].C(=O)(O)[O-].[Na+]>ClCCl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.O>[Cl:1][CH2:2][O:3][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([NH:23][C:21](=[O:22])[CH2:20][NH:19][C:17]([O:16][CH2:15][C:14]2[CH:33]=[CH:34][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][CH:13]=2)=[O:18])=[CH:25][CH:26]=1
Reactant: O=S(=O)(Cl)OCCl
Reactant: O=C(CNC(=O)OCc1ccc([N+](=O)[O-])cc1)Nc1ccc(C(=O)O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: ClCCl
Product: O=C(CNC(=O)OCc1ccc([N+](=O)[O-])cc1)Nc1ccc(C(=O)OCCl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
A solution of chloromethylchlorosulphate (2.21 g) in dichloromethane (5 ml) was added dropwise to a stirred mixture of 4-[N-(4-nitrobenzyloxycarbonyl)glycylamino]-benzoic acid (4.00 g), sodium bicarbonate (3.00 g) and tetrabutylammonium hydrogen sulphate (0.493 g) in dichloromethane-water (1:1, 50 ml). The mixture was stirred at room temperature for 3 h. The organic phase was separated and the aqueous phase washed with dichloromethane (50 ml). The combined organic extracts were dried (MgSO4), concentrated to low volume and applied to a column of Kieselgel 60. Elution with 50% ethyl acetate/hexane afforded the title compound as a white solid (46%); m.p. 163°-5° (ethyl acetate), (Found: C, 51.49; H, 3.79; N, 9.76. C18H16N3O7Cl requires C, 51.26; H, 3.82; N, 9.96%); νmax (Nujol) 3400, 3300, 1740, 1685, and 1610 cm-1 ; δH (CDCl3 /D6 -DMSO) 3.95 (2H, d, J 6.0 Hz), 5.25 (2H, s), 5.97 (2H, s), and 7.35-8.20 (10H, m).
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([N+:23]([O-:25])=[O:24])=[C:12]([N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:13]=2)=[CH:5][CH:4]=1)#[N:2].[N:28]([Sn](CCCC)(CCCC)CCCC)=[N+:29]=[N-:30]>C1(C)C=CC=CC=1>[CH3:22][N:14]([C:12]1[CH:13]=[C:8]([O:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]3[NH:30][N:29]=[N:28][N:2]=3)=[CH:27][CH:26]=2)[CH:9]=[CH:10][C:11]=1[N+:23]([O-:25])=[O:24])[C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(C#N)cc2)ccc1[N+](=O)[O-]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-c3nnn[nH]3)cc2)ccc1[N+](=O)[O-]
Yield: 97.2 %

Procedure:
A mixture of t-butyl N-[5-(4-cyanophenoxy)-2-nitrophenyl]-N-methylcarbamate (2.95 g), azidotributyltin (7.97 g) and anhydrous toluene (30 ml) was heated at reflux for 23 hours. The reaction mixture was concentrated and then partitioned between ethyl acetate and water. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reversed-phase liquid chromatography using water/acetonitrile=1/1 as the eluant to give the title compound (3.20 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11](=[O:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:20]N(CN(C)C)C.C(OC(=O)C)(=O)C>>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11](=[O:19])[C:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH2:20]
Reactant: COc1ccc(C(=O)Cc2ccccc2)c(Cl)c1Cl
Reactant: CN(C)CN(C)C
Solvent: CC(=O)OC(C)=O
Product: C=C(C(=O)c1ccc(OC)c(Cl)c1Cl)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2',3' -Dichloro-4'-methoxy-2-phenylacetophenone (300 g.) is suspended in 1000 ml. of N,N,N,N-tetramethylmethanediamine at 25°C. under nitrogen, and acetic anhydride (1000 ml.) is added dropwise. The reaction mixture is maintained below 40°C. by cooling in an ice-water bath and regulating the rate of anhydride addition. The reaction mixture is left at 25°C. for 1 hour then slowly added to crushed ice-water (8 liters) with stirring. The white solid precipitate is collected by suction filtration, washed with water, and air-dried at 25°C. for 2 days. Yield: 310.5 g. (99%), mp 87°-89°C. A sample recrystallized from benzene-hexane melts at 87°-89°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:6][CH2:7]O.C(Br)(Br)(Br)[Br:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:15][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(CCO)cc1OC
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CCBr)cc1OC

Procedure:
Part A. A solution of 3,4-dimethoxyphenethyl alcohol (7.30 g, 40.1 mmol) and carbon tetrabromide (17.3 g, 52.1 mmol) in methylene chloride (100 mL)was cooled to 0° C., and a solution of triphenylphosphine (13.7 g, 52.1 mmol) in methylene chloride (50 mL) was added dropwise with stirring.After 20 hours, the reaction mixture was evaporated, and separated by flashchromatography (1:9 ethyl acetate-hexane) to afford the product, 1-(2-bromoethyl)-3,4-dimethoxybenzene, as a waxy solid, mp 72°-73° C. (9.48 g, 38.7 mmol, 96%). 1H NMR (CDCl3): δ 6.82 (1H, d, J=8.1 Hz); 6.75 (1H, dd, J=8.1, 1.8 Hz); 6.73 (1H, d, J=1.8 Hz); 3.88 (3H, s); 3.87 (3H, s); 3.55 (2H, t, J=7.7 Hz); 3.11 (2H, t, J=7.7 Hz). Mass spectrum (NH3 -CI/DDIP): m/z 264 (93%); 262 (100%); 245 (9%); 165 (6%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11].S(=O)(=O)(O)[OH:13].Cl>C(O)(=O)C.C(OC(=O)C)(=O)C.O1CCOCC1.C(OCC)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:11]=[O:13]
Reactant: Cc1ccc([N+](=O)[O-])cc1Br
Reactant: O=S(=O)(O)O
Agent: [Cr+6]
Agent: Cl
Agent: [O-2]
Solvent: CC(=O)OC(C)=O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: O=Cc1ccc([N+](=O)[O-])cc1Br
Reaction time: 0.25 h

Procedure:
2-Bromo-4nitrotoluene (6.29 g, 29.1 mmol) was dissolved in a mixture of glacial acetic acid 46 mL, and acetic anhydride 46 mL, and cooled in an ice bath. Concentrated sulfuric acid (6.9 mL) was added dropwise. Chromium trioxide (8.08 g, 80.8 mmol) was added portionwise over 1 h. The reaction mixture was stirred for an additional 15 min then poured onto ice. The precipitate was isolated by filtration and dissolved in 16 mL of 1,4-dioxane. Concentrated hydrochloric acid (3 mL) was added and the solution was refluxed for 2 h. The reaction mixture was diluted with ethyl acetate (150 mL) and washed with water, saturated sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate and evaporated to yield 1.09 g of 2-bromo-4-nitrobenzaldehyde. The aldehyde was dissolved in methanol (50 mL) and potassium carbonate (0.82 g, 5.96 mmol) and tosylmethyl isocyanide (1.16 g, 5.96 mmol) was added. The reaction mixture was refluxed for 3 h, cooled to room temperature and concentrated. The residue was dissolved in methylene chloride (200 mL) and the organic layer was washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to yield 1.53 g. (96%) of 5-(4-nitro-2-bromophenyl)oxazole. 5-(4-Nitro-2-bromophenyl)oxazole (500 mg, 1.86 mmol) was dissolved in a mixture of 10 mL of ethanol and 20 ml of ethyl acetate. Tin dichloride dihydrate 1.74 g (7.72 mmol) was added and the reaction mixture heated to 80° C. for 0.5 h. The reaction mixture was poured into 400 mL of ice/water and neutralized with sodium carbonate. The suspension was extracted with ethyl acetate (3×100 mL), and the combined organic layer was washed with brine, separated and dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to yield 463 mg of 5-(4-amino-2-bromophenyl)oxazole. 93% pure by HPLC method A. Mass spectrum M+H+=240.95, 1H 400 MHz NMR (CD3OD): 8.09 (s, 1H), 7.40 (s, 1H), 7.34 (d, 1H J=8.5 Hz), 6.89 (d, 1H, J=8.5 Hz), 6.60 (m, 1H).
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[C:4](OC)=[N:5][C:6]([Cl:13])=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>CO>[NH2:1][C:4]1[C:3]([Cl:2])=[CH:8][C:7]([C:9]([F:12])([F:11])[F:10])=[C:6]([Cl:13])[N:5]=1
Reactant: N
Reactant: COc1nc(Cl)c(C(F)(F)F)cc1Cl
Solvent: CO
Product: Nc1nc(Cl)c(C(F)(F)F)cc1Cl
Yield: 28.3 %

Procedure:
12.4 g (0.73 mol) of gaseous ammonia were injected into a stirred mixture of 12.8 g (0.052 mol) of 3,6-dichloro-2-methoxy-5-trifluoromethylpyridine in 100 ml of methanol in an autoclave at 140° C., during which process the pressure climbed up to 200 bar. After half an hour, no starting material was detected in a sample. The reaction solution was concentrated and partitioned between methylene chloride and water. After drying, concentration, trituration of the residue with n-pentane, filtration with suction and drying, 3.4 g (28% of theory) of 2-amino-3,6-dichloro-5-trifluoromethylpyridine of m.p. 110°-112° C. were obtained. HPLC analysis revealed that the concentrated pentane filtrate (5 g) was composed of a further 19% of 2-amino-3,6-dichloro-5-trifluoromethylpyridine and 5 other compounds.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[CH:26][C:27]([F:36])=[C:28]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:29]=2)[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([NH:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:25]=[CH:26][C:27]([F:36])=[C:28]([NH:30][C:31](=[O:35])[CH:32]([CH3:33])[CH3:34])[CH:29]=4)[CH2:20][CH2:19]3)=[O:13])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Reactant: CC(C)C(=O)Nc1cc(C2CCN(CCCN)CC2)ccc1F
Product: CC(C)C(=O)Nc1cc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CC3)CC2)ccc1F

Procedure:
Example 47 was prepared from 1-(4-chlorophenyl)cyclopropanecarboxylic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 8.32–8.18 (m, 1H), 7.43–7.25 (m, 5H), 7.08–6.93 (m, 1H), 6.93–6.79 (br, 1H), 5.74–5.59 (br, 1H), 3.35–3.15 (m, 2H), 3.93–2.75 (m, 2H), 2.65–2.49 (m, 1H), 2.49–2.34 (m, 1H), 2.34–2.19 (m, 2H), 2.00–1.83 (m, 2H), 1.82–1.68 (m, 2H), 1.68–1.48 (m, 4H), 1.36–1.17 (m, 2H), 1.27 (d, 6H, J=6.8 Hz), 1.0 (s, 2H); ESMS m/e: 500.3 (M+H)+; Anal. Calc. for (HCl salt) C28H36Cl2FN3O2.0.45CHCl3: C, 57.85; H, 6.22; N, 7.11. Found: C, 57.61; H, 6.37; N, 7.30.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH2:7][NH:8][CH2:9][CH:10]([OH:32])[CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:20]([O:23]CC2C=CC=CC=2)=[C:19]2[C:14]=1[CH2:15][CH2:16][C:17](=[O:31])[NH:18]2.C(O)C.[ClH:41]>CO.[C].[Pd]>[ClH:41].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH2:7][NH:8][CH2:9][CH:10]([OH:32])[CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]2[C:14]=1[CH2:15][CH2:16][C:17](=[O:31])[NH:18]2
Reactant: COc1ccc(CCNCC(O)COc2ccc(OCc3ccccc3)c3c2CCC(=O)N3)cc1OC
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: COc1ccc(CCNCC(O)COc2ccc(O)c3c2CCC(=O)N3)cc1OC
Temperature: 25 °C

Procedure:
2.0 g of 5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-8-benzyloxy-3,4-dihydrocarbostyril was suspended in 50 ml of methanol, and ethanol containing hydrogen chloride was added to the suspension until the suspension showed acidity to form a homogeneous solution. 0.7 g of 10% palladium carbon was added to the resulting solution, and the mixture was stirred at room temperature and at atmospheric pressure to absorb hydrogen. The reaction completed at the point when the absorption of hydrogen ceased. The catalyst was removed by filtration, and the methanol evaporated. To the residue was added a small amount of ethanol to crystallized followed by recrystallization from ethanol to obtain 1.5 g of 5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-8-hydroxy-3,4-dihydrocarbostyril hydrochloride as colorless powdery crystals having a melting point of 171°-173° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:6]([CH:19]=1)[CH2:7][NH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=1.[OH-].[Na+]>CO.C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:6]([CH:19]=1)[CH2:7][NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(NCc2cc(Br)ccc2CCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(NCc2cc(Br)ccc2CCc2ccccc2)cc1
Yield: 95.1 %

Procedure:
Methyl 4-[N-(5-bromo-2-(phenethyl)benzyl)amino]benzoate (0.25 g) and 2N aqueous NaOH (5 ml) were heated at reflux in a mixture of methanol (5 ml) and THF (5 ml) for 2 hours. The organic solvents were evaporated, the residue acidified with 2N HCl and extracted with ethyl acetate. The extracts were washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by crystallisation from diethyl ether and hexane to give the title compound (0.23 g; mpt 132-134° C.).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[C:6](Cl)(=[O:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH-].[Na+]>O.CCOCC>[C:6]([NH:1][CH2:2][C:3]([OH:5])=[O:4])(=[O:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: NCC(=O)O
Reactant: CCCCCCCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCCCCCCC(=O)NCC(=O)O
Yield: 27.6 %

Procedure:
Glycine (20 mmol) was reacted with octanoyl chloride (22 mmol) in the presence of NaOH (40 mmol) in a mixture of water and ether using the method described in Example 1 Part A. The crude crystalline product (3.06 g, 76%) was recrystallized from EtOAc (15 ml) to give the title compound (1.11 g, 28%), m.p. 105°-107° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH:10](=O)[CH:11]([CH3:13])[CH3:12]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:10]/[CH:11]([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C=O
Reactant: CC(C)(C)OC(=O)CN
Solvent: ClCCl
Product: CC(C)/C=N/CC(=O)OC(C)(C)C
Yield: 97.2 %

Procedure:
In a manner similar to the method described in Example 1a, glycine tert-butyl ester (0.65 g, 5 mmol) was reacted with isobutyraldehyde (Aldrich) (0.4 g, 5 mmol) in CH2Cl2 at room temperature for 20 h to give [2-methyl-prop-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (0.9 g, 97%).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[C:27]([O:31][C:32]([O:34][CH2:35]I)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:35][O:34][C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:33])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CC(C)(C)OC(=O)OCI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)OC(C)(C)C)=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Yield: 95.9 %

Procedure:
In the same manner as in Example 81, 214 mg of the title compound was prepared from 176 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 135 mg of t-butoxycarbonyloxymethyl iodide.
Reaction SMILES: CCCCCC[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH:22]([OH:30])[C@H:23]1[O:27][CH2:26][C@H:25]([OH:28])[C@H:24]1[OH:29])=[O:19]>O>[CH3:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH:22]([OH:30])[C@H:23]1[O:27][CH2:26][C@H:25]([OH:28])[C@H:24]1[OH:29])=[O:19]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC(O)[C@H]1OC[C@H](O)[C@H]1O
Solvent: O
Product: CCCCCCCCCCCC(=O)OCC(O)[C@H]1OC[C@H](O)[C@H]1O

Procedure:
sorbitan monostearate-30% in H2O
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([NH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)=[O:11])[S:7][CH:8]=1)(=O)[CH3:2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:36][NH2:37]>O1CCCC1>[Cl:21][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[Cl:20])[CH2:13][NH:12][C:10]([NH:9][C:6]1[S:7][CH:8]=[C:4]([CH:1]([NH:37][CH3:36])[CH3:2])[N:5]=1)=[O:11]
Reactant: CC(=O)c1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CNC(C)c1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
156 mg of 1-(4-acetylthiazol-2-yl)-3-(3,4-dichlorobenzyl)urea was dissolved in 5 ml of 2 M methylamine solution in tetrahydrofuran. To the solution, 2.0 eq. of sodium triacetoxyborohydride was added and stirred overnight at room temp. The volatile was removed by evaporation and the residue was purified by column chromatography using 0-10% gradient of 7 N ammonia/MeOH and DCM to give the title compound.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:8][C:9](N)=[O:10].N>O>[CH:1]1([NH:7][C:9]([NH2:8])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(N)=O
Reactant: NC1CCCCC1
Agent: N
Solvent: O
Product: NC(=O)NC1CCCCC1
Yield: 89.7 %

Procedure:
495 g (5 mols) of cyclohexylamine and 390 g (6.5 mols) of urea are heated under reflux in 750 ml of water. After the splitting-off of ammonia is complete, the mixture is cooled down and the product is filtered off with suction. After washing and drying, 638 g of N-cyclohexylurea (90% of theory) are obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH:9](B1OC(C)(C)C(C)(C)O1)=[CH2:10].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([CH:9]=[CH2:10])=[CH:6][CH:7]=1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: Clc1ccc(Cl)nn1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1ccc(Cl)nn1
Temperature: 80 °C
Yield: 91.8 %

Procedure:
A mixture of 3,6-dichloropyridazine (6 g, 40.3 mmol), vinyl boronic acid pinacol ester (6.21 g, 6.83 mL, 40.3 mmol), potassium carbonate (120 mmol, 16.7 g), 1,4-dioxane (60 mL) and water (24 mL) was degassed for 15 min with nitrogen gas. Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.4 mmol, 292 mg) was then added and the mixture heated to 80° C. for 4 hours. The aqueous phase was then removed via pipette and the organic phase concentrated onto silica gel and purified via flash column chromatography (SiO2, hexane:ethyl acetate 100:0-60:40) to return 3-chloro-6-vinyl-pyridazine as a white solid (5.2 g, 92% yield). 1H NMR (CDCl3) δ 5.75 (1H, d), 6.25 (1H, d), 7.05 (1H, dd), 7.49 (1H, d), 7.59 (1H, d). MS m/z=141 (M+H+)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[C:22](Cl)([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>O.O1CCOCC1>[CH2:25]([O:24][C:22]([N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][C@H:10]1[C:14]([OH:16])=[O:15])=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](C(=O)O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)[C@H](C(=O)O)C1
Temperature: 25 °C
Yield: 82.2 %

Procedure:
To a stirred suspension of (S)-4-(tert-butoxycarbonyl) piperazine-2-carboxylic acid (1.0 g, 4.34 mmol) in water (5 mL) was added solid NaHCO3 (0.73 g, 8.68 mmol) at room temperature. The reaction mixture was stirred at room temperature to get clear solution. Solution of CBZ-Cl (1.22 mL, 8.68 mmol) in 1,4-dioxane (10 mL) was added dropwise and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The aqueous layer was acidified with 0.5M aqueous HCl to pH 5 and extracted with EtOAc (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (1.30 g) as white solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5].CO[C:10](OC)([CH3:12])[CH3:11].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C1COCC1>[CH3:11][C:10]1([CH3:12])[O:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2][O:1]1
Reactant: COC(C)(C)OC
Reactant: OCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)OCC(CO)CO1
Reaction time: 60 h
Yield: 43.7 %

Procedure:
2-(Hydroxymethyl)-1,3-propanediol (1.0 g, 9.4 mmol), 2,2-bis(methyloxy)propane (2.3 mL, 18.8 mmol) and p-toluenesulfonic acid monohydrate (0.09 g, 0.5 mmol) were dissolved in THF and stirred for ˜60 h. To the solution was added triethyl amine (1.0 mL) and the solvent was evaporated. Purification was accomplished by column chromatography (CH2Cl2:MeOH) to afford the title compound (0.6 g, 44%) as a oil. 1H NMR (400 MHz, DMSO-d6): δ ppm 4.52 (t, 1H), 3.80 (dd, 2H), 3.59 (dd, 2H), 3.36 (dd, 2H), 1.63-1.72 (m, 1H), 1.28 (d, 6H).