Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([O:12][CH3:13])[CH:5]=1.[CH3:14][O:15][CH2:16][CH2:17][O:18][CH2:19]Cl.O>O1CCCC1.CN(C)C=O>[CH3:13][O:12][C:6]1[CH:5]=[C:4]([O:3][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[CH:11]=[CH:10][C:7]=1[CH:8]=[O:9]
Reactant: COc1cc(O)ccc1C=O
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCOc1ccc(C=O)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
1.8 g (41.2 mmol) of 60% sodium hydride is added in portions to a solution at 0° C. of 5.7 g (37.5 mmol) of 4-hydroxy-2-methoxy-benzaldehyde diluted in 30 ml of tetrahydrofuran and 30 ml of dimethylformamide. The reaction mixture is stirred at room temperature for 30 minutes and then 4.7 ml (41.2 mmol) of 2-methoxyethoxymethyl chloride is added dropwise. The reaction mixture is stirred at room temperature for 45 minutes and then the reaction mixture is treated by adding water and extracted with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered, and evaporated. The raw product is purified by silica column chromatography, eluted with a heptane/ethyl acetate mixture 70/30 to give 8.6 g (95%) of 2-methoxy-4-(2-methoxy-ethoxymethoxy)-benzaldehyde in the form of a colorless oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH3:18])=[CH:5][CH2:6][CH2:7][C:8]([CH3:17])=[CH:9][CH2:10][CH2:11][C:12]([CH3:16])(O)[CH:13]=[CH2:14].O.COCC(C)=CCCC(C)=CCC=C(C)C=C>CCOCC.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:1][O:2][CH2:3][C:4]([CH3:18])=[CH:5][CH2:6][CH2:7][C:8]([CH3:17])=[CH:9][CH2:10][CH2:11][C:12](=[CH2:16])[CH:13]=[CH2:14]
Reactant: C=CC(C)(O)CCC=C(C)CCC=C(C)COC
Agent: [Cu+2]
Agent: C=CC(C)=CCC=C(C)CCC=C(C)COC
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CCOCC
Product: C=CC(=C)CCC=C(C)CCC=C(C)COC
Temperature: 180 °C
Yield: 47 %

Procedure:
5 g of copper sulfate pentahydrate are suspended in 20 g of paraffin oil, with vigorous stirring, and the suspension is heated at 180° C under 20 mm Hg. The water of crystallization which is eliminated is removed through a descending condenser. After the reaction has ended, 25 g (0.1 mole) of 12-methoxy-3,7,11-trimethyl-dodeca-1,6,10-trien-3-ol are added dropwise to the suspension and water and reaction product are distilled off simultaneously (reaction time about 30 minutes). After completion, the distillate is taken up in 100 ml of ether, the ether solution is washed with sodium carbonate solution, then washed neutral with water and dried over sodium sulfate, and the drying agent is then filtered off. After distilling off the ether, the product which remains is fractionated, giving 11 g of a 2:1 mixture of 12-methoxy-3,7,11-trimethyl-dodeca-1,3,6,10-tetraene and 12-methoxy-3-methylene-7,11-dimethyl-dodeca-1,6,10- -triene (yield 47%).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([N:7]=[C:8]=[O:9])=[CH:3][CH:2]=1.[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:17]([S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])=[CH:16][C:14]=1[NH2:15]>CCOC(C)=O>[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:17]([S:20]([C:23]([F:24])([F:25])[F:26])(=[O:21])=[O:22])=[CH:16][C:14]=1[NH:15][C:8]([NH:7][C:4]1[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=1)=[O:9]
Reactant: Cc1ccc(N=C=O)cc1
Reactant: COc1ccc(S(=O)(=O)C(F)(F)F)cc1N
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)C(F)(F)F)cc1NC(=O)Nc1ccc(C)cc1
Reaction time: 18 h
Yield: 55.9 %

Procedure:
p-Tolyl isocyanate (0.19 mL, 1.55 mmol) was added to a solution of 2-methoxy-5-(trifluoromethanesulfonyl)aniline (0.330 g, 1.29 mmol) in EtOAc (5 mL), and the reaction mixture was stirred at room temp. for 18 h. The resulting precipitate was collected by filtration and washed with Et2O to give a white solid (0.28 g). This material was then purified by HPLC (C-18 column, 50% CH3CN/50% H2O) and the resulting solids were triturated with Et2O to provide the title compound (0.198 g): 1H-NMR (CDCl3) δ 7.08 (d, J=8.5 Hz, 2H), 7.33 (d, J=8.5 Hz, 2H), 7.40 (d, J=8.8 Hz, 1H), 7.71 (dd, J=2.6, 8.8 Hz, 1H), 8.66 (s, 1H), 8.90 (d, J=2.6 Hz, 1H), 9.36 (s, 1H); FAB-MS m/z 389 ((M+1)+). B1c. General Method for the Reaction of an Aryl Amine with an Aryl Isocyanate
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4]O.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[N:28]1[C:29]2[N:30]([C:41]3[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=3[N:43]=2)[CH:31]=[CH:32][C:33]=1[C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[N:28]1[C:29]2[N:30]([C:41]3[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=3[N:43]=2)[CH:31]=[CH:32][C:33]=1[C:34]1[CH:35]=[CH:36][C:37]([NH:38][CH2:4][CH2:3][CH2:2][F:1])=[CH:39][CH:40]=1
Reactant: Nc1ccc(-c2ccn3c(n2)nc2ccccc23)cc1
Reactant: OCCCF
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: FCCCNc1ccc(-c2ccn3c(n2)nc2ccccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
To 3-fluoropropan-1-ol (4 mg, 0.05 mmol) in 0.5 mL DCM was added Dess-Martin reagent (42 mg, 0.1 mmol). The mixture was stirred at rt for 1 h and filtered directly into a mixture of 4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)aniline (4 mg, 0.015 mmol) and NaBH(OAc)3 (43 mg, 0.2 mmol) with stirring. After vigorously stirred for 5 min, reaction was quenched by adding 0.5 M NaOH (2 mL). The mixture was extracted with EtOAc (3×10 mL) and the organic phase was dried over MgSO4 and concentrated. The crude product was purified by HPLC to afford 4-(Benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)-N-(3-fluoropropyl)aniline as a yellow solid (2.7 mg, 33%). 1H NMR (400 MHz, CDCl3): δ 8.76 (d, J=7.2 Hz, 1H), 7.88 (m, 4H), 7.55 (d, J=7.2 Hz, 1H), 7.53 (m, 1H), 7.40 (m, 1H), 6.47 (d, J=9.2 Hz, 1H), 4.68 (t, J=5.2 Hz, 1H), 4.56 (t, J=5.2 Hz, 1H), 3.34 (t, J=6.8 Hz, 2H), 2.09 (m, 1H), 2.02 (m, 1H); MS (ESI): 321 (M+H+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([B-](F)(F)F)([CH3:9])=[CH2:8].[K+].Br[C:16]1[C:17]([O:25][CH3:26])=[N:18][CH:19]=[C:20]([N+:22]([O-])=O)[CH:21]=1.[H][H]>O1CCOCC1.O.[Pd].CO>[CH:7]([C:16]1[CH:21]=[C:20]([NH2:22])[CH:19]=[N:18][C:17]=1[O:25][CH3:26])([CH3:9])[CH3:8]
Reactant: [H][H]
Reactant: C=C(C)[B-](F)(F)F
Reactant: COc1ncc([N+](=O)[O-])cc1Br
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: COc1ncc(N)cc1C(C)C
Temperature: 80 °C
Reaction time: 3 h
Yield: 101.5 %

Procedure:
Argon was bubbled through a slurry of potassium carbonate (4.45 g, 32.2 mmol), potassium isopropenyltrifluoroborate (3.18 g, 21.46 mmol), bis(4-(di-tert-butylphosphino)-N,N-dimethylbenzenamine)palladium dichloride (Aldrich, St. Louis, Mo., 0.152 g, 0.215 mmol), and 3-bromo-2-methoxy-5-nitropyridine (2.50 g, 10.73 mmol) in 50 mL dioxane and 20 mL water for 5 min. The reaction was sealed and heated to 80° C. for 1 h. The dark red reaction was cooled and partitioned between water and DCM. The aqueous layer was extracted with DCM 3 times, and the combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo, to give a red solid, which was used without further purification. The solid was treated 10% palladium on carbon (50% water wet) (2.62 g, 2.464 mmol) and 75 mL MeOH and was fitted with hydrogen balloon and stirred rapidly for 3 h. The reaction was flushed with nitrogen, filtered through Celite® (diatomaceous earth), rinsing with 400 mL MeOH, and concentrated in vacuo to give 5-isopropyl-6-methoxypyridin-3-amine (1.81 g, 10.89 mmol, quantitative yield) as a brown oil. m/z (ESI, +ve ion) 167 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J=2.9 Hz, 1H), 6.94 (d, J=2.7 Hz, 1H), 3.90 (s, 3H), 3.13 (m, 1H), 1.14-1.22 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26]([OH:28])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:33][C:34]1[CH:39]=[CH:38][N:37]=[C:36]([C:40]2([NH2:43])[CH2:42][CH2:41]2)[N:35]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:28])[NH:43][C:40]5([C:36]6[N:35]=[C:34]([CH3:33])[CH:39]=[CH:38][N:37]=6)[CH2:41][CH2:42]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: Cc1ccnc(C2(N)CC2)n1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5nccc(C)n5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.04 g, 0.092 mmol, 1 eq), 1-(4-methylpyrimidin-2-yl)cyclopropanamine (130 mg, crude), Py-Bop (0.062 g, 0.12 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.028 g, 0.3 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative HPLC. Yield: 0.028 g (53%). 1H NMR (400 MHz, CD3OD): δ 8.49 (d, J=5.3 Hz, 1H), 8.07-7.95 (m, 2H), 7.92 (s, 1H), 7.69-7.51 (m, 2H), 7.39-7.23 (m, 3H), 7.16 (d, J=5.3 Hz, 2H), 4.08 (s, 3H), 2.95 (s, 3H), 2.49 (s, 3H), 2.37 (s, 3H), 1.87-1.76 (m, 2H), 1.57-1.45 (m, 2H). 19F NMR (376.47 MHz, CD3OD): δ −78.09 (TFA), −113.44 LCMS: (ES+) m/z=565.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:28]([N:29]([CH3:44])[C:30](=[O:43])[CH2:31][N:32]2C(=O)C3=CC=CC=C3C2=O)=[CH:27][CH:26]=[C:25]([Cl:45])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[C:11]2[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.O.NN>C(O)C>[NH2:32][CH2:31][C:30]([N:29]([C:28]1[C:2]([Cl:1])=[C:3]([C:25]([Cl:45])=[CH:26][CH:27]=1)[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[C:11]2[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH3:44])=[O:43]
Reactant: Cc1cc(OCc2ccccn2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN4C(=O)c5ccccc5C4=O)c3Cl)c2n1
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1cc(OCc2ccccn2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Yield: 65.2 %

Procedure:
A mixture of 8-[2,6-dichloro-3-[N-methyl-N-(phthalimidoacetyl)amino]benzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoline (750 mg), hydrazine monohydrate (117 mg) and ethanol was heated under reflex for 4 hours. The precipitate was removed by filtration and filtrate was evaporated in vacua. The residue was dissolved with a mixture of chloroform and methanol (10:1, V/V), precipitate was removed by filtration and filtrate was evaporated in vacua. The residue was purified by column chromatography on silica gel eluting with chloroform--methanol to afford 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoline (390 mg) as an amorphous powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][OH:23])[CH2:17][CH2:16]1.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][OH:23])[CH2:17][CH2:16]2)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: OCCC1CCNCC1
Reactant: COc1ccc(CC(=O)O)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(CC(=O)N2CCC(CCO)CC2)cc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
To an ice-cold solution of 3,4-dimethoxyphenylacetic acid (7.60 g, 38.7 mmol), N,N-dimethylaminopyridine (DMAP; 11.4 g, 93 mmol), and 4-piperidin-ethanol (5 g, 39 mmol) in dry dichloromethane (DCM; 80 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC.HCl; 9.65 g, 50.3 mmol) in one portion. The cooling bath was removed and the reaction was allowed to warm to room temperature. After five hours, HPLC analysis revealed the 3,4-dimethoxyphenylacetic acid was consumed. The reaction mixture was washed once with 1 N HCl(aq) (90 mL) and concentrated in vacuo. The residue was chromatographed to yield the title compound (A; 10.67 g, 90% yield) as viscous oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([CH:18]=1)[NH2:17]>>[Br:11][C:12]1[CH:18]=[C:16]([NH:17][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1cccc(Br)c1
Product: O=[N+]([O-])c1cccnc1Nc1cccc(Br)c1
Yield: 132.2 %

Procedure:
2-Chloro-3-nitropyridine (2.0 g, 12.6 mmol, 1 eq) was reacted with 5-bromoaniline (4.12 ml, 37.8 mmol, 3 eq) for 20 minutes at 180° C. in a microwave reactor. The product was isolated by column chromatography to provide the title compound as a red solid (4.9 g). [M+H] calc'd for C11H8BrN3O2, 293; found 293.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:38])[CH2:9][N:10]2[C:15](=[O:16])[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)=[C:13]([CH2:32][CH2:33][CH3:34])[N:12]3[N:35]=[CH:36][N:37]=[C:11]23)=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.O1CCCC1.FC(F)(F)S(O[Si:58]([C:61]([CH3:64])([CH3:63])[CH3:62])([CH3:60])[CH3:59])(=O)=O>C(OCC)(=O)C>[Si:58]([O:38][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)=[C:13]([CH2:32][CH2:33][CH3:34])[N:12]2[N:35]=[CH:36][N:37]=[C:11]12)([C:61]([CH3:64])([CH3:63])[CH3:62])([CH3:60])[CH3:59]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(O)c2ccc(F)cc2)c2ncnn12
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(O[Si](C)(C)C(C)(C)C)c2ccc(F)cc2)c2ncnn12
Temperature: 25 °C
Reaction time: 5 h
Yield: 58 %

Procedure:
To a mixture of 4′-({4-[2-(4-fluorophenyl)-2-hydroxyethyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.78 g), 2,6-lutidine (0.27 mL) and tetrahydrofuran (20 mL) was added tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.53 mL), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.56 g, 58%).
Reaction SMILES: [C:1]([OH:5])(=O)[CH:2]=[O:3].Cl.[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[NH:15][NH2:16]>Cl.O>[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[NH:15][N:16]=[C:1]([OH:5])[CH:2]=[O:3]
Reactant: NNc1ccc(Cl)cc1Cl
Reactant: O=CC(=O)O
Agent: Cl
Solvent: O
Product: O=CC(O)=NNc1ccc(Cl)cc1Cl
Yield: 69 %

Procedure:
In a manner similar to that disclosed by HO House, et al (Organic Synthesis, Vol V, 258-263) the reaction of 3.4 g (0.046 mole) of glyoxylic acid in 40 mL of 2.5 N hydrochloric acid and 60 mL of water with a solution of 9.8 g (0.046 mole) of 2,4-dichlorophenylhydrazine hydrochloride in 30 mL of water produced 7.4 g of 2-oxoacetic acid 2,4-dichlorophenylhydrazone as a solid (m.p. 160° C., dec.).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9](=[C:12](OC)[CH3:13])[C:10]#[N:11])[S:8][C:4]=2[CH:3]=1.O.[NH2:19][NH2:20]>CO>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[C:12]([CH3:13])=[N:20][NH:19][C:10]=3[NH2:11])[S:8][C:4]=2[CH:3]=1
Reactant: COC(C)=C(C#N)c1nc2ccc(Br)cc2s1
Reactant: NN
Solvent: CO
Solvent: O
Product: Cc1n[nH]c(N)c1-c1nc2ccc(Br)cc2s1
Temperature: 25 °C
Yield: 5 %

Procedure:
A solution of 2-(6-bromobenzothiazol-2-yl)-3-methoxybut-2-enenitrile (0.96 g, 3.1 mmol) and hydrazine hydrate (0.3 mL, 5.4 mmol) in methanol (30 mL) was heated to reflux overnight. The reaction was then cooled to room temperature. The resulting solid was isolated by filtration and was purified by flash chromatography to yield the title product. MS (m/z, ES+): 308.9 (Br79M+1, 100%), 310.9 (Br81 M+1, 100%). Yield=5%.
Reaction SMILES: Br.[C@@H:2]1([NH:13][C:14]2[S:15][CH:16]=[C:17]([C:19]([O:21]CC)=O)[N:18]=2)[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[NH3:24]>CO>[C@@H:2]1([NH:13][C:14]2[S:15][CH:16]=[C:17]([C:19]([NH2:24])=[O:21])[N:18]=2)[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: CCOC(=O)c1csc(N[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n1
Reactant: N
Agent: Br
Solvent: CO
Product: NC(=O)c1csc(N[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Ethyl 2-(N-β-D-glucopyranosyl)aminothiazole-4-carboxylate hydrobromide (4.15 g., 0.01 mole) was added to a solution of methanol (50 ml.) saturated with ammonia at 0° in a pressure bottle. The reaction mixture was magnetically stirred at room temperature for 48 hours with the stopper well closed. The mixture was evaporated to dryness in vacuo. The residue was mixed with a small amount of ethyl acetate and chromatographed on a column of silica gel (2.54×20 cm) using acetone as the first solvent (300 ml.) and methanol as the second solvent (300 ml.). The methanol effluent was concentrated to ca. 75 ml., and ethyl acetate (500 ml.) was added to give a precipitate. The creamy yellow precipitate was filtered and dried at room temperature in vacuo, yielding 2.77 g. (76.2%); m.p. over 96° (dec.).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18](=[CH2:20])[CH3:19].C(=O)=O>C(Cl)Cl.S(=O)(=O)(O)O>[C:18]([O:15][C:14](=[O:16])[C@H:12]([CH3:13])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])([CH3:20])([CH3:19])[CH3:17]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: C=C(C)C
Agent: O=C=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzyloxycarbonyl-L-alanine (15.0 g) (67.2 mmol) was dissolved in methylene chloride with about 1 mL of concentrated sulfuric acid. Isobutylene was added via a dry-ice, cold finger trap. The solution was allowed to warm to room temperature and left stirring overnight. The solution was charged with isobutylene again and left stirring overnight. The solution was extracted with 0.8N aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered and evaporated under vacuum to give benzyloxycarbonyl-L-alanine t-butyl ester. 1H NMR (CDCl3) δ7.35 (s, 5H), 5.12 (s, 2H), 4.23 (m, 2H), 1.45-1.30 (s/d, 12H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.[CH2:10]([Mg]Br)[CH3:11]>O1CCCC1>[CH2:10]([C:6]1([OH:9])[CH2:7][CH2:8][CH:3]([CH2:2][OH:1])[CH2:4][CH2:5]1)[CH3:11]
Reactant: O=C1CCC(CO)CC1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC1(O)CCC(CO)CC1
Temperature: 25 °C

Procedure:
4-(Hydroxymethyl)cyclohexanone (1.22 g) in tetrahydrofuran (20 mL) was treated with 1M ethylmagnesium bromide in tetrahydrofuran (28.6 mL) at 0° C. The reaction was warmed to room temperature over 4 hours and quenched with methanol (2 mL) and water (2 mL). The resulting mixture was concentrated and the residue was suspended in ethyl acetate. The precipitates were filtered off and the filtrate was concentrated and purified by flash chromatography, eluted with 0-100% ethyl acetate in hexane to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([CH:19]([CH3:30])[CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:31](Cl)(=[O:35])[CH:32]([CH3:34])[CH3:33].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([CH:19]([CH3:30])[CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]([C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(CCNC(=O)OC(C)(C)C)C1(c2ccccc2)NN=C(c2cccc(F)c2)S1
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)N1N=C(c2cccc(F)c2)SC1(c1ccccc1)C(C)CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 3-(5-(3-fluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)butylcarbamate (50 mg, 116 mmol) in anhydrous DCM (5 mL) was added isobutyryl chloride (16 μL, 151 mmol) followed by triethylamine (21 μL, 151 mmol). After stirring at room temperature for 16 hours the mixture was partitioned between sat. NaHCO3 (20 mL) and DCM (20 mL). The aqueous layer was extracted with DCM (10 mL) and the combined organic phases were washed with brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was chromatographed (19:1, hexanes/ethyl acetate) to afford two diastereomeric pairs, diastereomer pair A (more polar, 13.1 mg) and diastereomer pair B (less polar, 11 mg).
Reaction SMILES: CS[C:3]1[CH2:4][C:5](=[O:21])[N:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:8]=2[N:9]=1.[C:22]([O:26][C:27](=[O:30])[NH:28][NH2:29])([CH3:25])([CH3:24])[CH3:23]>CN(C)C=O>[C:22]([O:26][C:27]([NH:28][NH:29][C:3]1[CH2:4][C:5](=[O:21])[N:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:8]=2[N:9]=1)=[O:30])([CH3:25])([CH3:24])[CH3:23]
Reactant: CSC1=Nc2ccc(Cl)cc2N(c2ccccc2)C(=O)C1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NNC1=Nc2ccc(Cl)cc2N(c2ccccc2)C(=O)C1

Procedure:
3.16 g of 2-(methylthio)-7-chloro-5-phenyl-3H-1,5-benzodiazepin-4-one and 1.41 g of t-butylcarbazate in 60 ml of dimethyl formamide are refluxed for 20 hours while a slow stream of nitrogen is bubbled through the reaction. The reaction is worked up as described in Example 29, Method A, to give the title compound.
Reaction SMILES: C([O:5][C:6]([CH2:8][C@@H:9]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[C:6]([CH2:8][C@@H:9]([CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
The product from Example 22 (0.52 g, 1.47 mmol) was dissolved in a 1:1 (v:v) solution (6 ml) of trifluoroacetic acid and dichloromethane and stirred at room temperature for 1 h. The volatiles were removed in vacuo to provide the title compound (0.437 g, 100%) as an oil which crystallized on standing. The unpurified material was of sufficient purity to employ in subsequent steps. Mass spectrum: (M)+ =298.
Reaction SMILES: [CH2:1]([O:5][CH:6]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)[CH2:2][CH2:3][CH3:4].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28](Cl)[C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[CH:24][CH:23]=1>C(#N)C>[Cl-:19].[CH2:1]([O:5][CH:6]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[CH2:7][N+:8]1[CH:12]=[CH:11][N:10]([CH:28]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C:25]2[CH:24]=[CH:23][C:22]([Cl:21])=[CH:27][CH:26]=2)[CH:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Fc1ccc(C(Cl)c2ccc(Cl)cc2)cc1
Reactant: CCCCOC(Cn1ccnc1)c1ccc(Cl)cc1Cl
Solvent: CC#N
Product: CCCCOC(C[n+]1ccn(C(c2ccc(F)cc2)c2ccc(Cl)cc2)c1)c1ccc(Cl)cc1Cl
Product: [Cl-]

Procedure:
6.3 Parts of 1-(β-butoxy-2,4-dichlorophenethyl)-imidazole and 5.1 parts of (p-chlorophenyl) (p-fluorophenyl)methyl chloride are mixed together in 80 parts of acetonitrile and the resulting mixture is stirred at reflux temperature overnight. Thereafter, the solvent is vaporized off to obtain as residue a 1-(β-butoxy-2,4-dichlorophenethyl)-3-[p-chloro-α-(p-fluorophenyl)benzyl]imidazolium chloride product.