Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:9]=1[NH:10][CH:11]([CH3:13])[CH3:12])=[O:4].[CH3:20][C:21]1[CH2:22][CH:23]([C:26](O)=[O:27])[CH2:24][CH:25]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C(=O)N(Cl)C(=O)C1>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:8][C:9]=1[N:10]([CH:11]([CH3:13])[CH3:12])[C:26]([CH:23]1[CH2:24][CH:25]=[C:21]([CH3:20])[CH2:22]1)=[O:27])=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC(C)C
Reactant: CC1=CCC(C(=O)O)C1
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CC=C(C)C1)C(C)C
Yield: 60.8 %

Procedure:
The coupling of the 3-Isopropylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester (82 mg, 0.3 mmol) and the 3-Methyl-cyclopent-3-enecarboxylic acid (45 mg, 0.357 mmol) using PPh3 (95.4 mg, 0.363 mmol) and NCS (48.5 mg, 0.363 mmol) furnished the 3-[Isopropyl-(3-methyl-cyclopent-3-enecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (70 mg, 61% yield) 1H NMR (CDCl3, 400 MHz 1:1 mixture of, rotamers), 7.68-7.64 (m, 4H), 7.5-7.4 (m, 6H), 7.1 (s, 1H), 7.09 (s, 1H), 5.2 (s, 1H), 5.1 (s, 1H), 5.06-4.98 (m, 2H), 3.88 (s, 3H), 3.87 (s, 3H), 3.08-3.0 (m, 2H), 2.85-2.76 (m, 2H), 2.5-2.42 (m, 2H), 2.3-2.1 (m, 4H), 1.69 (s, 3H), 1.64 (s, 3H), 1.24 (d, J=6.7 Hz, 3H), 1.23 (d, J=6.7 Hz, 3H), 1.01 (d, J=6.9 Hz, 3H), 1.007 (d, J=6.8 Hz, 3H).
Reaction SMILES: O=[C:2]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([Si](C(C)C)(C(C)C)C(C)C)[CH:10]=[CH:9]2)[CH2:3][C:4]#[N:5].O.NN.NC1C=C[NH:31][N:30]=1>CCO>[NH:11]1[C:12]2[C:8](=[CH:7][C:6]([C:2]3[CH:3]=[C:4]([NH2:5])[NH:30][N:31]=3)=[CH:14][CH:13]=2)[CH:9]=[CH:10]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(C(=O)CC#N)ccc21
Reactant: Nc1cc[nH]n1
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1cc(-c2ccc3[nH]ccc3c2)n[nH]1
Yield: 41 %

Procedure:
To a solution of 3-Oxo-3-(1-triisopropylsilanyl-1H-indol-5-yl)-propionitrile (490 mg, 1.44 mmol) in 15 mL of absolute EtOH, 720 μL of hydrazine monohydrate (14.4 mmol) were added and the reaction refluxed for 18 hours. LC-MS showed complete conversion to the aminopyrazole and also silyl deprotection. The mixture was concentrated under reduced pressure, and purified with SiO2 column (eluent gradient from 100% DCM to DCM:MeOH 9:1) to afford the title compounds (120mg, yield: 41%)
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.Cl.Cl[CH2:13][C:14]1[C:19]([CH3:20])=[C:18]([S:21][CH2:22][C:23]2[O:24][C:25]([CH2:28][N:29]([CH3:31])[CH3:30])=[CH:26][CH:27]=2)[CH:17]=[CH:16][N:15]=1>>[CH3:31][N:29]([CH2:28][C:25]1[O:24][C:23]([CH2:22][S:21][C:18]2[CH:17]=[CH:16][N:15]=[C:14]([CH2:13][S:1][C:2]3[NH:6][C:5]4[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=4[N:3]=3)[C:19]=2[CH3:20])=[CH:27][CH:26]=1)[CH3:30]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: Cc1c(SCc2ccc(CN(C)C)o2)ccnc1CCl
Agent: Cl
Product: Cc1c(SCc2ccc(CN(C)C)o2)ccnc1CSc1nc2ccccc2[nH]1

Procedure:
Following the procedure described in Example 1, the reaction of 2-mercapto-1H-benzimidazole with 2-chloromethyl-4-{[(5-dimethylaminomethyl-2-furyl)methyl]thio}-3-methylpyridine hydrochloride gives the title compound after chromatography on silica gel (dichloromethane/methanol/triethylamine 9:1:0.1 to 2:1:0.1).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][N+:6]([O-:8])=[O:7].[CH3:14][N:15]([CH3:19])[C:16](=[S:18])[S-:17].C[NH2+]C.C(=S)=S>CO>[CH3:14][N:15]([CH3:19])[C:16](=[S:17])[S:18][CH:4]([CH2:5][N+:6]([O-:8])=[O:7])[C:3]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:2]=1[Cl:1]
Reactant: O=[N+]([O-])C=Cc1ccc(Cl)cc1Cl
Reactant: CN(C)C(=S)[S-]
Agent: C[NH2+]C
Solvent: CO
Solvent: S=C=S
Product: CN(C)C(=S)SC(C[N+](=O)[O-])c1ccc(Cl)cc1Cl
Reaction time: 2 h

Procedure:
2,4-Dichloro-β-nitrostyrene (6.6 grams, 0.030 mole) was added to a stirred solution of dimethylammonium dimethyldithiocarbamate (5.1 grams, 0.030 mole) and carbon disulfide (1.8 ml., 0.030 mole) in methanol (30 ml.). The temperature of the resulting reaction was 16° - 32° C. After 2 hours at room temperature, the precipitated product was filtered off, washed with cold methanol, and dried in air. Recrystallization without heating was accomplished by dissolving the sample in acetone and then adding absolute ethanol to give 2,4-dichloro-α-(nitromethyl)benzyl dimethyldithiocarbamate melting at 127° - 128° C.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[N:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[N+:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1)([O-:33])=[O:32]>ClCCl>[N+:31]([C:34]1[CH:35]=[CH:36][C:37]([C:38]([NH:1][C:2]2[CH:23]=[CH:22][C:5]3[N:6]([CH:9]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[N:8][C:4]=3[CH:3]=2)=[O:39])=[CH:41][CH:42]=1)([O-:33])=[O:32]
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2cc(N)ccc21
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC(c1ccccc1)n1cnc2cc(NC(=O)c3ccc([N+](=O)[O-])cc3)ccc21
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of ethyl 3-(5-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate (100 mg, 324 μmol) in dichloromethane (6 mL) was added triethylamine (100 μL, 710 μmol) and 4-nitrobenzoyl chloride (132 mg, 712 μmol). The solution was stirred at room temperature for 96 hours, and was evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane and methanol (97:3) to afford the title compound, [LCMS (Method A, Mobile Phase I) RT=4.92 min, MH+ 459].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[C:3]=1[C:10](=[O:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH:21]=[CH2:22]>O1CCCC1>[OH:1][C:2]1[C:7]([CH2:22][CH:21]=[CH2:20])=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[C:3]=1[C:10](=[O:12])[CH3:11]
Reactant: C=CCBr
Reactant: CC(=O)c1c(O)cc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCc1c(O)cc(O)c(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.4 %

Procedure:
In 15 ml of anhydrous tetrahydrofuran was dissolved 3.0 g of 2',4',6'-trihydroxyacetophenone, and 7.4 g of anhydrous potassium carbonate was added to the solution and the mixture was stirred at room temperature for 30 minutes. Then, 2.5 g of 3-bromo-1-propene was added to the mixture and reaction was carried out at room temperature for 3 hours. After the reaction, the reaction mixture was extracted with 500 ml of diethyl ether, and the solvent was removed from the extract by distillation. The obtained residue was recrystallized from benzene to obtain 1.5 g (yield=41.5%) of 2',4',6'-trihydroxy-3'-(2-propenyl)acetophenone in the form of a colorless prism.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:10][S:9][CH2:8][CH2:7][N:6]1[S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])=[O:4].[Li+].[OH-].C(OCC)(=O)C>CO>[C:17]1([CH3:20])[CH:16]=[CH:15][C:14]([S:11]([N:6]2[CH2:7][CH2:8][S:9][CH2:10][C@H:5]2[C:3]([OH:4])=[O:2])(=[O:13])=[O:12])=[CH:19][CH:18]=1
Reactant: COC(=O)[C@@H]1CSCCN1S(=O)(=O)c1ccc(C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)O)cc1
Reaction time: 48 h
Yield: 97.1 %

Procedure:
8.3 g of (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid methyl ester was dissolved in 157 mL of methanol and 52.5 ml 1 mol/L of LiOH solution was added dropwise in the above solution at 0° C. The mixture was stirred for 48 h and ethyl acetate (60, 60 ml) was added into the reaction mixture and separated to collect mother liquid. The mother liquid was acidified by 100 ml 1 mol/L hydrogen chloride to adjust pH value to 2. Filtrated and collected the white solid to obtain 7.7 g product. Yield 97.0%□mp149-150° C.
Reaction SMILES: [CH:1]([O-])([O-])OCC.[CH3:7][C:8]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](=[N:23][O:24][CH3:25])[C:19]([NH:21][NH2:22])=[O:20]>O>[CH3:25][O:24][N:23]=[C:18]([C:19]1[O:20][CH:1]=[N:22][N:21]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][O:10][C:9]1[CH:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:8]=1[CH3:7]
Reactant: CCOC([O-])[O-]
Reactant: CON=C(C(=O)NN)c1ccccc1COc1cc(C)ccc1C
Solvent: O
Product: CON=C(c1nnco1)c1ccccc1COc1cc(C)ccc1C
Yield: 19.8 %

Procedure:
Ethyl orthoformate (2 ml) was added to 2-(2,5-dimethylphenoxymethyl)-α-methoxyiminophenylacetohydrazide (0.49 g, 1.5 mmol), and the mixture was stirred under reflux for 4 hours. After completion of the reaction, water (100 ml) was added, and the mixture was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give 2-(2,5-dimethylphenoxymethyl)phenyl 1,3,4-oxadiazol-2-yl ketone O-methyloxime (0.10 g, 19.8%) as colorless crystals.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[C:14]([C:27]#[N:28])=[C:15]([NH:17][C:18](=[O:26])[CH2:19][CH2:20][C:21]3O[CH:23]=[CH:24][CH:25]=3)[S:16][C:10]=2[CH2:9]1)=O)(C)(C)C.[C:29](O)([C:31](F)(F)F)=O>ClCCl>[C:27]([C:14]1[C:11]2[CH2:12][CH2:13][NH:8][CH2:9][C:10]=2[S:16][C:15]=1[NH:17][C:18](=[O:26])[CH2:19][CH2:20][C:21]1[CH:25]=[CH:24][CH:23]=[CH:31][CH:29]=1)#[N:28]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc(NC(=O)CCc3ccco3)c2C#N)C1
Solvent: ClCCl
Product: N#Cc1c(NC(=O)CCc2ccccc2)sc2c1CCNC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
200 mg of 3-cyano-2-(3-furan-2-yl-propanoylamino)-4,7-dihydro-5H-thieno[2,3-c]pyridine-6-carboxylic acid tert-butyl ester are dissolved in 7 ml of a mixture of dichloromethane and TFA and stirred at room temperature for 3 h. Evaporation of the solvent gives 250 mg of the desired product as TFA salt in sufficient purity for the next steps.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([N:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:12]=[CH:13][CH:14]([CH3:16])[CH3:15])[N:3]=1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:9][CH2:10]2)[N:5]=[C:4]([N:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:12][CH2:13][CH:14]([CH3:16])[CH3:15])[N:3]=1
Reactant: Cc1cc(C2CC2)nc(N(N=CC(C)C)c2ccccc2)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(C2CC2)nc(N(NCC(C)C)c2ccccc2)n1
Reaction time: 1 h

Procedure:
8.55 g (0.029 mol) of N-(4-methyl-6-cyclopropylpyrimidin-2-yl)-N-phenylisobutyraldehyde hydrazone are dissolved in 30 ml of methanol and 2 ml of glacial acetic acid. 2.14 g (0.029 mol) of sodium cyanoborohydride are then added in portions with stirring. The reaction proceeds exothermically; the temperature is maintained at 10°-15° C. by cooling. After 1 hour, the batch is worked up by extraction with ethyl acetate and water and the organic phase is concentrated using a rotary evaporator to give 8.5 g of crude product. Purification by column chromatography on silica gel (eluant: 85% hexane/15% ethyl acetate) affords 7.6 g (89% of the theoretical yield) of the title compound in the form of an oil having a refractive index of [n]D25 =1.5733.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]1[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)=[O:18])[CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:32]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]([CH3:32])[CH2:9][CH2:10][CH:11]1[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)=[O:18])[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCC1CN(C(=O)OCc2cc(Cl)cc(Cl)c2)CCO1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(CCC1CN(C(=O)OCc2cc(Cl)cc(Cl)c2)CCO1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture comprising of 3,5-dichlorobenzyl 2-(2-((tert-butoxycarbonyl)amino)ethyl)morpholine-4-carboxylate (Example 11, step 1) (1 g, 2.308 mmol) and sodium hydride (60% in oil) (0.111 g, 2.77 mmol) in DMF (20 mL) was stirred at 0° C. for 15 minutes. Iodomethane (0.216 mL, 3.46 mmol) was added and the mixture was left to stir at room temperature for 16 hours. The reaction was quenched with water (10 ml) to form a suspension. The suspension was diluted with H2O (100 ml) and extracted with EtOAc (200 ml). The organic portion was separated and washed with H2O (100 ml), dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound;
Reaction SMILES: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16](C3C=NN(C)C=3)=[C:12]2N=C(C2CCC(CC(OCC)=O)CC2)C=1.[CH3:45][Si:46]([CH3:84])([CH3:83])[CH2:47][CH2:48][O:49][CH2:50][N:51]([CH2:75][O:76][CH2:77][CH2:78][Si:79]([CH3:82])([CH3:81])[CH3:80])[C:52]1[N:57]2[N:58]=[CH:59][C:60](I)=[C:56]2[N:55]=[C:54]([CH:62]2[CH2:67][CH2:66][N:65]([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[CH2:64][CH2:63]2)[CH:53]=1.C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1N2N=CC(I)=C2N=C(C2CCC(CC(OCC)=O)CC2)C=1>>[CH3:45][Si:46]([CH3:84])([CH3:83])[CH2:47][CH2:48][O:49][CH2:50][N:51]([CH2:75][O:76][CH2:77][CH2:78][Si:79]([CH3:82])([CH3:81])[CH3:80])[C:52]1[N:57]2[N:58]=[CH:59][C:60]([C:16]3[CH:15]=[N:14][N:13]([CH3:8])[CH:12]=3)=[C:56]2[N:55]=[C:54]([CH:62]2[CH2:67][CH2:66][N:65]([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[CH2:64][CH2:63]2)[CH:53]=1
Reactant: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnn(C)c4)c3n2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Agent: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Product: Cn1cc(-c2cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)cc(C4CCN(C(=O)OC(C)(C)C)CC4)nc23)cn1

Procedure:
tert-Butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate was synthesized in a manner similar to the synthesis of ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate, but with tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate substituted for ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH3:19])[C:6]([CH:8]=[CH:9][C:10](O)=[O:11])=O.C(=O)([O-])[O-].[K+].[K+].Cl.O.[NH2:28][NH2:29]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[CH:8]=[CH:9][C:10](=[O:11])[NH:28][N:29]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH3:19]
Reactant: NN
Reactant: CCCOc1ccc(C(=O)C=CC(=O)O)cc1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCCOc1ccc(-c2ccc(=O)[nH]n2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.6 g of 3-(3-methoxy-4-n-propoxybenzoyl)acrylic acid and 6.1 g of potassium carbonate are dissolved in 100 ml of methanol and the solution is stirred overnight at room temperature. It is acidified with 7.4 ml of concentrated hydrochloric acid, 2.2 g of 100% pure hydrazine hydrate are added to the mixture and the mixture is boiled under reflux for 3 hours. It is then acidified to pH 1 with 1 ml of hydrochloric acid and 75 ml of methanol are distilled off in the course of 2 hours. The mixture is allowed to cool and the crystal mass is filtered off with suction, suspended several times in 50 ml of water each time, filtered off with suction and, finally, dried in vacuo. 6.6 g (63.7% of theory) of the title compound of m.p. 169°-171° are obtained. After recrystallization from ethanol/ethyl acetate, the m.p. rises to 172°.
Reaction SMILES: Cl.[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3].[C:17]([NH:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25])(=[O:20])[CH2:18][CH3:19]>>[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=2[NH:21][C:17](=[O:20])[CH2:18][CH3:19])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3]
Reactant: CC(C)NCC(=O)c1ccc(O)c(O)c1
Reactant: CCC(=O)Nc1ccccc1C(=O)Cl
Agent: Cl
Product: CCC(=O)Nc1ccccc1C(=O)Oc1ccc(C(=O)CNC(C)C)cc1O

Procedure:
Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and o-propionamidobenzoyl chloride instead of isovaleryl chloride, there is obtained 3-hydroxy-4-(o-propionamidobenzoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with methanesulfonic acid there is obtained the methanesulfonate salt. When this methanesulfonate is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-hydroxy-4-(o-propionamidobenzoyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol and methanesulfonate.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]2[C:5]([C:6](=[O:14])C(=O)[NH:8]2)=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=1.[OH-].[Na+].OO.C(O)(=[O:25])C>O>[Cl:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([NH2:8])[C:5](=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=1)[C:6]([OH:14])=[O:25]
Reactant: COc1c(Cl)cc(C(F)(F)F)c2c1NC(=O)C2=O
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1c(Cl)cc(C(F)(F)F)c(C(=O)O)c1N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.3 %

Procedure:
6-Chloro-7-methoxy-4-trifluoromethylisatin (13 mg, 0.046 mmol) was dissolved in NaOH (0.68M, 0.20 mL, 0.13 mmol) and H2O (0.20 mL) and then cooled to +7 C. Hydrogen peroxide (30%, 14 L, 0.14 mmol) dissolved in NaOH (0.68M, 0.49 mL, 0.33 mmol) was added dropwise during 1 min. The reaction mixture was stirred for 1 h 15 min at room temperature. Additional H2O2 (10 L) was added at 7 C. and then stirring was continued at room temperature for 2 h. Acetic acid (54 L, 0.94 mmol) was added, but no precipitation occured. Ethyl acetate (2 mL) was added and pH was raised to 6 with NaHCO3 (aq, sat.). The water phase was washed with EtOAc (3) and the combined organic layers were evaporated and co-evaporated with toluene (2). Purification by flash chromatography (SiO2, gradient EtOAc EtOAc-HOAc 100:1) yielded the title compound (5 mg). 1H NMR (CD3OD): 6.98 (s, 1H), 3.87 (s, 3H). MS (EI, 70 eV): m/z (rel. int.) 271/269 (M+, 17/48).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([NH:7][CH3:8])=O.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[N-:30]=[N+:31]=[N-:32].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[N:7]([CH3:8])[N:32]=[N:31][N:30]=2)[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1
Reactant: CNC(=O)c1cc(Br)cc([N+](=O)[O-])c1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: Cn1nnnc1-c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
To a solution of 3-bromo-N-methyl-5-nitro-benzamide (0.6 g) in DCM (15 ml) at −15° C. was added triflic anhydride (0.6 ml) and the reaction stirred for 30 min. Sodium azide (226 mg) was added and the reaction allowed to warm to room temperature and stirred further overnight. NaHCO3(aq) was added to neutralise the reaction and the mixture extracted into EtOAc. The organic layer was separated, dried and concentrated in vacuum and the residue purified by flash chromatography (9:1 to 2:8 cyclohexane:EtOAc) to give the title compound (290 mg). R1=0.51 (3:2 cyclohexane:EtOAc).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([S:17]([OH:20])(=[O:19])=[O:18])[CH2:11][C:12]([O:14]CC)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([S:17]([OH:20])(=[O:18])=[O:19])[CH2:11][C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(CNC(=O)OC(C)(C)C)S(=O)(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCC(CC(=O)O)S(=O)(=O)O
Reaction time: 8 h
Yield: 89.8 %

Procedure:
1-(tert-Butoxycarbonylamino)-4-ethoxy-4-oxobutane-2-sulfonic acid (402 mg, 1.29 mmol) in the mixture of THF/H2O (1:2, 60 ml) was added lithium hydroxide monohydrate (2.0 g, 47.6 mmol). The mixture was stirred under Ar overnight, concentrated, purified on C-18 column (2×30 cm) eluted with from 100% water to 10% methanol in water to afford 328 mg (90%) of the title compound. 1H NMR (DMSO), 6.78 (s, 1H), 4.03 (m, 1H), 3.57 (dd, 1H, J=4.2, 13.4 Hz), 3.41 (m, 1H), 2.89 (m, 1H), 2.61 (m, 1H), 1.39 (s, 9H); 13C NMR 174.21, 155.82, 79.85, 59.95, 42.06, 32.52, 28.88, 14.55; ESI MS 281.8 (M−H);
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[N:8]=[CH:7]1)([CH3:5])[CH:3]=O.[CH3:14][C:15]([CH3:19])([CH3:18])[CH2:16][NH2:17]>>[CH3:14][C:15]([CH3:19])([CH3:18])[CH2:16][NH:17][CH2:3][C:2]([CH3:1])([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[N:8]=[CH:7]1)[CH3:5]
Reactant: CC(C)(C=O)n1cnc([N+](=O)[O-])c1
Reactant: CC(C)(C)CN
Product: CC(C)(C)CNCC(C)(C)n1cnc([N+](=O)[O-])c1

Procedure:
2-Methyl-2-(4-nitro-imidazol-1-yl)-propionaldehyde was reacted with 2,2-dimethyl-propyl amine to provide the title compound: H1 NMR (400 MHz, CDCl3) 0.74 (s, 9H), 1.52 (s, 6H), 2.2 (s, 2H), 2.8 (s, 2H), 7.6 (s, 1H), 7.9 (s, 1H); MS m/z 255.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1.[CH2:10](O)[CH2:11][CH2:12][OH:13].O>C1(C)C=CC=CC=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[O:13][CH2:12][CH2:11][CH2:10][O:7]2)=[CH:4][N:3]=1
Reactant: O=Cc1ccc(Br)nc1
Reactant: OCCCO
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1ccc(C2OCCCO2)cn1
Temperature: 25 °C
Yield: 87 %

Procedure:
To a solution of 6-bromopyridine-3-carbaldehyde 7 (47.2 g, 254 mmol) in toluene (130 mL) in a 250 mL round-bottom flask was added 1,3-propanediol (38.6 g, 508 mmol) and 10-camphorsulfonic acid (2.95 g, 12.69 mmol). The reaction mixture was heated to reflux, with azeotropic removal of the evolved water, for 1 h, cooled down to r.t. and concentrated. The residue was partitioned between EtOAc (150 mL) and NaHCO3 soln (100 mL). Organic phase was collected and the aqueous phase was extracted with EA (2×150 mL). Combined organic fractions were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to yield a brown solid which was triturated with Et2O/Hex (10/150 mL) for 1 h, filtered to give 28 (53.98 g, 221 mmol, 87% yield) as a beige solid. MS (m/z): 243.1 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14]Br)[CH:6]=1.[C:17]1([CH:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:24][NH2:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CS(C)=O.O>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:25][CH2:24][CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=1
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: COC(=O)Cc1cccc(OCCCBr)c1
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)Cc1cccc(OCCCNCC(c2ccccc2)c2ccccc2)c1
Yield: 96.3 %

Procedure:
A solution of [3-(3-bromo-propoxy)-phenyl]-acetic acid methyl ester (2) (2.0 g, 0.007 mol) and 2,2-diphenylethylamine (2.5 g, 0.013 mol) in DMSO (5 mL) was stirred at room temperature for 18 hours. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, concentrated to an oil, which was purified by flash chromatography (9:1 CH2Cl2/MeOH) to give the desired product as oil 2.72 g in 96% yield. 1H NMR (CDCl3) δ 7.24 (m, 7H), 7.19 (t, 3H), 6.85 (d, 1H), 6.74 (s, 1H), 6.72 (d, 2H), 5.26 (s, 1H), 4.22 (t, 1H), 3.96 (t, 2H), 3.68 (s, 3H), 3.57 (d, 2H), 3.26 (d, 2H), 2.84 (t, 2H), 1.92 (m, 2H). 13C NMR (CDCl3) δ 173.3, 160.5, 144.4, 136.7, 130.9, 130.1, 129.5, 129.4, 127.9, 122.9, 116.9, 114.6, 67.6, 56.0, 53.5, 52.6, 48.3, 42.6, 31.0.