Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=O.[NH2:12][OH:13].O>CC(O)C>[Br:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=[N:12][OH:13]
Reactant: O=Cc1c(F)cc(Cl)cc1Br
Reactant: NO
Solvent: CC(C)O
Solvent: O
Product: ON=Cc1c(F)cc(Cl)cc1Br
Temperature: 40 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
To a solution of 2-bromo-4-chloro-6-fluoro-benzaldehyde (15 g, 63.16 mmol) in 2-propanol (130 ml) was added hydroxylamine (50% solution in water, 4.55 g, 68.90 mmol) at 25° C. and the mixture was warmed to 40° C. for 2 h. Water (55 ml) was then added slowly to this mixture and the slurry was aged for 1 h at 20° C. The reaction mixture was filtered and the remaining solid was washed with a mixture of 2-propanol and water (1.5:1) and dried under vacuum to yield the title compound (12.5 g, 77%) as white solid.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[C:8]([F:16])[CH:7]=1)[CH2:3][CH2:4][OH:5].[CH3:17][C:18]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])[CH3:19].CCN(C(C)C)C(C)C.C(Cl)Cl>CN(C1C=CN=CC=1)C.O>[Si:21]([O:5][CH2:4][CH2:3][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[C:8]([F:16])[CH:7]=1)[NH2:1])([C:18]([CH3:20])([CH3:19])[CH3:17])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: NC(CCO)c1ccc(C(F)(F)F)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCC(N)c1ccc(C(F)(F)F)c(F)c1
Yield: 70.9 %

Procedure:
solution of 276 (0.200 g, 0.843 mmol), TBDMS-Cl (0.153 g, 1.01 mmol), DIPEA (0.294 mL, 1.69 mmol), DMAP (0.0103 g, 0.0843 mmol) and DCM (6 mL) was stirred for 1 h at RT and then poured into H2O, and extracted with DCM. The combined organic fractions were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH (500:5) to afford 0.210 g (70.9%) of 3-(tert-butyldimethylsilyloxy)-1-(3-fluoro-4-(trifluoromethyl)phenyl)propan-1-amine (278).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]([OH:38])[CH2:10][NH:11][C:12](=[O:37])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH2:23][C:22]([C:28]3[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=3)([C:24]([F:27])([F:26])[F:25])[O:21][N:20]=2)=[CH:15][C:14]=1[CH3:36])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH2:8][CH:9]([OH:38])[CH2:10][NH:11][C:12](=[O:37])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH2:23][C:22]([C:28]3[CH:29]=[C:30]([Cl:35])[CH:31]=[C:32]([Cl:34])[CH:33]=3)([C:24]([F:26])([F:27])[F:25])[O:21][N:20]=2)=[CH:15][C:14]=1[CH3:36]
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC(O)CNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC(O)CN
Reaction time: 10 h
Yield: 78.3 %

Procedure:
A solution of (3{4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoylamino}-2-hydroxy-propyl)-carbamic acid tert-butyl ester (0.2 g) in dichloromethane (10 ml) was cooled to 0° C., treated with trifluoroacetic acid (0.5 ml) and stirred for 10 h. The reaction mixture was concentrated in vacuo and diluted with dichloromethane (50 ml), washed with saturated aqueous solution of sodium bicarbonate (20 ml) and finally with water (2×20 ml). The organic layer was separated, dried over sodium sulfate and concentrated to give the title compound (0.13 g). LCMS (Method G) 2.84 min, MH+ 490. 1HNMR (CDCl3, 400 MHz): 8.05 (t, 1H), 7.81 (m, 1H), 7.80 (brs, 2H), 7.59 (m, 4H), 7.48 (d, 1H), 4.36 (dd, 2H), 3.85 (m, 2H), 3.28 (m, 2H), 2.50 (m, 1H), 2.37 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][CH:3]1[CH2:18][CH3:19].[OH-:20].[Na+].[CH2:22]=O.Cl>O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH2:18][CH3:19])[CH2:22][OH:20]
Reactant: CCC1Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Reactant: [OH-]
Reactant: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCC1(CO)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Reaction time: 48 h

Procedure:
To a solution of (1-oxo-2-ethyl-6,7-dichloro-5-indanyloxy)acetic acid (3.03 g., 0.01 mole) and sodium hydroxide (0.5 g., 0.0125 mole) in water (90 ml.) is added aqueous formaldehyde (1 ml., 0.012 mole). The resulting solution is stirred at 20°-25° C. for 41/2 days and acidified with hydrochloric acid. The tan powder which precipitates is recrystallized from ethanol-water affording 1.2 g. of (1-oxo-2-ethyl-2-hydroxymethyl-6,7-dichloro-5-indanyloxy)acetic acid which melts at 155°-157° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].O.[NH2:17][NH2:18]>C(O)C>[Cl:1][C:2]1[C:3]([NH:17][NH2:18])=[N:4][CH:5]=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)(C)OC(=O)c1cnc(Cl)c(Cl)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)c1cnc(NN)c(Cl)c1
Temperature: 75 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl 5,6-dichloronicotinate (2.0 g, 8.1 mmol)) in ethanol (40.3 mL) was added hydrazine hydrate (1.18 mL, 24.2 mmol). The mixture was heated 75° C. After 18 h, the mixture was cooled to ambient temperature. The mixture was concentrated to dryness: LC-MS [M+1]=244.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[C:1]([O:5][C:6]([N:7]([CH3:8])[C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:13][CH2:14]1)=[O:20])([CH3:3])([CH3:2])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](CCCCO)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](CCCCOS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred, ice-cooled solution of 1.37 g (4.8 mmol) of trans-[4-(4-Hydroxy-butyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester and 0.95 ml NEt3 in 15 ml CH2Cl2 was added 0.5 ml (6.8 mmol) methanesulfonyl chloride. After stirring at RT for 2 h, the reaction mixture was partitioned between Et20, 1M HCl and water. The ether-layer was concentrated in vacuo to give 1.745 g of clean trans-Methanesulfonic acid 4-[4-(tert-butoxycarbonyl-methyl-amino)-cyclohexyl]-butyl ester, that was treated in 5 ml CH2Cl2 with 5 ml of trifluoro acetic acid. After stirring the solution for 30 min at RT, the solution was evaporated under reduced pressure to dryness to give 2.25 g (quant.) trans-Methanesulfonic acid 4-(4-methylamino-cyclohexyl)-butyl ester.trifluoro-acetic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][C@@:10]2([CH2:12][OH:13])[C@H:8]([CH2:9]2)[N:7]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:5])[CH3:2].[H-].[Na+].IC.[C:25]([O-])(O)=O.[Na+]>C1COCC1.C(Cl)Cl>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][C@@:10]2([CH2:12][O:13][CH3:25])[C@H:8]([CH2:9]2)[N:7]1[C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1C[C@]2(CO)C[C@@H]2N1C(=O)OC(C)(C)C
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1C[C@]2(COC)C[C@@H]2N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(1R,3S,5S) and (1S,3S,5R)-5-hydroxymethyl-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester 3-ethyl ester as mixture of diastereoisomers (35:65 (1R,3S,5S)/(1S,3S,5R)) (840 mg, 2.94 mmol) were slowly added at 0° C. under Argon to a suspension of NaH (60% in mineral oil, 141 mg, 3.53 mmol) in THF (9 mL). The reaction mixture was stirred at 0° C. for 30 min and iodomethane (0.28 mL, 4.42 mmol) was added slowly at 0° C. The reaction mixture was further stirred at RT overnight. Saturated NaHCO3 and CH2Cl2 were added, the layers were separated and the aqueous one back-extracted twice with CH2Cl2. The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude material was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 2:8) to give the title compound as an unseparable mixture of diastereosisomers. TLC, Rf (c-hexane/EtOAc 1:1)=0.70; MS (UPLC/MS): 300.3 [M+H]+, 599.5 [2M+H]+; tR (HPLC conditions a): 3.45 min. The absolute stereochemistry of the diastereoisomers was tentatively assigned by NMR and based on the test results for the final compounds Example 214 and Example 184 in the biological assay.
Reaction SMILES: [C:1]([NH:5][CH3:6])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:14][CH2:15][CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[C:1]([N:5]([CH3:6])[S:18]([CH2:17][CH2:16][CH2:15][Cl:14])(=[O:20])=[O:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC(C)(C)C
Reactant: O=S(=O)(Cl)CCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(C)(C)C)S(=O)(=O)CCCCl
Temperature: 0 °C
Yield: 72.7 %

Procedure:
1.74 g(0.02 mol) of t-butylmethylamine and 2 equivalents of triethylamine were dissolved in 100 ml of dichloromethane, which was stirred at 0° C. 3.54 g(0.02 mol) of 3-chloropropane sulfonyl chloride dissolved in 50 ml. of dichloromethane was added dropwise and the mixture was stirred for 1 hour at room temperature. The organic layer was washed with 1N HCl aqueous solution and dried over MgSO4 to obtain 3.31 g of the title compound(yield 73%).
Reaction SMILES: CO[C:3]1[CH:4]=[CH:5][C:6]2[C:15]3[N:14]=[C:13]([NH:16][NH2:17])[N:12]=[CH:11][C:10]=3[CH2:9][CH2:8][C:7]=2[CH:18]=1.[CH2:19]([O:21][C:22](=[O:30])[C:23](=[CH:26]OCC)[C:24]#[N:25])[CH3:20]>C(O)(=O)C>[CH2:19]([O:21][C:22]([C:23]1[CH:26]=[N:17][N:16]([C:13]2[N:12]=[CH:11][C:10]3[CH2:9][CH2:8][C:7]4[CH:18]=[CH:3][CH:4]=[CH:5][C:6]=4[C:15]=3[N:14]=2)[C:24]=1[NH2:25])=[O:30])[CH3:20]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: COc1ccc2c(c1)CCc1cnc(NN)nc1-2
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn(-c2ncc3c(n2)-c2ccccc2CC3)c1N
Yield: 45.5 %

Procedure:
A mixture of (8-Methoxy-5,6-dihydro-benzo[h]quinazolin-2-yl)-hydrazine (100 mg, 0.41 mM), ethyl(ethoxymethylene)cyanoacetate (76 mg, 0.44 mM) in acetic acid (1 ml) was heated for 16 hr then evaporated. The residue was partitioned between dichloromethane and sodium bicarbonate (sat., 50 ml), the organic phase dried with sodium sulfate, filtered and evaporated to a solid. The solid was triturated with ethyl acetate and isolated via filtration and dried under reduced pressure to afford 5-Amino-1-(5,6-dihydro-benzo[h]quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (63 mg, 42% yield) as a tan solid. ES-MS MH+ 366.3. 1H NMR (300 MHz, ppm, DMSO-d6): 8.65 (s, 1H), 8.17 (d, 1H), 7.78 (s, 1H), 7.55 (br s, 2H), 7.02 (d, 1H), 6.98 (s, 1H), 4.25 (q, 2H), 3.86 (s, 3H), 2.95 (m, 4H), 1.30 (t, 3H).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]([C:11](=[O:31])[NH:12][C:13]1[N:18]=[C:17]2[N:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:20](=[O:22])[NH:21][C:16]2=[CH:15][CH:14]=1)[CH3:10])C)(C)(C)C>CO.[Pd]>[ClH:30].[ClH:30].[CH2:23]([N:19]1[C:17]2=[N:18][C:13]([NH:12][C:11](=[O:31])[CH:9]([NH:7][CH3:6])[CH3:10])=[CH:14][CH:15]=[C:16]2[NH:21][C:20]1=[O:22])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C(=O)Nc1ccc2[nH]c(=O)n(Cc3ccc(Cl)cc3)c2n1)N(C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CNC(C)C(=O)Nc1ccc2[nH]c(=O)n(Cc3ccccc3)c2n1
Product: Cl
Yield: 95.5 %

Procedure:
{1-[3-(4-Chloro-benzyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-ylcarbamoyl]ethyl}-methyl-carbamic acid tert-butyl ester (100 mg, 0.22 mmol) (Example 1, product from Step 4) was dissolved in MeOH and stirred with Pd/C (50 mg) under hydrogen for 16 hours. The solution was filtered and evaporated in vacuo. Treatment with HCl (in an analogous fashion to General procedure 3) gave the title compound (38 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6): 11.26 (1H, s), 10.86 (1H, s), 9.50 (1H, s), 9.03 (1H, s), 7.78 (1H, d), 7.42 (1H, d), 7.37-7.22 (5H, m), 5.01 (2H, s), 4.06-3.95 (1H, m), 2.55-2.52 (3H, m), 1.48 (3H, d). MS: [M+H]+=326.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.[C:13]1([C@H:19]([NH2:21])[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H][H]>C(O)(C)C.[C].[Pd].C(N(CC)CC)C>[CH3:6][O:5][C:4]1[CH:3]=[C:2]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[CH2:1][NH:21][C@@H:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:20]
Reactant: [H][H]
Reactant: COc1ccc(C=O)cc1OC
Reactant: C[C@@H](N)c1ccccc1
Agent: [Pd]
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: COc1ccc(CN[C@H](C)c2ccccc2)cc1OC
Temperature: 55 °C
Reaction time: 1.5 h
Yield: 102264.9 %

Procedure:
Veratraldehyde (174.5 g, 1.05 mole) was dissolved in isopropanol (600 ml) at 10-40° C. and (R)-1-phenylethylamine (121.2 g, 1.00 mmole) was added at 50-60° C. over 1-2 hr in a thin stream. Further, after stirring at 50-60° C. for 1-2 hr, the mixture was cooled to 20° C. To this solution were added triethylamine (5.1 g, 50.0 mmole) and 5% palladium carbon (50% wet, 5.4 g) at 20-30° C. and the mixture was stirred under 1 atm hydrogen atmosphere at 40-45° C. for 7-8 hr. The catalyst was filtered off and the filtrate was concentrated to give the title compound (277.5 g, pure amount 252.5 g, yield 93.05%) (Quantitative analysis by HPLC).
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:17]=[C:18]([CH2:22]O)[CH:19]=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(#N)C.P(Br)(Br)[Br:28]>N1C=CC=CC=1>[Br:28][CH2:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:17]=1
Reactant: BrP(Br)Br
Reactant: CCCCCCCCCCCCCCOc1cccc(CO)c1
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCOc1cccc(CBr)c1

Procedure:
The title compound is prepared by the procedure of Example 20 using 2.5 g of product from Example 24, 10 ml acetonitrile, 0.339 g of pyridine and 2.11 g of phosphorus tribromide. The product, 2.27 g, is obtained as colorless needles.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[NH2:7])([O-:3])=[O:2].[CH3:14][S:15](Cl)(=[O:17])=[O:16].N1C=CC=CC=1>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][S:15]([CH3:14])(=[O:17])=[O:16])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reaction time: 24 h

Procedure:
A mixture of 3,4-dinitroaniline (5.27 g, 28.8 mmol), methanesulfonyl chloride (3.36 mL, 43.1 mmol) and pyridine (5.82 mL, 71.9 mmol) in CH2Cl2 (100 mL) was stirred for 24 h. Mixture was concentrated under vacuum to provide a crude semi-solid title compound that was used without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([NH2:6])=[N:2]1.[C:7]1([CH:13]([C:19](OCC)=[O:20])[C:14](OCC)=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(N(CCCC)CCCC)CCC.[OH-].[Na+]>[C:7]1([C:13]2[C:14]([OH:15])=[N:6][C:3]3[N:2]([N:1]=[CH:5][N:4]=3)[C:19]=2[OH:20])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Nc1nc[nH]n1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCN(CCCC)CCCC
Product: Oc1nc2ncnn2c(O)c1-c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of 10 g 1,2,4-triazol-3-amine and 33.7 g diethyl phenylmalonate in N,N-dibutylbutan-1-amine was stirred at 185° C. over night. The solution was diluted with 10% w/w NaOH solution, the resulting mixture was stirred for 30 min and the organic phase was separated. The aqueous layer was extracted with diethylether, acidified with concentrated HCl until precipitation of the product was complete and the precipitate collected by filtration to yield the product, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:12]2[O:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[C:4](N)[N:3]=1.NC1N=C2C(N=CN2[C@@H]2O[C@H](CO)[C@@H](OCCCCN3C=CN=C3)[C@H]2[OH:42])=C(N)N=1.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1O>CS(C)=O>[N:18]1([CH2:17][CH2:16][CH2:15][CH2:14][O:13][C@@H:12]2[C@H:23]([OH:24])[C@@H:25]([CH2:27][OH:28])[O:26][C@H:11]2[N:8]2[C:9]3[N:10]=[C:2]([NH2:1])[NH:3][C:4](=[O:42])[C:5]=3[N:6]=[CH:7]2)[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](OCCCCn4ccnc4)[C@H]3O)c2n1
Reactant: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3OCCCCn3ccnc3)c2n1
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: CS(C)=O
Product: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCCCn2ccnc2)c(=O)[nH]1

Procedure:
A mixture of the 2,6-diamino-9-[2-O-(imidazol-1-yl)butyl-β-D-ribofuranosyl]purine and 2,6-diamino-9-[3-O-(imidazol-1-yl)butyl-β-D-ribofuranosyl]purine isomers in 0.1M tris buffer (pH 7.4), 0.1M NaSO4 buffer (pH 7.4) and DMSO will treated with adenosine deaminase at RT for 5 days as per the procedure of Example 3. The product containing fractions will be purified by silica gel chromatography and the product containing fraction evaporated to give the product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH3:29])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[S:19][CH:20]=[C:21]([CH2:23]Cl)[N:22]=4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.[CH3:30][NH2:31].O.[OH-].[Na+]>CCO>[Cl:1][C:2]1[C:3]([N:27]([CH3:29])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[S:19][CH:20]=[C:21]([CH2:23][NH:31][CH3:30])[N:22]=4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3nc(CCl)cs3)c1)=N2
Reactant: CN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CNCc1csc(-c2cccc(C3=Nc4cc(N(C)C)c(Cl)cc4NC(=O)C3)c2)n1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
A mixture of 8-chloro-4-[3-(4-chloromethyl-thiazol-2-yl)-phenyl]-7-dimethylamino-1,3-dihydro-benzo[b][1,4]diazepin-2-one (89 mg) and KI (3 mg) in a 8M solution of methylamine in EtOH (1 mL) was stirred at 20° C. for 20 h. H2O (25 mL) was added and the pH of the mixture was set to 11 by addition of 2N NaOH. The precipitate was collected by filtration and purified by chromatography on silica gel using MeOH as eluent. The product was stirred with 20% aqueous MeOH (10 mL) and the solid was isolated by filtration to give the title compound (49 mg) as a yellow powder.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:10]2[C:6]([S:7][C:8]([C:11]3[C@H:12]([CH3:35])[C@@H:13]4[C@@H:30]([C@H:31]([OH:33])[CH3:32])[C:29](=[O:34])[N:14]4[C:15]=3[C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)=[O:17])=[CH:9]2)=[C:5]([S:36][CH3:37])[N:4]=1.ClC1C=CC=C(C(OO)=[O:46])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[OH:33][C@@H:31]([C@H:30]1[C:29](=[O:34])[N:14]2[C:15]([C:16]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=3)=[O:17])=[C:11]([C:8]3[S:7][C:6]4=[C:5]([S:36]([CH3:37])=[O:46])[N:4]=[C:3]([S:2][CH3:1])[N:10]4[CH:9]=3)[C@H:12]([CH3:35])[C@H:13]12)[CH3:32]
Reactant: CSc1nc(SC)n2cc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CSc1nc(S(C)=O)c2sc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)cn12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.4 %

Procedure:
4-Nitrobenzyl(1S,5R,6S)-2-[5,7-bis(methylthio)imidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (140 mg) was dissolved in 2.5 ml of dichloromethane. m-Chloroperbenzoic acid (56 mg) was added to the solution. The mixture was stirred at room temperature for 15 min. An aqueous sodium thiosulfate solution (5 ml) was added thereto, followed by separation. The organic layer was washed with 10 ml of a semisaturated aqueous sodium hydrogencarbonate solution and 10 ml of semisaturated brine and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=20:1) to give 97 mg of 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfinyl-5-methylthioimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers).
Reaction SMILES: [F:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C@H:8]([CH3:18])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:21][C:22]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]2[C:23]=1[CH:24]=[N:25][C:26]([CH3:33])=[N:27]2>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C@H:8]([CH3:18])[CH2:9][C@@:10]([C:13]([F:14])([F:15])[F:16])([OH:17])[CH:11]=[N:21][C:22]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]3[C:23]=2[CH:24]=[N:25][C:26]([CH3:33])=[N:27]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ncc2c(N)ccc(F)c2n1
Reactant: COc1c(F)cccc1[C@H](C)C[C@@](O)(C=O)C(F)(F)F
Agent: [Ti+4]
Agent: CC[O-]
Product: COc1c(F)cccc1[C@H](C)C[C@@](O)(C=Nc1ccc(F)c2nc(C)ncc12)C(F)(F)F

Procedure:
In the same way as in Example 1, 150 mg (0.5 mmol) of (2R*,4R*)-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal, 90 mg (0.5 mmol) of 5-amino-8-fluoro-2-methylquinazoline and 0.2 ml of titanium tetraethoxide are reacted to give (2R*,4R*)-4-(3-fluoro-2-methoxyphenyl)-1-[(8-fluoro-2-methylquinazolin-5-yl)imino]-2-(trifluoromethyl)pentan-2-ol. 230 mg of resultant crude imine are cyclized in the same way as in Example 1 at −30° C. using 4 ml (4 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 50%) yields 42 mg of product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:12]2[N:13]([S:23]([N:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[CH:14]=[C:15]([CH2:17][C:18]([CH3:22])([CH3:21])[CH2:19][CH3:20])[N:16]=2)([OH:11])[CH3:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:43]2[CH:44]=[N:45][NH:46][CH:47]=2)O1.O>CN(C)C=O.O>[CH3:21][C:18]([CH3:22])([CH2:19][CH3:20])[CH2:17][C:15]1[N:16]=[C:12]([C:9]([OH:11])([CH3:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:43]3[CH:44]=[N:45][NH:46][CH:47]=3)=[CH:3][CH:4]=2)[N:13]([S:23]([N:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[CH:14]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(C)(O)Cc2ccc(Br)cc2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(C)(O)Cc2ccc(-c3cn[nH]c3)cc2)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (57 mg, 0.07 mmol) was added to a degassed, ambient temperature solution of 2-[2-(4-bromophenyl)-1-hydroxy-1-methylethyl]-4-(2,2-dimethylbutyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (329 mg, 0.70 mmol), sodium carbonate (222 mg, 2.1 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (217 mg, 1.4 mmol) in N,N-dimethylformamide/water (2:1) (30 mL). After stirring at 80° C. overnight, the reaction mixture was cooled, poured into water and extracted with diethyl ether. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-40% ethyl acetate/hexane afforded 4-(2,2-dimethylbutyl)-2-{1-hydroxy-1-methyl-2-[4-(1H-pyrazol-4-yl)phenyl]ethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide.