Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[CH3:6][CH:7]([C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=1)[C:8]([OH:10])=[O:9].BrCC=C.S(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:6][C:7]([CH2:3][CH:2]=[CH2:1])([C:11]1[CH:12]=[C:13]([C:21]([F:22])([F:23])[F:24])[CH:14]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:16]=1)[C:8]([OH:10])=[O:9]
Reactant: [Li]CCCC
Reactant: CC(C(=O)O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCC(C)(C(=O)O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 48.9 %

Procedure:
n-Butyllithium (2.5M solution in hexanes, 61.0 mL, 153 mmol) was added slowly to a stirred, cooled (−78° C.) solution of (RS)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetic acid (Description 7, 19.0 g, 66.4 mmol) in tetrahydrofuran (400 mL) and the mixture was stirred at −78° C. for 2 hours. Further n-butyllithium (2.5M solution in hexanes, 8.0 mL, 20 mmol) was added slowly and the mixture was stirred at −78° C. for 20 minutes. Further n-butyllithium (2.5M solution in hexanes, 8.0 mL, 20 mmol) was added slowly and the mixture was stirred at −78° C. for 20 minutes. 3-Bromo-1-propene (8.62 mL, 12.05 g, 100 mmol) was added slowly and the mixture was stirred at −78° C. for 30 minutes, then at room temperature for 1 hour. The mixture was poured into aqueous sodium bisulfite (10%, 500 mL) and extracted with ethyl acetate (2×500 mL). The combined organic fractions were washed with brine, dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was triturated with hexane and the solid was collected and dried iii vacuo to give the title compound as a colourless solid (10.59 g, 49%). 1H NMR (400 MHz, CDCl3) δ 7.82 (2H, s), 7.81 (1H, s), 5.57 (1H, m), 5.13 (1H, s), 5.10 (1H, m), 2.86 (1H, m), 2.73 (1H, m), and 1.69 (3H, s).
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1OS(C(F)(F)F)(=O)=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:15][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccccc1
Reactant: Cc1ccccc1OS(=O)(=O)C(F)(F)F
Product: Cc1ccccc1Nc1ccccc1
Yield: 95 %

Procedure:
The general procedure B using 51.7 mg (0.215 mmol) of o-tolyltriflate and 29.4 μl (0.323 mmol) of aniline gave 95% yield of N-(2-methylphenyl)aniline after sublimation (130° C., 0.1 torr).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[C:8]([CH3:23])=[C:9]([CH3:22])[C:10]2[O:14][C:13]([CH3:16])([CH3:15])[CH:12]([C:17]([OH:19])=[O:18])[C:11]=2[C:20]=1[CH3:21]>ClCCl>[OH:6][C:7]1[C:8]([CH3:23])=[C:9]([CH3:22])[C:10]2[O:14][C:13]([CH3:16])([CH3:15])[CH:12]([C:17]([OH:19])=[O:18])[C:11]=2[C:20]=1[CH3:21]
Reactant: COc1c(C)c(C)c2c(c1C)C(C(=O)O)C(C)(C)O2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1O)C(C(=O)O)C(C)(C)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
Boron tribromide (0.42 mL of 1M solution in dichloromethane, 0.42 mmol) is added dropwise at -78° C. and under nitrogen to a solution of 5-methoxy-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-carboxylic acid (100 mg, 0.38 mmol) in dichloromethane (4 mL). The reaction mixture is allowed to warm to room temperature and stirred overnight. The reaction is quenched by addition of water (10 mL) and extracted with dichloromethane (2×20 mL). The organic phase is dried (magnesium sulfate) and evaporated to dryness to give 90 mg (95%) of 5-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-carboxylic acid as a white solid. A sample is recrystallized in heptane/ethyl acetate, mp=182°-184° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]#[N:13].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=1)=[O:17]>CN(C=O)C.ClCCl>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([C:16](=[O:17])[CH2:15][N:7]2[CH:11]=[CH:10][CH:9]=[C:8]2[C:12]#[N:13])=[CH:19][CH:20]=1
Reactant: N#Cc1ccc[nH]1
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cccn1CC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.53 g (40.0 mmol) Potassium carbonate is added to a solution of 1.70 ml (20.0 mmol) pyrrole-2-carbonitrile and 8.34 g (30.0 mmol) 2,4′-dibromoacetophenone in 40 ml DMF. The resulting suspension is stirred for 1 hour at room temperature. The reaction mixture is diluted with dichloromethane and filtered with suction. The residue is washed with dichloromethane. The filtrate is evaporated and the residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to give 1-[2-(4-bromo-phenyl)-2-oxo-ethyl]-1H-pyrrole-2-carbonitrile as light orange solid; HPLC/MS 2.80 (B), [M+H] 289/291.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:15][CH:16]2[C:20]3([CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:19][NH:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.[C:25]([CH2:27][C:28](O)=[O:29])#[N:26].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[C:3]([NH:15][CH:16]2[C:20]3([CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:19][N:18]([C:28](=[O:29])[CH2:27][C:25]#[N:26])[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: N#CCC(=O)O
Reactant: Cc1cnc(Nc2cnn(C)c2)nc1NC1CNCC12CCCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cnc(Nc2cnn(C)c2)nc1NC1CN(C(=O)CC#N)CC12CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
To a solution of 5-methyl-N2-(1-methyl-1H-pyrazol-4-yl)-N4-(2-azaspiro[4.4]nonan-4-yl)pyrimidine-2,4-diamine (130 mg, 0.39 mmol) and 2-cyanoacetic acid (36 mg, 0.42 mmol) in a mixture of DCM (5 mL) and DMF (2 mL) were added Et3N (80 mg, 0.79 mmol) and HATU (0.3 g, 0.79 mmol) and the reaction mixture was stirred at rt for 1 h, then concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=10/1) to give the product as a yellow solid (0.11 g, 70%).
Reaction SMILES: [C:1]1([CH:11]=[CH:12][CH2:13]Cl)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[S:17][C:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23][C:24]=2[N:25]=1.C(Cl)(Cl)Cl.CO>C(Cl)(Cl)Cl>[NH2:15][C:16]1[S:17][C:18]2[CH2:19][CH2:20][N:21]([CH2:13][CH:12]=[CH:11][C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[CH2:22][CH2:23][C:24]=2[N:25]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: ClCC=Cc1cccc2ccccc12
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Nc1nc2c(s1)CCN(CC=Cc1cccc3ccccc13)CC2
Yield: 31 %

Procedure:
Prepared from 3-(1-naphthyl)allyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6 H-thiazolo[5,4-d]azepine in chloroform for 3 days at 20° C. Yield: 31% of theory, Melting point: 178°-180° C. (chloroform/methanol =100:1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[NH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:9]2)=[CH:4][C:3]=1[CH2:20][N:21]([C:25]1[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=1)[CH2:22][C:23]#[CH:24].[Cl-].[Li+].[Cl-].[H-].[Na+].[CH3:43][N:44]([CH3:48])[CH2:45][CH2:46]Cl>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[N:7]([CH2:46][CH2:45][N:44]([CH3:48])[CH3:43])[C:8]([CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)=[N:9]2)=[CH:4][C:3]=1[CH2:20][N:21]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])=[CH:36][CH:37]=1)[CH2:22][C:23]#[CH:24]
Reactant: C#CCN(Cc1cc2c(=O)[nH]c(CN3CCCCC3)nc2cc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: CN(C)CCCl
Agent: [Cl-]
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C#CCN(Cc1cc2c(=O)n(CCN(C)C)c(CN3CCCCC3)nc2cc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 4 °C
Reaction time: 0.25 h
Yield: 7.4 %

Procedure:
To a solution of of tert-butyl 4-[N-[7-chloro-4-oxo-2-piperidin-1-ylmethyl-3,4-dihydroquinazolin-6-ylmethyl]-N-(prop-2-ynyl)amino]benzoate (0.250 g, 1.69 mmol) in anhydrous DMF (10 ml) under argon was added lithium chloride (0.071 g, 6.24 mmol). When the lithiumn chloride had dissolved the reaction mixture was cooled to 4° C. in an ice-bath and then sodium hydride (60% dispersion in mineral oil, 21 mg, 0.52 mmol) in one portion followed by 2-dimethylaminoethyl chloride (free base, 0.690 g, 6.40 mmol). Stirring was continued at 4° C. for 15 min and then for an additional 16 h at room temperature. The reaction mixture was then heated to 70° C. and then more sodium hydride (60% dispersion in mineral oil, 10 mg, 0.25 mmol) was added followed by 2-dimethylaminoethyl chloride (free base, 0.690 g, 6.40 mmol). Stirring was continued at this temperature for 2 hours under argon; the the solvent was removed in vacuo and the residue was partitioned between ethyl acetate (150 ml) and water (200 ml). The organic layer was washed with more water (150 ml). The aqueous washings were extracted with more ethyl acetate (2×50 ml). The combined ethyl acetate extracts were washed with brine ((50 ml), dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography on elution with ether/hexanes/MeOH (v/v/v: 5:4: 1) afforded a white solid (0.074 g, 26%), mp 75-77° C.; 1H-NMR (DMSO-d6) 1.35-1.49 (m, 15H, tBu, piperidine CH2CH2CH2), 2.19 (s, 6H, NMe2), 2.40 (m, 4H, piperidine CH2NCH2), 2.53 (t (obscured), 2H, Me2NCH2), 3.27 (s, 1H, C≡CH), 3.61 (s, 2H, 2-CH2), 4.23 (t, J=7.0 Hz, 2H, N3—CH2), 4.40 (s, 2H, CH2C≡C), 4.79 (s, 2H, 6-CH2), 6.77 (d, J=9.0 Hz, 2H, 3′,5′-ArH), 7.72 (d, J=8.9 Hz, 2′,6′-ArH), 7.82, 7.87 (2×s, 2H, 5-H, 8-H); MS (ESI, m/z) 592, 594 [(M+H)+, 100%, 38% respectively; Cl isotopic pattern].
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:13]([OH:26])[C:14]([F:25])([F:24])[CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=O)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:20]([O:19][C:17]([NH:16][CH2:15][C:14]([F:24])([F:25])[CH:13]([OH:26])[CH:12]([NH2:11])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCC(F)(F)C(O)C(Cc1ccccc1)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC(F)(F)C(O)C(N)Cc1ccccc1
Yield: 9.1 %

Procedure:
A solution of N4 -benzyloxycarbonyl-N1 -tert-butoxycarbonyl-2,2-difluoro-3-hydroxy-5-phenyl-1,4-pentanediamine (0.464 g, 1 mmol) in ethanol (20 mL) was stirred at room temperature in the presence of 10% Palladium on charcoal (0.020 g) under a hydrogen atmosphere for 5 hours. The hydrogen atmosphere was then replaced by a nitrogen atmosphere and the catalyst was filtered. The solvent was removed in vacuo leaving 0.030 g of the expected product (98% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[Cl:19][C:20]1[CH:21]=[C:22]([N:26]=[C:27]=[S:28])[CH:23]=[CH:24][CH:25]=1>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:26][C:27](=[S:28])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])[CH:23]=[CH:24][CH:25]=1
Reactant: S=C=Nc1cccc(Cl)c1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1cccc(Cl)c1
Yield: 77.1 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.218 g, 0.90 mmol) and 3-chlorophenyl isothiocyanate (0.12 mL, 0.92 mmol) to give the product (0.286 g); m.p. 165-168° C.
Reaction SMILES: [CH:1]1([C:7]2[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=2[O:9][CH2:10][CH:11]2[CH2:13][O:12]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:29][CH2:28][NH:27][C:26]2=[O:30])=[CH:21][CH:20]=1>C(O)(C)C>[CH:1]1([C:7]2[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=2[O:9][CH2:10][CH:11]([OH:12])[CH2:13][NH:18][C:19]2[CH:20]=[CH:21][C:22]([N:25]3[CH2:29][CH2:28][NH:27][C:26]3=[O:30])=[CH:23][CH:24]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc(C2CCCCC2)c(OCC2CO2)c1
Reactant: Nc1ccc(N2CCNC2=O)cc1
Solvent: CC(C)O
Product: O=C1NCCN1c1ccc(NCC(O)COc2ccccc2C2CCCCC2)cc1

Procedure:
A solution of 3.24 g o-(cyclohexyl)-phenoxymethyloxirane (see Example 3) and 2.65 g of 1-(4-aminophenyl)-2-imidazolidinone in 60 ml isopropanol is stirred at reflux for 18 hours. The reaction mixture is filtered and the filtrate concentrated in vacuo. The residue is dissolved in 50 ml ethyl acetate and acidified to pH=1 with a solution of hydrogen chloride gas in ethyl acetate. The supernatant is decanted from the dark gum that forms and the residue is treated with ethyl acetate and 5% aqueous sodium carbonate. The ethyl acetate solution is separated, washed with 10% aqueous sodium carbonate and twice with water. After drying over anhydrous sodium sulfate the solution is treated with charcoal, filtered and concentrated in vacuo leaving a dark viscous gum. The gum is chromatographed by passing through a column of silica gel using methylene chloride/methyl alcohol as eluent to yield 1-{4-[3-(o-cyclohexylphenoxy)-2-hydroxypropylamino]-phenyl}-2-imidazolidinone, which is used directly in the next step.
Reaction SMILES: CC(C)N=C=NC(C)C.[NH:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:12][C:13]([OH:15])=[O:14].[CH3:23][CH:24]([CH2:26][CH2:27][CH2:28][C@H:29]([C@@H:31]1[C@:49]2([CH3:50])[C@H:34]([C@H:35]3[C@H:46]([CH2:47][CH2:48]2)[C@:44]2([CH3:45])[C:38]([CH2:39][C@H:40]([CH2:42][CH2:43]2)[OH:41])=[CH:37][CH2:36]3)[CH2:33][CH2:32]1)[CH3:30])[CH3:25].S([O-])(O)(=O)=O.[K+]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:25][CH:24]([CH2:26][CH2:27][CH2:28][C@H:29]([C@@H:31]1[C@:49]2([CH3:50])[C@H:34]([C@H:35]3[C@H:46]([CH2:47][CH2:48]2)[C@:44]2([CH3:45])[C:38]([CH2:39][C@H:40]([CH2:42][CH2:43]2)[OH:41])=[CH:37][CH2:36]3)[CH2:33][CH2:32]1)[CH3:30])[CH3:23].[C:16]([NH:10][CH2:11][CH2:12][C:13]([O-:15])=[O:14])([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(=O)[O-]
Reaction time: 0.5 h

Procedure:
DIC (510 μl) was added to a solution of Boc-β-Ala-OH (1.25 g, 6.60 mmol) in dichloromethane (15 ml) under an inert atmosphere. The reaction mixture was stirred for 30 minutes and then transferred to a flask containing a solution of cholesterol (1.16 g, 3.00 mmol) and DMAP (367 mg, 3.00 mmol) in dichloromethane (15 ml). The reaction mixture was stirred for 2 hours and then poured onto an aqeous solution of potassium hydrogen sulphate. After phase separation the aqueous phase was extracted with chloroform. The combined organic phases were washed with aqueous potassium hydrogen sulphate and water and dried (MgSO4). After filtration and evaporation the crude product was chromatographed (silica, chloroform/methanol 99:1) to give 1.63 g (97%) of white solid. The structure was confirmed by 1H NMR (500 MHz).
Reaction SMILES: [F:1][C:2]([F:25])([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)[C:3]1[N:7]2[N:8]=[C:9]([C:12](=O)[CH3:13])[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.Cl.[NH:27]([C:29]([NH2:31])=[O:30])[NH2:28]>CO>[F:1][C:2]([F:25])([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)[C:3]1[N:7]2[N:8]=[C:9](/[C:12](=[N:28]/[NH:27][C:29]([NH2:31])=[O:30])/[CH3:13])[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1
Reactant: CC(=O)c1ccc2nnc(C(F)(F)c3ccc4ncccc4c3)n2n1
Reactant: NNC(N)=O
Agent: Cl
Solvent: CO
Product: C/C(=N\NC(N)=O)c1ccc2nnc(C(F)(F)c3ccc4ncccc4c3)n2n1
Yield: 77 %

Procedure:
A solution of 1-(3-(difluoro(quinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (100 mg, 0.295 mmol) and hydrazinecarboxamide hydrochloride (44.3 mg, 0.589 mmol) in MeOH was stirred at room temperature for overnight. Solvent was evaporated and the residue was dissolved in a small amount of MeOH. Solid was filtered and dried to give the title compound as a white solid (90 mg, 75%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.90 (s, 1H), 9.06 (d, 1H), 8.62 (d, 1H), 8.49 (m, 2H), 8.34 (d, 1H), 8.20 (d, 1H), 8.03 (d, 1H), 7.70 (m, 1H), 6.82 (broad, 2H), 2.07 (s, 3H). LCMS (method B): [MH]+=397.1, tR=2.08 min.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][C:17]1[CH:22]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:20]=[CH:19][C:18]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[CH3:2].C(O)(=O)CS>>[CH2:1]([NH:3][CH2:16][C:17]1[CH:22]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:20]=[CH:19][C:18]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2ccccc2)c(CN(CC)S(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Agent: O=C(O)CS
Product: CCNCc1cc(C(=O)OCC)ccc1-c1ccccc1

Procedure:
Ethyl 2-({ethyl[(2-nitrophenyl)sulfonyl]amino}methyl)biphenyl-4-carboxylate was treated with thioglycolic acid in the presence of a base to obtain ethyl 2-[(ethylamino)methyl]biphenyl-4-carboxylate.
Reaction SMILES: [C:1]([CH2:4][O:5][N:6]=[C:7]([C:25]1[N:26]=[C:27]([NH:30]C(=O)C(F)(F)F)[S:28][CH:29]=1)[C:8]([NH:10][CH:11]1[C:23](=[O:24])[N:13]2[C:14]([C:20]([OH:22])=[S:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]12)=[O:9])([OH:3])=[O:2].C([O-])(=O)C.[Na+].Cl>O>[NH2:30][C:27]1[S:28][CH:29]=[C:25]([C:7](=[N:6][O:5][CH2:4][C:1]([OH:3])=[O:2])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[S:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:26]=1
Reactant: C=CC1=C(C(O)=S)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3csc(NC(=O)C(F)(F)F)n3)[C@H]2SC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: C=CC1=C(C(O)=S)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3csc(N)n3)[C@H]2SC1
Yield: 83.1 %

Procedure:
A solution of 7-[2-carboxymethoxyimino-2-{2-(2,2,2-trifluoroacetamido)thiazol-4-yl}acetamido]-3-vinylthio-3-cephem-4-carboxylic acid (syn isomer) (1 g) and sodium acetate (1.41 g) in water (21 ml) was stirred at ambient temperature over night. The mixture was adjusted to pH 2 with 1N hydrochloric acid to give a precipitate. The precipitate was collected by filtration, washed with water and dried over phosphorus pentoxide to give 7-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-vinylthio-3-cephem-4-carboxylic acid (syn isomer) (690 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[S:13][C:12]([C:14]#[C:15][C@H:16]([N:18]([OH:22])[C:19]([NH2:21])=[O:20])[CH3:17])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[S:13][C:12](/[CH:14]=[CH:15]/[C@H:16]([N:18]([OH:22])[C:19]([NH2:21])=[O:20])[CH3:17])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: C[C@H](C#Cc1ccc(Cc2ccc(F)cc2)s1)N(O)C(N)=O
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: C[C@H](/C=C/c1ccc(Cc2ccc(F)cc2)s1)N(O)C(N)=O
Temperature: 25 °C
Yield: 18.7 %

Procedure:
To a solution of (R)-N-{3-[5-(4-fluorophenylmethyl)thien-2-yl]-1-methyl-2-propynyl}-N-hydroxyurea (0.316g, 1.05 mmol), prepared as in Example 1, step 4, in THF (8 mL) at -70° C. was added DIBAL (5.23 mL, 5.25 mmol). The reaction was slowly allowed to warm to ambient temperature over 17 hours. The reaction was quenched into an aqueous 1M H3PO4 solution and extracted with ethyl acetate. The combined organic layers were washed with aqueous NaHCO3, dried (MgSO4) and evaporated. The residue was purified by chromatography on silica gel (50% ethyl acetate/hexanes/1% acetic acid). The resulting solid was crystallized from hot ethyl acetate/hexanes to yield 0.063 g (20% ) of E-N-[3-(5-(4-Fluorophenylmethyl)-thien-2-yl)-1-(R)-methyl-2-propenyl]-N-hydroxyurea. m.p. 143°-4° C). MS (DCI/NH3) m/e 321 (M+H)+, 338 (M+NH4)+. 1H NMR (DMSO-d6, 300 MHz) δ1.17(d, J=7.2 Hz, 3H), 4.08 (s, 2H), 4.73 (m, 1H), 5.88 (dd, J=6.3, 15.6 Hz, 1H), 6.33 (s, 2H), 6.55 (d, J=15.6 Hz, 1H), 6.77 (d, J=4.2 Hz, 1H), 6.83 (d, J=4.2 Hz, 1H), 7.12 (m, 2H), 7.29 (m, 2H), 9.02 (s, 1H). Anal Calcd for C17H17FN2O2S: C, 59.98; H, 5.35; N, 8.74. Found C, 60.15; H, 5.11; N, 8.75.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1([F:20])[O:12][C:11]2[CH:13]=[CH:14][C:15]([C:17](O)=[O:18])=[CH:16][C:10]=2[O:9]1.O.[OH-].[Na+]>C1COCC1>[F:20][C:8]1([F:7])[O:12][C:11]2[CH:13]=[CH:14][C:15]([CH2:17][OH:18])=[CH:16][C:10]=2[O:9]1
Reactant: O=C(O)c1ccc2c(c1)OC(F)(F)O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc2c(c1)OC(F)(F)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
To a suspension of LAH (12.6 g, 0.33 mol) in THF (100 mL) was added dropwise a solution of 2,2-difluorobenzo-1,3-dioxole-5-carboxylic acid (30 g, 0.15 mol) in THF (200 mL) at 0° C. under N2. The mixture was allowed to warm to room temperature and stirred for one hour at this temperature. Then, water (12.6 g) and aq. NaOH (10%, 12.6 g) were added dropwise at 0° C. The resulting mixture was filtered. The filtrate was dried over anhydrous Na2SO4 and evaporated under vacuum to give crude (2,2-difluoro-1,3-benzodioxol-5-yl)-methanol (25.5 g, 91.3%), which was used directly in the next step.
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:13]=[CH:12][N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26](F)=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)([CH3:3])C.Cl[C:31]1N=CN=C2C=1N=CN2CCCN1CCN(C2C=CC(F)=CC=2)CC1.C(N)(C)C>>[CH2:1]([NH:4][C:5]1[N:13]=[CH:12][N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH2:14][CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:22]1)[CH2:3][CH3:31]
Reactant: CC(C)Nc1ncnc2c1ncn2CCCN1CCN(c2ccc(F)cc2)CC1
Reactant: Fc1ccc(N2CCN(CCCn3cnc4c(Cl)ncnc43)CC2)cc1
Solvent: CC(C)N
Product: CCCNc1ncnc2c1ncn2CCCN1CCN(c2ccccc2)CC1
Yield: 58 %

Procedure:
N6 -isopropyl-9-{3-[4-(4-fluorophenyl)-piperazino]-propyl}-adenine from 6-chloro-9-{3-[4-(4-fluorophenyl)-piperazino]-propyl}-purine and isopropylamine; yield 58% of theory; m.p. of the dihydrochloride 232°-233° C after recrystallization from methanol.
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[C:25]([C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:42][C:41]([C:43]([OH:45])=O)=[C:40]([CH3:46])[CH:39]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1)(=[O:27])[NH2:26].[NH2:50][CH2:51][C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1>>[C:25]([C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:42][C:41]([C:43]([NH:50][CH2:51][C:52]4[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=4)=[O:45])=[C:40]([CH3:46])[CH:39]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1)(=[O:27])[NH2:26]
Reactant: Cc1cc(N2CCN(Cc3ccc(C(N)=O)cc3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(Cc3ccc(C(N)=O)cc3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 71 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-carbamoylbenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a cream solid in 71% yield: mp 188° C. (dec.): 1H NMR (300 MHz, DMSO-6) δ 8.53 (s, 1H), 8.45 (d. J=4.0 Hz, 1H), 8.31, (t, J=5.8 Hz, 1H), 7.97 (s, 1H), 7.86 (d, J=8.0 Hz, 2H), 7.71 (d, J=7.8 Hz, 1H), 7.42-7.32 (m, 4H), 6.24 (s, 1H), 4.44 (s, 2H), 4.39 (d, J=5.8 Hz, 2H), 3.84 (t, J=7.8 Hz, 2H), 3.45 (t, J=7.8 Hz, 2H), 2.37 (s, 3H): 13C NMR (75 MHz, DMSO-d6) δ 167.5, 162.9, 155.5, 148.8, 147.8, 140.0, 139.0, 135.4, 135.0, 133.4, 127.7, 127.4, 123.3, 119.9, 112.0, 46.8, 42.5, 41.5, 15.7: MS (ES+) m/z 450.4 (M+1).
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[C:29]([CH3:30])=[CH:28][S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:20]=1>>[N:24]1[CH:23]=[CH:22][C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[C:29]([CH3:30])=[CH:28][S:27][C:17]=3[N:18]=2)=[CH:26][CH:25]=1
Reactant: Cc1csc2nc(-c3ccncc3)nc(Cl)c12
Reactant: NCCc1ccc2c(c1)OCCO2
Product: Cc1csc2nc(-c3ccncc3)nc(NCCc3ccc4c(c3)OCCO4)c12

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-4-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-ethylenedioxyphenethylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.