Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH:5]([NH:11][C:12]1[CH:13]=[N:14][C:15]([O:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[N:23]=[CH:22]3)=[CH:16][CH:17]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].Br[CH2:37][CH2:38][CH2:39]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:9]([O:8][C:6]([C:5]1([C:4]([O:3][CH2:1][CH3:2])=[O:35])[CH2:39][CH2:38][CH2:37][N:11]1[C:12]1[CH:13]=[N:14][C:15]([O:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[N:23]=[CH:22]3)=[CH:16][CH:17]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(Nc1ccc(Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)nc1)C(=O)OCC
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)OCC)CCCN1c1ccc(Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)nc1
Temperature: 55 °C

Procedure:
1-{6-[1-(4-Fluoro-phenyl)-1H-indazol-5-yloxy]-pyridin-3-yl}-pyrrolidine-2,2-dicarboxylic acid diethyl ester is prepared by dissolving 2-{6-[1-(4-Fluoro-phenyl)-1H-indazol-5-yloxy]-pyridin-3-ylamino}-malonic acid diethyl ester (9.25 mmol) in dimethylformamide (90 mL), followed by addition of 1,3 dibromopropane (938 μL, 9.25 mmol) and cesium carbonate (6 grams, 18.5 mmol). The reaction mixture is stirred for approximately 24 hours to 48 hours. The mixture is filtered through celite, and then concentrated under vacuum while heating to 55° C. to remove the dimethylformamide (azeotroping with toluene). The crude product obtained is chromatographed on silica gel (ISCO MPLC purification, 40 minutes, 0-50% ethyl acetate gradient, Biotage flash 40m column) to provide the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:37])([CH3:36])[C:3]([NH:5][C:6]1[CH:7]=[C:8]([C:13]2[N:14]=[C:15]3[N:20]([CH:21]=2)[N:19]=[C:18]([NH:22][C:23]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][C:33](O)=[O:34])[CH:28]=[CH:29][CH:30]=2)=[O:24])[CH:17]=[CH:16]3)[CH:9]=[CH:10][C:11]=1[CH3:12])=[O:4].[O:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH:39]1[O:44][NH2:45].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(#N)C>[CH3:1][C:2]([CH3:37])([CH3:36])[C:3]([NH:5][C:6]1[CH:7]=[C:8]([C:13]2[N:14]=[C:15]3[N:20]([CH:21]=2)[N:19]=[C:18]([NH:22][C:23](=[O:24])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]=[CH:32][C:33](=[O:34])[NH:45][O:44][CH:39]4[CH2:40][CH2:41][CH2:42][CH2:43][O:38]4)[CH:26]=2)[CH:17]=[CH:16]3)[CH:9]=[CH:10][C:11]=1[CH3:12])=[O:4]
Reactant: NOC1CCCCO1
Reactant: Cc1ccc(-c2cn3nc(NC(=O)c4cccc(C=CC(=O)O)c4)ccc3n2)cc1NC(=O)C(C)(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(-c2cn3nc(NC(=O)c4cccc(C=CC(=O)NOC5CCCCO5)c4)ccc3n2)cc1NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 20-mL vial is charged with acetonitrile (0.4 mL), 3-[3-[[2-[3-(2,2-dimethylpropanoylamino)-4-methyl-phenyl]imidazo[2,1-f]pyridazin-6-yl]carbamoyl]phenyl]prop-2-enoic acid (0.025 g, 0.05 mmol), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.0088 g, 0.08 mmol), triethylamine (0.021 mL, 0.15 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (0.033 g, 0.08 mmol). The mixture is stirred at room temperature for 2 hr, concentrated and taken up into saturated aqueous Na2CO3 (2 mL), extracted with EtOAc and CH2Cl2. Organic layers are combined, dried and concentrated to give crude N-[2-[3-(2,2-dimethylpropanoylamino)-4-methyl-phenyl]imidazo[2,1-f]pyridazin-6-yl]-3-[3-oxo-3-(tetrahydropyran-2-yloxyamino)prop-1-enyl]benzamide. This is taken up in a mixture of aqueous HCl (1 mL, 1M) and MeOH (1 mL), and is stirred at 50° C. for 1 hour. The mixture is concentrated, taken up in DMSO (1 mL) and purified on a Gilson preparative HPLC (reverse phase) to afford the title compound (0.015 g). LCMS (m/z)=513.5 [M+H]+, tR=2.31 min.
Reaction SMILES: [NH2:1][C:2]1([C:5]([OH:7])=[O:6])[CH2:4][CH2:3]1.[CH3:8][O:9][C:10]1[C:11]([CH3:19])=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](Cl)=O>N1C=CC=CC=1.CCOCC>[CH3:8][O:9][C:10]1[C:11]([CH3:19])=[C:12]([C:13]2[O:6][C:5](=[O:7])[C:2]3([CH2:4][CH2:3]3)[N:1]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: COc1cccc(C(=O)Cl)c1C
Reactant: NC1(C(=O)O)CC1
Solvent: CCOCC
Solvent: c1ccncc1
Product: COc1cccc(C2=NC3(CC3)C(=O)O2)c1C
Temperature: 25 °C
Yield: 78.3 %

Procedure:
To a stirred solution of 1-aminocyclopropanecarboxylic acid (1.06 g, 10.5 mmol) in pyridine (20 mL) cooled to ˜5° C., solid 3-methoxy-2-methylbenzoyl chloride (4.35 g, 23.6 mmol) was added. The mixture was stirred at room temperature for 1 week and evaporated under reduced pressure to leave an oily solid. This material was taken up in 20% ether in hexanes (175 mL), washed with water (50 mL), 5% aqueous HCl (2×50 mL) and saturated aqueous NaHCO3 (50 mL). The organic layer was dried over MgSO4 and evaporated under reduced pressure to leave 5-(3-methoxy-2-methyl-phenyl)-6-oxa4-aza-spiro[2.4]hept-4-en-7-one (1.90 g) as a yellow solid. 1H NMR (CDCl3) δ(ppm): 1.80 (m, 2H), 1.90 (m, 2H), 2.49 (s, 3H), 3.85 (s, 3H), 7.01 (d, 1H), 7.22 (t, 1H), 7.40 (d, 1H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[NH2:14][C:15]1[S:16][CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=1.C(N(CC)CC)C.O>O1CCCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=1)=[O:12]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: CCOC(=O)c1csc(N)n1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1csc(NC(=O)c2ccc3ccccc3c2)n1
Reaction time: 16 h

Procedure:
4.7 g (24.9 mmol) of 2-naphthoyl chloride, dissolved in 50 ml of anhydrous tetrahydrofuran, were added dropwise at 0° C. to 4 g (23.3 mmol) of ethyl 2-aminothiazole-4-carboxylate and 6.4 ml (46.5 mmol) of triethylamine in 150 ml of anhydrous tetrahydrofuran. The entire mixture was then stirred for 16 h. The reaction solution was then poured into plenty of water and extracted with ethyl acetate. The organic phase was then washed with aqueous sodium hydrogencarbonate solution, dried and concentrated in vacuo. The residue was purified by chromatography (eluent: methylene chloride), 5.6 g (82%) of the product being obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:4]=1[CH2:5][NH:6][C:7](=[O:9])[CH3:8].[H][H]>[Pd].C(O)C>[C:7]([NH:6][CH2:5][C:4]1[CH:10]=[C:11]([CH:12]=[CH:13][C:3]=1[O:2][CH3:1])[NH2:14])(=[O:9])[CH3:8]
Reactant: [H][H]
Reactant: COc1ccc([N+](=O)[O-])cc1CNC(C)=O
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N)cc1CNC(C)=O

Procedure:
N-(2-Methoxy-5-nitrobenzyl)acetamide (5 g), with palladium on carbon (1 g) in ethanol (50 ml) was hydrogenated at room temperature under 104 tms. of hydrogen. The reaction was filtered through celite and the ethanol distilled from the filtrate. The residue was recrystallised from benzene to give 3-(acetylaminomethyl)-4-methoxyaniline as pale brown needles. MP; 123-125° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]=[C:8]2Cl.[NH2:14][C:15]1[C:16]([CH3:21])=[CH:17][CH:18]=[CH:19][CH:20]=1.CCOCC>C1(OC)C=CC=CC=1.CO>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]=[C:8]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]
Reactant: COc1cccc2c(Cl)nccc12
Reactant: Cc1ccccc1N
Solvent: COc1ccccc1
Solvent: CCOCC
Solvent: CO
Product: COc1cccc2c(Nc3ccccc3C)nccc12
Reaction time: 4 h
Yield: 30.2 %

Procedure:
5-Methoxy-1-chloroisoquinoline (1.5 g, 0.00777 mol) and o-toluidine (0.835 gm, 0.00777 mol) were mixed in anisole (10 ml) and heated with stirring in an oil-bath at 140° for four hours. After cooling the mixture was dissolved in methanol and ether was added to precipitate a tacky solid. The solvent was decanted off and the precipitate washed with more ether. The insoluble residue was equilibrated between N. HCl and ether, the aqueous acid solution filtered and basified with saturated aqueous Na2CO3 to precipitate a buff solid which was collected, washed with water and dried (0.77 g). This material was crystallised from diethyl ether to give the title compound (0.62 g) as fluffy, light-buff needles, m.p. 111°-112°.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10](=O)[C:9](=[CH:12]N3CCOCC3)[CH2:8][CH2:7][C:5]=2[N:6]=1.[N+]([O-])(O)=O.[N:23]1([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH2:38])=[NH:37])=[CH:31][CH:30]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.[OH-].[Na+]>COCCO>[CH3:1][C:2]1[S:3][C:4]2[C:10]3[N:38]=[C:36]([NH:35][C:32]4[CH:31]=[CH:30][C:29]([N:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)=[CH:34][CH:33]=4)[N:37]=[CH:12][C:9]=3[CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: N=C(N)Nc1ccc(N2CCOCC2)cc1
Reactant: Cc1nc2c(s1)C(=O)C(=CN1CCOCC1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: COCCO
Product: Cc1nc2c(s1)-c1nc(Nc3ccc(N4CCOCC4)cc3)ncc1CC2
Yield: 2.1 %

Procedure:
A mixture of 2-methyl-6-morpholin-4-ylmethylene-5,6-dihydro-4H-benzothiazol-7-one (200 mg, 7.6 mmol), N-(4-morpholin-4-yl-phenyl)-guanidine nitrate (215 mg, 7.6 mmol), NaOH (30 mg, 7.6 mmol), and 2-methoxyethanol (2 mL) was heated under reflux for 20 h. The reaction mixture was concentrated under vacuum. Flash column chromatography (5% MeOH:CH2Cl2), followed by crystallisation from EtOAc gave the pure title product as dark orange crystals (60 mg, 21%): mp 236-237° C. Anal. RP-HPLC: tR 13.4 min (0-60% MeCN, purity 100%). 1H-NMR (DMSO-d6): δ 9.26 (s, 1H, NH), 8.20 (s, 1H, Py-H), 7.58 (d, 2H, J 9.2, Ph-H), 6.84 (d, 2H, J 9.2, Ph-H), 3.70 (t, 4H, J 4.8, 2×CH2), 2.99 (t, 4H, J 4.8, 2×CH2), 2.90 (m, 4H, CH2—CH2), 2.66 (s, 3H, CH3).
Reaction SMILES: [H-].[Na+:2].C[Si](C#[C:8][C:9]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[C:10]=1[NH:11][C:12]([O:14][CH2:15][CH3:16])=O)(C)C.C(OCC)(=O)C.CCCCCC>C(O)C>[O-:14][CH2:15][CH3:16].[Na+:2].[F:21][C:19]1[CH:20]=[C:9]2[C:10](=[C:17]([F:22])[CH:18]=1)[NH:11][CH:12]=[CH:8]2
Reactant: CCOC(=O)Nc1c(F)cc(F)cc1C#C[Si](C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: CC[O-]
Product: Fc1cc(F)c2[nH]ccc2c1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
Fresh sodium ethoxide is prepared by carefully adding NaH (16 g of 60% oil dispersion, 400 mmol) to 550 mL of ethanol under N2. 2-(Trimethylsilylethynyl)-4,6-difluoro-N-carbethoxyaniline (28 g, 100 mmol) in 150 mL of ethanol is added and reaction is stirred at room temperature approximately 45 minutes, while monitoring by TLC (20% ethyl acetate/hexane, UV) until all the starting material is consumed. The mixture is heated to reflux and monitored by TLC until the intermediate material is consumed (approx. 1 hour). Reaction is cooled to room temperature, concentrated, diethylether is added, washed with H2O, brine, dried (Na2SO4), filtered, concentrated, and is purified by flash chromatography (SiO2, ethyl acetate/hexane gradient) to yield 12 g of 5,7-difluoro-indole (78%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([F:18])[C:6]2[O:10][N:9]=[C:8]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:7]=2[CH:17]=1.[C:19]([O:23][C:24](=[O:35])[NH:25][C@H:26]1[CH2:31][CH2:30][C@H:29]([CH2:32][CH:33]=O)[CH2:28][CH2:27]1)([CH3:22])([CH3:21])[CH3:20].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:19]([O:23][C:24](=[O:35])[NH:25][C@H:26]1[CH2:27][CH2:28][C@H:29]([CH2:32][CH2:33][N:14]2[CH2:13][CH2:12][N:11]([C:8]3[C:7]4[CH:17]=[C:3]([F:2])[CH:4]=[C:5]([F:18])[C:6]=4[O:10][N:9]=3)[CH2:16][CH2:15]2)[CH2:30][CH2:31]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Reactant: Fc1cc(F)c2onc(N3CCNCC3)c2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCN(c3noc4c(F)cc(F)cc34)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution in CH2Cl2 (20 ml) of 5,7-difluoro-3-piperazin-1-yl-benzo[d]isoxazole hydrochloride (1.35 g, 4.9 mmol) and trans-[4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (1.77 g, 7.3 mmol; prepared according to WO2007/093540) was stirred 15 min at r.t. before addition of Na(AcO)3BH (1.87 g, 8.8 mmol). The reaction mixture was stirred 2 h at r.t., then sat. aq. NaHCO3 was added and the product was extracted with 3 portions of CH2Cl2. After drying (Na2SO4) and evaporation of the solvent the product was purified by flash chromatography (50 g SiO2, EtOAc/MeOH 100:0→90:10) to obtain 2.59 g (quant.) of title compound as a white solid. m/z=465.3 ([M+H]+); 409.3 ([M+H—C4H8]+).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].[CH3:8][CH2:9][CH2:10][CH2:11][SnH:12]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH2:15][CH3:16].B(CC)(CC)CC.[F:28][C:29]1[C:34]([F:35])=[CH:33][C:32]([F:36])=[C:31]([F:37])[C:30]=1O.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.C1COCC1>[CH2:13]([Sn:12]([CH2:11][CH2:10][CH2:9][CH3:8])([CH2:17][CH2:18][CH2:19][CH3:20])[C:4](=[CH2:5])[CH2:3][CH2:2][C:1]([O:7][C:30]1[C:29]([F:28])=[C:34]([F:35])[CH:33]=[C:32]([F:36])[C:31]=1[F:37])=[O:6])[CH2:14][CH2:15][CH3:16]
Reactant: Oc1c(F)c(F)cc(F)c1F
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCB(CC)CC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=C(CCC(=O)Oc1c(F)c(F)cc(F)c1F)[Sn](CCCC)(CCCC)CCCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
To a solution of 4-pentynoic acid (308 mg, 3.1 mmol) in toluene (7.0 mL) under N2 was added Bu3SnH (1.7 mL, 6.3 mmol) followed by Et3B (0.30 mL, 1.0 M solution ion hexanes, 0.30 mmol). The resulting solution was stirred at room temperature for 13/4 hours after which the solvent was evaporated under reduced pressure. The resulting oil was dissolved in EtOAc and washed with saturated NaCl. The EtOAc layer was dried over MgSO4, filtered and concentrated under reduced pressure to afford 2.0 gr of crude product. To a solution of the crude product in anhydrous THF (15 mL) was added a solution 2,3,5,6-tetrafluorophenol (554 mg, 3.4 mmol) in THF (1.0 mL) followed by a solution of dicyclohexylcarbodiimide (652 mg, 2.3 mmol) in THF (1.0 mL). The resulting solution was stirred at room temperature overnight during which time a white precipitate formed. The THF was evaporated under reduced pressure and the residue was suspended in CH3CN. The insoluble precipitate was filtered off and the filtrate was purified via flash chromatography (silica gel, 25 mm×90 mm, 5% EtOAc/hexanes) to afford 833 mg (50%) of 2,3,5,6-tetrafluorophenyl 4-(tri-n-butylstannyl)-4-pentenoate as a mixture of isomers. 1H NMR (200 MHz, CDCl3) S 6.90 (m, 1H), 6.20 (m, 2H), 2.78 (bq, 2H, J=7 Hz), 2.60 (m, 2H), 1.65-1.20 (m, 18H), 1.90 (t, 9H, J=9 Hz); 13CNMR (50.3Hz, CDCl3) S 169.75, 145.95, 145.80, 132.14, 130.77, 106.70 (t, J=23 Hz). 103.63 (t, J=23 Hz), 34.04, 33,13, 32.62, 32,23, 29.32, 27.63, 13.96, 10.53, 9.71.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Si:27]([O:34][CH2:35][C:36]1[CH:37]=[C:38]([C:42]([C:44]2[N:45]=[CH:46][N:47]3[CH:51]=[C:50]([Sn](CCCC)(CCCC)CCCC)[S:49][C:48]=23)=[O:43])[CH:39]=[N:40][CH:41]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>>[Si:27]([O:34][CH2:35][C:36]1[CH:37]=[C:38]([C:42]([C:44]2[N:45]=[CH:46][N:47]3[CH:51]=[C:50]([C:8]4[C@H:9]([CH3:10])[C@@H:5]5[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:25](=[O:26])[N:6]5[C:7]=4[C:12]([O:14][CH2:15][C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=4)=[O:13])[S:49][C:48]=23)=[O:43])[CH:39]=[N:40][CH:41]=1)([C:30]([CH3:31])([CH3:32])[CH3:33])([CH3:29])[CH3:28]
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)c3cncc(CO[Si](C)(C)C(C)(C)C)c3)c2s1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5cncc(CO[Si](C)(C)C(C)(C)C)c5)c4s3)[C@H](C)[C@H]12
Yield: 70.5 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-2-[7-[5-(t-butyldimethylsilyloxymethyl)pyridin-3-yl]carbonylimidazo[5,1-b]-thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (707 mg) was prepared in the same manner as in step a) of Example 1, except that 509 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 926 mg of 7-[5-(t-butyldimethylsilyloxymethyl)pyridin-3-yl]carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29].[NH2:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][OH:38]>>[CH3:31][N:2]([CH3:1])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][OH:38])=[O:25])[C:6]1=[O:29]
Reactant: NCCOCCO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Product: CN(C)C(=O)Cn1c(=O)c(C(=O)NCCOCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from ethyl 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-[(2-aminoethyl)oxy]ethanol employing methods similar to those described in Example 245 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (d6-DMSO) δ 10.22 (1H, br t), 8.51 (1H, s), 7.74 (1H, s), 7.31 (2H, dd, J=8.4, 5.7 Hz), 7.12 (2H, t, J˜9 Hz), 5.12 (2H, s), 4.59 (1H, t, J=5 Hz), 4.11 (2H, s), 3.57-3.38 (8H, m), 3.12 (3H, s), 2.82 (3H, s); HRMS calcd for C24H27FN4O6+H: 487.1993. Found: 487.2007.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.Cl.[Cl:12][C:13]1[CH:14]=[C:15]([NH:19]N)[CH:16]=[CH:17][CH:18]=1.[CH3:21][N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1>C(N(CC)CC)C>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][N:19]2[C:15]3[CH:14]=[C:13]([Cl:12])[CH:18]=[CH:17][C:16]=3[C:24]3[CH2:23][N:22]([CH3:21])[CH2:27][CH2:26][C:25]2=3)=[CH:5][CH:6]=1
Reactant: Clc1ccc(CCBr)cc1
Reactant: CN1CCC(=O)CC1
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: CN1CCc2c(c3ccc(Cl)cc3n2CCc2ccc(Cl)cc2)C1

Procedure:
The title compound is prepared by following Method 8 by using 1-(2-bromoethyl)-4-chlorobenzene, 3-chlorophenylhydrazine hydrochloride, triethylamine and N-methyl-4-piperidone
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([O:21][CH3:22])([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1[O:24][CH3:25])[C@H:13]1[NH:23][C@H:12]1[CH2:11]3.[OH-].[K+].C(=O)=O.[O:31]([CH2:38]CO)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CCOCC>[C:18](=[O:17])([OH:19])[NH2:20].[OH:17][CH2:16][CH:15]1[C:6]2[C:4](=[O:5])[C:3]([O:24][CH2:25][CH2:38][O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:2]([CH3:1])[C:8](=[O:9])[C:7]=2[N:10]2[CH2:11][CH:12]3[NH:23][CH:13]3[C:14]12[O:21][CH3:22]
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Reactant: OCCOc1ccccc1
Agent: O=C=O
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: COC12C(CO)C3=C(C(=O)C(C)=C(OCCOc4ccccc4)C3=O)N1CC1NC12
Product: NC(=O)O
Yield: 71 %

Procedure:
A solution of mitomycin A (100 mg) in 2 l of 2-phenoxyethanol was stirred at room temperature under nitrogen for 45 minutes with 500 mg of a 1.6% solution of KOH in 2-phenoxyethanol. The reaction product was diluted with ether then decomposed with dry ice. Components of etherial solution were separated on a silica gel column using triethylamine, which elutes the 2-phenoxyethanol, and then a mixture of chloroform and methanol 9:1, which elutes the product. The product was further purified by preparative thin layer chromatography on silica gel with a mixture of chloroform and acetone 6:4. This procedure gave 93 mg (71%) of the title compound, having a melting point of 153°-155° C. and providing the following analysis:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])[CH:7]=O)([CH3:3])[CH3:2].[S:16]([CH2:22][C:23]#[N:24])([CH2:19][C:20]#[N:21])(=[O:18])=[O:17]>C(O)C.N1CCCCC1>[C:20]([CH2:19][S:16](/[C:22](=[CH:7]/[C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:11]([OH:12])=[C:10]([CH:13]([CH3:15])[CH3:14])[CH:9]=1)/[C:23]#[N:24])(=[O:18])=[O:17])#[N:21].[C:20](/[C:19](/[S:16](/[C:22](=[CH:7]/[C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:11]([OH:12])=[C:10]([CH:13]([CH3:15])[CH3:14])[CH:9]=1)/[C:23]#[N:24])(=[O:18])=[O:17])=[CH:7]\[C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:11]([OH:12])=[C:10]([CH:13]([CH3:15])[CH3:14])[CH:9]=1)#[N:21]
Reactant: N#CCS(=O)(=O)CC#N
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1O
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)c1cc(/C=C(\C#N)S(=O)(=O)/C(C#N)=C/c2cc(C(C)C)c(O)c(C(C)C)c2)cc(C(C)C)c1O
Product: CC(C)c1cc(/C=C(\C#N)S(=O)(=O)CC#N)cc(C(C)C)c1O

Procedure:
A mixture of 500 mg of 3,5-diisopropyl-4-hydroxybenzaldehyde and 700 mg of sulphonyl diacetonitrile in 6 ml of ethanol was refluxed with a few drops of piperidine for 4 hours. Ethanol was removed in a rotavap and the mixture worked up with ethyl acetate, diluted acid and brine. A portion of the crude was then purified by HPLC on a C-18 column to provide 50 mg of the titled compound along with 30 mg of (E,E)-2-[[1-Cyano-2-(3,5-diisopropyl-4-hydroxyphenyl)ethenyl]sulfonyl]-3-(3,5-diisopropyl-4-hydroxyphenyl)acrylonitrile.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[C:13](N1C=CN=C1)(N1C=CN=C1)=[O:14].[CH2:25]([O:32][C:33](=[O:50])[C:34]([CH3:49])([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH:43]2[CH2:48][CH2:47][CH2:46][NH:45][CH2:44]2)[CH:38]=1)[CH3:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl>C1(C)C=CC=CC=1.O>[CH2:25]([O:32][C:33](=[O:50])[C:34]([CH3:35])([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH:43]2[CH2:48][CH2:47][CH2:46][N:45]([C:13](=[O:14])[NH:8][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:4][CH:5]=3)[CH2:44]2)[CH:38]=1)[CH3:49])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(Oc1cccc(C2CCCNC2)c1)C(=O)OCc1ccccc1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(Oc1cccc(C2CCCN(C(=O)NCc3ccc(C(F)(F)F)cc3)C2)c1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.7 %

Procedure:
To a solution of 4-trifluoromethylbenzyl amine (170 mL, 1.19 mmol) in 5 mL toluene was added 1,1′-carbonyldiimidazole (193 mg, 1.19 mmol). This solution was stirred 18 h at ambient temperature. 2-methyl-2-(3-piperidin-3-yl-phenoxy)-propionic acid benzyl ester (Preparation 2, Method C; 421 mg, 1.19 mmol) was added in 5 mL toluene and the resultant solution was stirred 18 h at ambient temperature. The reaction was diluted with water (100 mL), acidified with 1N aqueous hydrochloric acid and extracted with ethyl acetate (2×50 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was flash chromatographed with 35% ethyl acetate/hexanes to yield 473 mg (72%) of the desired 2-methyl-2-{3-[1-(4-trifluoromethyl-benzylcarbamoyl)-piperidin-3-yl]-phenoxy}-propionic acid benzyl ester as a clear oil.