Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[C:13]3([CH2:17][CH2:16][C:15](=O)[NH:14]3)[CH:11]3[CH2:12][CH:8]2[CH:9]=[CH:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:20].[O-2].[Ca+2]>>[C:1]1([CH:7]2[C:13]3([CH2:17][CH2:16][C:15](=[S:20])[NH:14]3)[CH:11]3[CH2:12][CH:8]2[CH:9]=[CH:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1CCC2(N1)C1C=CC(C1)C2c1ccccc1
Agent: [Ca+2]
Agent: [O-2]
Product: S=C1CCC2(N1)C1C=CC(C1)C2c1ccccc1

Procedure:
20 mmoles of 3-phenyl-spiro[bicyclo[2.2.1]-hept-5-ene-2,2'-pyrrolidin]-5'-one, 4 g of phosphorus pentasulfide and 3 g of calcium oxide are stirred at 50°C. for 2 hours and the mixture is filtered hot into a saturated sodium carbonate solution. The residue is substantially disintegrated with concentrated hydrochloric acid, the mixture is diluted with water and the solutions are combined. The mixture is extracted several times by shaking with toluene and the organic phases are separated off, dried and evaporated in vacuo. Recrystallization of the residue from ethyl acetate gives colorless crystals of melting point 204° C. (decomposition).
Reaction SMILES: C(OC)(=O)C(C)=C.C=CC1C=CC=CC=1.[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]=[CH2:25])=[CH2:17].C1(S(OCCCCCCCCCCCC)(=O)=O)C=CC=CC=1.[Na]>O>[CH2:24]1[CH:19]2[CH:18]([CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:16][CH2:17][CH2:25]1
Reactant: C=Cc1ccccc1C=C
Agent: C=C(C)C(=O)OC
Agent: CCCCCCCCCCCCOS(=O)(=O)c1ccccc1
Agent: [Na]
Solvent: O
Solvent: C=Cc1ccccc1
Product: C1CCC2CCCCC2C1
Temperature: 80 °C

Procedure:
To a 50 kgf/cm2 pressure resistant autoclave equipped with a stirrer, methyl methacrylate 200 parts, styrene 150 parts, a cross-linkable monomer constituted by divinyl benzene 5 parts, sodium dodecyl benzenesulfonate 10 parts, ion exchanged water 1200 parts, and a polymerization initiator constituted by azobis butyronitrile 10 parts were charged. The mixture was sufficiently stirred, then was heated to 80° C. to perform the polymerization. Further, after the start of polymerization, when the amount of consumption of the monomer reached 99.8%, the mixture was cooled to stop the polymerization reaction and thereby obtain a latex of the polymer particles D. The obtained latex of the polymer particles D had a solid content concentration of 39%. Note that, polymer particles D are particles which do not have a core-shell structure. Further, the obtained polymer particles D had an average particle size of 190 nm. Next, to the obtained latex of the polymer particles D, decalin: 15,000 parts were added and the particles were sufficiently dispersed. After that, the moisture was removed by drying in vacuo to thereby obtain a decalin dispersion of the polymer particles D. The obtained dispersion had a solid content concentration of 5%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([C:18](=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:20]=2)[CH:15]([CH3:17])[CH3:16])[C@H:10]([C:34](C)(C)[O:35][SiH2]C(C)(C)C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(Cl)Cl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([CH2:34][OH:35])[C@H:11]([CH2:13][N:14]([C:18](=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:20]=2)[CH:15]([CH3:16])[CH3:17])[CH2:12]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1ccc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C(C)(C)O[SiH2]C(C)(C)C)C(C)C)cc1OCCCOC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CO
Solvent: ClCCl
Product: CCc1ccc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CO)C(C)C)cc1OCCCOC

Procedure:
From (3S,4R)-3-(tert-butyl-dimethyl-silanyloxymethyl)-4-({[4-ethyl-3-(3-methoxy-propoxy)-benzoyl]-isopropyl-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (13.1 g, 21.6 mmol) and TBAF (17 g, 54 mmol), and purification by flash chromatography on silica gel (CH2Cl2/MeOH 95:5) to give the title compound as yellow oil. TLC, Rf (AcOEt)=0.4,MS (LC-MS): 437.3 [M+H-tBu]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 6.74 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][CH:7]=1)=[O:5])[CH3:2].[Br:13]N1C(=O)CCC1=O>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[Br:13])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1csc(CC)c1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(CC)sc1Br
Reaction time: 4 h
Yield: 40.8 %

Procedure:
5-Ethyl-thiophene-3-carboxylic acid ethyl ester (1.2 g, 6.52 mmol) was dissolved in acetic acid (10 mL). N-Bromosuccinimide (7.1 mmol) was added and the reaction was stirred for 4 hours. The solvent was removed under vacuum and the product purified by flash chromatography on silica, eluting with 0%-30% t-butylmethylether in cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.7 g). 1H NMR (400 MHz, CHCl3-d): δ 7.05 (s, 1H), 4.3 (q, 2H), 2.75 (q, 2H), 1.4 (t, 3H), 1.3 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.CCCCCC.[C:16]1([C:26](Cl)=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1>O1CCCC1.C([Li])CCC>[C:16]1([C:26]([C:7]2[C:2]([Cl:1])=[CH:3][C:4]([CH3:9])=[CH:5][C:6]=2[Cl:8])=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cc(Cl)cc(Cl)c1
Reactant: O=C(Cl)c1cccc2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(Cl)c(C(=O)c2cccc3ccccc23)c(Cl)c1
Temperature: -60 °C
Reaction time: 1 h
Yield: 104.1 %

Procedure:
To a stirred, cold (-60° C.) solution of 3,5-dichlorotoluene (3.5 g, 21.7 mmol) in dry tetrahydrofuran (30 ml), 2.6 M n-butyllithium in hexane (8.78 ml, 22.8 mmol) was added dropwise over 15 minutes. The reaction mixture was stirred for one hour at -60° C. and then treated with a solution of 1-naphthoyl chloride (4.14 g, 21.7 mmol) in 15 ml of dry tetrahydrofuran over a period of 15 minutes. The mixture was stirred for 3.5 hours at -60° C. and then quenched with 4.8 ml of saturated NH4Cl solution. The mixture was permitted to warm to room temperature and then diluted with 30 ml of water and 30 ml of ether. The layers were thoroughly mixed and then separated. The etheral layer was backed-washed with brine and dried with anhydrous magnesium sulfate. Concentration afforded 7.12 g of crude product which was chromatographed on silica gel (20:1 hexane:ethyl acetate) to give 1.59 g (23 %).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29].[CH:30]1([NH2:33])[CH2:32][CH2:31]1>>[CH:30]1([NH:33][C:6]2[C:5]3[C:10](=[CH:11][C:2]([F:1])=[C:3]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[CH:4]=3)[N:9]=[C:8]([N:12]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]3)[N:7]=2)[CH2:32][CH2:31]1
Reactant: NC1CC1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(-c4ccccc4C)cc3c(=O)[nH]2)c1
Product: Cc1ccccc1-c1cc2c(NC3CC3)nc(-n3cc(C(=O)O)cn3)nc2cc1F

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-fluoro-4-oxo-6-(o-tolyl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and cyclopropyl amine in step E. MS (ESI): predicted mass calcd. for C22H18FN5O2, 403.1
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Na+].CN(C)P(N(C)C)(N(C)C)=O.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].O>C1COCC1>[CH2:19]([C:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1)[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: c1cc[cH-]c1
Reactant: CCCCCBr
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCCCCC1=CC=CC1
Temperature: -55 °C
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
To a solution of sodium cyclopentadienide (71 mmole, 1.89 M in THF) in 20 ml of THF was added 10 ml of hexamethylphosphoramide. The solution was cooled to -55° C. and 1-bromopentane (10.5 g. 70 mmole) was added dropwise with stirring over a period of 30 min. After the addition was completed, the reaction mixture was stirred at -30°-40° C. for 30 minutes and at autogeneous temperature for 30 minutes, then poured into cold water and extracted with pentane, (3×80 ml). The pentane extracts were combined, washed with water (3×100 ml) dried over anhydrous sodium sulfate, filtered and concentrated in a rotary evaporator (water bath temperature 20° C.). The residue was distilled to give 8.1 g (85%) of pentylcyclopentadiene, b.p. 52°/8 mm Hg.
Reaction SMILES: [C:1]([Si:5]([CH3:25])([CH3:24])[O:6][CH2:7][CH2:8][CH:9]=[CH:10][Sn](CCCC)(CCCC)CCCC)([CH3:4])([CH3:3])[CH3:2].OS(C(F)(F)F)(=O)=O.[C:34]([C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:38][CH:37]=1)#[N:35]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([Si:5]([CH3:24])([CH3:25])[O:6][CH2:7][CH2:8][CH:9]=[CH:10][C:45]1[CH:44]=[CH:43][C:42]([C:39]2[CH:38]=[CH:37][C:36]([C:34]#[N:35])=[CH:41][CH:40]=2)=[CH:47][CH:46]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCC[Sn](C=CCCO[Si](C)(C)C(C)(C)C)(CCCC)CCCC
Reactant: N#Cc1ccc(-c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCC=Cc1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 25 °C

Procedure:
A solution of Example 31B (4.95 g, 10.4 mmol), 4′-cyanobiphenyl triflate (3.1 g, 9.48 mmol, prepared from 4′-hydroxybiphenyl-4-carbonitrile by standard methods), and Pd(PPh3)2Cl2 (0.332 g, 0.47 mmol) in DMF (20 mL) was stirred at 80° C. overnight. The mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (97.5:2.5 hexane/ethyl acetate) to provide the title compound. 1H NMR (300 MHz, CDCl3): δ 0.07 (s, 6H), 0.91 (s, 9H), 2.46 (q, J=6 Hz, 2H), 3.75 (t, J=6 Hz, 2H), 6.32 (d, J=16 Hz, 1H), 6.48 (d, J=16 Hz, 1H), 7.44 (d, J=9 Hz, 2H), 7.54 (d, J=9 Hz, 2H), 7.65-7.74 (m, 4H). MS (DCl—NH3) m/z 364 (M+H)+, m/z 359 (M+NH4)+.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+].C(O)C>[Fe].O>[NH2:1][C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)=[CH:6][CH:5]=1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ncn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(Oc2cc(N)ncn2)cc1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
After suspending 6-(4-nitrophenoxy)pyrimidin-4-ylamine (306 mg, 1.32 mmol), iron powder (369 mg, 6.60 mmol) and ammonium chloride (706 mg, 13.2 mmol) in an ethanol (20 ml)-water (5 ml) mixed solvent, the suspension was heated and stirred at 80° C. for 20 minutes. After completion of the reaction, the reaction mixture was filtered with celite and washed in ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was concentrated to obtain the title compound (266 mg, 1.32 mmol, 100%) as light yellow crystals.
Reaction SMILES: CS(C)=O.C(Cl)(=O)[C:6](Cl)=[O:7].[F:11][C:12]1[CH:13]=[C:14]([CH:18](O)[CH2:19]C)[CH:15]=[CH:16][CH:17]=1.CCN(CC)CC>O.C(Cl)Cl>[F:11][C:12]1[CH:13]=[C:14]([CH:18]([CH3:19])[CH:6]=[O:7])[CH:15]=[CH:16][CH:17]=1
Reactant: CCC(O)c1cccc(F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O
Product: CC(C=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.3 %

Procedure:
Anhydrous CH2Cl2 (10 mL) was cooled to −78° C., and anhydrous DMSO (0.546 g, 7.00 mmol) was added, followed, dropwise, by oxalyl chloride (0.380 g, 3.00 mmol). Once gas evolution ceased, compound 40 (0.308 g, 2 mmol) was added dropwise and the resulting milky solution was stirred for 15 min. Et3N (1.17 mL, 8.4 mmol) was added slowly and the mixture was stirred for 15 min at −78° C. and then warmed to room temperature and stirred for 1 h. The yellow mixture was diluted with H2O (30 mL) and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×15 mL), and the organic layers were washed with H2O and sat. aq. NaCl (15 mL each). The solution was dried over anhydrous sodium sulfate, concentrated, and the resulting residue was purified by flash column chromatography (SiO2), eluting with a gradient of hexanes to 10% EtOAc in hexanes to yield the title aldehyde as a colorless volatile oil (0.220 g, 72%). 1H-NMR (500 MHz; CDCl3): δ 9.82 (s, 1 H), 7.27-7.23 (m, 1 H), 6.97 (d, J=7.6 Hz, 1 H), 6.92-6.89 (m, 2 H), 2.96 (t, J=7.5 Hz, 2 H), 2.81-2.78 (m, 2 H).
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[OH:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:43])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][C@H:27]1[CH2:31][S:32][CH2:33][CH2:34][CH2:35][C:36]([F:42])([F:41])[C:37]([F:40])([F:39])[F:38].I([O-])(=O)(=O)=[O:45].[Na+]>CO.O>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[OH:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:43])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][C@H:27]1[CH2:31][S:32]([CH2:33][CH2:34][CH2:35][C:36]([F:42])([F:41])[C:37]([F:38])([F:39])[F:40])=[O:45]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCN4CCC[C@H]4CSCCCC(F)(F)C(F)(F)F)[C@H]3[C@@H]1CC[C@@H]2O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCN4CCC[C@H]4CS(=O)CCCC(F)(F)C(F)(F)F)[C@H]3[C@@H]1CC[C@@H]2O
Yield: 66 %

Procedure:
A solution of 300 mg of 11β-fluoro-7α-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidin-1-yl]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol in 4.3 ml of methanol and 2.1 ml of water is stirred with 131 mg of sodium periodate for 4 hours at room temperature. Then, it is added to water, extracted three times with ethyl acetate, washed with common salt solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane/ethyl acetate. 203 mg of 11β-fluoro-7α-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentanesulfinylmethyl)-pyrrolidin-1-yl]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol is obtained. [α]D22=+11.8° (c=0.53% in methanol).
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:13][C:14]1[CH:15]=[C:16]([C:24](OC)=[O:25])[C:17]([C:20](OC)=[O:21])=[CH:18][CH:19]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl>C1COCC1>[F:13][C:14]1[CH:15]=[C:16]2[C:17](=[CH:18][CH:19]=1)[C:20]([OH:21])=[C:2]([C:1]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:24]2[OH:25]
Reactant: COC(=O)c1ccc(F)cc1C(=O)OC
Reactant: CCOC(=O)CCC(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(=O)OCC)c(O)c2cc(F)ccc2c1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 28.9 %

Procedure:
Diethyl succinate (16.26 ml, 98.1 mmol) was added to dimethyl 4-fluoro-1,2-benzenedicarboxylate (10.4 g, 49.1 mmol) and LHMDS (1M in THF, 196 ml, 196 mmol) in THF (150 ml) at 10° C. (internal) over 30 minutes. Allowed to warm to room temperature slowly. After 20 hours, 2M HCl (˜500 ml) was added to acidify to pH 5. The mixture was extracted with EtOAc, then the organics washed with water, brine, dried over magnesium sulphate and concentrated in vacuo to give a brown oil. This was purified by chromatography on silica gel eluting with EtOAc/hexane (2:98) to yield the title compound as a yellow solid (4.58 g, 14.2 mmol).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.Cl.[C:19]1([C:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)C(C)C)C>C(O)C>[OH:17][CH2:16][CH2:15][NH:14][C:4]1[N:5]=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[C:7]([C:8]#[N:9])=[C:2]([N:28]2[CH2:27][CH:26]=[C:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:30][CH2:29]2)[N:3]=1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCCO
Reactant: C1=C(c2ccccc2)CCNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: N#Cc1c(NCCO)nc(NCCO)nc1N1CC=C(c2ccccc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 4-phenyl-1,2,3,6-tetrahydro-pyridine hydrochloride in ethanol in the presence of N-ethyl-diisopropylamine at 80° C. to yield 2,4-bis-(2-hydroxy-ethylamino)-6-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-pyrimidine-5-carbonitrile as an amorphous, brown solid; MS: [M+H]+=381.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:41]1[N:42]=[C:43]([NH:46][CH:47]=[O:48])[S:44][CH:45]=1)[C:5]([NH:7][CH:8]1[C:39](=[O:40])[N:10]2[CH:11]([C:23]([O:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[C:12]([CH:15]=[CH:16][C:17]3[N:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][S:14][C@H:9]12)=[O:6].ClC1C=CC=C(C(OO)=[O:57])C=1>C(Cl)Cl>[CH3:1][O:2][N:3]=[C:4]([C:41]1[N:42]=[C:43]([NH:46][CH:47]=[O:48])[S:44][CH:45]=1)[C:5]([NH:7][CH:8]1[C:39](=[O:40])[N:10]2[C:11]([C:23]([O:25][CH:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:24])=[C:12]([CH:15]=[CH:16][C:17]3[N:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:13][S:14](=[O:57])[C@H:9]12)=[O:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(C=Cc3cccnn3)=CS[C@H]12)c1csc(NC=O)n1
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=Cc3cccnn3)CS(=O)[C@H]12)c1csc(NC=O)n1
Yield: 86.1 %

Procedure:
To a solution of benzhydryl 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-[2-(3-pyridazinyl)vinyl]-2-cephem-4-carboxylate (syn isomer) (trans isomer) (2.1 g) in methylene chloride (40 ml) was added a solution of 70% m-chloroperbenzoic acid (0.87 g) in methylene chloride (20 ml) at -35° C. with stirring. The reaction mixture was stirred at the same temperature for 20 minutes. The resultant solution was washed with 5% aqueous sodium bicarbonate. The separated organic layer was concentrated under reduced pressure and the residue was triturated in diisopropyl ether to give benzhydryl 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-[2-(3-pyridazinyl)vinyl]-3-cephem-4-carboxylate-1-oxide (syn isomer) (trans isomer) (1.85 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])=[C:7]([CH2:19][CH2:20][CH3:21])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:4][CH:3]=1.[CH3:27][N:28]=[C:29]=[O:30]>C(Cl)(Cl)Cl>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:29]([NH:28][CH3:27])=[O:30])[CH:10]=2)[C:6]([C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])=[C:7]1[CH2:19][CH2:20][CH3:21]
Reactant: CN=C=O
Reactant: CCCc1c(C(=O)C(C)C)c2ccc(N)cc2n1Cc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: CCCc1c(C(=O)C(C)C)c2ccc(NC(=O)NC)cc2n1Cc1ccccc1Cl
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 6-amino-1-(2-chlorobenzyl)-3-isobutyryl-2-propylindole (100 mg) in chloroform (2 ml) was added methylisocyanate (0.5 ml) at 0° C. The reaction mixture was stirred at 20° C. for 1 hour, then evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:1) to give crystals which were recrystallized from a mixture of ethyl acetate and hexane to give 1-(2-chlorobenzyl)-3-isobutyryl-6-(3-methylureido)-2-propylindole (75 mg) as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH2:23]O)[CH:19]=[CH:20][C:21]=1[F:22]>>[F:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:23][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccc(F)c(F)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(F)c(F)c2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (3,4-difluorophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.19 (2H, s), 5.73 (1H, d, J=2.0 Hz), 7.16-7.34 (3H, m), 7.41-7.42 (1H, m), 7.57 (1H, s, J=2.0 Hz), 8.04 (1H, s), 8.70 (1H, s, J=4.4 Hz). [M+H] Calc'd for C16H10F2N4O, 313; Found, 313.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[N:9][NH:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl[CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1>>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[N:9][N:10]([CH2:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[C:11]2=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=c1[nH]ncc2ccc([N+](=O)[O-])cc12
Reactant: ClCc1cccnc1
Agent: Cl
Product: O=c1c2cc([N+](=O)[O-])ccc2cnn1Cc1cccnc1

Procedure:
Step (b) of Example 125 was repeated, except that the compound prepared in step (b) of Example 137 and 3-(chloromethyl)pyridine hydrochloride were used as the starting compounds. Thus, 7-nitro-2-(pyridin-3-yl)methyl-2H-phthalazin-1-one was obtained.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.CCCCCC.[F:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24]([CH:28]=1)[C:25]([OH:27])=[O:26].CI>C1COCC1>[F:19][C:20]1[C:28]([CH3:1])=[C:24]([C:23]([O:29][CH3:30])=[CH:22][CH:21]=1)[C:25]([OH:27])=[O:26]
Reactant: CC(C)NC(C)C
Reactant: COc1ccc(F)cc1C(=O)O
Agent: [Li]CCCC
Solvent: CI
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(F)c(C)c1C(=O)O
Temperature: -78 °C
Reaction time: 1 h
Yield: 229.6 %

Procedure:
Diisopropyl amine (478 g, 4.725 mol) and anhydrous THF (2.8 L) were charged to a 10 L 4-neck flask equipped with gas inlet, addition funnel, thermometer and mechanical stirrer. The solution was degassed with N2 for 5 min then cooled to −78° C. with dry ice acetone bath under N2 flow. A solution of n-BuLi in n-hexane (1.8 L, 2.5 M, 4.5 mol) was added to the stirring mixture at −20° C.˜−10° C. over 40 min. After the addition, the reaction was stirred at −20° C. for 40 min A solution of 5-fluoro-2-methoxybenzoic acid 60 (297.5 g, 1.75 mol) in anhydrous THF (1.3 L) was added to the reaction mixture at −55° C.—45° C. with stirring over 60 min. The resulting brown mixture was stirred at −15˜−25° C. for 3.5 h. The reaction mixture turned to red brown. Another para-reaction same with above reaction was set at same time. A 20 L four-neck flask equipped with gas inlet, addition funnel, thermometer and mechanical stirrer was charged with neat MeI (1500 g, 10.5 mol) and anhydrous THF (2.6 L). The mixture was degassed with N2 for 5 min and cooled to −20˜−15° C. with dry ice acetone bath under small N2 flow. The obtained solution from the above two para-reactions was transferred to the 20 L flask containing MeI at −15˜−5° C. with stirring over 20 min. The resulting cloudy mixture was stirred at −20˜−15° C. for 2 h and brought to ambient temperature over 1.5 h. The obtained brown suspension was stirred at 25-30° C. for 16 h. The reaction was then quenched with aqueous HCl (5.0 L, 2N) at 20-25° C. and diluted MTBE (3.0 L). After being stirred for 5 min at 20° C., the two phase mixture was separated, and the upper layer was concentrated to dryness under vacuum to give black oil. The aqueous layer was extracted with EtOAc (5×1.5 L) and all the organic layers were combined with the black oil. The resulting solution was washed with water (2×μL) and brine (3×1 L). The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduce pressure to afford crude 3-fluoro-6-methoxy-2-methylbenzoic acid 61 (740 g, >100%) as brown crystal solid that was used in the next step without further purification: 1H NMR (400 MHz, CDCl3) δ 7.06 (dd, J=9.8, 8.5 Hz, 1H), 6.75 (dd, J=9.8, 3.7 Hz, 1H), 3.86 (s, 3H), 2.34 (d, J=2.4 Hz, 3H); MS (ESI) m/z 185.12 (M+H).