Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C:14](=[O:15])[N:4]2[C:5]([C:11]([OH:13])=[O:12])=[C:6]([CH2:9][OH:10])[CH2:7][S:8][C@H:3]12.[OH-].[Na+:17].C(=O)([O-])O.[Na+].[CH3:23][S:24]([CH2:27][CH2:28][O:29][C:30](Cl)=[O:31])(=[O:26])=[O:25]>O.O1CCCC1>[CH3:23][S:24]([CH2:27][CH2:28][O:29][C:30]([NH:1][C@@H:2]1[C:14](=[O:15])[N:4]2[C:5]([C:11]([O-:13])=[O:12])=[C:6]([CH2:9][OH:10])[CH2:7][S:8][C@H:3]12)=[O:31])(=[O:26])=[O:25].[Na+:17]
Reactant: CS(=O)(=O)CCOC(=O)Cl
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)CCOC(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CO)CS[C@H]12

Procedure:
In 50 ml of water is suspended 4.60 g of 7β-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid and, with ice-cooling and stirring, 20 ml of 1N aqueous sodium hydroxide solution is added to the suspension for dissolving the acid. To the solution is added 1.85 g of sodium hydrogen carbonate and, then, a solution of 4.11 g of 2-methylsulfonylethoxycarbonyl chloride in 40 ml of tetrahydrofuran is added dropwise. The mixtrue is stirred with ice-cooling for 2 hours, then adjusted to pH 6.5, washed with ethyl acetate, and concentrated under reduced pressure. The residue is subjected to column chromatography on XAD-II (600 ml). Elution is performed with water and the eluate is concentrated under reduced pressure and freeze-dried to give 3.10 g of sodium 7β-(2-methylsulfonylethoxycarbonylamino)-3-hydroxymethyl-3-cephem-4-carboxylate as light yellow powders.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:4]2[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=2[S:6][C:7]=1[NH2:8].N1C=CC=CC=1.Cl[S:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>C1COCC1.CCOC(C)=O>[CH3:2][C:3]1[C:4]2[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=2[S:6][C:7]=1[NH:8][S:20]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:30][CH:31]=1)(=[O:22])=[O:21]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1c(N)sc2ccccc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1c(NS(=O)(=O)c2ccc(C(=O)O)cc2)sc2ccccc12
Temperature: 5 °C
Reaction time: 72 h
Yield: 84.6 %

Procedure:
A 12-L 4-neck flask equipped with an overhead mechanical stirrer, N2 inlet/outlet adapter, and thermocouple was charged with THF (3.26 L) and compound 757-A (326 g, 1.6 mol) followed by pyridine (265 mL, 3.3 mol). The reaction mixture was cooled to 5° C. using a ice bath, to which was added a solution of 4-(chlorosulfonyl)benzoic acid (396 g, 1.8 mol) dissolved in THF (2.44 L), drop-wise. The reaction was allowed to stir at ambient temperature for 72 h, diluted with EtOAc (4 L), washed with 1N HCl (1 L), brine (1 L), the organic layer dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified by triturating with EtOAc/heptane (1:1/1 L). The slurry was filtered, washed with heptane (2×250 mL) and dried in a vacuum oven at 40° C. for 18 h to afford 470 g of compound 306-C as a white solid. 1H-NMR (DMSO-d6): δ 13.51 (br s, 1H), 10.65 (br s, 1H), 8.12 (d, 2H), 7.86 (d, 2H), 7.83-7.79 (m, 1H), 7.66-7.63 (m, 1H), 7.37-7.33 (m, 1H), 2.03 (s, 3H).
Reaction SMILES: [CH2:1]([OH:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20].[C:22]([O:27]Br)(=[O:26])[CH:23]([CH3:25])[CH3:24].[OH-].[Na+].O>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:1]([O:21][C:23]([CH3:25])([CH3:24])[C:22]([O:27][C:23]([CH3:25])([CH3:24])[CH3:22])=[O:26])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20]
Reactant: CC(C)C(=O)OBr
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCOC(C)(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 44.4 %

Procedure:
A mixture of (5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-ol, (0.83 g, 3.14 mmol), tetrabutylammonium chloride (0.24 g, 0.85 mmol) and t-butyl □-bromo isobutyrate (3.50 g, 15.7 mmol) was dissolved in toluene (15 mL) and placed under nitrogen. An aqueous solution of sodium hydroxide (50%, 5 mL) was added slowly under vigorous stirring at room temperature. The resulting mixture was heated to 60° C. and stirred for six hours. The mixture was cooled, added water and extracted three times with ether. The combined organic extract was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel using a gradient of 5-10% ethyl acetate in heptane as eluent. Concentration of the appropriate fractions afforded 0.60 g (44% yield) of the title compound as an oil. MS (electro spray): 453.3 [M+Na]+.
Reaction SMILES: [C:1]([C:3](=[CH:13]OCC)[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5])#[N:2].Cl.[NH:18]([C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([O:25][CH3:26])=[O:24])[NH2:19].CCN(C(C)C)C(C)C.CCOCC>C(O)C>[NH2:2][C:1]1[N:18]([C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=2)[C:23]([O:25][CH3:26])=[O:24])[N:19]=[CH:13][C:3]=1[C:4](=[O:5])[NH:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CCOC=C(C#N)C(=O)NC1CCCCC1
Reactant: COC(=O)c1cccc(NN)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: COC(=O)c1cccc(-n2ncc(C(=O)NC3CCCCC3)c2N)c1
Temperature: 70 °C
Yield: 47.4 %

Procedure:
2-cyano-N-cyclohexyl-3-ethoxy-prop-2-enamide (Intermediate #17) (605 mg, 2.73 mmol) and methyl 3-hydrazinylbenzoate hydrochloride (552 mg, 2.73 mmol) were suspended in ethanol (20 mL). DIPEA (352 mg, 2.73 mmol) was added and the mixture heated to 70° C. for 1 h. The reaction mixture was cooled to ambient and concentrated to a small volume. Water (50 mL) was added and the resulting solid recovered by filtration, redissolved in ethyl acetate (50 mL), dried (MgSO4) and evaporated to give a brown solid which was slurried with ether and recovered by filtration to give the title compound as light brown solid (443 mg, 47%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O.Cl.S(=O)=O>>[O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([Cl:19])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Agent: Cl
Agent: O=S=O
Product: O=C(Cl)c1cccc(Oc2ccccc2)c1

Procedure:
In a well ventilated hood, a mixture of m-phenoxy benzoic acid (200 g, 0.933 mole) (Aldrich) and thionyl chloride (105 mL, 1.44 moles) was placed in a one liter, round-bottomed flask. The flask was fitted with a magnetic stirring bar (or mechanical stirring bar for larger quantity preparation) and a reflux condenser with calcium chloride drying tube, which was attached to an exit tube, for evolved hyrogen chloride and sulfur dioxide, leading to a gas absorption trap. The mixture was heated on a heating mantle cautiously at first until a brownish-green solution was obtained (about 11/2 hours). The resulting solution was then heated gently for an additional 11/2 hours. The resulting brown solution was then cooled, and excessive thionyl chloride was distilled off at 40° C. To the resulting oil was added toluene (75 mL), and the solution was evaporated to remove a small amount of thionyl chloride. Addition and evaporation of toluene (75 mL) was repeated once more. The resulting acid chloride was then dissolved in 100 mL of tetrahydrofuran (THF dried over molecular sieves 3A), and ready to use freshly for reaction.
Reaction SMILES: O[C@:2]12[CH2:19][CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3=[O:20])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:22])[CH2:4][CH2:5][C:6](=[O:21])[CH:7]=1.ClS(O)(=O)=O.O>C(Cl)Cl>[CH3:17][C@:16]12[CH2:18][CH:19]=[C:2]3[C@@H:11]([CH2:10][CH2:9][C:8]4[C@:3]3([CH3:22])[CH2:4][CH2:5][C:6](=[O:21])[CH:7]=4)[C@@H:12]1[CH2:13][CH2:14][C:15]2=[O:20]
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)CC[C@@]12O
Agent: O=S(=O)(O)Cl
Solvent: O
Solvent: ClCCl
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 0.07 h

Procedure:
9α-Hydroxyandrostenedione (20.00 g.) is dissolved in methylene chloride (150 ml.) and cooled to -19°. Chlorosulfonic acid (10 ml.) is added while maintaining the temperature at less than or equal to -9°. After only a few minutes the reaction is shown to be nearly complete as measured by TLC. Additional chlorosulfonic acid (1 ml.) is added. Water (50 ml.) is added to the reaction mixture with the temperature rising from -18° to -1°. The phases are separated and the aqueous phase is extracted with methylene chloride (125 ml.). The organic phase is washed with aqueous sodium bicarbonate solution (10%, 50 ml.). The aqueous phases are combined and back extracted with methylene chloride. The organic phases are combined and concentrated under vacuum to approximately 80 ml. at a temperature of about 20°-23°. Heptane (100 ml.) is added and the mixture stirred for approximately 4 minute at approximately 19°. The mixture is concentrated under vacuum to approximately 100 ml. at a temperature of about 25°-30°. Heptane (50 ml.) is again added and the mixture again concentrated to approximately 100 ml. The mixture is cooled to 25° and stirred for 15 minutes, filtered, and the crystalline material washed with heptane (25 ml.) and dried under vacuum at 50° to give androsta-4,9(11)-diene-3,17-dione, 17.96 g. (89.8% weight yield, 95.3 % chemical yield); m.p. 197.5°-203.5°; [α]D +220° (chloroform); UV (methanol)λmax =240 nm (ε=16,200).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:22])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19]CC)=[O:18])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>C1COCC1.C[C@H]1O[C@H]2[C@H](O)[C@@H](O)[C@H](OC3C4C(=CC5OCOC=5C=4)[C@@H](C4C=C(OC)C(O)=C(OC)C=4)[C@@H]4[C@@H]3COC4=O)O[C@@H]2CO1.C1COP(NCCCl)(=O)N(CCCl)C1.[NH2-].[NH2-].Cl[Pt+2]Cl>[C:1]1([NH:7][C:8](=[O:22])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)Nc2ccccc2)cc1
Agent: Cl[Pt+2]Cl
Agent: COc1cc([C@@H]2c3cc4c(cc3C(O[C@@H]3O[C@@H]5CO[C@@H](C)O[C@H]5[C@H](O)[C@H]3O)[C@H]3COC(=O)[C@H]23)OCO4)cc(OC)c1O
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(NC(=O)Nc2ccccc2)cc1
Temperature: 25 °C
Yield: 93.2 %

Procedure:
To a stirred solution of ethyl 4-(N′-phenylureido)phenylacetate (9.64 g, 32.3 mmol) in THF (80 ml) was added 0.5 N NaOH (80 ml) and the reaction mixture was heated under reflux for 5 hr. After cooled to room temperature, the mixture was poured into ice-1 N HCl. The resulting precipitate was collected under a reduced pressure and the crude solid was recrystallized from MeOH—CHCl3 to give 4-(N′-phenylureido)phenylacetic acid (8.14 g, 93%) as a white crystalline powder. MS (FAB) m/z 271 (M++1); Anal. Calcd. for C15H14N2O3: C, 66.66; H, 5.22; N, 10.36. Found: C, 66.45; H, 5.22; N, 10.30.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:17][C:16]3[CH:18]=[C:19]([Br:22])[CH:20]=[CH:21][C:15]=3[O:14][CH2:13]2)(=O)=O)=CC=1.[CH:24](=[N:31][CH2:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.[I-].[K+]>[CH:24](=[N:31][CH2:32][CH:33]1[CH2:34][CH2:35][N:36]([CH2:11][C@@H:12]2[O:17][C:16]3[CH:18]=[C:19]([Br:22])[CH:20]=[CH:21][C:15]=3[O:14][CH2:13]2)[CH2:37][CH2:38]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(Br)cc3O2)cc1
Reactant: C(=NCC1CCNCC1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Brc1ccc2c(c1)O[C@@H](CN1CCC(CN=Cc3ccccc3)CC1)CO2
Reaction time: 24 h

Procedure:
A mixture of (R)-7-bromo-1,4-benzodioxan-2-ylmethyl 4-toluenesulphonate (6.5 g, prepared as described in WO97/03071), N-benzylidene-4-piperidylmethylamine (3.0 g), potassium carbonate (4.1 g), and potassium iodide (10 mg) in acetonitrile (200 ml) was heated at reflux, with stirring, under nitrogen for 24 hours. The reaction was cooled, filtered and concentrated under reduced pressure to afford (S)-N-benzylidene-1-[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methylamine (6.3 g) as an orange-brown viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][O:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=1.[CH3:15]CN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CO.C(Cl)Cl>[CH3:15][O:13][C:12](=[O:14])[CH2:11][O:10][CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: O=C(O)COCCc1cccc(F)c1
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: COC(=O)COCCc1cccc(F)c1
Yield: 92.6 %

Procedure:
A solution of [2-(3-fluoro-phenyl)-ethoxy]-acetic acid (1.20 g, 6.05 mmol), EDCI (1.28 g, 6.66 mmol), HOBt (0.90 g, 6.66 mmol) and DIPEA (1.56 ml, 9.08 mmol) in methanol (4 ml) was stirred at 0° C. for 2 hours. The reaction mixture was brought to dryness, dissolved in CH2Cl2 and washed twice with 1M NaOH and brine. The organic layers were dried over MgSO4, filtrated, the solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, EtOAc/heptane, 1/4) to yield [2-(3-fluoro-phenyl)-ethoxy]-acetic acid methyl ester (1.20 g, 5.6 mmol; 93%) as colorless liquid. MS (m/e): 213.2 [M+H]+.
Reaction SMILES: C(O)(=O)C(O)=O.[C:7]([O:11][C:12](=[O:32])[CH2:13][N:14]1[CH2:19][CH2:18][NH:17][C@@H:16]([CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:15]1=[O:31])([CH3:10])([CH3:9])[CH3:8].[NH:33]([C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[CH2:34][C:35](O)=[O:36].Cl.C(N=C=NCCCN(C)C)C>C(=O)([O-])O.[Na+].CC(C)=O>[C:7]([O:11][C:12](=[O:32])[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:35](=[O:36])[CH2:34][NH:33][C:38]([O:40][CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[O:39])[C@@H:16]([CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:15]1=[O:31])([CH3:9])([CH3:8])[CH3:10]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CN1CCN[C@@H](CCCNC(=O)OC(C)(C)C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)CN1CCN(C(=O)CNC(=O)OCc2ccccc2)[C@@H](CCCNC(=O)OC(C)(C)C)C1=O
Yield: 99.9 %

Procedure:
In a saturated aqueous solution of sodium hydrogencarbonate was dissolved (S)-3-(3-t-butoxycarbonylaminopropyl)-2-oxopiperazine-1-acetic acid t-butyl ester oxalate (1.6 g, 3.47 mmol). The solution was subjected to extraction with ethyl acetate, and the extract solution was concentrated under reduced pressure. The concentrate and N-Z-Gly-OH (0.87 g, 4.16 mmol) were dissolved in 16.0 cc of acetone. To the solution was added, at 15° C. under stirring, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.87 g, 4.51 mmol). The mixture was stirred for one hour at room temperature, and the reaction mixture was concentrated under reduced pressure. The concentrate was washed with a 5% aqueous solution of potassium hydrogensulfate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was concentrated under reduced pressure, and the concentrate was purified by means of a silica gel column chromatography (ethyl acetate) to afford 1.95 g (100%) of the titled compound as a colorless amorphous powdery product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:13]#[N:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-].[K+].O>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]1[CH:3]=[C:4]([C:12]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:13]#[N:14])[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: N#CC(c1ccc(F)cc1)c1cc(F)cc(C(F)(F)F)c1
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#CC(Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(C(F)(F)F)c1
Reaction time: 0.08 h
Yield: 59 %

Procedure:
To a solution of 2-(3-fluoro-5-(trifluoromethyl)phenyl)-2-(4-fluorophenyl)acetonitrile (200 mg, 0.67 mmol) in toluene (7 mL) was added tetrabutylammonium bromide (65 mg, 0.20 mmol) and benzyl bromide (0.095 mL, 0.80 mmol) followed by an aqueous solution of 50% KOH (2.2 mL). The reaction mixture was vigorously stirred for 5 min, then poured into H2O (20 mL) and extracted with diethyl ether (2×20 mL). The combined organic portions were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to yield a residue. The residue was crystallized from methanol to give 2-(3-fluoro-5-(trifluoromethyl)phenyl)-2-(4-fluorophenyl)-3-phenylpropanenitrile (153 mg, 59% yield) as a white solid. LCMS: RT=2.11 min [M+H] 388.3 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H (CDCl3) ppm 3.59 (d, J=12.75 Hz, 1 H), 3.65 (d, J=13.18 Hz, 1 H), 6.87 (d, J=7.03 Hz, 2 H), 7.08 (t, J=8.35 Hz, 2 H), 7.18-7.32 (m, 8 H).
Reaction SMILES: [CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[CH:8]=[CH:7][C:6]=1[CH2:17][OH:18])[CH2:2][CH2:3][CH3:4].CS(C)=O.C(Cl)(=O)C(Cl)=O>ClCCl>[CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[CH:8]=[CH:7][C:6]=1[CH:17]=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(CO)ccc2ccc(OC)cc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCCCc1c(C=O)ccc2ccc(OC)cc12

Procedure:
As in Example 136, 1-butyl-7-methoxy-2-naphthalenemethanol (2.25 g) was oxidized by using the reagent prepared from dimethylsulfoxide (0.54 mL) and oxalyl chloride (0.9 mL) in dry dichloromethane (25 mL). The usual work up gave 2 g of 1-butyl-7-methoxy-2-naphthalenecarboxaldehyde and distillation of a sample on a Kugelrohr apparatus (138°-140° C.; 0.1 mm) furnished the analytical specimen. Anal. Calcd for C16H18O2 : C, 79.31; H, 7.49 Found: C, 79.11; H, 7.49
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH:4]=[N:5][OH:6].ClN1C(=O)CCC1=O.C([O-])(O)=O.[Na+].[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=1[CH2:32][O:33][CH2:34][C:35]([CH3:37])=[CH2:36]>ClCCCl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.CN(C)C=O>[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=1[CH2:32][O:33][CH2:34][C:35]1([CH3:37])[O:6][N:5]=[C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])[CH2:36]1
Reactant: ON=Cc1ccccc1F
Reactant: C=C(C)COCc1c(F)cccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(COCc2c(F)cccc2F)CC(c2ccccc2F)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
200 mg of 2-fluorobenzaldehyde oxime was dissolved in 4 mL of 1,2-dichloroethane, and then, 230 mg of N-chlorosuccinimide and 0.4 mL of dimethylformamide were slowly added thereto at a temperature of 0° C. The reaction mixture was stirred at room temperature for 1 hour, and then, the reaction state was confirmed by TLC. When the oxime, which was a starting material, disappeared, the reaction mixture was cooled to a temperature 0° C., and then, 182 mg of NaHCO3, 27 mg of tetrabutylammonium iodide, and 342 mg of 1,3-difluoro-2-((2-methylallyloxy)methyl)benzene were sequentially, slowly added thereto. The reaction mixture was stirred at room temperature overnight, and then, diluted with dichloromethane, and then, washed with water, and the obtained organic layer was dried by using magnesium sulfate and concentrated, and the concentrate was separated by silicagel column chromatography to obtain 385 mg of 5-((2,6-difluorobenzyloxy)methyl)-3-(2-fluorophenyl)-5-methyl-4,5-dihydroisoxazole.
Reaction SMILES: [N+:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])([O-:3])=[O:2].C(N(CC)C(C)C)(C)C.[CH:19]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])OCC.C(=O)(O)[O-].[Na+]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl.C(O)C>[CH2:27]([O:26][CH:19]([O:23][CH2:24][CH3:25])[CH:4]([N+:1]([O-:3])=[O:2])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:28]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)C[N+](=O)[O-]
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(C(OCC)OCC)[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 68 %

Procedure:
Ethyl nitroacetate (1.70 ml, 15.31 mmol) was dissolved in dichloromethane (50 ml). Mixture was cooled to −10° C. Titanium(IV) chloride (1.90 ml, 17.23 mmol) was added to the mixture drop-wise. Mixture was held at −10° C. with stirring for 15 minutes. A solution of N,N-diisopropylethylamine (3.0 ml, 17.22 mmol) in 10 mL dichloromethane was added to the mixture drop-wise over 25 minutes. Mixture was held at −10° C. with stirring for 1.25 hours. Triethyl orthoformate (6.4 ml, 38.5 mmol) was added to the mixture drop-wise. Reaction was held at −10° C. with stirring for 2 hours. Reaction mixture was poured into a mixture of 40 mL ethanol and 100 mL aqueous sodium bicarbonate to quench. Mixture was stirred vigorously for 10 minutes. Organic solvents were removed from the mixture by roto-vap. Residue was treated with ethyl acetate and celite. Slurry was filtered over celite. Filtrate layers were separated. Aqueous phase was back extracted twice with ethyl acetate. Organic phases were combined. Material was dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as yellow oil in 68% yield. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 5.19-5.26 (m, 1 H) 5.10-5.17 (m, 1 H) 4.26 (q, J=6.95 Hz, 2 H) 3.68-3.85 (m, 2 H) 3.52-3.68 (m, 2 H) 1.28 (t, J=7.14 Hz, 3 H) 1.12-1.21 (m, 6 H).
Reaction SMILES: Cl.[F:2][C@@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][CH2:16][O:17][C:18]1[CH:19]=[N:20][C:21]2[C:26]([CH:27]=1)=[N:25][CH:24]=[CH:23][C:22]=2[Cl:28].[I-].[Na+]>CN(C=O)C>[Cl:28][C:22]1[CH:23]=[CH:24][N:25]=[C:26]2[C:21]=1[N:20]=[CH:19][C:18]([O:17][CH2:16][CH2:15][N:5]1[CH2:6][CH2:7][C@@H:3]([F:2])[CH2:4]1)=[CH:27]2
Reactant: F[C@@H]1CCNC1
Reactant: Clc1ccnc2cc(OCCBr)cnc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: F[C@@H]1CCN(CCOc2cnc3c(Cl)ccnc3c2)C1
Reaction time: 16 h
Yield: 53.8 %

Procedure:
A 25 mL round bottom flask at rt was charged with (R)-3-fluoropyrrolidine hydrochloride (124 mg, 0.99 mmol). To this was added potassium carbonate (365 mg, 2.64 mmol), 3-(2-bromoethoxy)-8-chloro-1,5-naphthyridine (190 mg, 0.66 mmol), sodium iodide (149 mg, 0.99 mmol) and DMF (2 mL). Reaction mixture placed in oil bath preheated to 60° C. and allowed to stir for 16 hrs. Reaction mixture passed through celite cake, rinsed with 10% MeOH/DCM and filtrate concentrated to afford yellow oil. This was purified by ISCO silica gel chromatography (20-40% EtOAC/Hexanes) to afford (R)-8-chloro-3-(2-(3-fluoropyrrolidin-1-yl)ethoxy)-1,5-naphthyridine (105 mg, 54% yield). MS [M+H]=296.2. Calc'd for C14H15ClFN3O=295.7.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:21]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]#[N:19])[CH:8]=1)=[O:5].C([O-])([O-])=[O:32].[K+].[K+].OO>CS(C)=O.O.Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:21]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=[C:9]([C:18]([NH2:19])=[O:32])[CH:8]=1)=[O:5]
Reactant: N#Cc1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2ccccc2)n1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.5 %

Procedure:
To a solution of 2-chloro-N-(3-cyano-1-phenyl-1H-pyrazol-5-yl)-5-(3-fluoropyridin-2-yl)benzamide (Example 90, 100 mg, 0.24 mmol) in DMSO (3 mL) was added K2CO3 (66 mg, 0.48 mmol) and H2O2 (30% aqueous solution, 1.5 mL) and the reaction was stirred at room temperature for 18 hours. The reaction was diluted with water (1 mL), and 2M aqueous HCl (3 mL) was added resulting in precipitation of a white solid. The solid was filtered, washed with water and dried to afford the title compound as a colourless solid (52.8 mg, 51%).