Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:35]([CH3:36])=[CH:34][C:14]2[N:15]=[C:16]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[N:23]([CH3:27])[N:22]=[C:21]4[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[S:17][C:13]=2[C:12]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CCO>[C:1]([O:5][C@@H:6]([C:11]1[C:35]([CH3:36])=[CH:34][C:14]2[N:15]=[C:16]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[N:23]([CH3:27])[N:22]=[C:21]4[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[S:17][C:13]=2[C:12]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)c(-c3ccccn3)nn4C)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc2nc(-c3ccc4c(c3)c(-c3ccccn3)nn4C)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C

Procedure:
To a vial was dissolved (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-3-(pyridin-2-yl)-1H-indazol-5-yl)benzo[d]thiazol-6-yl)acetate (122 mg, 0.2 mmol) in THF (3 mL) and EtOH (1.5 mL). 1M NaOH (1.5 mL) was added, and the mixture was heated to 50° C. overnight. The reaction was cooled to rt, and filtered (0.45 micron teflon syringe filter). The filtrate was purified by reverse phase HPLC, eluting with 5-100% acetonitrile in H2O with 0.1% TFA to give the desired product as a bright yellow powder. LCMS-ESI+: calc'd for C33H30ClN4O3S: 597.1 (M+H+); Found: 597.2 (M+H+). 1H NMR (400 MHz, CD3OD) δ 8.79 (s, 1H), 8.66 (d, J=4.7 Hz, 1H), 8.33 (d, J=8.1 Hz, 1H), 8.23 (dd, J=11.1, 4.5 Hz, 1H), 8.02 (dd, J=8.9, 1.3 Hz, 1H), 7.76 (s, 1H), 7.75-7.68 (m, 1H), 7.65-7.53 (m, 5H), 5.26 (s, 1H), 4.14 (s, 3H), 2.61 (s, 3H), 0.98 (s, 9H).
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[CH:5][S:4][CH:3]=1.C(NCC)C.[CH:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:7][C:6]1[C:2]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:3][S:4][CH:5]=1
Reactant: Brc1cscc1Br
Reactant: C#CCCCCCC
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: CCCCCCC#Cc1cscc1Br
Temperature: 60 °C
Reaction time: 40 h
Yield: 25.7 %

Procedure:
Into a 250 mL 4 necked RB flask equipped with a magnetic stirring bar, thermometer, rubber septum, argon inlet and reflux condenser with argon outlet (tubed to a silicon oil bubbler) is added 59.4 g (246 mmol) of 3,4-dibromothiophene, 44.0 g of diethylamine, 27.0 g (245 mmol) of 1-octyne, 148 mg of triphenylphosphine, 106 mg of copper iodide and 295 mg dichlorobis(triphenylphosphine) palladium(II). The mixture is heated with a silicon oil bath to 60° C. under argon with stirring for 40 hrs. The cooled mixture is then concentrated on a rotary evaporator at reduced pressure and the residue taken up in 200 mL of pentane and washed with 2×25 mL of water and the pentane phase dried over sodium sulfate and then concentrated on a rotary evaporator. The residue is then distilled at 55-60 ° C. and 0.40 torr to remove 2.3 g of unreacted 3,4-dibromothiophene. The residue was chromatographed through silica gel eluting with hexanes to yield 17.1 g of 3-bromo-4(oct-1-ynyl)thiophene as a light yellow-orange oil which was used directly to prepare 2-hexylselenolo[2,3-c]thiophene.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:15][CH2:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc([N+](=O)[O-])ccc1CBr
Yield: 103.8 %

Procedure:
A mixture of methyl 2-methyl-5-nitrobenzoate (2.51 g, 12.9mmol) and benzoyl peroxide (containing approx. 25% water) (164 mg, 0.51 mmol) in carbon tetrachloride (50 ml) was purged with nitrogen before removing 12 ml of the solvent by distillation. N-Bromosuccinimide (2.30 g, 12.9 mmol) was then added in small portions to the refluxing mixture under irradiation (60W) and the mixture heated at reflux for 2.5 h under nitrogen. The succinimide was removed by filtration and the filtrate evaporated in vacuo to give crude methyl 2-bromomethyl-5-nitrobenzoate (3.67 g) as a yellow oil. To this was added sodium sulphite (2.43 g, 19.3 mmol) and water (10 ml) and the mixture heated at 90° C. for 3 h. The resulting solution was allowed to cool to room temperature and the solid formed was collected, washed with cold water (2×5 ml), then diethyl ether (3×10 ml), and dried under high vacuum in the presence of phosphorus pentoxide. Two more crops were similarly collected to afford the title product (1.46 g, 38%) as a white solid. mp 290°-297° C. 1H NMR (360 MHz, D6-DMSO) δ 3.84 (3H, s), 4.34 (2H, s), 7.68 (1H, d, J=8.5 Hz),8.30 (1H, dd, J=8.5 and 2.6 Hz), 8.41 (1H, d, J=2.5 Hz). MS (FAB) 274 (M-1).
Reaction SMILES: [CH2:1]=[CH:2][C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C:10](=[CH:11][C:12](=[O:22])[CH2:13][CH2:14]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1C=CC=CC=1.CCOCC>[CH2:1]=[CH:2][C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C:10](=[CH:11][C:12](=[O:22])[CH:13]=[CH:14]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1
Reactant: C=C[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOCC
Solvent: c1ccccc1
Product: C=C[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Yield: 22.1 %

Procedure:
Pregna-4,20-dien-3-one (1, 1.19 g. 3.99 mmol) was refluxed for 24 h with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 2.72 g, 12.1 mmol) in 40 ml of benzene under Argon. The cooled suspension was diluted with ether and washed with two 100 ml portions of 5% (w/w) sodium hydroxide, two 100 ml portions of water and once with 100 ml of brine. Ether (100 ml) was added to the resulting emulsion, which was dried over sodium sulfate and then filtered through a column of sodium sulfate (20 g). After washing the residue twice with 50 ml portions of ether the combined filtrates were concentrated under reduced pressure and then flash chromatographed (25% ethyl acetate/hexanes on silica gel) to give a slightly yellow crystalline solid (0.26 g, 0.88 mmol, 22%).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH3:7])[CH2:5][OH:6].[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:22]=[N:23][C:24]([NH:27][C:28]3[N:29]=[CH:30][C:31]4[CH:37]=[C:36](F)[C:35](=[O:39])[N:34]([CH:40]5[CH2:44][CH2:43][CH2:42][CH2:41]5)[C:32]=4[N:33]=3)=[CH:25][CH:26]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>CCCCCC>[C:8]([O:12][C:13]([N:15]1[CH2:16][CH2:17][N:18]([C:21]2[CH:22]=[N:23][C:24]([NH:27][C:28]3[N:29]=[CH:30][C:31]4[CH:37]=[C:36]([O:6][CH2:5][CH:4]([CH3:7])[CH3:3])[C:35](=[O:39])[N:34]([CH:40]5[CH2:41][CH2:42][CH2:43][CH2:44]5)[C:32]=4[N:33]=3)=[CH:25][CH:26]=2)[CH2:19][CH2:20]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)CO
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc4cc(F)c(=O)n(C5CCCC5)c4n3)nc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: CC(C)COc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 95 °C
Yield: 37 %

Procedure:
60% Sodium hydride in oil (0.182 g, 4.4 mmol) was washed with hexane and added to 2-methyl-1-propanol (10 ml). This mixture effervesced and formed a solution. To this solution was added 4-[6-(8-cyclopentyl-6-fluoro-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.225 g, 0.44 mmol, prepared as in Example 17) and the mixture was heated at 95° C. for 72 hours. The solvents were evaporated, and the residue was dissolved in diethyl ether then filtered. The filtrate was evaporated to provide 4-[6-(8-cyclopentyl-6-isobutoxy-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester as a crystalline solid (0.092 g, 37%). MS (APCI) M++1: Calc'd, 564.3. Found 564.3.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Na].Cl.[CH2:14]([N:21]1[CH:25]=[CH:24][N:23]=[C:22]1[CH2:26]Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[C:1]([CH:2]([CH2:26][C:22]1[N:21]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:25]=[CH:24][N:23]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: ClCc1nccn1Cc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(Cc1nccn1Cc1ccccc1)C(=O)OCC
Temperature: 0 °C

Procedure:
Diethyl malonate (52.45 g) in ethanol (50 ml) was added dropwise to a solution of sodium (11.3 g) in dry ethanol (300 ml) with stirring. The mixture was cooled to 0° C. and a solution of 1-benzyl-2-chloromethylimidazole hydrochloride (40.0 g, prepared as described in J.A.C.S. 1949, 383) in dry ethanol (250 ml) was added over 30 minutes with stirring. The mixture was stirred at ambient temperature for 2 hours and then the ethanol removed under reduced pressure. Ice cold 2M hydrochloric acid (400 ml) was added to the residue and the mixture was washed with ether. The aqueous layer was basified with solid sodium carbonate and then extracted with dichloromethane to give ethyl 2-carbethoxy-3-(1-benzyl-1H-imidazol-2-yl)propanoate as an oil.
Reaction SMILES: [ClH:1].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]1[CH2:11][CH2:10][CH2:9][CH:8]1[NH2:12].Cl.[C:14]1([C@H:20]2CCC[C@H:21]2[NH2:25])[CH:19]=[CH:18][CH:17]=CC=1>>[ClH:1].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]1[CH2:11][CH2:10][CH2:9][CH:8]1[N:12]=[C:21]1[CH2:20][CH2:14][CH2:19][CH2:18][CH2:17][NH:25]1
Reactant: N[C@@H]1CCC[C@@H]1c1ccccc1
Reactant: NC1CCCC1c1cccs1
Agent: Cl
Product: c1csc(C2CCCC2N=C2CCCCCN2)c1

Procedure:
By the procedure described in U.S. Pat. No. 2,520,516 (1950) 2-(2-thienyl)cyclopentylamine hydrochloride, M.P. 168°-172° C., was prepared and substituted for cis-2-phenylcyclopentylamine hydrochloride in Example 1 to give the desired product, M.P. 144°-151° C.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:17]1([C:26]([OH:28])=O)[CH:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[CH:19][CH:18]=1>CCOC(C)=O>[CH2:2]([O:9][C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:26](=[O:28])[C:17]1[CH:18]=[CH:19][C:20]([C:23]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]2[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:16])=[O:25])=[CH:21][CH:22]=1)=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)c1ccc(C(=O)N2CCC[C@@H]2C(=O)OCc2ccccc2)cc1
Yield: 71.8 %

Procedure:
Using General Procedure A with 5.8 g (24.0 mmol) D-Proline benzyl ester hydrochloride and 2.0 g (12.0 mmol) benzene-1,4-dioic acid afforded, after flash chromatography (EtOAc), 4.66 g (72%) of the title compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](OC)=[O:10].[H-].[Na+].[CH:15]([O:17][CH2:18][CH3:19])=[O:16]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[CH:9][OH:10])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC=O
Reactant: COC(=O)Cc1ccccc1Br
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(=CO)c1ccccc1Br
Yield: 87 %

Procedure:
To a stirred solution of methyl 2-(2-bromophenyl)acetate (5.2 g, 22.7 mmol) in ethyl formate (40 mL) was added in portions the powder of sodium hydride (100%, 2.18 g, 90.8 mmol) over a period of 1 hour at 10-15° C. After the mixture was stirred for an additional hour, the reaction was quenched with ice water (100 mL) and the two layers were separated. The aqueous layer was acidified with 10% hydrochloric acid aqueous solution and then extracted with ethyl acetate (30 mL×3). The organic layers were combined and washed with water (2×20 mL), saturated sodium bicarbonate solution (2×40 mL) and brine in turns. Then organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give ethyl 2-(2-bromophenyl)-3-hydroxyacrylate as a pink oil (5.33 g, 87%). 1H NMR (300 MHz, CDCl3): δ 11.99 (d, J=12.7 Hz, 1H), 7.59 (dd, J=7.8 Hz, 0.9 Hz, 1H), 7.46-6.98 (m, 4H), 4.25 (q, J=7.2 Hz, 2H), 1.24 (t, J=7.2 Hz, 3H).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([Cl:13])[N:5]=1.[C:14]([O:18][CH3:19])(=[O:17])[CH2:15][OH:16]>O1CCOCC1>[Cl:13][C:6]1[N:5]=[C:4]([O:16][CH2:15][C:14]([O:18][CH3:19])=[O:17])[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=1
Reactant: COC(=O)CO
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)COc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride is added to a mixture of 2,6-dichloro-3-nitropyridine, methyl glycolate and 1,4-dioxane at 10° C. The mixture is stirred at room temperature for 2 hours, then, poured into ice water, and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, and concentrated. The residue is subjected to silica gel column chromatography to obtain 6-chloro-2-(methoxycarbonyl)methoxy-3-nitropyridine.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[N:6]([CH3:8])[CH3:7].[O:12]1[CH2:14][C@@H:13]1[C@@H:15]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[CH3:7][N:6]([CH3:8])[C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][CH:9]=1)[CH2:2][NH:1][CH2:14][C@@H:13]([OH:12])[C@@H:15]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN(C)c1cccc(CN)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1
Solvent: ClCCl
Product: CN(C)c1cccc(CNC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)c1
Temperature: 50 °C

Procedure:
3-(aminomethyl)-N,N-dimethylaniline (1.2 eq) was dissolved in the minimum amount of anhydrous CH2Cl2 under Ar, followed by the addition of tert-butyl (S)-1-((S)-oxiran-2-yl)-2-phenylethylcarbamate (1 eq) with stirring. Anhydrous CH2Cl2 was added dropwise until all of the epoxide had dissolved. The reaction was heated to 50° C. After heating overnight all of the solvent was gone leaving a solid in the flask. Purification via flash chromatography yielded tert-butyl (2S,3R)-4-(3-(dimethylamino)benzylamino)-3-hydroxy-1-phenylbutan-2-ylcarbamate.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7]([CH2:10]O)[CH:8]=[CH:9][C:2]1=2.C(N(CC)CC)C.CS([Cl:23])(=O)=O>ClCCl>[O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7]([CH2:10][Cl:23])[CH:8]=[CH:9][C:2]1=2
Reactant: OCc1ccc2c(c1)CCO2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: ClCc1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a solution of (2,3-dihydrobenzo[b]furan-5-yl)methanol (1.5 g, 10 mmol) in dichloromethane (10 mL) were added under ice-cooling triethylamine (1.67 mL, 12 mmol) and methanesulfonyl chloride (0.85 mL, 10 mmol) and the mixture was stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure and the obtained residue was dissolved in ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give an almost pure title compound (1.6 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10](/[C:13](/[C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([Cl:24])=[CH:18][C:17]=3F)=[N:14]/[OH:15])=[C:9]([CH2:26][CH2:27][CH3:28])[CH:8]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:24][C:19]1[C:20]([O:22][CH3:23])=[CH:21][C:16]2[C:13]([C:10]3[CH:11]=[CH:12][C:7]([O:6][C:5]4[CH:29]=[CH:30][C:2]([Cl:1])=[CH:3][CH:4]=4)=[CH:8][C:9]=3[CH2:26][CH2:27][CH3:28])=[N:14][O:15][C:17]=2[CH:18]=1
Reactant: CCCc1cc(Oc2ccc(Cl)cc2)ccc1/C(=N/O)c1cc(OC)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1-c1noc2cc(Cl)c(OC)cc12
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of the oxime from Step 4 (1.2 g, 2.7 mmol) and cesium carbonate (1.7 g, 5.4 mmol) in DMF (20 mL) was stirred at 80° C. for 18 h. The reaction was diluted with ethyl acetate and washed with water. The crude product was purified by chromatography on silica gel to give the title product.
Reaction SMILES: C([O:5][C:6](=[O:40])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH3:15])=[C:9]([N:16]=[C:17]2[N:21]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:20](=[O:29])[C:19](=[C:30]3[N:34]([CH3:35])[C:33]4[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=4[S:31]3)[S:18]2)[CH:8]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH2:22]([N:21]1[C:20](=[O:29])[C:19](=[C:30]2[N:34]([CH3:35])[C:33]3[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=3[S:31]2)[S:18][C:17]1=[N:16][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[NH:13][CH2:14][CH3:15])[C:6]([OH:40])=[O:5])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCNc1ccc(C(=O)OC(C)(C)C)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNc1ccc(C(=O)O)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
The product of Example 90 was treated with 55% TFA/DCM for 1 h, concentrated under reduced pressure, diluted with DCM, concentrated once again, diluted with DCM, allowed to stand over solid NaHCO3, filtered and concentrated to afford the title product. MS(ESI): 517 (MH+).
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([CH2:9][CH3:10])O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:19]C(=O)C)C.[N-]=C=O.N1C=CC=CC=1>CCOCC>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH2:10][OH:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(C)=O
Reactant: CCC(O)(c1ccccc1)c1ccccc1
Agent: [N-]=C=O
Solvent: CCOCC
Solvent: c1ccncc1
Product: OCCC(c1ccccc1)c1ccccc1

Procedure:
3.2 G of diphenyl-ethyl-carbinol, 1.9 g of isocyanate acetic acid ethyl ester and 1.6 ml of pyridine are heated at 50° C for 72 hours. The solution is diluted with 50 ml of ether, washed several times at 0° C with 0.1-molar citric acid solution and water, dried over sodium sulfate, and completely evaporated under reduced pressure. After elimination of 2.3 g of diphenylethylcarbinol by means of petroleum ether, 1,1-diphenyl-propyloxycarbonyl-glycine-ethyl ester is obtained in the form of an oil; Rf = 0.2 in the thin-layer chromatogram in chloroform.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]#[N:20])[CH:14]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.CS(C)=[O:25].OO.C(=O)([O-])[O-].[K+].[K+]>O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH2:20])=[O:25])[CH:14]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:21][CH:22]=1
Reactant: N#Cc1cc(-c2cccnc2Oc2ccc(N)cc2)ccn1
Reactant: CS(C)=O
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Product: NC(=O)c1cc(-c2cccnc2Oc2ccc(N)cc2)ccn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared according to the reference: Katritzky, A. R.; Pilarski, B.; Urogdi, L. Synthesis 1989, 949. As described, a solution of 4-(2-(4-aminophenoxy)pyridin-3-yl)picolinonitrile (764 mg, 2.65 mmol) in DMSO (0.883 mL, 2.65 mmol) was cooled to 0° C. 2.7 mL of 30% Hydrogen peroxide in water was added followed by potassium carbonate (37 mg, 0.27 mmol). The solution became a thick, milky white suspension. The mixture was warmed to rt. After 10 min, 1 mL of H2O2 and 20 mg of K2CO3 were added. After 20 min, LC-MS showed that the reaction was completed. The white solid was filtered off and washed with water. The product was dried under vacuum, to afford 4-(2-(4-aminophenoxy)pyridin-3-yl)picolinamide. MS m/z=307 [M+1]+. Calcd for C17H14N4O2: 306.11.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]2[C:27]1=[O:36])(OCC)=O>O>[C:27]1(=[O:36])[N:1]([CH:2]([C:7]2[CH:8]=[CH:9][C:10]([C:13]#[N:14])=[CH:11][CH:12]=2)[CH2:3][C:4]([OH:6])=[O:5])[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: N#Cc1ccc(C(N)CC(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1
Reaction time: 2 h
Yield: 23.4 %

Procedure:
To a stirred mixture of 3-amino-3-(4-cyanophenyl)propionic acid (3.80 g, 20.0 mmol) and sodium carbonate (2.23 g, 21 mmol) in 100 mL of water is added N-carboethoxyphthalimide (4.52 g, 20.0 mmol). After 2 hour, the reaction slurry is filtered and the pH of the stirred filtrate adjusted to 1-2 with 4 N hydrochloric acid. The resulting gel is extracted with ethyl acetate (3×30 mL). The extract is dried over magnesium sulfate and concentrated in vacuo. The crude product is recrystallized from 10% aqueous acetonitrile and then recrystallized from 20% aqueous methanol. The product is dried in vacuo (60° C.,<1 mm) to afford 1.5 g (23%) of 3-phthalimido-3-(4-cyanophenyl)propionic acid as a white powder: mp 134-137° C.; 1H NMR (DMSO-d6, 250 MHz)δ 12.5 (br s, 1H), 7.95-7.56 (m, 8H),.5.76 (t, 1H, J=7.7), 3.57-3.15 (m, 2H); 13C NMR (DMSO-d6)δ 171.5, 167.6, 144.2, 134.8, 132.6, 131.1, 128.1, 123.3, 118.5, 49.7, 35.5.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:15]Br.C(OCC)C>C(O)(=O)C>[Br:15][CH2:2][C:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccc(OCC(=O)O)cc1
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C(O)COc1ccc(C(=O)CBr)cc1
Reaction time: 48 h
Yield: 46 %

Procedure:
2-(4-acetylphenoxy)acetic acid (2.81 g, 14.5 mmol) was dissolved in acetic acid (100 mL) and treated with bromine (740 μL, 14.5 mmol) and stirred 48 hours. Bromine (370 mL, 7.25 mmol) was added and solution was stirred for an additional 16 hours. Volatiles were removed under reduced pressure to provide a brown solid which was titrated with diethyl ether to provide 2-(4-(2-bromoacetyl)phenoxy)acetic acid (1.82 g) as a light brown solid.
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6][C:7]([F:25])([F:24])[C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])([OH:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH2:5][CH2:4]1.[CH3:26]I.O>CN(C)C=O>[CH:3]1([S:6][C:7]([F:24])([F:25])[C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])([O:15][CH3:26])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH2:5][CH2:4]1
Reactant: OC(Cn1cncn1)(c1ccc(F)cc1F)C(F)(F)SC1CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(Cn1cncn1)(c1ccc(F)cc1F)C(F)(F)SC1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
To a solution of 60% sodium hydride (75 mg, 1.87 mmol) in N,N-dimethylformamide (50 ml), 1-(cyclopropylthio)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol (0.50 g, 1.44 mmol) was added dropwise under ice cooling, followed by stirring at room temperature for 30 minutes. Methyl iodide (270 mg, 1.87 mmol) was then added dropwise to the reaction mixture under ice cooling and the resulting mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with ether. The ether solution was washed with water and dried over sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was subjected to a silica gel column and from the chloroform eluate fraction, 1-[3-(cyclopropylthio)-2-(2,4-difluorophenyl)-3,3-difluoro-2-methoxypropyl]-1H-1,2,4-triazole (0.31 g, yield: 60%) was obtained as a colorless oil.