Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]3[C:19]4[N:20]([CH:25]=[CH:26][N:27]=4)[CH:21]=[C:22]([Br:24])[N:23]=3)[CH:15]=2)[CH:10]=[CH:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Br:24][C:22]1[N:23]=[C:18]([NH:17][C:14]2[CH:15]=[C:16]3[C:11]([CH:10]=[CH:9][NH:8]3)=[CH:12][CH:13]=2)[C:19]2[N:20]([CH:25]=[CH:26][N:27]=2)[CH:21]=1
Reactant: CC(C)(C)OC(=O)n1ccc2ccc(Nc3nc(Br)cn4ccnc34)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Brc1cn2ccnc2c(Nc2ccc3cc[nH]c3c2)n1

Procedure:
A quantity of 0.23 g (1 mmole) of 6-Amino-indole-1-carboxylic acid tert-butyl ester is treated with 0.27 g (1 mmole) of 6,8-Dibromo-imidazo[1,2-a]pyrazine in acetonitrile with 3 eq. of K2CO3 at reflux for 16 hrs. The reaction mixture is cooled partitioned between ethyl acetate and water, the organic extracts are dried over anhydrous MgSO4 and evaporated in vacuo to afford 6-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-indole-1-carboxylic acid tert-butyl ester. 6-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-indole-1-carboxylic acid tert-butyl ester is treated with an excess of TFA in dichloromethane at room temperature for 2 hrs. The reaction solution is evaporated in vacuo and partitioned between saturated Na2CO3 and ethyl acetate; the organic extracts are dried over anhydrous MgSO4 and evaporated in vacuo to afford (6-Bromo-imidazo[1,2-a]pyrazin-8-yl)-(1H-indol-6-yl)-amine.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=[C:4]([Cl:12])[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CN(C=O)C.O>[Cl:12][C:4]1[N:3]=[C:2]([N:23]2[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]2)[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=1
Reactant: Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(c2nc(Cl)cc(N)c2[N+](=O)[O-])CC1
Reaction time: 0.08 h

Procedure:
A solution of 2,6-dichloro-3-nitro-pyridin-4-ylamine (0.500 g, 2.40 mmol) in DMF (5 mL) was treated with K2CO3 (1.66 g, 12.0 mmol) and 1-methylpiperazine (0.267 mL, 2.40 mmol) at room temperature for 18 h. The resulting mixture was diluted with water (75 mL) and extracted three times with EtOAc (50 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 24-g SEPRA Si 50 SPE column (Isco system: Flow rate=15 mL/min; Eluent=EtOAc-hexanes, 3:1 v/v for 5 min, then 3:1 to 1:0 v/v over 40 min) to yield 6-chloro-2-(4-methyl-piperazin-1-yl)-3-nitro-pyridin-4-ylamine as a bright yellow solid. 1H-NMR (400 MHz, CD3OD) δ: 6.22 (s, 1H), 3.39-3.45 (m, 4H), 2.49-2.55 (m, 4H), 2.34 (s, 3H). Mass Spectrum (LCMS, APCI pos.): Calculated for C10H14ClN5O2: 272.1 (M+H). Measured: 272.1.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:13]([F:16])([F:15])[F:14])=[N:5][N:6]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:7]=1[Cl:8].CN(C)C=O.O.[SH-:23].[Na+]>C(OCC)C>[C:9]([N:6]1[C:7]([Cl:8])=[C:3]([CH2:2][SH:23])[C:4]([C:13]([F:16])([F:15])[F:14])=[N:5]1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)n1nc(C(F)(F)F)c(CBr)c1Cl
Reactant: [SH-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)n1nc(C(F)(F)F)c(CS)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
43.5 g (136.1 mmoles) of 4-bromomethyl-1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole was added to 300 ml of a N,N-dimethylformamide solution containing 21.8 g (272.2 mmoles) of sodium hydrosulfide hydrate (purity: 70%). The mixture was stirred at room temperature overnight to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into ice water and extraction with diethyl ether was conducted. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein, to obtain 32.3 g (yield: 87.0%) of (1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-yl)-metha-nethiol.
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:7]=[CH:8][C:9](F)=[N:10][CH:11]=1)[CH3:5])=[N+:2]=[N-:3].[S:13]1[CH:17]=[CH:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:21](C3C=CN=CC=3C(O)C)[C:14]1=2>>[N:1]([CH:4]([C:6]1[CH:11]=[N:10][CH:9]=[CH:8][C:7]=1[C:21]1[C:14]2[S:13][CH:17]=[CH:16][C:15]=2[CH:18]=[CH:19][CH:20]=1)[CH3:5])=[N+:2]=[N-:3]
Reactant: CC(N=[N+]=[N-])c1ccc(F)nc1
Reactant: CC(O)c1cnccc1-c1cccc2ccsc12
Product: CC(N=[N+]=[N-])c1cnccc1-c1cccc2ccsc12

Procedure:
Using a procedure similar to the one used for 5-(1-azido-ethyl)-2-fluoro-pyridine above, prepare the title intermediate from 1-(4-(benzo[b]thiophen-7-yl)pyridin-3-yl)ethanol as a brown oil (0.66 g, 93%). MS (ES) m/z 280 [M+1]+.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[C:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)#[N:31]>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:35]3[CH:36]=[CH:37][C:32]([C:30]#[N:31])=[CH:33][CH:34]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccc(C#N)cc2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 4-cyanophenylboronic acid. The title compound was obtained in 45% yield as yellow foam. MS (m/e): 507.4 (MH+, 100%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)([CH3:11])[CH2:9][OH:10])(C)(C)C.C(OC(=O)C)C.[ClH:26]>C(OCC)(=O)C>[ClH:26].[NH2:7][C:8]([C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)([CH3:11])[CH2:9][OH:10]
Reactant: CC(C)(C)OC(=O)NC(C)(CO)c1ccc(F)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(N)(CO)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an ethyl acetate (1 mL) solution of (1-(4-fluorophenyl)-2-hydroxy-1-methylethyl)carbamic acid tertiary butyl ester (252 mg), 4 N hydrochloric acid ethyl acetate solution (3 mL) was added, and the reaction solution was agitated at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain 192 mg of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][N:16]2C(=O)C3C(=CC=CC=3)C2=O)([F:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:15][NH2:16])([F:14])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(F)(CN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(F)(CN)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The 4-[(1,3-dioxoisoindolin-2-yl)methyl]-4-fluoropiperidinecarboxylic acid tert-butyl ester was dissolved in ethanol (200 mL), and then hydrazine monohydrate (10.0 mL) was added. After stirring at room temperature for 2 hours, the precipitated solid was filtered out and the filtrate was concentrated under reduced pressure. The obtained crudely purified product was further purified by silica gel column chromatography (5% MeOH/CH2Cl2) to obtain 4-(aminomethyl)-4-fluoropiperidinecarboxylic acid tert-butyl ester. The compound was identified by 1H-NMR. The yield was 3.23 g (76%).
Reaction SMILES: [CH2:1]([N:8]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@@H:9]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@@H:10]([CH:12]1[NH:18][C:17](=O)[CH:16]=[CH:15][CH2:14][CH2:13]1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(=O)C>C1COCC1.C(OCC)C>[NH:18]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C@@H:10]([OH:11])[C@@H:9]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1C=CCCC([C@@H](O)[C@H](Cc2ccccc2)N(Cc2ccccc2)Cc2ccccc2)N1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: O[C@H](C1CCCCCN1)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Yield: 18.1 %

Procedure:
Dissolve 7-((1R,2S)-2-dibenzylamino-1-hydroxy-3-phenylpropyl)-1,5,6,7-tetrahydroazepin-2-one (Isomer 1) (40 mg, 0.09 mmol) in THF (5 mL) and add BH3SMe2 (2 M in diethyl ether, 0.14 mL, 0.27 mmol). Stir the reaction at 50° C. for 3 hour. Add saturated aqueous citric acid (10 mL). Extract aqueous twice with ethyl acetate, combine organics and wash with saturated sodium chloride, dry (magnesium sulfate) and concentrate under reduced pressure. Add 20% palladium hydroxide on carbon (90 mg) and methanol (10 mL) and stir under 1 atmosphere of hydrogen overnight. Filter and evaporate to give a foam. Purify the product using a SCX column to give a thick residue (0.007 g, 40%).
Reaction SMILES: O.O.[Sn](Cl)Cl.[Cl:6][C:7]1[N:12]=[C:11]([C:13]#[N:14])[C:10]([N+:15]([O-])=O)=[C:9]([NH:18][CH3:19])[CH:8]=1.C(OCC)(=O)C.[OH-].[NH4+]>C(O)C>[NH2:15][C:10]1[C:11]([C:13]#[N:14])=[N:12][C:7]([Cl:6])=[CH:8][C:9]=1[NH:18][CH3:19]
Reactant: CNc1cc(Cl)nc(C#N)c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNc1cc(Cl)nc(C#N)c1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.5 %

Procedure:
Tin(II) chloride dihydrate (21 g) was added to a suspension of 6-chloro-4-methylamino-3-nitro-pyridine-2-carbonitrile (6.6 g) in ethanol (150 ml). The mixture was stirred at room temperature for 3 hours. To above red-brown coloured solution was then added ethyl acetate (1000 ml) and followed by 10% aqueous ammonium hydroxide (200 ml). The organic layer were seperated, the sticky solid pad was washed with ethyl acetate (5×200 ml). Combined organic layer was then washed with saturated sodium chloride aqueous solution (2×200 ml), dried over sodium sulphate, solvent removed to give a brown solid as expected product (5.7 g).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH2:13]1)[CH3:2].[C:24](Cl)(=[O:28])[C:25](Cl)=[O:26]>C(OCC)C>[CH2:1]([N:3]1[C:4]2[C:9](=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[CH2:13]2)[C:25](=[O:26])[C:24]1=[O:28])[CH3:2]
Reactant: CCNc1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Product: CCN1C(=O)C(=O)c2c(OC)ccc(C3CCc4cc(OC)ccc4C3)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (260 mg) in diethyl ether (30 ml) was added dropwise oxalyl chloride (0.21 ml) on an ice bath, and the solution was stirred for 30 minutes at room temperature. The reaction solution was concentrated in vacuo, the total amount of the resulting {ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amino}oxoacetyl chloride (crude product) was stirred in dichloromethane (5 ml), a solution of aluminum chloride (220 mg) in dichloromethane (20 ml) was added dropwise thereto on an ice bath, and the solution was stirred overnight at room temperature. The reaction mixture was diluted with ice water, extracted with chloroform, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (160 mg).
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH:15]([CH3:17])[CH3:16])([CH2:8][CH2:9][C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[O:5][C:4](=[O:18])[CH:3]=1.C([SiH2][O:24][C:25](C)(C)[C:26]1[S:30][C:29]([CH:31]([CH3:33])[CH3:32])=[C:28]([S:34]S(C2C=CC(C)=CC=2)(=O)=O)[CH:27]=1)(C)(C)C.CCN(CC)CC.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O.C1COCC1.C(#N)C>[OH:1][C:2]1[CH2:7][C:6]([CH:15]([CH3:16])[CH3:17])([CH2:8][CH2:9][C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[O:5][C:4](=[O:18])[C:3]=1[S:34][C:28]1[CH:27]=[C:26]([CH2:25][OH:24])[S:30][C:29]=1[CH:31]([CH3:33])[CH3:32]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C(C)(C)O[SiH2]C(C)(C)C)sc2C(C)C)cc1
Reactant: CC(C)C1(CCc2ccsc2)CC(O)=CC(=O)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)c1sc(CO)cc1SC1=C(O)CC(CCc2ccsc2)(C(C)C)OC1=O
Reaction time: 0.5 h

Procedure:
The title compound was prepared according to General Method 16b using 4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one (Example E-20; 0.200 g, 0.75 mmol), toluene-4-thiosulfonic acid S-[5-(tert-butyl-dimethyl-silanyloxymethyl)-2-isopropyl-thiophen-3-yl]ester (Example BB-9; 0.377 g, 0.83 mmol), NEt3 (0.209 mL, 1.50 mmol), and acetonitrile (1.5 mL). As part of the purification, the silylether was cleaved by dissolving the crude coupled product in THF (50 mL) and then treated with a 1.0 M THF solution of tetrabutylammoniumflouride (1.5 mL, 1.5 mmol). After 30 minutes, the mixture was diluted with H2O and extracted with EtOAc. The organic layers were then combined, dried (MgSO4), and concentrated. The resulting residue was then submitted to column chromatography (eluting with 3% MeOH in CH2Cl2) to provide the title compound, mp 52-54° C.
Reaction SMILES: [C:1]([O:8]CCCC)(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:6])=[O:5].[CH2:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(OOC(C)(C)C)(C)(C)C>C(OCC)(=O)C>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[CH2:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCCCOC(=O)/C=C\C(=O)[O-]
Agent: CC(C)(C)OOC(C)(C)C
Solvent: CCOC(C)=O
Solvent: C=Cc1ccccc1
Product: O=C(O)/C=C\C(=O)O
Reaction time: 2 h

Procedure:
Into a four-necked flask equipped with a stirrer, reflux condenser, thermometer and gas-inlet tube were introduced 600 parts of ethyl acetate which was heated and kept at 75° to 78° C. under a stream of nitrogen gas. A monomer mixture composed of 249 parts of monobutyl maleate, 151 parts of styrene and 4 parts of di-tert-butyl peroxide as a polymerization initiator was added dropwise into the flask taking about 2 hours to form a polymerization mixture which was agitated for further 2 hours at the same temperature to effect copolymerization of the monomers. After completion of the polymerization reaction, the polymerization mixture was freed from the solvent by stripping under reduced pressure to give a solid copolymeric resin of maleic acid and styrene.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl.[CH3:10][C:11](=O)[CH:12]=[CH:13][CH3:14].[OH-].[Na+]>C(OCC)(=O)C>[CH3:10][C:11]1[CH:12]=[C:13]([CH3:14])[C:7]2[C:2](=[C:3]([OH:8])[CH:4]=[CH:5][CH:6]=2)[N:1]=1
Reactant: CC=CC(C)=O
Reactant: Nc1ccccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1cc(C)c2cccc(O)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.1 %

Procedure:
In a three-necked flask were placed 33 g of o-aminophenol and 207 g of concentrated hydrochloric acid and the mixture was heated to the reflux temperature and stirred for 1 hour. To the mixture being heated under reflux was slowly added 51 g of 3-penten-2-one with a purity of 65% over 2 hours and stirring was continued for another 2 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature, 300 ml of a 48% aqueous solution of NaOH was added until the aqueous phase became alkaline. Ethyl acetate was added further, the organic layer was recovered and the solvent was distilled off under reduced pressure. The crude product thus obtained was purified by gas chromatography, recrystallized from hexane and the crystals collected by filtration were washed with hexane and dried at 80° C. under reduced pressure to give 18.9 g of 2,4-dimethyl-8-quinolinol.
Reaction SMILES: C([S:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[CH2:17][C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])(=O)C1C=CC=CC=1>N>[SH:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[CH2:17][C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19]
Reactant: O=C(O)CNC(=O)Cc1ccc(Cl)cc1SC(=O)c1ccccc1
Agent: N
Product: O=C(O)CNC(=O)Cc1ccc(Cl)cc1S
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
4.9g (0.065 mol) of glycine was dissolved in 250 ml of 0.5 N--NaOH and then to the solution was added dropwise 14.6g (0.054 mol) of 2-bromo-p-chlorophenylacetyl chloride over 1 hour while stirring and cooling with a freezing mixture. After completion of the addition, the reaction mixture was stirred at room temperature for an additional 2 hours. During stirring, the pH of the mixture was adjusted to 8. The filtrate which had been prepared by dissolving 11.6g (0.08 mol) of thiobenzoic acid in 40 ml of 2N--KOH and filtering the solution to remove undissolved substances was added to the reaction mixture followed by stirring at room temperature overnight. The next morning, the mixture was acidified with hydrochloric acid while ice-cooling to precipitate crystals. These crystals were recovered by filtration, washing with water and washing with benzene to give 15.1g of crude N-(2-benzoylmercapto-p-chlorophenylacetyl)glycine. The product had a melting point of 158° - 159°C after recrystallization from ethyl acetate-benzene. 11.0g (0.03 mol) of N-(2-benzoylmercapto-p-chlorophenylacetyl)glycine was dissolved in 75 ml of concentrated aqueous ammonia followed by stirring at room temperature for 1 hour. After removal of benzamide by extraction with ethyl acetate, the resulting aqueous layer was treated in a similar manner in accordance with Example I to give 6.0g of N-(2-mercapto-p-chlorophenylacetyl)glycine, ClC6H4CH(SH)--CONHCH2COOH. (m.p. 148° - 149°C, Purity; 100 % (iodometry))
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[C:20]2[C:15](=[CH:16][N:17]=[C:18]([CH2:21][OH:22])[CH:19]=2)[O:14][CH:13]=1.CCN(CC)CC>C1COCC1.C(Cl)Cl>[Cl:11][C:12]1[C:20]2[C:15](=[CH:16][N:17]=[C:18]([CH:21]=[O:22])[CH:19]=2)[O:14][CH:13]=1
Reactant: OCc1cc2c(Cl)coc2cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=Cc1cc2c(Cl)coc2cn1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 77.1 %

Procedure:
Oxalyl chloride (231 μL, 2.6 mmol) is combined with CH2Cl2 (10 mL), cooled to −78° C., treated dropwise with DMSO (373 μL, 5.3 mmol) and stirred for 20 min. The cooled solution is treated dropwise with a solution of (3-chlorofuro[2,3-c]pyridin-5-yl)methanol (420 mg, 2.3 mmol) in THF (5 mL)/CH2Cl2 (5 mL), stirred for 1 h, then treated dropwise with Et3N (1.59 mL, 11.45 mmol). The mixture is stirred for 30 min at −78° C., then 30 min at 0° C. The mixture is washed with saturated NaHCO3 (20 mL) and the organics dried over K2CO3 and concentrated in vacuo to a yellow solid (410 mg). The crude material is chromatographed over 20 g slurry-packed silica gel, eluting with 15% EtOAc/hexane. The appropriate fractions are combined and concentrated in vacuo to afford 322 mg (77%) of 3-chlorofuro[2,3-c]pyridine-5-carbaldehyde as a white solid. 1H NMR (CDCl3): δ 7.89, 8.33, 9.02, 10.18 ppm. 3-Chlorofuro[2,3-c]pyridine-5-carbaldehyde (317 mg, 1.74 mmol) is dissolved in THF (10 mL)/t-BuOH (5 mL)/H2O (5 mL), treated with a single portion of sodium chlorite (592 mg, 5.24 mmol) and KH2PO4 (473 mg, 3.48 mmol) and stirred at rt for 18 h. The reaction mixture is concentrated in vacuo to dryness, suspended in water (10 mL), acidified to pH 3.5 with concentrated HCl and stirred at rt for 2 h. The resulting solid is filtered, washed with water and dried in a vacuum oven at 40° C. for 18 h to afford 364 mg of 3-chlorofuro[2,3-c]pyridine-5-carboxylic acid as a white solid. MS (EI) m/z: 197 (M+).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].[H-].[Na+].[CH3:18][C:19]([CH3:21])=O>C(COC)OC.O>[CH2:2]([O:3][C:4](=[O:5])[C:6]([F:7])=[C:19]([CH3:21])[CH3:18])[CH3:1]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(F)=C(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.5 %

Procedure:
Triethyl 2-fluoro-2-phosphonoacetate (20 g, 82.6 mmol) (Aldrich) was added dropwise to a stirred solution of sodium hydride (3.6 g, 90.8 mmol) in dimethoxyethane (100 mL) at 0° C. After stirring at room temperature for 20 min, acetone (4.78 g, 82.6 mmol) was added and the reaction mixture was refluxed for overnight. The two phase mixture was cooled, diluted with water and extracted with ether. The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified with chromatography (Hexanes) to give 2-fluoro-3-methyl-but-2-enoic acid ethyl ester as colorless oil (Yield: 9.0 g, 61.6%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18]CC)=[O:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+].Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)Cc1ccc(-c2ccc(OC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2ccc(CC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 232.6 %

Procedure:
To a solution of 250 mg (0.93 mmol) of ethyl 4-(4-methoxyphenyl)phenylacetate in 30 ml of ethanol was added, with cooling with ice, 5 ml of 40% sodium hydroxide aqueous solution. This mixture was stirred at room temperature for 2 days. The reaction mixture was neutralized with 3 M hydrochloric acid, and the solvent was then removed by evaporation under reduced pressure. Thereafter, the pH of the resulting mixture was adjusted to 1 with 3 M hydrochloric acid, and this mixture was subjected to extraction with 200 ml of ether. The resulting ether solution was washed with saturated sodium chloride aqueous solution, dried with anhydrous magnesium sulfate, filtered, and then concentrated. Thus, 524 mg (yield 94%) of 4-(4-methoxyphenyl)-phenylacetic acid was obtained.
Reaction SMILES: [CH3:1][CH:2]([CH3:4])[O-:3].[Na+].Cl[CH2:7][C:8]1[N:9]=[C:10]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:21]=2[C:22]([F:25])([F:24])[F:23])[O:11][C:12]=1[CH:13]1[CH2:15][CH2:14]1>CC(O)C>[CH:13]1([C:12]2[O:11][C:10]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[C:22]([F:25])([F:24])[F:23])=[N:9][C:8]=2[CH2:7][O:3][CH:2]([CH3:4])[CH3:1])[CH2:15][CH2:14]1
Reactant: CC(C)[O-]
Reactant: FC(F)(F)c1ccncc1-c1nc(CCl)c(C2CC2)o1
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)OCc1nc(-c2cnccc2C(F)(F)F)oc1C1CC1

Procedure:
A freshly prepared solution of sodium isopropoxide (20 mg of Na, 5 ml of 2-propanol) was added to a solution of 4-chloromethyl-5-cyclopropyl-2-(4-trifluoromethyl-3-pyridyl)-oxazole (200 mg) in 2-propanol (5 ml), and the mixture was heated under reflux for 10 hours. The reaction mixture was subsequently concentrated, mixed with water and extracted with dichloro-methane. The organic phase was washed with saturated sodium chloride solution, dried (MgSO4) and filtered through silica gel. Concentration of the organic phase gave the product in pure form as a pale yellow oil.