Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[C:13]2[C:8](=[C:9]([O:14][CH3:15])[CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:6]=1)=O.[C:23]([C:27]([O:29][CH2:30][C:31]([NH2:33])=[S:32])=[O:28])([CH3:26])([CH3:25])[CH3:24]>C(O)C>[CH:17]1([CH2:16][N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][C:9]=3[O:14][CH3:15])[C:5]([C:3]3[N:33]=[C:31]([CH2:30][O:29][C:27]([C:23]([CH3:26])([CH3:24])[CH3:25])=[O:28])[S:32][CH:2]=3)=[CH:6]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: COc1cccc2c(C(=O)CCl)cn(CC3CCCCC3)c12
Reactant: CC(C)(C)C(=O)OCC(N)=S
Solvent: CCO
Product: COc1cccc2c(-c3csc(COC(=O)C(C)(C)C)n3)cn(CC3CCCCC3)c12
Yield: 99.7 %

Procedure:
2-Chloro-1-[1-(cyclohexyl)methyl-7-methoxy-1H-indol-3-yl]ethanone (0.73 g, 2.30 mmol) and 2-(tert-butylcarbonyloxy)thioacetamide (1.21 g, 6.89 mmol) were suspended in ethanol (10 ml) and the resulting mixture subjected to microwave irradiation at 150° C. for 10 min using an Emrys™ Optimizer EXP. The reaction mixture was concentrated in vacuo and the residue obtained was purified by flash column chromatography eluting with 5% (v/v) ethyl acetate in n-heptane to afford 1-(cyclohexyl)methyl-7-methoxy-3-{2-[(tertbutylcarbonyloxy)methyl]thiazol-4-yl}-1H-indole as a yellow oil (1.01 g).
Reaction SMILES: [OH:1][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[OH-].[K+].[CH2:17](I)[CH3:18].Cl>CS(C)=O.O>[CH2:17]([O:1][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4])[CH3:18]
Reactant: CCI
Reactant: CC(C)C(O)(C(=O)O)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(C(=O)O)(c1ccccc1)C(C)C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To a solution of 2-hydroxy-3-methyl-2-phenylbutanoic acid (Compound (5), 30.0 g) in dimethyl sulfoxide (250 ml) was added 85% powdered potassium hydroxide (60 g) and the mixed solution was stirred for one hour. Under ice cooling, ethyl iodide (55 ml) was added and the resulting mixture was stirred at room temperature for 3 days. After the addition of water (100 ml), the resulting mixture was stirred at 80° C. for 6 hours. The reaction mixture was acidified with 1N hydrochloric acid, followed by extraction with ether. The ether layer was dried over anhydrous sodium sulfate and removed under reduced pressure. To the residue, hexane (200 ml) was added. After the resulting mixture was allowed to stand overnight, the crystals so precipitated were removed by filtration. The filtrate was removed under reduced pressure to obtain the title compound (27.0 g, 78.7%) as an oil.
Reaction SMILES: [C:1]([NH:9][CH:10]([CH2:16][CH2:17][S:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:11]([O:13]CC)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[C:1]([NH:9][CH:10]([CH2:16][CH2:17][S:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(CCSc1ccccc1)NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NC(CCSc1ccccc1)C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A solution comprised of ethyl 2-benzoylamino-4-phenylsulfanylbutyrate (340 mg, 1.0 mmol) in methanol (4 mL) was treated with 1 N aqueous sodium hydroxide (2 mL) and stirred at ambient temperature for 3 hours. The reaction mixture was cooled on ice, acidified to pH 1 and then extracted with ethyl acetate. The extract was concentrated to provide 2-benzoylamino-4-phenylsulfanylbutyric acid (304 mg, 1.0 mmol).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26](O)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:58][C:59]1[CH:60]=[C:61]([CH:64]=[C:65]([Cl:67])[CH:66]=1)[CH2:62][NH2:63]>ClCCl>[Br:58][C:59]1[CH:60]=[C:61]([CH2:62][NH:63][C:26]([C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:14][CH2:15][O:16][CH2:17][CH2:18]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:32][CH3:33])=[O:22])[CH:24]=2)=[O:27])[CH:64]=[C:65]([Cl:67])[CH:66]=1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Reactant: NCc1cc(Cl)cc(Br)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(Cl)cc(Br)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[({[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoic acid (677 mg, 1.5 mmol) was suspended in dichloromethane (DCM) (50 ml), and HBTU (569 mg, 1.5 mmol) was added, followed sequentially by 3-bromo-5-chlorobenzylamine (331 mg, 1.5 mmol), and TEA (0.418 mL, 3.0 mmol). The reaction mixture was stirred overnight under argon at room temperature to give a clear-colorless solution. The solvent was removed on a rotovap and the residue was partitioned between ethyl acetate (100 mL) and 1N NaOH (20 mL). The phases were separated and the organic phase was washed 2× with 1N NaOH (20 mL), and then 1× with brine (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude product was taken up in dichloromethane and absorbed on Isolute® Sorbent and purified by CombiFlash on a 40 g silica column eluted with 0-10% DCM/MeOH to give the title compound as white solid. LC-MS m/z 652.9 (M+H)+, 2.08 min (ret time); mp 109-112° C.; analytical HPLC shows 97.6% purity, (ret time 13.921 min).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][C:29]([N:31]([CH3:33])[CH3:32])=[O:30]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][C:29]([N:31]([CH3:33])[CH3:32])=[O:30])=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)CCl
Reactant: COc1ccccc1N1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Product: COc1ccccc1N1CCN(C(=O)c2cn(CC(=O)N(C)C)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-N,N-dimethyl-acetamide gave the title compound.
Reaction SMILES: [N:1]1S[N:4]=[C:3]2[CH:6]=[C:7]([CH2:10][C@H:11]([CH3:14])[CH2:12][OH:13])[CH:8]=[CH:9][C:2]=12.Cl.[NH4+].[OH-].O1CCO[CH:20](O)[CH:19]1O>CCO.[Zn]>[CH3:14][C@@H:11]([CH2:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[N:1]=[CH:20][CH:19]=[N:4]2)[CH2:12][OH:13]
Reactant: OC1OCCOC1O
Reactant: C[C@H](CO)Cc1ccc2nsnc2c1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: C[C@H](CO)Cc1ccc2nccnc2c1
Reaction time: 0.75 h

Procedure:
A solution of (S)-3-benzo[1,2,5]thiadiazol-5-yl-2-methyl-propan-1-ol (5 g, 24 mmol) in EtOH (60 ml) is cooled to 0° and then treated with half concentrated HCl (40 ml, ca. 200 mmol). Zn dust (8.5 g, 130 mmol) is added in 1 g portions at 0°, one portion every 5 minutes. After the last addition, the mixture is stirred at 10° to 15° for 45 minutes. Under ice cooling, half concentrated NH4OH (40 ml, ca. 290 mmol) is added dropwise. The mixture is filtered over Hyflo, the filtrate concentrated under reduced pressure and the remaining aqueous phase twice extracted with EtOAc (150 ml, 50 ml). Drying over Na2SO4 and evaporation give the diamnino intermediate as a brownish, clear oil which tends to darken upon exposure to light and air. This intermediate is dissolved in absolute EtOH (60 ml) and cooled to 0°. 1,4dioxane-2,3-diol (3.75 g, 31.2 mmol) is added at once and the solution stirred at room temperature for 2 h. The mixture is evaporated to dryness, the residue distributed between brine (50 ml) and DCM (50 ml), the organic phase washed with brine (25 ml), dried over Na2SO4 and evaporated to afford (S)-2-methyl-3-quinoxalin-6-yl-propan-1-ol as a brownish, clear, viscous oil of sufficient purity for the next step. ee=91% (HPLC on chiral stat. phase). TLC (silicagel, DCM/MeOH/NH4OH 85:15:1): rf 0.68.
Reaction SMILES: [Li+].[C:2]1([CH3:27])[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]3[S:20][C:21]([C:24]([O-])=[O:25])=[CH:22][N:23]=3)[CH:14]=2)[O:9]1.CN(C)C=O.ON1C2C=CC=CC=2N=N1.C[N:44]1CC[O:47][CH2:46][CH2:45]1.C(CN)O>O>[OH:47][CH2:46][CH2:45][NH:44][C:24]([C:21]1[S:20][C:19]([O:18][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[O:9][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:27])[CH2:17][CH2:16]3)=[N:23][CH:22]=1)=[O:25]
Reactant: CN1CCOCC1
Reactant: Cc1ccccc1C1CCc2cc(Oc3ncc(C(=O)[O-])s3)ccc2O1
Agent: On1nnc2ccccc21
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: NCCO
Solvent: O
Product: Cc1ccccc1C1CCc2cc(Oc3ncc(C(=O)NCCO)s3)ccc2O1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(2-o-tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid lithium salt (100 mg, 0.27 mmol) in dimethylformamide (2 ml) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (72 mg, 0.38 mmol, 1.4 eq), 1-hydroxy-benzotriazole (51 mg, 0.38 mmol, 1.4 eq) and N-methylmorpholine (68 mg, 0.67 mmol, 2.5 eq) were added and the mixture was stirred at room temperature for 15 min. Ethanolamine (25 mg, 0.40 mmol, 1.5 eq) was added and stirring was continued for 16 h. The mixture was diluted with water and the aqueous layer extracted with ethyl acetate. The combined organic layers were washed with a diluted aqueous solution of sodium carbonate and brine, dried over sodium sulfate and filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel, ethyl acetate/methanol gradient). The desired compound was obtained as a white powder (43 mg, 39%).
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:15]4=[N:16][C:17]([C:20]5[CH:21]=[N:22][N:23]([CH2:25][CH2:26][O:27]C6CCCCO6)[CH:24]=5)=[CH:18][N:19]=[C:14]4[N:13]=[N:12]3)=[CH:9][C:4]2=[CH:3][CH:2]=1.N1C2=NC=CC=C2C(CN2C3=NC(C4C=NN(C)C=4)=CN=C3N=N2)=C1.C1C(=O)N(Br)C(=O)C1>C(Cl)(Cl)Cl>[N:1]1[N:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:15]4=[N:16][C:17]([C:20]5[CH:21]=[N:22][N:23]([CH2:25][CH2:26][OH:27])[CH:24]=5)=[CH:18][N:19]=[C:14]4[N:13]=[N:12]3)=[CH:9][C:4]2=[CH:3][CH:2]=1
Reactant: c1cc2cc(Cn3nnc4ncc(-c5cnn(CCOC6CCCCO6)c5)nc43)ccn2n1
Agent: Cn1cc(-c2cnc3nnn(Cc4c[nH]c5ncccc45)c3n2)cn1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: OCCn1cc(-c2cnc3nnn(Cc4ccn5nccc5c4)c3n2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-6-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine 311-a (10 mg, 0.022 mmol) (prepared according to the procedure of Compound 1) in CHCl3 was added NBS (4.4 mg, 0.025 mmol). The reaction mixture was stirred at rt for 1 h, then concentrated. The resulting residue was dissolved in CHCl3 (2 mL) and MeOH (2 mL), followed by the addition of 6N HCl in MeOH. The resulting mixture was stirred for 30 min, then treated with NH3.H2O to bring pH to 8. The mixture was concentrated and purified by prep-TLC to afford the title compound. MS (m/z): 439.9 (M+1)+.
Reaction SMILES: [C:1]1([C:7]2[O:8]C3C=C(C(OC)=O)C=CC=3N=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-].O.[ClH:23]>C1COCC1.CO>[C:7]([Cl:23])(=[O:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)oc2c1
Reactant: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of methyl 2-phenyl-benzooxazole-6-carboxylate 1u (0.37 g, 1.46 mmol) and LiOH (0.10 g, 4.2 mmol) in THF (4 mL), MeOH (4 mL), and H2O (4 mL) was stirred at room temperature for 6 h. Aqueous 1N HCl solution was added to the mixture to adjust pH to 3-4. The resulting mixture was extracted with EtOAc (2×). The organic solution was washed with aq. NaCl, dried over Na2SO4 and concentrated to give 1t (0.34 g).
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH3:14][C:15](=[CH:17][CH2:18][CH2:19][CH:20]([CH2:22][CH2:23]O)[CH3:21])[CH3:16]>C1CCCCC1.CCOCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:21][CH:20]([CH2:19][CH2:18][CH:17]=[C:15]([CH3:16])[CH3:14])[CH2:22][CH2:23][O:6][C:5](=[O:7])[CH2:4][CH2:3][C:2](=[O:1])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCC(=O)CCC(=O)O
Reactant: CC(C)=CCCC(C)CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: C1CCCCC1
Product: CCCCCCC(=O)CCC(=O)OCCC(C)CCC=C(C)C
Yield: 91 %

Procedure:
A solution of 20.0 g 4-oxo-1-decanoic acid (Synthesis, 1987, 408), 16.8 g citronellol extra and 0.5 g p-toluene-sulfonic acid in 150 ml of cyclohexane was refluxed in a flask equipped with a Dean-Stark trap for 3 hours. Then the reaction mixture was cooled, diluted with ether, washed with saturated NaHCO3 and water. The organic phase was dried, filtered and evaporated to dryness. The resulting oil was purified by chromatography to yield 31.7 g of a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11](=[O:13])[CH3:12])[CH:5]=[C:6]([F:10])[C:7]=1[S:8][CH3:9].[Br:14]Br.O>Br.C(O)(=O)C>[Br:14][CH2:12][C:11]([C:4]1[CH:3]=[C:2]([F:1])[C:7]([S:8][CH3:9])=[C:6]([F:10])[CH:5]=1)=[O:13]
Reactant: BrBr
Reactant: CSc1c(F)cc(C(C)=O)cc1F
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CSc1c(F)cc(C(=O)CBr)cc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 85.4 %

Procedure:
To a solution of 1-[3,5-difluoro-4-(methylthio)-phenyl]ethanone (prepared in Step 1 of Example 1) (6.2 g, 30 mmol) in 30% HBr in acetic acid (10 mL) was added bromine (4.8 g, 30 mmol) dropwise, and the reaction mixture stirred at room temperature for 45 minutes. The mixture was treated with water and extracted with ethyl acetate (1×250 mL, 1×100 mL). The combined extracts were washed with dilute sodium chloride solution, dried with magnesium sulfate, and concentrated. To the residue was added hexanes (100 mL) and the mixture concentrated. The residue was dissolved in 30% HBr in acetic acid (10 mL) and treated with bromine (0.80 g, 5.0 mmol). After stirring at room temperature for 30 minutes, the mixture was treated with water and extracted with dichloromethane (1×200 mL, 1×100 mL). The combined extracts were washed with water, dried with magnesium sulfate and concentrated. To the residue was added hexanes (100 mL), and the mixture concentrated. Purification of the product by silica gel chromatography using 10% ethyl acetate in hexanes gave 2-bromo-1-[3,5-difluoro-4-(methylthio)-phenyl]ethanone as an orange solid (7.2 g, 86%), MP 30.5-33.2° C. 1H NMR (CDCl3/400 MHz) 7.46-7.50 (m, 2H), 4.33 (s, 2H), 2.57 (t, 3H, J=1.1). ESHRMS m/z 278.9260 (M−H+, Calcd 278.9291). Anal. Calcd for C9H7BrF2OS: C, 38.45; H, 2.52. Found: C, 38.19; H, 2.34.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH2:9][CH:10]2[CH2:15][CH:14]3[N:16](C(OC(C)(C)C)=O)[CH:11]2[CH2:12][CH2:13]3)=[N:6][CH:7]=1.Cl>O1CCOCC1.CC(O)C>[F:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH2:9][CH:10]2[CH2:15][CH:14]3[NH:16][CH:11]2[CH2:12][CH2:13]3)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1C(COc1ncc(F)cn1)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Fc1cnc(OCC2CC3CCC2N3)nc1
Temperature: 40 °C

Procedure:
To the title compound from step A (474 mg, 1.5 mmol) in 1,4-dioxane (1.5 mL) was added 6N HCl in iPrOH (1.5 mL). The reaction was heated to 40° C. for 1.5 h and concentrated to give the title compound that was used without further purification in subsequent steps. MS (ESI) mass calcd. for C11H14FN3O, 223.1; m/z found 224.0 [M+H]+.
Reaction SMILES: C[O:2]CC.OO.FC(F)(F)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].FC(F)(F)C(Cl)=O.[C-]#N.[Na+]>C(O)(C)(C)C>[C:9]([OH:10])(=[O:2])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC
Reactant: O=C(c1ccccc1)C(F)(F)F
Agent: O=C(Cl)C(F)(F)F
Agent: OO
Agent: [C-]#N
Solvent: CC(C)(C)O
Product: O=C(O)c1ccccc1

Procedure:
For example, according to J. Org. Chem. 34, 2543 (1969), sodium cyanide is reacted with α,α,α-trifluoroacetophenone in 1,2-dimethoxyethane, then alkylated with dimethyl sulphate, then the nitrile is hydrolysed to give the amide and, finally, the amide is hydrolysed to give the acid. In a variation of this process, instead of the methoxyethane, t-butanol is used and the hydrolyses are carried out using alkaline hydrogen peroxide solution (Tetrahedron 42, 547 (1986)). In both cases, disadvantages are the poor availability of the trifluoroacetophenone, the preparation 20 of which involves the handling of gaseous trifluoroacetyl chloride (boiling point: +2° C.), and the fact that trifluoroacetophenone is only obtainable in moderate yields. In addition, toxic sodium cyanide has to be handled, which signifies extra expenditure, including for disposal. Finally, the hydrolyses produce benzoic acid as secondary component, which because of its ability to sublime, can only be removed with difficulty, as a result of which this method generally only gives products containing benzoic acid.
Reaction SMILES: C[O:2][C:3](=[O:42])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([N:14]2[CH2:18][C@@H:17]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C@@:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[F:33])([C:24]#[N:25])[C@H:15]2[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=2[Cl:41])=[O:13])=[CH:6][CH:5]=1.[Li+].[OH-]>C1COCC1.CO>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C@@:16]2([C:24]#[N:25])[C@H:17]([CH2:19][C:20]([CH3:23])([CH3:21])[CH3:22])[CH2:18][N:14]([C:12]([NH:11][CH2:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:42])=[O:2])=[CH:5][CH:6]=3)=[O:13])[C@@H:15]2[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=2[Cl:41])=[C:27]([F:33])[CH:28]=1
Reactant: COC(=O)c1ccc(CNC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1CN(C(=O)NCc2ccc(C(=O)O)cc2)[C@H](c2cccc(Cl)c2Cl)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
To a mixture of rac-4-({[(2S,3S,4S)-2-(2,3-dichloro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-methyl)-benzoic acid methyl ester (44.2 mg, 0.07 mmol) in THF/MeOH (0.6 mL/0.2 mL) was added 4 N LiOH (0.2 mL), and the reaction mixture was stirred at rt overnight. The reaction mixture was concentrated and quenched with 2 NH2SO4, extracted with EtOAc, and washed with water, brine. The organic phase was separated, and dried over Na2SO4. The mixture was then concentrated to give rac-4-({[(2S,3S,4S)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,3-dichloro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-methyl)-benzoic acid (43.0 mg, 99.6%). LC-MS (ES+/−) m/z Calcd for C31H29Cl3FN3O3: 617; Found: 617.
Reaction SMILES: C(OC([NH:6][C:7]([NH:16][CH2:17][CH2:18][CH2:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1)=[N:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=O)C>Cl>[NH:23]1[CH:24]=[C:20]([CH2:19][CH2:18][CH2:17][NH:16][C:7]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)=[NH:6])[N:21]=[CH:22]1
Reactant: CCOC(=O)NC(=NCC1CCCCC1)NCCCc1c[nH]cn1
Agent: Cl
Product: N=C(NCCCc1c[nH]cn1)NCC1CCCCC1

Procedure:
1.5 mmol of the compound obtained in Example 52 are brought to reflux for 30 min in 15 ml of 1N hydrochloric acid and are then concentrated to dryness. The residual dry form is crystallized from diethyl ether.
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3].[Cl:17][C:18]1[CH:19]=[C:20]([C:24]2[O:28][CH:27]=[N:26][C:25]=2[C:29](O)=[O:30])[CH:21]=[CH:22][CH:23]=1>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:29]([C:25]3[N:26]=[CH:27][O:28][C:24]=3[C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[CH:19]=3)=[O:30])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3]
Reactant: O=C(O)c1ncoc1-c1cccc(Cl)c1
Reactant: CC(F)(F)c1csc(Cn2ncc(N)n2)n1
Product: CC(F)(F)c1csc(Cn2ncc(NC(=O)c3ncoc3-c3cccc(Cl)c3)n2)n1

Procedure:
Following general procedure Z2, starting from 2-[4-(1,1-difluoro-ethyl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-chloro-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:9]2)=[CH:4][CH:3]=1.[SiH](CC)(CC)CC.CN([CH:28]=[O:29])C>>[O:15]1[CH2:16][CH2:17][N:12]([C:8]2[CH:7]=[N:6][C:5]3[C:10]([N:9]=2)=[CH:11][C:2]([CH:28]=[O:29])=[CH:3][CH:4]=3)[CH2:13][CH2:14]1
Reactant: CN(C)C=O
Reactant: Brc1ccc2ncc(N3CCOCC3)nc2c1
Agent: CC[SiH](CC)CC
Product: O=Cc1ccc2ncc(N3CCOCC3)nc2c1
Temperature: 90 °C
Reaction time: 12 h
Yield: 82.3 %

Procedure:
To a solution of 4-(7-bromoquinoxalin-2-yl)morpholine (59 g, 0.2 mol, 1.0 eq.) in DMF (500 mL) was added TEA (139 mL, 1.0 mol, 5.0 eq.), Et3SiH (127 mL, 0.8 mol, 4.0 eq) and Pd(dppf)Cl2CH2Cl2 (8.16 g, 0.01 mol, 0.05 eq.). The resulting mixture was stirred at 90° C. for 12 h in an autoclave under CO (1 MPa), then cooled and concentrated. The resulting residue was purified by flash column chromatography (EA/PE=1/1) to afford 3-morpholinoquinoxaline-6-carbaldehyde as a yellow solid (40 g, 82.3%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10](O)(=[O:13])[CH:11]=C.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:8][CH2:9][CH2:11][C:10]2=[O:13]
Reactant: COc1ccc(F)cc1
Reactant: C=CC(=O)O
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: O=C1CCOc2ccc(F)cc21
Temperature: -78 °C
Reaction time: 4.5 h

Procedure:
Using the procedure established in Example 1, the reactor was charged with p-fluoroanisole (31.5 grams), acrylic acid (27 grams) and phenothiazine (0.02 grams) before being sealed, evacuated, and cooled to -78° C. The anhydrous hydrogen fluoride (110 grams) was vacuum transferred into the reactor and the mixture warmed to 40° C. for one hour then 100° C. for 4.5 hours. The excess hydrogen fluoride was then vented and the reactor cooled to 5° C. before being opened and the contents washed with D.I. water. Analysis by HPLC indicated the presence of para-fluoroanisole and 6-Fluoro-4-Chromanone. The para-fluoroanisole was removed by distillation and the desired 6-Fluoro-4-Chromanone isolated by extraction and characterized.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:12]I.[OH-].[K+]>CO>[CH3:12][S:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cc(S)cc(Cl)c1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CSc1cc(Cl)cc(C(=O)O)c1
Yield: 70 %

Procedure:
In a manner similar to procedure of Example 14, 3-mercapto-5-chlorobenzoic acid is contacted with methyl iodide in methanol containing potassium hydroxide as the base to yield the desired product in 70% yield, m.p. 148°-150° C.
Reaction SMILES: C(O)C.Cl.[NH2:5][OH:6].[C:7]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:23][CH2:22]3)[CH2:17][C:16]2=[O:33])=[CH:11][CH:10]=1)#[N:8]>C(N(CC)CC)C>[OH:6][NH:5][C:7]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([CH:21]3[CH2:22][CH2:23][N:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:25][CH2:26]3)[CH2:17][C:16]2=[O:33])=[CH:11][CH:10]=1)=[NH:8]
Reactant: CCOC(=O)CN1CCC(N2CCN(c3ccc(C#N)cc3)C(=O)C2)CC1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CN1CCC(N2CCN(c3ccc(C(=N)NO)cc3)C(=O)C2)CC1
Yield: 69.5 %

Procedure:
Ethanol (38 ml), 0.90 g of Hydroxylamine hydrochloride, and 1.64 g of triethylamine were added to 3.0 g of ethyl 4-[4-(4-cyanophenyl)-3-oxo-1-piperazinyl]-1-piperidineacetate, and the mixture was heated under reflux for 3 hours. The crystals formed were collected by filtration at the temperature of about 30° C, and recrystallized from chloroform-ethanol to give 2.27 g of ethyl 4-[4-(4-hydroxyamidinophenyl)-3-oxo-1-piperazinyl]-1-piperidineacetate