Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([OH:8])=O.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[C:10]1([NH:9][C:6]([C:2]2[NH:1][CH:5]=[CH:4][N:3]=2)=[O:8])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)c1ncc[nH]1
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1ncc[nH]1
Temperature: 25 °C
Reaction time: 21 h
Yield: 95.2 %

Procedure:
To a solution of 1H-imidazole-2-carboxylic acid (0.975 g, 8.7 mmol) in DMF (30 mL) were added aniline (0.67 mL, 8.7 mmol), EDC.HCl (2.54 g, 13.05 mmol) and HOBt (1.76 g, 13.05 mmol). The reaction mixture was stirred at room temperature for 21 hours. Then, it was poured into water and extracted with ethyl acetate. The combined organic layer was dried over sodium sulphate, filtered and concentrated. The crude residue was purified by flash chromatography (2% to 3% methanol in dichloromethane) to yield 1.55 g (96% yield) of the title compound.
Reaction SMILES: [NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:2]([C:18]([O:20][CH3:21])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7]C(OCC1C=CC=CC=1)=O.C(OCC)(=O)C>CO.[Pd]>[NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:2]([C:18]([O:20][CH3:21])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7]
Reactant: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)[C@H](CCCCN)NC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
1.0 g of Boc-Lys(Cbz)-OMe (5) was dissolved in 40 mL MeOH:Ethyl acetate. 100 mg of Palladium on active carbon (Pd/C) was added to the solution. The solution was stirred under hydrogen for 2 hrs. The organic solution was filtered through Celite and washed with 10 mL MeOH. The filtrate was evaporated under reduced pressure to yield Boc-Lys-OMe of formula (6)
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.[OH-].[Na+]>CN(C=O)C>[CH3:12][N:9]1[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][CH2:3][O:20][C:17]2[CH:18]=[CH:19][C:14]([NH2:13])=[CH:15][CH:16]=2)[CH2:7][CH2:8]1
Reactant: CN1CCN(CCCCl)CC1
Reactant: Nc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CN1CCN(CCCOc2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 93.2 %

Procedure:
1-(3-Chloro-propyl)-4-methyl-piperazine hydrochloride (1.7 g, 9.6 mmol, 1.2 eq.) is added in one portion to a mixture of 4-aminophenol (893 mg, 8.0 mmol) and finely powdered sodium hydroxide (808 mg, 20 mmol, 2.5 eq.) in DMF (27 ml). The reaction mixture is stirred for 17 h at RT. The resulting dark suspension is filtered. The filtrate is diluted with DCM (200 ml) and washed with brine (2×50 ml). The aqueous layer is back-extracted with DCM. The organic phase is dried (sodium sulfate), filtered and concentrated. Purification of the residue by silica gel column chromatography (DCM/MeOH, 7:3) provides 1.86 g of the title compound as a yellow-brown oil: ESI-MS: 250.2 [MH]+; TLC: Rf=0.31 (DCM/MeOH, 7:3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12]Cl)=[CH:8][C:7]=1[CH3:14].[N-:16]=[N+:17]=[N-:18].[Na+].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:16]=[N+:17]=[N-:18])=[CH:8][C:7]=1[CH3:14]
Reactant: COC(=O)CCc1ccc(CCl)cc1C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCc1ccc(CN=[N+]=[N-])cc1C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
To a solution of 3-(4-Chloromethyl-2-methyl-phenyl)-propionic acid methyl ester (0.52 g, 2.31 mmol) in DMF (7 mL) is added sodium azide (0.25 g, 3.84 mmol). The mixture is stirred overnight. Water is added, and the mixture is extracted with EtOAc. The organics are dried with Na2SO4 and concentrated to yield the title compound (0.49 g, 91%). The material is used without further purification.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=O.[Br:12][C:13]1[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=1>C(#N)C>[Br:12][C:13]1[C:14]2[N:15]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=3)[N:19]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ncccc1Br
Reactant: O=C(CBr)c1ccc(O)cc1
Solvent: CC#N
Product: Oc1ccc(-c2cn3cccc(Br)c3n2)cc1
Temperature: 110 °C
Yield: 63.2 %

Procedure:
432 mg (corresponding to 2.01 mmol) of 2-bromo-4′-hydroxyacetophenone and 348 mg (corresponding to 2.01 mmol) of 3-bromo-2-aminopyridine were dissolved in 20 mL of acetonitrile. The resulting solution was refluxed in an oil bath at 110° C. for 6 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered and recovered. The precipitates were washed with acetonitrile and dried under reduced pressure. The resulting crude crystals were suspended in a mixed solution of 8 mL of water and 8 mL of methanol. Then, about 8 mL of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was sonicated for 5 minutes using an ultrasonic washing machine. Precipitates were filtered and recovered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure, to obtain 368 mg (corresponding to 1.27 mmol) of 8-bromo-2-(4′-hydroxyphenyl)imidazo[1,2-a]pyridine (FIG. 13, Step 2).
Reaction SMILES: [C:1](Cl)(=[O:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[Cl:13][C:14]1[C:15]([OH:21])=[CH:16][C:17](=[O:20])[NH:18][CH:19]=1>N1C=CC=CC=1>[Cl:13][C:14]1[C:15]([O:21][C:1](=[O:11])[C:2]2[CH:10]=[CH:9][C:8]3[O:7][CH2:6][O:5][C:4]=3[CH:3]=2)=[CH:16][C:17](=[O:20])[NH:18][CH:19]=1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Solvent: c1ccncc1
Product: O=C(Oc1cc(=O)[nH]cc1Cl)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 5 %

Procedure:
A 3.80 g quantity of piperonyloyl chloride was added to a suspension of 2.00 g of 5-chloro-4-hydroxy-2-pyridone in 60 ml of pyridine, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was filtered and the filtrate was concentrated. The concentrate was washed successively with ethyl acetate, water and chloroform and then purified by silica gel column chromatography using as an eluent 2% methanol-chloroform, thereby producing 200 mg of the title compound in a yield of 5%.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[Cl:19][C:20]1[S:24][N:23]=[C:22]([C:25]2[S:29][C:28]([S:30](Cl)(=[O:32])=[O:31])=[CH:27][CH:26]=2)[N:21]=1>>[Cl:19][C:20]1[S:24][N:23]=[C:22]([C:25]2[S:29][C:28]([S:30]([NH:18][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[C:7]([F:8])[C:6]=3[NH:9][C:10]3[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=3[F:17])(=[O:32])=[O:31])=[CH:27][CH:26]=2)[N:21]=1
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: O=S(=O)(Cl)c1ccc(-c2nsc(Cl)n2)s1
Product: O=S(=O)(Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F)c1ccc(-c2nsc(Cl)n2)s1

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine (0.182 mmol) was reacted with 5-(5-chloro-1,2,4-thiadiazol-3-yl)thiophene-2-sulfonyl chloride (0.5 mmol) to obtain 5-(5-chloro-1,2,4-thiadiazol-3-yl)-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)thiophene-2-sulfonamide. 1H NMR (300 MHz, CDCl3)) δ 5.8 (dt, 1H), 5.95 (s, 1H), 6.95 (d, 1H), 7.4 (m, 2H), 7.6 (d, 1H), 7.8 (s, 1H).
Reaction SMILES: FC1C(O[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[C:14]3=[N:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=2)=[O:10])=C(F)C(F)=C(F)C=1F.[NH2:37][CH2:38][C:39]1[O:40][CH:41]=[CH:42][CH:43]=1>>[O:40]1[CH:41]=[CH:42][CH:43]=[C:39]1[CH2:38][NH:37][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]2=[N:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](=[O:31])(=[O:32])[NH2:30])=[CH:25][CH:24]=1)=[O:10]
Reactant: NCc1ccco1
Reactant: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(C(=O)Oc4c(F)c(F)c(F)c(F)c4F)cc32)cc1
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(C(=O)NCc4ccco4)cc32)cc1

Procedure:
The title compound was prepared from 2-oxo-3[(4-sulfamoyl-phenyl)-hydrazono]-2,3-dihydro-1H-indole-5-carboxylic acid pentafluorophenyl ester and 2-aminomethylfuran according to Procedure K: mp>250° C.; 1H NMR (DMSO-d6): δ4.51 (d, J=5.5 Hz, 2H), 6.31 (d, J=3 Hz, 1H), 6.44 (d, J=3 Hz), 7.02 (d, J=8.3, 1H), 7.30 (s, 2H), 7.66 (m, 3H), 7.88 (m, 3H), 8.18 (s, 1H), 9.02 (br t, J=5.5 Hz, 1H), 11.4 (s, 1H), 12.8 (s, 1H); APCI−MS m/z438 (M−H)−; Anal. Calcd for C20H17N5O5S.1/2H2O: C, 53.57; H, 4.05; N, 15.62; S, 7.15. Found: C, 53.91; H, 4.01; N, 15.13; S, 6.78.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:7][CH2:6][CH:5]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([OH:31])=O)[CH:24]=3)=[CH:19][CH:18]=2)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:66]([NH2:74])[CH2:67][C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1>CN(C=O)C>[CH3:32][C:2]1([CH3:1])[CH2:3][CH2:4][CH:5]([N:8]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:74][CH2:66][CH2:67][C:68]4[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=4)=[O:31])[CH:24]=3)=[CH:21][CH:22]=2)[C:9](=[O:10])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:6][CH2:7]1
Reactant: NCCc1ccccc1
Reactant: CC1(C)CCC(N(Cc2ccc(-c3cccc(C(=O)O)c3)cc2)C(=O)OC(C)(C)C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CCC(N(Cc2ccc(-c3cccc(C(=O)NCCc4ccccc4)c3)cc2)C(=O)OC(C)(C)C)CC1
Reaction time: 0.08 h

Procedure:
To a solution of 4′-[((4,4-dimethylcyclohexyl){[(1,1-dimethylethyl)oxy]carbonyl}amino)-methyl]-3-biphenylcarboxylic acid (0.100 g; 0.23 mmol) in DMF (2 mL) was added DIEA (0.035 mL; 0.25 mmol), and HATU (0.095 g; 0.25 mmol). The solution was aged 5 min at room temperature and phenethylamine (0.031 mL; 0.25 mmol) was added. After 45 min the mixture was partitioned between EtOAc and half-satd Na2CO3, layers were separated and the aqueous layer was extracted with EtOAc (×2). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording the title compound as a colorless gum. LC/MS (method E) tR 1.19 min; m/z 541 (M+H).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH:14]1([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1>C1COCC1>[CH:14]1([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([OH:31])([C:8]#[C:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:27]([F:29])([F:30])[F:28])=[CH:22][CH:21]=2)[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: C#Cc1ccccc1
Reactant: O=C(c1ccc(NC2CCCC2)cc1)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(C#Cc1ccccc1)(c1ccc(NC2CCCC2)cc1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.4 ml of phenylacetylene (3.6 mmol in 10 ml of THF at −78° C. was added 1.9 ml (4.75 mmol) of a 2.5 M solution of n-butyllithium in hexanes. The color of the solution turned dark blue and the reaction mixture was stirred at −78° C. for 30 min. After this time, a solution of 450 mg of 1-(4-cyclopentylamino-phenyl)-2,2,2-trifluoro-ethanone (1.75 mmol) in 2 ml of THF was added and the resultant mixture stirred at −78° C. for 1.5 h before being allowed to warn to room temperature and stirred for a further 14 h. After this time, the reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica (hexanes:EtOAc, 3:1) to give the title compound. 1H-NMR (CDCl3) δ 1.48–1.56 (m, 2H), 1.68–1.76 (m, 4H), 2.03–2.14 (m, 2H), 3.76–3.85 (m, 1H), 6.65 (d, J=8.6 Hz, 2H), 7.36–7.82 (m, 10H). Mass Spectrum (CI+) m/e=360.1 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:25])[CH:5]([O:8][C:9]1[CH:24]=[CH:23][C:12]2[C:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:14][O:15][C:11]=2[CH:10]=1)[CH2:6][CH3:7])C.[OH-].[Na+]>CO>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[C:12]3[CH:23]=[CH:24][C:9]([O:8][CH:5]([CH2:6][CH3:7])[C:4]([OH:25])=[O:3])=[CH:10][C:11]=3[O:15][N:14]=2)=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(CC)Oc1ccc2c(-c3ccc(Cl)cc3)noc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(Oc1ccc2c(-c3ccc(Cl)cc3)noc2c1)C(=O)O

Procedure:
A solution of 3.6 g of ethyl-2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}butyrate, 30 ml of 15% sodium hydroxide solution and 30 ml of methanol, is stirred under reflux for 3 hr. The methanol is evaporated and the solution is poured into dilute hydrochloric acid/ice affording a flocculate precipitate. The precipitate is collected, dried in vacuo and recrystallized from toluene to afford 2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}butyric acid, mp 144° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:14])[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.[CH2:15]([O:22][C:23](ON1C(=O)CCC1=O)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)(Cl)Cl.C(Cl)Cl>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([O:5][CH2:4][C@H:3]([OH:14])[CH2:2][NH:1][C:23](=[O:24])[O:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:7][CH:8]=1)#[N:11]
Reactant: N#Cc1ccc(OC[C@H](O)CN)cc1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc(OC[C@H](O)CNC(=O)OCc2ccccc2)cc1
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 4{[(2R)-3-amino-2-hydroxypropyl]oxy}benzonitrile (see step (ii) above; 3.4 g, 17.7 mmol), TEA (2.69 g, 26.6 mmol) and CHCl3 (20 mL) was cooled to 0° C. before N-(benzyloxycarbonyloxy)succinimide (4.86 g, 19.5 mol) in CHCl3 (15 mL) was added slowly. The mixture was allowed to reach rt, and was stirred at that temperature overnight. The solvent was evaporated to give a residue that was dissolved in DCM. This solution was washed with water and brine and then dried (Na2SO4). Evaporation of the solvent gave 5.79 g (100%) of the sub-title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.CN(C)C=O.[NH:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([C:23]([OH:25])=[O:24])[CH2:18]1.C(N(C(C)C)CC)(C)C>>[NH2:8][C:6]1[N:7]=[C:2]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([C:23]([OH:25])=[O:24])[CH2:18]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: O=C(O)[C@@H]1CCCNC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(N2CCC[C@@H](C(=O)O)C2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A solution of 6-chloro-3-nitropyridin-2-amine in N,N-dimethylformamide (70 mL, 12.25 mmol, 0.175M) was added to (R)-piperidine-3-carboxylic acid (12.25 mmol) followed by diisopropylethylamine (4.55 mL, 24.5 mmol). The reaction mixture was stirred at 80° C. for 16 h. The solvent was removed under reduced pressure to afford (R)-1-(6-amino-5-nitropyridin-2-yl)piperidine-3-carboxylic acid which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@@H:11]([CH3:12])[O:10]1.[SH:19]CCC(OC)=O.C[O-].[Na+].CO.P(=O)(O)(O)O>CO.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([C@@H:11]([SH:19])[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: COC(=O)CCS
Reactant: C[C@H]1O[C@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: C[O-]
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@H](S)[C@@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
A mixture of (2S,3R)-2-(2,4-difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane (30 mg), methyl 3-mercaptopropionate (0.09 ml) and 28% sodium methoxide-methanol (0.08 ml) in methanol (2 ml) was refluxed for 2 hours, after which 28% sodium methoxide-methanol (0.04 ml) was added and the mixture was refluxed for another hour. Then, methyl 3-mercaptopropionate (0.04 ml) was added and the mixture was further refluxed for 2 hours. The reaction mixture was cooled, diluted with water (2 ml), neutralized with 5% aqueous phosphoric acid solution and extracted with methylene chloride (3 ml×2). The extract was dried over anhydrus sodium sulfate and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (1×5 cm) using ethyl acetate-hexane (3:1) as the eluent. The desired fraction was concentrated and the residue was crystallized from ethyl acetate-isopropyl ether to give (2S,3S)-2-(2,4-difluorophenyl)-3-mercapto- 1-(1H-1,2,4-triazol-1-yl)-2-butanol (compound 42:11 mg) as colorless prisms.
Reaction SMILES: [S:1]1[CH2:6][C:5](=[O:7])[NH:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20].CC([O-])(C)C.[K+].O>CN(C=O)C>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][N:4]1[C:5](=[O:7])[CH2:6][S:1][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]1=2
Reactant: O=C1CSc2ccccc2N1
Reactant: Fc1ccccc1CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CSc2ccccc2N1Cc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a mixture of 2H-benzo[b][1,4]thiazin-3(4H)-one (1.0 g, 6.1 mmole) and 1-(bromomethyl)-2-fluorobenzene (0.76 mL, 1.05 equiv) in DMF (10 mL) was added t-BuOK (0.75 g) at 0° C. The reaction mixture was warmed to room temperature and stirred overnight. Water was added and the resulted solid was filtrated, rinsed with water, and dried under vacuum to provide 4-(2-fluorobenzyl)-2H-benzo[b][1,4]thiazin-3(4H)-one (1.51 g, 91%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18]([OH:19])[C:13]=3[C:12]3[CH:22]=[C:23]([Br:26])[CH:24]=[N:25][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH2:30][CH3:31]>C1COCC1.C1(C)C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18]([O:19][CH2:30][CH3:31])[C:13]=3[C:12]3[CH:22]=[C:23]([Br:26])[CH:24]=[N:25][C:11]2=3)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1ncc2c(c1O)c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOc1c(C#N)ncc2c1c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.4 %

Procedure:
A solution of 9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (120 mg, 0.28 mmol) in anhydrous THF (5 mL) was cooled to 0° C. and treated with sodium hydride (60% dispersion in mineral oil; 12 mg, 0.30 mmol). After gas evolution had ceased, iodoethane (424 μL, 4.10 mmol) was added and the mixture stirred at ambient temperature overnight then heated at 60° C. for 5 h. The reaction was then allowed to cool, diluted with toluene and concentrated in vacuo. The residue was purified by column chromatography (silica, 2 g column, Si II SPE, 10-100% ethyl acetate in DCM) to afford the title compound as a yellow solid (30 mg, 23%). 1H NMR (DMSO-D6, 400 MHz): 8.86 (s, 1H), 8.77 (s, 2H), 8.24-8.22 (m, 1H), 8.22-8.20 (m, 1H), 7.81-7.75 (m, 1H), 7.68-7.61 (m, 2H), 4.75 (q, J=7.2 Hz, 2H), 1.64 (t, J=7.2 Hz, 3H). LCMS (Method B): RT=3.30 min, M+H+=457/459.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[CH:16]=[C:15]([C:17]([O-:19])=[O:18])[C:14]([CH3:20])=[CH:13][C:9]=1[C:10]([O-:12])=[O:11].CI>CN(C=O)C>[CH3:1][O:18][C:17]([C:15]1[C:14]([CH3:20])=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([CH3:7])[CH:16]=1)=[O:19]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C(=O)[O-])c(C)cc1C(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(C)c(C(=O)O)cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 76 mg portion of potassium carbonate was added to a 20 ml DMF solution of 214 mg 2,5-dimethylterephthalate and stirred at room temperature for 30 minutes. 0.068 ml of methyl iodide was added to the reaction solution successively and stirred overnight at room temperature. Successively, work-up and purification were carried out in the standard method to obtain 90 mg of 4-methoxycarbonyl-2,5-dimethylbenzoic acid as colorless solid. EN: 207.
Reaction SMILES: [CH3:1][O:2][Na].[F:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9]>CO>[F:4][C:5]1[CH:6]=[C:7]([C:8](=[NH:9])[O:2][CH3:1])[CH:10]=[CH:11][CH:12]=1
Reactant: N#Cc1cccc(F)c1
Reactant: CO[Na]
Solvent: CO
Product: COC(=N)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 1000.1 %

Procedure:
MeONa (2.35 g, 41 mmol) was added to a stirred solution of 3-fluorobenzonitrile (50.0 g, 413 mmol) in methanol (300 mL). The mixture was stirred at room temperature for 3 days and concentrated in vacuo. The residue was dissolved in ether (300 mL), washed with water (2×150 mL), brine (150 mL), dried with Na2SO4, and concentrated in vacuo to afford 62.8 g (99%) of methyl 3-fluorobenzenecarboximidoate. Methylhydrazine (21.8 mL, 410n mmol) was added to a stirred solution of methyl 3-fluorobenzenecarboximidoate (62.8 g, 410 mmol) in THF (350 mL). The mixture was stirred at room temperature for 3 days, then. Then methyl 2,2-diethoxyethanimidoate (66.1 g, 410 mmol) and acetic acid (37.5 mL, 656 mmol) were added. The mixture was stirred for 24 h. The reaction was diluted with CH2Cl2 (500 mL), and the formed precipitate was filtered off. The filtrate was washed with 10% citric acid (2×200 mL), water (300 mL), brine (200 mL), dried with Na2SO4, and concentrated in vacuo. The residue was subjected to flash chromatography on silica gel using 1% MeOH/CHCl3 as eluent to give 24.0 g (21%) of the title product.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:28][C:29]4[CH:34]=CC=CC=4)[CH:24]=3)[C:19]2=[O:35])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.[CH:36]1(N=C=N)[CH2:41]CCC[CH2:37]1.CN(C=O)C>ClCCl>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:28][CH2:29][CH:34]=[C:36]([CH3:41])[CH3:37])[CH:24]=3)[C:19]2=[O:35])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: N=C=NC1CCCCC1
Reactant: COc1cc(N2C(=O)c3ccc(Oc4ccccc4)cc3C2=O)ccc1OCCN1CCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(N2C(=O)c3ccc(OCC=C(C)C)cc3C2=O)ccc1OCCN1CCCC1

Procedure:
A mixture of this acid (67 mg, 0.27 mmol), 3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine [Example A4] (67 mg, 0.28 mmol) and N-cyclohexylcarbodiimide resin (1.69 mol. eq./g, 0.46 g, 0.78 mmol) was stirred in a 50:50 mixture of DMF and dichloromethane (1.5 ml) at room temperature under argon for 16 h. The mixture was filtered through filter-aid and the resin washed several times with dichloromethane. The filtrate was evaporated and the crude residue purified by flash chromatography on silica gel eluting with methanol in dichloromethane to yield the title compound as a brown oil;