Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH2:5][C:6](=O)[CH3:7])[C:2]([CH3:4])=O.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([Cl:17])[CH:11]=1>>[Cl:17][C:12]1[CH:11]=[C:10]([N:9]2[C:6]([CH3:7])=[CH:5][CH:1]=[C:2]2[CH3:4])[CH:15]=[CH:14][C:13]=1[OH:16]
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: CC(=O)CCC(C)=O
Product: Cc1ccc(C)n1-c1ccc(O)c(Cl)c1

Procedure:
Utilizing the general procedure outlined in EXAMPLE 1, acetonyl acetone (0.83 mL, 7.0 mmol) and 4-amino-2-chlorophenol (1.0 g, 7.0 mmol) reacted to give 1-(3-chloro-4-hydroxyphenyl)-2,5-dimethylpyrrole as a brown solid: 1H NMR (CDCl3, 500 MHz) δ 7.22 (d, 1H), 7.10 (d, 1H), 7.05 (dd, 1H), 5.88 (s, 2H), 5.66 (br s, 1H), 2.03 (s, 6H); MS (ESI) 222 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH2:33][C:34]2[NH:35][CH:36]=[CH:37][N:38]=2)[CH2:26][C:27]2[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=2)=[CH:20][CH:19]=1)[CH3:16])C1C=CC=CC=1>CO.C(O)C.[C].[Pd]>[NH:38]1[CH:37]=[CH:36][N:35]=[C:34]1[CH2:33][N:25]([CH2:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:15]([CH3:16])[CH2:14][CH2:13][CH2:12][CH2:11][NH2:10])=[CH:19][CH:20]=1)[CH2:26][C:27]1[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=1
Reactant: CN(CCCCNC(=O)OCc1ccccc1)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CN(CCCCN)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.9 %

Procedure:
The compound (502.6 mg) obtained in Example 103-6 was dissolved in methanol (2.5 ml) and cooled with ice. Then, the solution was added with a suspension of 10% palladium-carbon (251.3 mg) in ethanol (2 ml), followed by stirring at room temperature for 2 hours under a hydrogen atmosphere. After the reaction, the solution was filtrated through Celite and the solvent was then distilled off, thereby obtaining the subject compound (382.4 mg) as a white solid.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].[C:12](O)(=O)[CH2:13][CH2:14][C:15]#[CH:16].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>O1CCOCC1>[CH2:15]([C:16]1[O:1][N:2]=[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH3:10])[N:11]=1)[CH2:14][C:13]#[CH:12]
Reactant: Cc1ccccc1C(N)=NO
Reactant: C#CCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Product: C#CCCc1nc(-c2ccccc2C)no1
Temperature: 80 °C
Reaction time: 3 h
Yield: 31.8 %

Procedure:
In a reactor tube, a mixture of N′-hydroxy-2-methylbenzamidine (555 mg, 3.7 mmol), 4-pentynoic acid (363 mg, 3.7 mmol), HOBT (0.56 g, 3.7 mmol) and EDCI.HCl (1.06 g, 5.55 mmol) in dioxane (7.4 mL) was stirred at R.T for 3h. After this time the mixture was heated at 80° C. overnight in a reaction block. The mixture was concentrated. The organic layer was washed with water, NaOH 1N and water. The solvent was evaporated in a Genevac for 75 min at 40° C. using the low boiling point program. The crude product was purified by flash chromatography (Prepacked 10 g silicagel column) with DCM as eluent to afford 250 mg of 5-(but-3-ynyl)-3-o-tolyl-1,2,4-oxadiazole (Yield: 32%) as yellow oil.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)#[N:2].[Cl:14][C:15]([Cl:19])([Cl:18])[S:16]Cl.C(N(CC)CC)C>C(Cl)Cl>[C:1]([CH2:3][N:4]([S:16][C:15]([Cl:19])([Cl:18])[Cl:14])[C:5](=[O:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)#[N:2]
Reactant: N#CCNC(=O)Cc1ccccc1
Reactant: ClSC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCN(SC(Cl)(Cl)Cl)C(=O)Cc1ccccc1
Yield: 88.3 %

Procedure:
To a stirred mixture of 4.9 g (0.028 mole) N-cyanomethyl phenylacetamide (the product of Example 6) and 5.7 g (0.031 mole) trichloromethylsulfenyl chloride in ml methylene chloride which had been cooled in an ice bath, 3.5 g (0.035 mole) triethylamine in 25 ml methylene chloride were dropped in over 20 minutes. The reaction mixture was washed three times with 75 ml portions of water, dried over magnesium sulfate and stripped to give 8.0 g of a dark brown oil, which failed to crystallize.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][NH:11][CH2:10][CH:9]2[N:13]([CH3:28])[C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)=[CH:4][CH:3]=1.[CH3:29][C:30]1([C:33]([N:35]2[CH2:40][CH2:39][CH:38]([C:41](O)=[O:42])[CH2:37][CH2:36]2)=[O:34])[CH2:32][CH2:31]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][N:11]([C:41]([CH:38]3[CH2:37][CH2:36][N:35]([C:33]([C:30]4([CH3:29])[CH2:32][CH2:31]4)=[O:34])[CH2:40][CH2:39]3)=[O:42])[CH2:10][CH:9]2[N:13]([CH3:28])[C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([C:23]([F:24])([F:25])[F:26])[CH:16]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)N(C)C2CNCC2c2ccc(Cl)cc2)cc1C(F)(F)F
Reactant: CC1(C(=O)N2CCC(C(=O)O)CC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCN(C(=O)C4(C)CC4)CC3)CC2c2ccc(Cl)cc2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.6 %

Procedure:
To a solution of N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide (200 mg, 0.484 mmol) in DMF (2 mL) was added 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid (113 mg, 0.533 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (221 mg, 0.581 mmol) and N,N-diisopropyl ethyl amine (498 μl, 2.90 mmol). The solution was stirred for 3 h at ambient temperature. After diluting with ethyl acetate (15 mL) the solution was washed twice with water (15 mL) and brine (10 mL). The aqueous layers were extracted with ethyl acetate (15 mL) and dried over sodium sulfate. Purification by chromatography (SiO2, heptane:ethyl acetate:methanol=50:50:0 to 0:90:10) afforded the title compound (210 mg, 72%) as a light brown oil. MS m/e: 606.2 [M]+.
Reaction SMILES: Cl[C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].ClC1C2SC(S)=NC=2C=CC=1.[Cl:21][C:22]1[S:23]C2C=CC(Cl)=CC=2N=1>>[Cl:21][C:22]1[S:23][C:2]2[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=2[N:4]=1
Reactant: Nc1cccc(Cl)c1Cl
Reactant: Clc1ccc2sc(Cl)nc2c1
Agent: Sc1nc2cccc(Cl)c2s1
Product: Clc1nc2cccc(Cl)c2s1

Procedure:
The title compound was prepared from 2,3-dichloroaniline via 7-chloro-2-mercaptobenzothiazole as described for 2,5-dichloro-1,3-benzothiazole.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2(/[CH:15]=[CH:16]/CC#N)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.O.[C:21]([O:24][CH2:25]C)(=[O:23])[CH3:22]>CO>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2(/[CH:15]=[CH:16]/[CH2:22][C:21]([O:24][CH3:25])=[O:23])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: N#CC/C=C/C1(c2ccc(F)cc2)CCCCC1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: O
Solvent: CO
Product: COC(=O)C/C=C/C1(c2ccc(F)cc2)CCCCC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
HCl gas was bubbled through a solution of (E)-4-(1-(4-fluorophenyl)cyclohexyl)but-3-enenitrile (Intermediate I-11B, 769 mg, 3.16 mmol) in anhydrous methanol (20 mL), and the mixture was stirred in a sealed tube at 60° C. for 1 hr. After cooling, about 10 mL of water was added and the mixture was stirred at room temperature overnight. The mixture was then added to ethyl acetate and washed with water, brine dried over sodium sulfate and concentrated under reduced pressure to give the (E)-methyl 4-(1-(4-fluorophenyl)cyclohexyl)but-3-enoate (560 mg, 2.03 mmol, 64.1% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.30 (2H, dd, J=9.02, 5.28 Hz), 6.99 (2H, t, J=8.80 Hz), 5.51-5.56 (1H, m), 5.35-5.45 (1H, m), 3.68 (3H, s), 3.05 (2H, dd, J=6.82, 1.10 Hz), 1.90-2.00 (2H, m), 1.79-1.88 (2H, m), 1.45-1.63 (6H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.O.[CH3:19]O>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([O:7][CH3:19])=[O:6]
Reactant: CO
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)c1ccc([N+](=O)[O-])c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a stirred suspension of 3-methyl-4-nitrobenzoic acid (100 g, 0.55 mole) in methanol (400 mL) was added thionyl chloride (36 g, 0.30 mole), over a period of 1 hour (the temperature of the reaction mixture rising to about 35°-40° C.). The mixture was heated to reflux for 1.5 hours, then cooled to 50°-55° C. and maintained at this temperature for 30 minutes prior to cooling to ambient temperature. Water (100 mL) was added over 30 minutes, with cooling applied to maintain the temperature at 20°-25° C. Filtration was followed by washing of the solid with water (100 mL twice), and drying at 40° C. under vacuum, to afford 103 g (95%) of methyl 3-methyl-4-nitrobenzoate as a yellow solid; mp 83°-85° C.; NMR (250 MHz, CDCl3): 2.62 (s, 3H, ArCH3), 3.98 (s, 3H, CO2CH3), 8.01 (m, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([O:28][C:29](=[O:32])[CH:30]=[CH2:31])([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:24]([O:28][C:29](=[O:32])/[CH:30]=[CH:31]/[C:13]1[CH:12]=[CH:11][C:10]([N:16]2[CH2:17][C:18](=[O:23])[NH:19][S:20]2(=[O:22])=[O:21])=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
To a mixture of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (2.0 g, 4.49 mmol), Pd(OAc)2 (100 mg) and acrylic acid t-butyl ester (0.78 mL, 5.8 mmol) in acetonitrile (15 mL) in a pressure vessel is added triethylamine (3.13, 22.5 mmol) and the mixture is stirred at 100° C. for 6 h. The solution is filtered through Celite, washed with acetonitrile and concentrated to give the title compound. This is used directly in the next step.
Reaction SMILES: [CH2:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[C:10](Br)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:16]([C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)([O-:18])=[O:17]>>[CH2:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[C:10]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:16]([O-:18])=[O:17])[CH:24]=2)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Nc1ccc(Cc2ccccc2)cc1Br
Product: Nc1ccc(Cc2ccccc2)cc1-c1cccc([N+](=O)[O-])c1

Procedure:
4-benzyl-2-bromo-aniline and 3-nitrobenzene boronic acid were combined to form 4-benzyl-2-(3-nitrophenyl)aniline,
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=2[C:12]([O:14][CH3:15])=[O:13])[CH2:3]1.[H-].[Na+].[CH2:23](Br)[CH:24]=[CH2:25].C(OCC)(=O)C>CN(C)C=O.O1CCCC1>[CH2:25]([O:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=2[C:12]([O:14][CH3:15])=[O:13])[CH2:3]1)[CH:24]=[CH2:23]
Reactant: COC(=O)c1c(C)cccc1CO[C@@H]1CCC[C@H](O)C1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=CCO[C@H]1CCC[C@@H](OCc2cccc(C)c2C(=O)OC)C1
Reaction time: 0.67 h

Procedure:
4.3 g of methyl 2-((1R,3S)-3-hydroxycyclohexyloxymethyl)-6-methylbenzoate are dissolved in 40 ml of dimethylformamide and 1.3 g of sodium hydride (60% strength suspension in paraffin oil) are added. After 40 minutes of stirring, 4 ml of allyl bromide, dissolved in 20 ml of tetrahydrofuran, are added. After 3 hours, 300 ml of ethyl acetate are added and the mixture is washed three times with saturated sodium chloride solution. The combined organic phases are dried over sodium sulfate and the solvents are then removed under reduced pressure. The resulting residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate=50:1→5:1. This gives 2.1 g of methyl 2-((1R,3S)-3-allyloxycyclohexyloxymethyl)-6-methylbenzoate as a yellow oil. C19H26O4 (318.42), MS(ESI): 319 (M+H+).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([OH:19])=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([OH:18])=[O:17])[CH:11]=2)[CH:6]=[C:7]([F:9])[CH:8]=1.[N:20]([O-])=O.[Na+].[O:24]1[C:28]2[CH:29]=[CH:30][C:31]([N:33]3[C:37](=[O:38])[CH2:36][C:35]([CH3:39])=[N:34]3)=[CH:32][C:27]=2[CH2:26][CH2:25]1.C(=O)(O)[O-].[Na+]>Cl>[O:24]1[C:28]2[CH:29]=[CH:30][C:31]([N:33]3[C:37](=[O:38])[C:36](=[N:20][NH:2][C:3]4[C:4]([OH:19])=[C:5]([C:10]5[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([OH:18])=[O:17])[CH:11]=5)[CH:6]=[C:7]([F:9])[CH:8]=4)[C:35]([CH3:39])=[N:34]3)=[CH:32][C:27]=2[CH2:26][CH2:25]1
Reactant: O=N[O-]
Reactant: CC1=NN(c2ccc3c(c2)CCO3)C(=O)C1
Reactant: Nc1cc(F)cc(-c2cccc(C(=O)O)c2)c1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC1=NN(c2ccc3c(c2)CCO3)C(=O)C1=NNc1cc(F)cc(-c2cccc(C(=O)O)c2)c1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 19.9 %

Procedure:
3′-Amino-5′-fluoro-2′-hydroxy-biphenyl-3-carboxylic acid hydrochloride 2f (219 mg, 0.772 mmol) was dissolved in 3 mL of hydrochloric acid (1 N) upon cooling by an ice-water bath, followed by dropwise addition of 1 mL of aqueous sodium nitrite (59 mg, 0.85 mmol). After the mixture was stirred for 20 minutes, 2-(2,3-dihydro-benzofuran-5-yl)-5-methyl-2,4-dihydro-pyrazol-3-one 7c (150 mg, 0.69 mmol) was added. The mixture was adjusted to pH 8˜9 by batch addition of aqueous sodium bicarbonate (1.007 g, 11.57 mmol). The generated bubbles were quenched with 2 mL of ethanol. The reaction mixture was warmed up to room temperature and reacted overnight. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered and the filter cake was dissolved in 15 mL of water. After mixing well, the mixture was adjusted to pH 3˜4 with concentrated hydrochloric acid, filtered and dried. The crude product was purified by HPLC to obtain the title compound 3′-{N′-[1-(2,3-dihydro-benzofuran-5-yl)-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene]-hydrazino}-5′-fluoro-2′-hydroxy-biphenyl-3-carboxylic acid 14 (65 mg, yield 20.0%) as a red solid.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[C:7](OC(=O)C)([CH3:10])([CH3:9])[CH3:8].[Cl:15](O)(=O)(=O)=O>>[ClH:15].[C:7]([O:5][C:4](=[O:6])[C@H:2]([CH3:3])[NH2:1])([CH3:10])([CH3:9])[CH3:8]
Reactant: [O-][Cl+3]([O-])([O-])O
Reactant: CC(=O)OC(C)(C)C
Reactant: C[C@H](N)C(=O)O
Product: C[C@H](N)C(=O)OC(C)(C)C
Product: Cl

Procedure:
In a 2 L one-neck flask, L-alanine (6.23 g) is stirred for 4 days with 1.1 L of t-butylacetate at room temperature and perchloric acid (70%, 6.65 mL, 7.7. g). The mixture is concentrated to 1/4 of its original volume, and the residue extracted at 0°-5° C. with 0.5N HCl (4×60 mL). The aqueous phase is immediately neutralized with KHCO3 (solid). The pH is adjusted to 13 with 4N NaOH, and the solution extracted with Et2O (4×100 mL). The combined organic layers are washed with bicarbonate solution (2×50 mL), dried (MgSO4), and evaporated. The oily residue is dissolved in 10 mL of Et2O (anh.) and treated with HCl:Et2O under cooling. The precipitated salt is filtered and dried to yield 4 g of L-alanine-t-butyl ester hydrochloride having a m.p. 167° C.; [α]20 =+177 (c=2 in EtOH).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][C:8]=1[NH2:17])(=[O:5])=[O:4].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>N1C=CC=CC=1.ClCCl>[F:19][C:2]([F:18])([F:1])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][C:8]=1[NH:17][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])(=[O:4])=[O:5]
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(N)c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(NC(=O)OCc2ccccc2)c1
Temperature: 20 °C
Reaction time: 4.5 h

Procedure:
To a solution of 2-amino-4-methoxycarbonylphenyl trifluoromethanesulfonate (2.6 g) in a mixture of pyridine (5.6 ml) and dichloromethane (20 ml) was added benzyl chloroformate (2.08 ml) at 0° C., and the mixture was stirred at 20° C. for 4.5 hours. The mixture was diluted with dichloromethane and washed successively with diluted hydrochloric acid, aqueous sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with dichloromethane to give 2-benzyloxycarbonylamino-4-methoxycarbonylphenyl trifluoromethanesulfonate (2.61 g) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:27])=[C:7]([C:15]([NH:17][C@H:18]([C:20]([O:22]C(C)(C)C)=[O:21])[CH3:19])=[O:16])[C:8](=[O:14])[C:9]2([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:27])=[C:7]([C:15]([NH:17][C@H:18]([C:20]([OH:22])=[O:21])[CH3:19])=[O:16])[C:8](=[O:14])[C:9]2([CH3:12])[CH3:13])=[CH:4][CH:3]=1
Reactant: C[C@H](NC(=O)C1=C(O)c2ccc(Br)cc2C(C)(C)C1=O)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: C[C@H](NC(=O)C1=C(O)c2ccc(Br)cc2C(C)(C)C1=O)C(=O)O
Yield: 55.8 %

Procedure:
1,1-Dimethylethyl N-((7-bromo-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)-L-alaninate (184 mg, 436 μmol) was stirred in TFA (2 mL, 26924 μmol) at room temperature for 30 minutes. Water was added. The resulting precipitate was filtered and washed with water to give the desired product as a white solid (93 mg). MS (m/e)=382.1 (M+H)+. Calculated for C21H19NO5 381.02.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:11]([S-:13])#[N:12].[K+]>C(O)C.O>[S:13]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4])[C:11]#[N:12]
Reactant: O=C(CCl)c1ccccc1
Reactant: N#C[S-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CSCC(=O)c1ccccc1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
150 g of ω-chloroacetophenone are dissolved at 50° C. in 1000 ml of ethanol, followed by the addition of a solution of 102 g of KSCN in 40 ml of water. After stirring for 10 minutes at 50° C., the ω-thiocyano acetophenone formed is precipitated with water.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3](O)=O.C([C:10]1[CH:25]=[CH:24][C:13]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[CH:12][CH:11]=1)=O.N1CCCCC1.C(=O)=O>N1C=CC=CC=1.O>[CH2:17]([O:16][C:14]([C:13]1[CH:24]=[CH:25][C:10]([CH:3]=[CH:2][C:1]([OH:7])=[O:6])=[CH:11][CH:12]=1)=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=Cc1ccc(C(=O)OCc2ccccc2)cc1
Reactant: O=C(O)CC(=O)O
Agent: O=C=O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)C=Cc1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
245 g (2.4 mol) of malonic acid were dissolved in 360 ml of pyridine (exothermic, temperature raised to about 50° C.). Then 503 g of the crude benzyl 4-formylbenzoate obtained in step a) and 20 ml of piperidine were added, and the mixture was heated to reflux until the production of carbon dioxide had ceased (about 7 h). The mixture was cooled to room temperature, then 2 l of water were added and the product was precipitated by acidification of the stirred mixture with ca. 600 ml of concentrated hydrochloric acid to pH 1.8 at 10° C. The precipitated product was filtered off, washed with water and dried at 50° C. under reduced pressure. Combined yield of step a) and step b): 529.1 g (97%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([F:16])[CH:15]=1)[CH2:5][C:6]1[C:7](=[S:12])[NH:8][CH:9]=[CH:10][CH:11]=1.[CH3:17]I>CO>[F:16][C:14]1[CH:13]=[C:4]([CH:3]=[C:2]([F:1])[CH:15]=1)[CH2:5][C:6]1[C:7]([S:12][CH3:17])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: Fc1cc(F)cc(Cc2ccc[nH]c2=S)c1
Reactant: CI
Solvent: CO
Product: CSc1ncccc1Cc1cc(F)cc(F)c1

Procedure:
The reaction of 3-(3,5-difluorobenzyl)pyridine-2-thione, prepared in Example 10, with methyl iodide in methanol in the presence of base by standard techniques yields 3-(3,5-difluorobenzyl)-2-methylmercaptopyridine.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4](Cl)=[N:5][OH:6].[CH3:12][O:13][C:14](=[O:19])[CH2:15][C:16]([CH3:18])=O.C[O-].[Na+]>CO>[CH3:12][O:13][C:14]([C:15]1[C:4]([C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=2[F:1])=[N:5][O:6][C:16]=1[CH3:18])=[O:19]
Reactant: ON=C(Cl)c1ccccc1F
Reactant: COC(=O)CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2F)noc1C
Yield: 72.3 %

Procedure:
In a similar manner as described in Preparation Example 17, by using methanol (160 mL), 2-fluoro-N-hydroxybenzimidoyl chloride (8.00 g, 46.09 mmol), methylacetoacetate (10.07 g, 92.18 mmol) and sodium methoxide (7.47 g, 138.27 mmol), a white solid required compound (7.84 g, 33.33 mmol, 72%) was obtained.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[C:15](=[O:30])[NH:16][C:17](=[O:29])[C:18]=2[C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)=[CH:6]1.[N:31]1[CH:36]=CC=C[CH:32]=1.CS(OS(C)(=O)=O)(=O)=O.CNC>C1COCC1>[CH3:32][N:31]([CH3:36])[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[C:15](=[O:30])[NH:16][C:17](=[O:29])[C:18]=2[C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)=[CH:6]1
Reactant: O=C1NC(=O)C(c2cn(CCCO)c3ncccc23)=C1c1cccc2ccccc12
Reactant: c1ccncc1
Agent: CNC
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: C1CCOC1
Product: CN(C)CCCn1cc(C2=C(c3cccc4ccccc34)C(=O)NC2=O)c2cccnc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 22.4 %

Procedure:
To a solution of Compound 3 (25 mg, 0.063 mmol) in THF (5 mL) was added pyridine (24.9 mg, 0.315 mmol). The mixture was stirred at room temperature for 15 min and then methanesulfonic anhydride (43.9 mg, 0.25 mmol) was added and the mixture was heated to 50° C. for 2 h. TLC and mass spectra shown the formation of Compound 4a. To the crude product was added excess 1.0 M solution of dimethylamine in THF (1 mL). The mixture was heated from 50 to 65° C. overnight. The solvent was concentrated in vacuo. The crude product was extracted with ethyl acetate (100 mL). The organic phase was washed with saturated NaHCO3, brine, and evaporated in vacuo to give a crude product (50 mg). The crude product was separated by flash chromatography on silica gel (CH2Cl2/MeOH/NH4OH, from 98:2:0.2 to 95:5:0.5) to give 6 mg (22%) of Compound 4 as a yellow solid. 1H NMR (CDCl3) δ 8.33 (s, 1H), 8.08 (dd, J=1.5, 4.7 Hz, 1H), 7.94 (m, 1H), 7.86 (d, J=8.2 Hz, 1H), 7.68 (d, J=8.3 Hz, 1H), 7.54 (m, 2H), 7.41 (t, J=6.9 Hz, 1H), 7.28 (m, 1H), 6.44 (dd, J=4.7, 8.1 Hz, 1H), 6.26 (dd, J=1.5, 8.0 Hz, 1H), 4.37 (t, J=7.1 Hz, 2H), 2.29 (t, J=7.0 Hz, 2H), 2.25 (s, 6H), 2.07 (m, 2H). ES-MS m/z 425 MH+).