Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.FC(F)(F)C(O)=O.[NH:18]1[CH:22]=[C:21]([C:23]2[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=2)[C:26]#[N:27])[CH:20]=[N:19]1>>[NH:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([N:18]3[CH:22]=[C:21]([C:23]4[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=4)[C:26]#[N:27])[CH:20]=[N:19]3)=[C:3]2[CH:10]=[CH:9]1
Reactant: Brc1ccnc2[nH]ccc12
Reactant: N#Cc1cccc(-c2cn[nH]c2)c1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(-c2cnn(-c3ccnc4[nH]ccc34)c2)c1
Temperature: 180 °C

Procedure:
A mixture of 4-bromo-1H-pyrrolo[2,3-b]pyridine (25.0 mg, 0.000127 mol) and 3-(1H-pyrazol-4-yl)benzonitrile trifluoroacetate (23.6 mg, 0.0000833 mol) was heated at 180° C., neat overnight. The crude residue was purified by HPLC on a C-18 column eluting with a water; ACN gradient containing 0.2% TFA to give the title compound as an amorphous white solid, LC/MS (M+H)+: 286, 1H NMR (DMSO-d6) δ 11.85 (bs, 1H), 9.18(s, 1H), 8.42(s, 1H), 8.28(s, 1H), 8.25(d, 1H, J=5.0), 8.07(d, 1H, J=7.0), 7.64(d, 1H, J=7.0), 7.56(t, 1H, J=7.0), 7.51(m, 1H), 7.47(d, 1H, J=5.0), 7.03(m, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([OH:36])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[C@@H:14]3[C:25]3[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31](O)=[O:32])=[CH:27][CH:26]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:66][CH2:67][C:68]([NH:70][C@@H:71]([C:76]([OH:78])=[O:77])[C:72]([CH3:75])([CH3:74])[CH3:73])=[O:69]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([OH:36])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[C@@H:14]3[C:25]3[CH:26]=[CH:27][C:28]([O:29][CH2:30][C:31]([NH:66][CH2:67][C:68]([NH:70][C@@H:71]([C:76]([OH:78])=[O:77])[C:72]([CH3:73])([CH3:74])[CH3:75])=[O:69])=[O:32])=[CH:34][CH:35]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc4c(c3)OCO4)C(=O)N2c2ccc(F)cc2)cc1
Reactant: CC(C)(C)[C@@H](NC(=O)CN)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)[C@@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc4c(c3)OCO4)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Reaction time: 4 h

Procedure:
To a solution of {4-[(2R,3R)-3-{[2-(1,3-benzodioxol-5-yl)-2-hydroxyethyl]thio}-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetic acid (0.006 g, 0.012 mmol) and NMM (0.007 ml, 0.064 mmol) in DMF (3 ml) at RT was added TBTU (0.005 g, 0.016 mmol). The reaction mixture was stirred for 60 min after which glycyl-3-methyl-D-valine (Method 10) (0.003 g, 0.016 mmol) was added. The mixture was stirred for 4 h before the solution was purified by preparative HPLC using a gradient of 20-60% MeCN in a 0.1M ammonium acetate buffer as eluent. Freeze-drying of the pure fractions gave the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][C:10]#[N:11].[NH2:12][C:13]1[C:18]([CH:19]=O)=[CH:17][N:16]=[C:15]([CH3:21])[N:14]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[C:10]([NH2:11])=[N:12][C:13]2[N:14]=[C:15]([CH3:21])[N:16]=[CH:17][C:18]=2[CH:19]=1
Reactant: Cc1ncc(C=O)c(N)n1
Reactant: Cc1cccc(Cl)c1CC#N
Product: Cc1ncc2cc(-c3c(C)cccc3Cl)c(N)nc2n1

Procedure:
Following the procedure of Example 1, 2-chloro-6-methylphenylacetonitrile is condensed with 4-amino-2-methylpyrimidine-5-carboxaldehyde to give 6-(2-chloro-6-methylphenyl)-2-methylpyrido[2,3-d]-pyrimidin-7-amine, mp 267°-271° C., after recrystallization from isopropanol.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:27](O)=O)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37](=[N:39][OH:40])[NH2:38]>>[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]1[N:38]=[C:27]([CH:12]2[CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:24])([F:26])[F:25])=[CH:18][CH:17]=3)[CH2:15][N:10]([C:8]([N:5]3[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]3)=[O:9])[CH2:11]2)[O:40][N:39]=1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Reactant: NC(=NO)c1ccccc1F
Product: O=C(N1CCC(O)CC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3ccccc3F)no2)C1

Procedure:
100 mg (0.24 mmol) of 1-[(4-hydroxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 63A) and 56 mg (0.36 mmol, 1.5 eq.) of 2-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 2. Yield: 73 mg (57% of theory)
Reaction SMILES: [H-].[Na+].C(=NO)C.[OH:7][C:8]1[CH:27]=[CH:26][C:11]([C:12]([C:14]2[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[C:16](Cl)[CH:15]=2)=[O:13])=[CH:10][CH:9]=1.OC1C=CC(C(C2C=CC(OCC(O)=O)=CC=2Cl)=O)=CC=1>O.CN(C)C=O>[OH:7][C:8]1[CH:27]=[CH:26][C:11]([C:12]([C:14]2[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1
Reactant: O=C(O)COc1ccc(C(=O)c2ccc(O)cc2)cc1Cl
Agent: O=C(O)COc1ccc(C(=O)c2ccc(O)cc2)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC=NO
Solvent: CN(C)C=O
Product: O=C(O)COc1ccc(C(=O)c2ccc(O)cc2)cc1
Reaction time: 0.17 h

Procedure:
To a suspension of sodium hydride (4.32 g., 0.09 mole, 50% suspension in mineral oil) in 50 ml. of dimethylformamide was added by dropwise addition acetaldoxime (5.31 g., 0.09 mole) at 5°. The mixture was stirred for 10 minutes at 20°-25° and then treated by dropwise addition with a solution of 10 g. (0.03 mole) of ethyl 4-(4-nitrobenzoyl) phenoxy acetate in 50 ml. of dimethylformamide. The resulting mixture was stirred at room temperature for 5 hrs. and poured into cold water. Acidification with concentrated hydrochloric gave a solid which was collected by filtration and dried. There was obtained 7 g. of product. This material was used without purification for the next step. In a similar manner were prepared the following two compounds: 4-(4-hydroxybenzoyl)-2-chlorophenoxy acetic acid and 4-(4-hydroxybenzoyl)-3-chlorophenoxy acetic acid.
Reaction SMILES: [F:1][C:2]1[C:12]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([CH3:20])[NH:15][C:14]2=[O:21])=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.Cl[CH2:23][C:24]#[N:25]>>[C:24]([CH2:23][CH:8]1[C:7](=[O:10])[NH:6][C:5]2[CH:11]=[C:12]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([CH3:20])[NH:15][C:14]3=[O:21])[C:2]([F:1])=[CH:3][C:4]=2[O:9]1)#[N:25]
Reactant: N#CCCl
Reactant: Cc1cc(=O)n(-c2cc3c(cc2F)OCC(=O)N3)c(=O)[nH]1
Product: Cc1cc(=O)n(-c2cc3c(cc2F)OC(CC#N)C(=O)N3)c(=O)[nH]1

Procedure:
Analogously to the procedure described in Example 81, by alkylating 3-(3,4-dihydro-7-fluoro-3-oxo-2H-1,4-benzoxazin-6-yl)-6-methyl-2,4(1H,3H)-pyrimidinedione (see Example 21) with chloroacetonitrile there is obtained 3-(2-cyanomethyl-3,4-dihydro-7-fluoro-3-oxo-2H-1,4-benzoxazin-6-yl)-6-methyl-2,4(1H,3H)-pyrimidinedione, m.p.>230° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[N+:12]([O-])([OH:14])=[O:13]>O>[Br:1][C:2]1[C:3]([F:11])=[C:4]2[C:10]([N+:12]([O-:14])=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Fc1c(Br)cnc2[nH]ccc12
Reactant: O=[N+]([O-])O
Solvent: O
Product: O=[N+]([O-])c1c[nH]c2ncc(Br)c(F)c12
Reaction time: 0.17 h
Yield: 86.8 %

Procedure:
5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridine (0.100 g, 0.465 mmol, see Example 51) was added slowly to fuming HNO3 (5 mL) at 0° C. and stirred for 10 minutes. Ice was then added, followed by the addition of water. The resulting solid product was then filtered, and washed with water and dried to give 5-bromo-4-fluoro-3-nitro-1H-pyrrolo[2,3-b]pyridine (0.105 g, 86.8% yield).
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:6]2[CH:14]=[CH:15][C:16]([C:18]([OH:20])=O)=[CH:17][C:5]=2[N:4]=1.[NH2:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1O.CCN=C=NCCCN(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O.CN(C=O)C>[CH3:28][C:26]1[CH:25]=[CH:24][C:23]2[O:20][C:18]([C:16]3[CH:15]=[CH:14][C:6]4[N:7]([CH:8]5[CH2:9][CH2:10][O:11][CH2:12][CH2:13]5)[C:3]([CH3:2])=[N:4][C:5]=4[CH:17]=3)=[N:21][C:22]=2[CH:27]=1
Reactant: Cc1nc2cc(C(=O)O)ccc2n1C1CCOCC1
Reactant: Cc1ccc(O)c(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc2oc(-c3ccc4c(c3)nc(C)n4C3CCOCC3)nc2c1
Yield: 28.5 %

Procedure:
2-methyl-1-(tetrahydropyran-4-yl)benzimidazole-5-carboxylic acid HCl salt (see Working Example 4-3) (0.25 g, 0.96 mmol), 2-amino-4-methylphenol (0.13 g, 1.05 mmol), anhydrous DMF (500 mL) and WSC (0.22 g, 1.14 mmol) were stirred for 3 hours at room temperature. After the reaction was complete, water (50 mL) was added, the precipitated crystals were filtered off, and the filter residue was extracted with water/chloroform. After the organic layer was dried over anhydrous sodium sulfate, filtration and concentration gave crystals that were dissolved in toluene (5 mL), to which p-toluenesulfonic acid hydrate (0.43 g, 2.26 mmol) was added and this was stirred at reflux for 2 hours. After the solvent was concentrated at reduced pressure, water (5 mL) was added and the solid obtained was filtered off, and after washing with water, drying at reduced pressure at 50° C. yielded the title compound (95 mg, 28.5% yield) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[C:5]2[NH:6][C:7]([CH3:11])=[CH:8][C:9](=O)[N:4]2[N:3]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:24])=O.[OH-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:24][C:9]1[N:4]2[N:3]=[C:2]([CH3:1])[CH:12]=[C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=1
Reactant: Cc1cc2[nH]c(C)cc(=O)n2n1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: Cc1cc(Cl)n2nc(C)cc2n1
Temperature: 25 °C
Yield: 59.7 %

Procedure:
To a suspension of 2,5-dimethyl-4H-pyrazolo[1,5-a]pyrimidin-7-one (10.0 g, 61.3 mmol) in toluene (150 mL), add N,N-dimethylaniline (9.7 mL, 76.7 mmol). Add phosphorus oxychloride (11.2 mL, 122.6 mmol) dropwise to this white suspension. Reflux for 3 h under an inert atmosphere, cool to room temperature, and concentrate the reaction to a brown oil using reduced pressure. Dissolve the oil in ethyl acetate (250 mL) and basify with 1 N NaOH. Separate and extract the basic aqueous phase with additional ethyl acetate (2×100 mL). Combine the organic phases, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure to yield a brown solid. Purify the material using flash chromatography, eluting with 80% hexane/20% (30% THF/hexane) to 0% hexane/100% (30% THF/hexane) in a step gradient of 20% increments to provide a light green solid (6.65 g, 59%). ES/MS m/z (35Cl) 182.3 (M+1)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25](=[S:28])[NH:26][NH2:27].C(Cl)(Cl)Cl.[CH3:33][N:34]=[C:35]=[O:36]>>[CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[N:4][N:3]1[C:25]([NH:26][NH:27][C:35]([NH:34][CH3:33])=[O:36])=[S:28]
Reactant: CN=C=O
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(=S)NN)OCO3
Solvent: ClC(Cl)Cl
Product: CNC(=O)NNC(=S)N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2CC1C)OCO3
Yield: 88 %

Procedure:
To a stirred solution of 0.40 g (1.0 mmol) of compound XVIII in 15 ml of chloroform 0.07 ml (1.2 mmol) of methyl isocyanate was added. After 1 h the reaction mixture was washed with sodium hydrogen carbonate solution and water and after concentration the obtained solid material was purified by refluxing in ethanol. The desired product was 0.36 g, yield: 88%. Mp.: 200° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10](=[O:26])[N:11]([CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[CH:12]=1.[CH2:27]=O>C(Cl)(Cl)Cl>[C:20]1([CH2:19][N:16]2[CH2:17][CH2:18][CH:13]([N:11]3[C:12]4[CH:27]=[N:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=5[C:8]=4[NH:9][C:10]3=[O:26])[CH2:14][CH2:15]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C=O
Reactant: Nc1ccccc1-c1cn(C2CCN(Cc3ccccc3)CC2)c(=O)[nH]1
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c2c3ccccc3ncc2n1C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2.67 g (7.66 mmol) of 4-(2-aminophenyl)-1,3-dihydro-1-[1-(phenylmethyl)-4-piperidinyl]-2H-imidazol-2-one in 50 ml of chloroform was mixed with 3.0 g of paraformaldehyde and refluxed for 3.5 hours. The residue remaining after evaporation of the solvent was taken up in 100 ml of methanol and acidified with methanolic hydrogen chloride solution. After stirring for one hour at room temperature the mixture was poured into 300 ml of saturated sodium hydrogen carbonate solution. The resulting mixture was extracted thoroughly with ethyl acetate, the combined extracts were dried over sodium sulphate and evaporated down in vacuo. The residue was purified by column chromatography over silica gel using FM4 as eluant. From the appropriate fractions 0.5 g (18.2% of theory) of a colourless, amorphous substance were isolated, Rf=0.24 (FM4).
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8]#N)=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=2[F:17])[S:5][N:4]=1)[CH3:2].N([O-])=[O:19].[Na+].[OH2:22]>CC(=O)OCC>[CH2:1]([C:3]1[C:7]([C:8]([OH:19])=[O:22])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=2[F:17])[S:5][N:4]=1)[CH3:2]
Reactant: O=N[O-]
Reactant: CCc1nsc(-c2ccc(C)cc2F)c1C#N
Reactant: O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCc1nsc(-c2ccc(C)cc2F)c1C(=O)O
Temperature: 120 °C
Reaction time: 1 h

Procedure:
Into a 25-mL round-bottom flask, was placed 3-ethyl-5-(2-fluoro-4-methylphenyl)-1,2-thiazole-4-carbonitrile (200 mg, 0.81 mmol, 1.00 equiv). This was followed by the addition of sulfuric acid(conc.) (10 mL). The mixtures were stirred for 1 h at 120° C. To this was added a solution of NaNO2(aq) (168 mg, 2.43 mmol, 3 equiv) in water (0.5 mL) at 0-5° C. The resulting solution was stirred for 30 min at 50° C. The resulting solution was diluted with 50 mL of EA. The organic phase was washed with 1×20 mL of 2N HCl and 1×20 mL brine. The mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 150 mg (crude) of 3-ethyl-5-(2-fluoro-4-methylphenyl)-1,2-thiazole-4-carboxylic acid as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH3:3].[C:17](O)(=O)C.C=O.[CH3:23][N:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29][N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][C:31]1=[O:36].[OH-].[Na+]>C(Cl)Cl.CO>[CH3:23][N:24]1[C:28]([CH2:17][N:14]2[CH2:13][CH2:12][N:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][CH:2]([CH3:1])[CH3:3])[CH2:16][CH2:15]2)=[CH:27][CH:26]=[C:25]1[CH2:29][N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][C:31]1=[O:36]
Reactant: CC(C)Oc1ccccc1N1CCNCC1
Reactant: Cn1cccc1CN1CCCCC1=O
Reactant: CC(=O)O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC(C)Oc1ccccc1N1CCN(Cc2ccc(CN3CCCCC3=O)n2C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
A solution of 1-[2-(1-methylethoxy)phenyl]piperazine (9.38 g, 0.043 mole) as described in U.S. Pat. Nos. 4,547,505 and 4,438,115, glacial acetic acid (2.57 mL, 0.043 mole), and methanol (27 mL) was cooled in an ice bath and treated with 37% formalin (3.18 mL, 0.043 mole). A solution of 1-(1-methylpyrrol-2-ylmethyl)-2-piperidinone (8.19 g, 0.043 mole) and methanol (27 mL) was added and the resulting solution was stirred overnight at 25° C. under a dry nitrogen atmosphere. Methylene chloride (350 mL) was added followed by 3N sodium hydroxide solution (60 mL). After thorough mixing, the organic layer was separated, dried over anhydrous potassium carbonate, filtered and evaporated to give 18.20 g of 1-[[1-methyl-5-[[4-[2-(1-methylethoxy)phenyl]-1 -piperazinyl]methyl]-lH-pyrrol-2-yl]methyl]-2- piperidinone as a Yellow oil. This material (2.50 g) was dissolved in 6 mL ethanol and treated with 0.68 g of oxalic acid. The mixture was heated to effect solution, cooled and ether added until just cloudy. After cooling in an ice bath, a white solid was obtained by filtration. This was recrystallized twice from ethanol-ether using activated charcoal to give the oxalate salt, mp 139.5-140.5° C. (Ho).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]([C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([F:31])[CH:22]=2)([NH:14][S@@](C(C)(C)C)=O)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:6][CH:7]=1.Cl>CO.O1CCOCC1.CCOC(C)=O>[NH2:14][C@:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)([C:21]1[CH:26]=[C:25]([C:27]([F:28])([F:30])[F:29])[CH:24]=[C:23]([F:31])[CH:22]=1)[CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C[C@](N[S@](=O)C(C)(C)C)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C[C@](N)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Reaction time: 0.5 h

Procedure:
(S)-methyl 3-(5-chloropyridin-2-yl)-3-(3-fluoro-5-(trifluoromethyl)phenyl)-3-((R)-2-methylpropan-2-ylsulfinamido)propanoate (0.075 g, 0.16 mmol) was dissolved in MeOH (2 mL). At RT, 4.0M HCl in dioxane (2 mL) was added and the reaction mixture stirred for 30 min. The reaction mixture was diluted with EtOAc (50 mL), transferred to a separation funnel and washed with 1.0M NaOH (ca.20 mL). The organic portion was dried over anhydrous Na2SO4, decanted and concentrated yielding (S)-methyl 3-amino-3-(5-chloropyridin-2-yl)-3-(3-fluoro-5-(trifluoromethyl)phenyl)propanoate as a colorless oil, (0.062 g, crude quantitative yield). LCMS: 1.37 min [M+1] 377.1 (2 min gradient, MeOH/H2O 0.1% TFA).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][CH:22]([CH:25]=[C:26]=[O:27])[CH2:21][CH2:20]3)=[O:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].C1(C)C=CC([S:34]([OH:37])(=[O:36])=[O:35])=CC=1.[CH2:39]([OH:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[C:5]1([CH3:2])[C:10]([S:34]([OH:37])(=[O:36])=[O:35])=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][CH:22]([CH2:25][C:26]([O:46][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[O:27])[CH2:21][CH2:20]3)=[O:18])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)(=[NH:3])[NH2:4]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: N=C(N)c1ccc(-c2ccc(C(=O)N3CCC(C=C=O)CC3)cc2)cc1
Reactant: OCc1ccccc1
Agent: Cl
Product: Cc1ccccc1S(=O)(=O)O
Product: N=C(N)c1ccc(-c2ccc(C(=O)N3CCC(CC(=O)OCc4ccccc4)CC3)cc2)cc1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A mixture of 1.6 g of 4-amidino-4'-[(4-carbonylmethylpiperidino)carbonyl]biphenyl hydrochloride, 50 ml of benzyl alcohol and 1 g of p-toluenesulphonic acid is heated to 70° C. with stirring for 4 hours under 100 mbar and then evaporated down in a water jet vacuum at 140°-150° C. The residue was triturated with ether, the solid product obtained was filtered off and dissolved in dimethylformamide, the solution was evaporated down and the residue was triturated with ether.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:30])[N:5]=[C:6]([S:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)=[C:15]([CH:18]=2)[C:16]#[N:17])[NH:7][CH:8]=1)[CH3:2].[CH3:31]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[CH2:1]([C:3]1[C:4](=[O:30])[N:5]=[C:6]([S:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=3)=[C:15]([CH:18]=2)[C:16]#[N:17])[N:7]([CH3:31])[CH:8]=1)[CH3:2]
Reactant: CCc1c[nH]c(SCc2ccc(Oc3cccc(C(F)(F)F)c3)c(C#N)c2)nc1=O
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CI
Product: CCc1cn(C)c(SCc2ccc(Oc3cccc(C(F)(F)F)c3)c(C#N)c2)nc1=O
Yield: 38.8 %

Procedure:
The same procedure as E64 from 5-{[(5-ethyl-4-oxo-1,4-dihydro-2-pyrimidinyl)thio]methyl}-2-{[3-(trifluoromethyl)phenyl]oxy}benzonitrile (250 mg, 0.579 mmol), DIPEA (0.202 mL, 1.159 mmol) and MeI (0.054 mL, 0.869 mmol) in DCM (2 mL). to afford the title compound (100 mg, 38.7% yield). LCMS: rt=3.25 min, [M+H+]=446
Reaction SMILES: [OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([CH3:17])[CH3:16])=[C:10]([CH3:18])[CH:9]=2)[CH:3]=1.[CH3:19]N(C)C=O.[H-].[Na+].S(OC)(OC)(=O)=O>O>[CH:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]2[CH:3]=[C:2]([O:1][CH3:19])[N:6]([CH3:7])[N:5]=2)=[CH:9][C:10]=1[CH3:18])([CH3:16])[CH3:17]
Reactant: Cc1cc(-c2cc(O)n(C)n2)ccc1OC(C)C
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: COc1cc(-c2ccc(OC(C)C)c(C)c2)nn1C
Reaction time: 1 h

Procedure:
At room temperature, to mixture of 5-hydroxy-3-(4 isopropoxy-3-methyl-phenyl)-1-methyl-1H-pyrazole (described in Reference Preparation example 95) 9.5 g, and N,N-dimethylformamide 70 ml was added 55%-sodium hydride 2.5 g and was stirred for one hour, and thereto was then added dimethyl sulfate 9.7 g and stirred at 100° C. for 12 hours. Thereto was added water 50 ml and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, and was dried over anhydrous magnesium sulfate and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 3-(4-isopropoxy-3-methyl-phenyl)-5-methoxy-1-methyl-1H-pyrazole 5.8 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([O-:14])(=O)=[O:12].[Na+].S1(CCCC1)(=O)=O.P(Cl)(Cl)([Cl:25])=O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([Cl:25])(=[O:14])=[O:12]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)[O-])c1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O=S1(=O)CCCC1
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1
Temperature: 25 °C

Procedure:
To a mixture of 104 g of commercially available sodium 2-chloro-5-nitrobenzenesulfonate, 200 ml of acetonitrile and 200 ml of sulfolane stirred at 25° C., was added 153 ml of phosphorus oxychloride over a period of 30 minutes. The temperature was not allowed to exceed 40° C. After completion of the addition, the reaction mixture was heated to 70° C. for 1.5 hours. On cooling to 0°C., the reaction mixture was poured over ice. The resulting solid product was washed with cold water, filtered and air-dried to give 77.6 g of the title compound with a melting point of 87°-89° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10](=O)[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:4][CH:3]=1.[NH3:19]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:19][C:10](=[O:9])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:4][CH:3]=1
Reactant: N
Reactant: O=c1oc(-c2ccc(Br)cc2)cc2ccccc12
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c(-c2ccc(Br)cc2)cc2ccccc12
Temperature: 80 °C
Reaction time: 72 h

Procedure:
To a suspension of 3-(4-bromo-phenyl)-isochromen-1-one (1.05 g, 3.50 mmol) in DMF (7 ml) is added aqueous ammonia (25% by weight, 7 ml) and the mixture is stirred at 80° C. for 3 days. The reaction mixture is diluted with water. The resulting precipitate is filtered off, washed with water and dried under vacuum to afford 3-(4-bromo-phenyl)-2H-isoquinolin-1-one as brown powder; HPLC/MS 1.96 min (A), [M+H] 300/302;
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19])[CH:13]=O.C(CN)O>O>[CH3:21][O:20][C:16]1[CH:15]=[C:12]([CH:11]=[C:10]([O:9][CH3:8])[C:17]=1[O:18][CH3:19])[CH:13]=[C:7]1[NH:1][C:2](=[O:3])[NH:4][C:5]1=[O:6]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: O=C1CNC(=O)N1
Solvent: NCCO
Solvent: O
Product: COc1cc(C=C2NC(=O)NC2=O)cc(OC)c1OC
Yield: 87 %

Procedure:
50 g (0.5 mole) of hydantoine, 98.1 g (0.5 mole) of 3,4,5-trimethoxy-benzaldehyde and 46 g (0.7 mole) of ethanol amine are admixed with 500 ml of water at 70° C. The reaction is carried out further in accordance with Example 2. Thus 121 g of the desired compound are obtained, yield 87%. Mp.: 266°-268° C.