Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C@H:5]([NH:13][C:14]([C:16]2[C:25]3[C:20](=[C:21]([F:26])[CH:22]=[CH:23][CH:24]=3)[C:19](=[O:27])[N:18]([NH:28][CH2:29][CH2:30][CH3:31])[C:17]=2[CH2:32]Br)=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1.[F-:34].[K+]>O>[CH:1]1([C@H:5]([NH:13][C:14]([C:16]2[C:25]3[C:20](=[C:21]([F:26])[CH:22]=[CH:23][CH:24]=3)[C:19](=[O:27])[N:18]([NH:28][CH2:29][CH2:30][CH3:31])[C:17]=2[CH2:32][F:34])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: [F-]
Reactant: CCCNn1c(CBr)c(C(=O)N[C@H](c2cccc(F)c2)C2CCC2)c2cccc(F)c2c1=O
Agent: [K+]
Solvent: O
Product: CCCNn1c(CF)c(C(=O)N[C@H](c2cccc(F)c2)C2CCC2)c2cccc(F)c2c1=O

Procedure:
3-Bromomethyl-8-fluoro-1-oxo-2-propylamino-1,2-dihydro-isoquinoline-4-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide (27 mg, 0.052 mmol) N,N-Dimethylformamide (2 mL) and potassium fluoride (0.015 g, 0.26) were stirred at room temperature overnight. The reaction mixture was poured into water. The mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by preparative HPLC to give the title compound.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[OH:6][C:7]1[C:16]([OH:17])=[N:15][C:14]2[C:13]3=[N:18][N:19]([CH3:21])[N:20]=[C:12]3[CH:11]=[CH:10][C:9]=2[N:8]=1>>[OH:6][C:7]1[C:16]([OH:17])=[N:15][C:14]2[C:13]3=[N:18][N:19]([CH3:21])[N:20]=[C:12]3[C:11]([N+:1]([O-:4])=[O:2])=[CH:10][C:9]=2[N:8]=1
Reactant: Cn1nc2ccc3nc(O)c(O)nc3c2n1
Reactant: O=[N+]([O-])[O-]
Agent: [K+]
Product: Cn1nc2c([N+](=O)[O-])cc3nc(O)c(O)nc3c2n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 22.4 %

Procedure:
Finely powdered potassium nitrate (0.47 g, 4.6 mmol) was added to an ice-cooled solution of 7,8-dihydroxy-2-methyl-2H-1,2,3-triazolo[4,5-f]quinoxaline (1.0 g, 4.6 mmol). The mixture was stirred at 0° C. for 11/2 h, then at room temperature for 4 h and finally poured into ice/water. The resulting solution was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated to dryness giving 0.27 g (22%) of the nitro compound; m.p.>300° C.; IR (KBr): 1700 cm-1 ; 1H-NMR (DMSO-d6): 4.63 (s, 3H, CH3), 8.15 (s, 1H, ArH), 12.1 (broad s, 1H, OH), 13.0 (broad s, 1H, OH).
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15].[Cl:22][C:23]1[CH:24]=[C:25]([SH:30])[CH:26]=[C:27]([Cl:29])[CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:22][C:23]1[CH:24]=[C:25]([S:30][C:2]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:5]=[C:4]([CH3:13])[C:3]=2[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])[CH:26]=[C:27]([Cl:29])[CH:28]=1
Reactant: Cc1nn(-c2ccccc2)c(Cl)c1C(=O)c1ccccc1
Reactant: Sc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccccc2)c(Sc2cc(Cl)cc(Cl)c2)c1C(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 19 h
Yield: 74.3 %

Procedure:
A solution containing 2.0 g of (5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-phenyl-methanone, 2.0 g of 3,5-dichlorothiophenol and 1.7 g of potassium carbonate in 50 ml of N,N-dimethylformamide was stirred at 60° C. for 19 h. The mixture was partitioned between 100 ml of water and 100 ml of dichloromethane. The organic layer was dried over magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using methanol/dichloromethane for the elution to give 2.2 g of [5-(3,5-dichloro-phenylsulfanyl)-3-methyl-1-phenyl-1H-pyrazol-4-yl]-phenyl-methanone as a yellow oil. Mass spectrum (ES) m/z 439 [M+H]+, 480 [M+H+CH3CN]+.
Reaction SMILES: C(Cl)Cl.[NH2:4][CH:5]([CH:11]([OH:23])[C:12]1[S:13][C:14]([CH2:17][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:15][CH:16]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Cl-].[Na+]>C(N(CC)CC)C>[C:24]([NH:4][CH:5]([CH:11]([OH:23])[C:12]1[S:13][C:14]([CH2:17][N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)=[CH:15][CH:16]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)C(N)C(O)c1ccc(CN2CCCC2)s1
Reactant: O=C(Cl)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(NC(=O)c1ccccc1)C(O)c1ccc(CN2CCCC2)s1
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To methylene chloride solution (5 ml) of 180 mg ethyl 2-amino-3-hydroxy-3-[5-(1-pyrrolidinyl)methyl-2-thienyl]propionate diastereomers (A form and B form) was added triethylamine (300 μl), followed by dropwise addition of 80 mg of benzoyl chloride. After 30 minutes, a saturated sodium chloride aqueous solution was added to effect separation of layers, the thus separated organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. Then, the residue was subjected to silica gel column chromatography and elution was carried out with chloroform:methanol (30:1) mixed solution to obtain 110 mg of ethyl 2-benzoylamino-3-hydroxy-3-[5-(1-pyrrolidinyl)methyl-2-thienyl]propionate (diastereomer A form and B form).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.C(N(CC)CC)C.[Cl:22][C:23]1[C:28]([C:29](Cl)=[O:30])=[C:27]([Cl:32])[N:26]=[CH:25][N:24]=1>ClCCl>[Cl:22][C:23]1[C:28]([C:29]([NH:1][C:2]2[CH:3]=[C:4]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=2)=[O:30])=[C:27]([Cl:32])[N:26]=[CH:25][N:24]=1
Reactant: O=C(Cl)c1c(Cl)ncnc1Cl
Reactant: COc1cc(N)cc(NS(C)(=O)=O)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(NC(=O)c2c(Cl)ncnc2Cl)cc(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.2 %

Procedure:
N-(3-Amino-5-methoxyphenyl)methanesulfonamide (1 g, 87% purity, 4.02 mmol) was dissolved in dichloromethane (36 ml) and triethylamine (1.35 ml, 9.65 mmol) was added. Then a solution of 4,6-dichloropyrimidine-5-carbonyl chloride (1.52 g, 67% purity, 4.82 mmol, prepared according to E. V. Tarasov et al. Synlett 2000, 5, 625-626) was added dropwise and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then diluted with dichloromethane, washed with 4% sodium bicarbonate solution, dried over magnesium sulphate, filtered and evaporated. The crude was purified by flash chromatography (0% to 40%, hexane-ethyl acetate) using an Isolera® Purification System to give 617 mg (28% yield) of the title compound as a reddish oil. Purity 73%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:13][CH:14]=O)=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[O:16]1[C:20]2([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[O:16]1[C:20]2([CH2:25][CH2:24][N:23]([CH2:14][CH2:13][C:4]3[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[C:10]4[C:5]=3[CH:6]=[CH:7][CH:8]=[N:9]4)[CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: COc1ccc2ncccc2c1CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc2ncccc2c1CCN1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
0.72 g of (6-methoxyquinolin-5-yl)acetaldehyde and 0.75 g of 1,4-dioxa-8-azaspiro[4.5]decane were dissolved in 30 ml of methylene chloride. Then, 0.50 ml of acetic acid and 0.89 g of sodium triacetoxyborohydride were added to the reaction solution, and the obtained mixture was then stirred at room temperature overnight. Thereafter, a saturated sodium bicarbonate aqueous solution was added to the reaction solution, followed by extraction with methylene chloride. The extract was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate), so as to obtain 1.01 g of the subject compound.
Reaction SMILES: C=O.[CH3:3][NH:4][C:5]([NH:7][C:8]1[CH:12]=[C:11]([C:13]([CH2:16][O:17][CH3:18])([CH3:15])[CH3:14])[O:10][N:9]=1)=[O:6].CN.[CH3:21][N:22]([CH3:25])[CH:23]=O>O>[CH3:3][N:4]1[CH2:23][N:22]([CH3:25])[CH2:21][N:7]([C:8]2[CH:12]=[C:11]([C:13]([CH2:16][O:17][CH3:18])([CH3:14])[CH3:15])[O:10][N:9]=2)[C:5]1=[O:6]
Reactant: CN(C)C=O
Reactant: CNC(=O)Nc1cc(C(C)(C)COC)on1
Agent: C=O
Agent: CN
Solvent: O
Product: COCC(C)(C)c1cc(N2CN(C)CN(C)C2=O)no1
Reaction time: 0.5 h

Procedure:
16 ml of a 36% aqueous formaldehyde solution was added dropwise to a stirred solution of 4.1 g of 2D in 75 ml of dimethylformamide. The temperature of the mixture rose from 22° C. to 27° C. The mixture was stirred for 30 minutes, then 8 ml of a 40% solution of methylamine in water was added, drop-by-drop. The temperature of the mixture rose from 27° C. to 36° C. The mixture was refluxed for 3 hours, then the solvent was evaporated under reduced pressure. The residue was mixed with cold water, and the resulting mixture was extracted with ether. The solvent was evaporated from the extract, and the residue was crystallized when hexane was added, to give 2, as a white solid, m.p.: 49°-50° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.O1CCCC1.[Br:16]N1C(=O)CCC1=O>C(OCC)(=O)C>[Br:16][C:8]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=2[NH:10][CH:9]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Clc1ncnc2c(Br)c[nH]c12
Reaction time: 1 h

Procedure:
To 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (100 mg), tetrahydrofuran (5 mL) was added, and N-bromosuccinimide (116 mg) was further added thereto, followed by stirring for 1 hour. After completion of the reaction, the reaction mixture was mixed with ethyl acetate and washed with water. The washed mixture was dried over anhydrous sodium sulfate, and filtered and distilled under reduced pressure to obtain the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:19](=[O:25])[NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>C(Cl)Cl>[NH2:7][C@@H:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=1)[C:19]([NH:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:25]
Reactant: CC(C)(C)NC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1

Procedure:
A solution of the product from Example AJ ((S)-[2-(4-nitrophenyl)-1-tert-butylcarbamoyl-ethyl]-carbamic acid tert-butyl ester) (2, 2.0 g, 5.25 mmol) was stirred in a solution of TFA/CH2Cl2 (15 mL/15 mL) for 30 minutes and concentrated to dryness. This crude reaction product was redissolved in CH2Cl2 (50 mL) then washed with NaHCO3 (aq) and brine. The EtOAc solution was further dried over NaHCO3 and concentrated to dryness to yield the title compound (1.34 g).
Reaction SMILES: [CH2:1]([CH:4]([CH2:8][CH2:9][CH3:10])[C:5]([OH:7])=[O:6])[CH2:2][CH3:3].[CH2:11](O)[CH2:12][CH2:13][CH2:14][OH:15]>CS(O)(=O)=O.C1(C)C=CC=CC=1>[CH2:1]([CH:4]([CH2:8][CH2:9][CH3:10])[C:5]([O:7][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[O:6])[CH2:2][CH3:3]
Reactant: CCCC(CCC)C(=O)O
Reactant: OCCCCO
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CCCC(CCC)C(=O)OCCCCO
Yield: 99 %

Procedure:
2-propylpentanoic acid (40.16 g, 278.5 mmol) was mixed with butane-1-4-diol (114.65 g, 1272.2 mmol) and methyl-sulfonic acid (5 drops) in toluene (3500 ml) and the mixture was heated under reflux using a Dean Stark trap for 12 h. After that, toluene was removed under reduced pressure and the crude mixture was dissolved in chloroform (200 ml) and extracted with water (pH 5, 3×200 ml). The combined organic layers were dried over sodium sulfate and the volatiles were removed under reduced pressure giving a clear oil (99%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)COc1cc2ncnc(Nc3ccc(Cl)cc3F)c2cc1OC
Temperature: 90 °C
Yield: 47.9 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (3.0 g, 9 mmol), (prepared as described for the starting material in Example 4), ethyl bromoacetate (1.11 ml, 10 mmol) and potassium carbonate (2.84 g, 20.6 mmol) in NMP (60 ml) was heated at 90° C. for 3 hours. The mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO4) and concentrated by evaporation. Hexane was added, the mixture was cooled and the precipitated solid was collected by filtration to give 4-(4-chloro-2-fluoroanilino)-7-(ethoxycarbonylmethoxy)-6-methoxyquinazoline (1.75 g, 48%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([O:11]C)=O)[CH2:4][CH2:3]1.O.[NH2:14][NH2:15]>C(O)C>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]([NH:14][NH2:15])=[O:11])[CH2:6][CH2:7]1
Reactant: NN
Reactant: COC(=O)CN1CCN(C)CC1
Solvent: CCO
Solvent: O
Product: CN1CCN(CC(=O)NN)CC1

Procedure:
A solution of 2-(4-methyl-1-piperazinyl)acetic acid, methyl ester (16.3 g., 0.0946 mole) and hydrazine monohydrate (7.0 ml., 0.142 mole) in ethanol (100 ml.) was refluxed for 17 hours and the solvent was removed under vacuum. The residue was triturated with ether with cooling at -78° and the resulting solid was filtered. The product was triturated again with ether-ethyl acetate to give 2-(4-methyl-1-piperazinyl)acetic acid, hydrazide as a solid melting at 87°-89° C. (8.94 g., 55%).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OC(C(F)(F)F)=O.[NH:21]1[CH2:24][CH:23]([NH:25][C:26]([CH2:28][NH:29][C:30](=[O:41])[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=2)=[O:27])[CH2:22]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([N:21]3[CH2:24][CH:23]([NH:25][C:26]([CH2:28][NH:29][C:30](=[O:41])[C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:38])[F:39])[CH:32]=4)=[O:27])[CH2:22]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3ccccc3)CC2)C1

Procedure:
A solution of 4-phenyl-cyclohexanone (Aldrich, 1.5 g, 8.62 mmol) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide TFA salt (as prepared in the previous step, 3.89 g, 12.9 mmol) in DCM (20 mL) was treated with TEA (6 mL, 43 mmol) for 10 min followed by NaBH(OAc)3 (Aldrich, 3.65 g, 17.2 mmol) for another 4 hours at room temperature. The reaction was quenched with saturated sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted 3 times with a chloroform/IPA “cocktail” (˜3:1, v/v). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was then purified by a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the two title compounds as white solids.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[CH3:10][CH:11]([CH2:18][CH3:19])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[CH3:10][CH:11]([CH:12]([C:1]([OH:3])([CH3:2])[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:18][CH3:19]
Reactant: CC(=O)c1cccnc1
Reactant: CCOC(=O)CC(C)CC
Product: CCOC(=O)C(C(C)CC)C(C)(O)c1cccnc1

Procedure:
Analysis of the pyrolysis product mixture by gas chromatography and preparative thin layer chromatography indicates that the mixture consists of 12 milligrams of the hydroxy ester starting material, and 85 milligrams of a 1:1 mixture of 3-acetylpyridine and ethyl β-methylvalerate.
Reaction SMILES: S(Cl)(Cl)=O.C[N:6]([CH:8]=[O:9])C.[Cl:10][C:11]1[N:19]=[CH:18][C:17]([S:20](=[O:31])(=[O:30])[NH:21][C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=2)=[CH:16][C:12]=1C(O)=O.[OH-].[NH4+]>C1(C)C=CC=CC=1>[Cl:10][C:11]1[N:19]=[CH:18][C:17]([S:20](=[O:30])(=[O:31])[NH:21][C:22]2[CH:23]=[C:24]([F:29])[CH:25]=[C:26]([F:28])[CH:27]=2)=[CH:16][C:12]=1[C:8]([NH2:6])=[O:9]
Reactant: O=C(O)c1cc(S(=O)(=O)Nc2cc(F)cc(F)c2)cnc1Cl
Reactant: CN(C)C=O
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: NC(=O)c1cc(S(=O)(=O)Nc2cc(F)cc(F)c2)cnc1Cl
Yield: 72 %

Procedure:
0.288 ml (3.87 mmol) of thionyl chloride and a drop of DMF are added successively to 0.450 g (1.29 mmol) of 2-chloro-5-(N-(3,5-difluorophenyl)sulfamoyl)nicotinic acid in 5 ml of anhydrous toluene. The mixture is placed under stirring, at reflux of toluene, for 2 hours. The acid chloride reaction mixture is then added drop by drop to an iced solution, under stirring, of 4.5 ml of 25% ammonium hydroxide. A release of gas is observed. The reaction medium is left under stirring at room temperature for 30 minutes. The reaction medium is extracted several times with ethyl acetate. The combined organic phases are dried on anhydrous sodium sulfate and then concentrated. 0.315 g of 2-chloro-5-(N-(3,5-difluorophenyl)sulfamoyl)nicotinamide in the form of a light brown solid is obtained (yield=72%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH:9]([NH2:12])([CH3:11])[CH3:10].C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:12][CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)Nc1ccnc(Cl)n1

Procedure:
In analogy to compound 1.1, a solution of 0.347 g (2.33 mmol) of 2,4-dichloro-pyrimidine in 15 ml of acetonitrile is reacted with 0.22 ml (2.52 mmol) of isopropylamine in the presence of 0.39 ml (2.83 mmol) of triethylamine. Purification by chromatography (silica gel, ethyl acetate/hexane with ethyl acetate 0-100%) results in 0.26 g (65% of theory) of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([SH:17])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1.CI.[C:22](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([S:17][CH3:22])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1
Reactant: O=C1C2=C(CCCC2)C(S)N1c1ccc(Cl)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CSC1C2=C(CCCC2)C(=O)N1c1ccc(Cl)cc1F
Reaction time: 5 h
Yield: 89.1 %

Procedure:
In 10 ml of acetone was dissolved 1.5 g of 2-(4-chloro-2-fluorophenyl)-2,3,4,5,6,7-hexahydro-3-mercapto-1H-isoindol-1-one, and 1.5 g of methyl iodide and 1.3 g of potassium carbonate were added to the solution, followed by stirring at 40° to 50° C. for 5 hours. After cooling, the insoluble matter was filtered out, and the filtrate was concentrated under reduced pressure. The residual, oily substance was purified by means of column chromatography with the use of silica gel (developing solvent of acetone-hexane), thereby producing 1.4 g (yield of 90%) of the subject compound in white crystals, m.p. 97°-98° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)[N:4]=1.[CH2:17]([O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23])[CH3:18]>>[CH2:17]([O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([N:13]1[CH2:14][CH:15]2[CH:11]([CH2:10][N:9]([C:5]3[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][N:6]=3)[CH2:16]2)[CH2:12]1)=[O:23])[CH3:18]
Reactant: CCOc1ccccc1C(=O)O
Reactant: COc1ccnc(N2CC3CNCC3C2)n1
Product: CCOc1ccccc1C(=O)N1CC2CN(c3nccc(OC)n3)CC2C1

Procedure:
The title compound was prepared according to the procedure used for Example 15 utilizing 2-(4-methoxy-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole and 2-ethoxybenzoic acid. MS (ESI) mass calcd. for C20H24N4O3, 368.44; m/z found, 369.3 [M+H]+. 1H NMR (CDCl3): 8.07 (d, J=5.7 Hz, 1H), 7.37-7.28 (m, 2H), 6.99 (t, J=7.4 Hz, 1H), 6.91 (d, J=8.3 Hz, 1H), 6.02 (d, J=5.7 Hz, 1H), 4.07 (q, J=7.0 Hz, 2H), 4.01-3.85 (m, 5H), 3.84-3.70 (m, 2H), 3.65-3.45 (m, 3H), 3.34-3.22 (m, 1H), 3.16-2.92 (m, 2H), 1.35 (t, J=6.8 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[O:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][N:32]=2)[CH2:26][CH2:25]1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:34]5[CH:33]=[N:32][C:31]([NH:30][CH:27]6[CH2:28][CH2:29][O:24][CH2:25][CH2:26]6)=[CH:36][CH:35]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CC1(C)OB(c2ccc(NC3CCOCC3)nc2)OC1(C)C
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(NC5CCOCC5)nc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and (tetrahydro-pyran-4-yl)-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-amine (stage 214.1.1) to give the title compound as a white solid. (HPLC: tR 2.13 min (Method A); M+H=470 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.89 (s, 1H), 8.15-8.10 (m, 2H), 8.04-8.00 (m, 1H), 7.84-7.79 (m, 1H), 7.47-7.42 (m, 1H), 7.41-7.38 (m, 1H), 6.78-6.73 (m, 1H), 6.57-6.53 (m, 1H), 4.00-3.82 (m, 3H), 3.91 (s, 3H), 3.56 (s, 3H), 3.45-3.37 (m, 2H), 1.96 (s, 3H), 1.91-1.83 (m, 2H), 1.49-1.37 (m, 2H))
Reaction SMILES: CS([C:5]1[N:6]=[N:7][C:8]([CH:11]([NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:12])=[CH:9][N:10]=1)(=O)=O.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1>>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([NH:30][C:5]2[N:6]=[N:7][C:8]([CH:11]([NH:13][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH3:12])=[CH:9][N:10]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: CC(NC(=O)c1ccccc1)c1cnc(S(C)(=O)=O)nn1
Reactant: COc1cccc(N)c1
Product: COc1cccc(Nc2ncc(C(C)NC(=O)c3ccccc3)nn2)c1
Temperature: 50 °C

Procedure:
A mixture of N-{1-[3-(methylsulfonyl)-1,2,4-triazin-6-yl]ethyl}benzamide (Intermediate 73) (100 mg) and m-anisidine (1 mL) was heated at 50° C. overnight. The crude reaction mixture was then purified by chromatography on silica gel eluting with 30% ethyl acetate in petrol to give N-[1-(3-{[3-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]benzamide as a yellow solid (35 mg). 1H NMR (CDCl3): δ8.39 (s, 1H), 7.82 (m, 2H), 7.51-7.32 (m, 5H), 7.28-7.13 (m, 3H), 6.68 (m, 1H) 5.47 (m, 1H), 3.84 (s, 3H), 1.70 (d, J=6.9 Hz, 3H).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([O-:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.[Na+].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.C(O)CO>O>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([S:11]([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[CH:3][N:2]=[CH:1]3)(=[O:13])=[O:12])=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: O=S([O-])c1cccc2cnccc12
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [Na+]
Solvent: O
Solvent: OCCO
Product: O=[N+]([O-])c1ccc(S(=O)(=O)c2cccc3cnccc23)cc1
Yield: 19.1 %

Procedure:
A mixture of sodium 5-isoquinolinesulfinate 100 mg (0.5 mmol), 4-fluoronitrobenzene 70 mg (0.5 mmol), ethylene glycol 0.1 ml and ethyleneglycoldiethylether 0.1 ml was heated and refluxed for 3.5 hours. Water was added to the reaction mixture, and the solution was extracted with ethyl acetate, the organic layer washed with a saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was recrystallized from methanol to give 5-(4-nitrophenylsulfonyl)isoquinoline 30 mg (20.3%).