Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:12]=[O:13])[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[Br:22][CH2:23][CH2:24][CH2:25][CH2:26]Br>CN(C=O)C>[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][N:10]1[CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[C:9]1[CH:12]=[O:13]
Reactant: BrCCCCBr
Reactant: O=Cc1nc(-c2ccccc2)c[nH]1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1nc(-c2ccccc2)cn1CCCCBr
Temperature: 50 °C
Reaction time: 4 h
Yield: 65.7 %

Procedure:
A mixture of 4-phenyl-1H-imidazole-2-carbaldehyde (1.79 g, 10.4 mmol), potassium carbonate (2.87 g, 20.8 mmol), potassium iodide (2.94 g, 17.7 mmol) and 1,4-dibromobutane (4.49 g, 20.8 mmol) in dry DMF (35 mL) were heated to 50° C. and stirred for 4 hours. The mixture was poured into ice-water (100 mL), and washed with EtOAc (2×80 mL). The combined organic layers were washed with brine (2×100 mL). The organic layer was dried over sodium sulfate, filtered, concentrated and then purified by column chromatography to give 1-(4-bromobutyl)-4-phenyl-1H-imidazole-2-carbaldehyde as a colorless oil (2.1 g). MS (ESI): m/z 308 (M+H)+.
Reaction SMILES: O=[C:2]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][OH:21].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[OH:21][CH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][CH:2]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: Nc1ccccc1CO
Reactant: COC(=O)CC(=O)CC(=O)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COC(=O)CC(CC(=O)OC)Nc1ccccc1CO

Procedure:
There are added in succession, to a solution of dimethyl 3-oxopentanedioate (5 g; 28.71 mmol; 4.2 ml) in dichloroethane (125 ml) at 0° C., (2-aminophenyl)methanol (2.95 g; 23.93 mol), and then NaBH(OAc)3 (6 g; 28.71 mol) in small portions.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[C:15]2([OH:19])[CH2:18][O:17][CH2:16]2)[CH2:3][CH2:2]1.[NH2:20][C@@H:21]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22]([NH2:24])=[O:23]>>[C:22]([C@@H:21]([NH:20][C:12]([C:10]1[CH:9]=[CH:8][C:7]([C:15]2([OH:19])[CH2:18][O:17][CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[CH2:25][CH:26]([CH3:28])[CH3:27])(=[O:23])[NH2:24]
Reactant: O=C(O)c1ccc(C2(O)COC2)c(OCC2CC2)n1
Reactant: CC(C)C[C@H](N)C(N)=O
Product: CC(C)C[C@H](NC(=O)c1ccc(C2(O)COC2)c(OCC2CC2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3-hydroxy-oxetan-3-yl)-pyridine-2-carboxylic acid and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=378.2 [M+H]+.
Reaction SMILES: [C:1]([CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[C:9]([CH3:15])[CH:8]=1)([OH:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C)C=O>[CH2:22]([O:2][C:1]([CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[C:9]([CH3:15])[CH:8]=1)=[O:3])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(OCCC(=O)O)ccc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCCC(=O)OCc2ccccc2)ccc1C=O
Reaction time: 8 h

Procedure:
To a suspension of 4-(2-carboxyethoxy)-2-methylbenzaldehyde (7.2 g) and potassium carbonate (14.3 g) in N,N-dimethylformamide (70 mL) was added benzyl bromide (8.2 mL) at room temperature, and the mixture was stirred overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1-3/1) to give the title compound (6.47 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1.O>CN(C=O)C>[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[CH:4][C:3]=2[N+:18]([O-:20])=[O:19])=[CH:24][CH:23]=1
Reactant: Nc1ccc(S)cc1
Reactant: O=C(Nc1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(F)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(Sc2ccc(NC(=O)c3ccc(F)cc3)cc2[N+](=O)[O-])cc1
Temperature: 80 °C

Procedure:
To a solution of Example 238b (2.5 g, 8.5 mmol) in DMF (50 mL) was added CsCO3 (5.5 g, 17.0 mmol), and 4-aminothiophenol (1.0 g, 8.5 mmol). The mixture was heated at 80° C. for 16 h. The reaction was cooled and poured into water. The aqueous phase was extracted with ethyl acetate (2×). The combined organic phases were washed with water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the title compound. The residue was purified by silica gel chromatography eluting with hexanes/ethyl acetate/methanol (60:30:10) to give the desired product (1.5 g, 46%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:36])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30]OS(C)(=O)=O.[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([F:36])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:21])([CH3:22])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30][N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCOS(C)(=O)=O)c(F)cc(F)c3o2)cc1F
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCN4CCCC4)c(F)cc(F)c3o2)cc1F
Temperature: 50 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
709 mg (1.35 mmol) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-(3-methanesulfonyloxypropylamino)-4H-1-benzopyran-4-one obtained in Example 129 (2) was dissolved in 30 mL of dimethylformamide under argon atmosphere, 1.14 mL (13.5 mmol) of pyrrolidine and 1.86 g (13.5 mmol) of potassium carbonate were added and the mixture was stirred at 50° C. for 8 hours. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=100:9:1) to give 431 mg of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-[3-(pyrrolidin-1-yl)propylamino]-4H-1-benzopyran-4-one (yield: 64%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)Cc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1NCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The title B compound, (2-amino-phenyl) acetic acid methyl ester (4.2 g, 25.4 mmol) is dissolved in DMF (30 mL). Powdered potassium carbonate (8.78 g, 63.5 mmol) and t-butyl bromoacetate (4.12 mL, 27.9 mmol) are added and the reaction is stirred at room temperature for 18 h and then at 50° C. for 1 h. The reaction is diluted with water (300 mL) and extracted with EtOAc (2×200 mL). Combined EtOAc layers are washed with water (2×100 mL) then brine (100 mL), dried over anhydrous MgSO4, filtered and concentrated to give a viscous brown oil. This residue is chromatographed on a 110 g silica gel RediSep (Isco Inc.) column with a 30 mL/min gradient elution of 10:90 (EtOAc:hexane) to 25:75 over 30 min. Fractions containing product are combined and evaporated to yield [2-(t-butoxy-carbonylmethyl-amino)-phenyl]-acetic acid methyl ester as a clear amber oil: [M+1]+=280.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([NH2:14])=[C:12]([CH3:15])[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([NH:14][C:16](=[O:18])[CH3:17])=[C:12]([CH3:15])[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccnc(-c2ccc(F)cc2)c1N
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1c(C)ccnc1-c1ccc(F)cc1

Procedure:
10.44 g of the product of Step 3, above, and 40 ml of acetic anhydride are warmed slowly to 40° for 2 hours. The mixture is added to water, extracted with ethyl acetate, dried and reduced in volume. Petroleum ether is added to achieve the title product (mp 165° to 167°)
Reaction SMILES: [CH:1]1([CH:6]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][N:33]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:28][CH:27]=2)[C:7]([NH:9][C:10]2[C:11]([CH3:25])=[C:12]([CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]=[CH:14][CH:15]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.NN>C(O)C>[NH2:33][CH2:32][C:29]1[CH:30]=[CH:31][C:26]([CH:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C:7]([NH:9][C:10]2[C:11]([CH3:25])=[C:12]([CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:27][CH:28]=1
Reactant: Cc1c(CCC(=O)OC(C)(C)C)cccc1NC(=O)C(c1ccc(CN2C(=O)c3ccccc3C2=O)cc1)C1CCCC1
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1c(CCC(=O)OC(C)(C)C)cccc1NC(=O)C(c1ccc(CN)cc1)C1CCCC1
Temperature: 25 °C

Procedure:
8.5 g (14.6 mmol) of tert-butyl(+/−)-3-(3-(2-cyclopentyl-2-(4-((1,3-dioxoisoindolin-2-yl)methyl)phenyl)acetamido)-2-methylphenyl)propanoate were initially charged in 85 ml of ethanol, and 2.35 ml (48.3 mmol) of hydrazine hydrate were added. The reaction mixture was heated under reflux overnight. After cooling to room temperature, the precipitated solid was filtered off and washed with ethanol. The filtrate was concentrated, the residue was triturated with acetonitrile and the precipitated crystals were filtered off with suction and discarded. The mother liquor was concentrated and the residue was purified by flash chromatography on silica gel (mobile phase dichloromethane/methanol/aq. ammonia 100:5:1). This gave 4.51 g (68% of theory) of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)(Cl)Cl.CO[CH:26](OC)[CH2:27][NH2:28].C(O)(C)C>P(Cl)(Cl)(Cl)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:26]=[CH:27][N:28]=[C:10]2[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(NC(=O)c2ccncc2)cc1
Reactant: COC(CN)OC
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(C)O
Product: COc1ccc(-n2ccnc2-c2ccncc2)cc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
Preparation 87 (N-(4-methoxyphenyl)isonicotinamide, 1 g, 4.39 mmol) was dissolved in phosphorous oxychloride (POCl3) (5 mL) then phosphorous pentachloride (913 mg, 4.39 mmol) was added. The mixture was heated at 120° C. for 4 h. The POCl3 was removed in vacuo, aminoacetaldehyde dimethyl acetal (9.5 mL, 87.8 mmol) and isopropanol (10 mL) were added, and the mixture was stirred at 23° C. for ca. 16 h. The reaction mixture was concentrated in vacuo and concentrated hydrochloric acid (36.5%, 25 mL) in isopropanol (15 mL) was added. The reaction mixture was heated at 90° C. for 24 h. After cooling to 23° C., aqueous sodium hydroxide (1N) and aqueous sodium bicarbonate were added to obtain pH=8. The mixture was extracted with methylene chloride, was dried (MgSO4), and was filtered and concentrated in vacuo. The residue was purified by silica gel chromatography with ethyl acetate/hexanes/methanol (80:20:0 to 76:19:5) to afford 811 mg (74% yield) of the title compound; diagnostic 13C NMR signals (100 MHz, CDCl3) δ 160.069, 149.952, 144.142, 137.853, 131.004, 129.882, 127.414, 124.977, 122.195, 115.114, 55.808; MS (AP/Cl) 252.4 (M+H)+.
Reaction SMILES: [C:1]12([CH:7]3[CH2:8][CH2:9][CH:4]1[CH:5]1[C:13](=[O:14])[O:12][C:10](=[O:11])[CH:6]13)[CH2:3][CH2:2]2.[I:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>C(Cl)(Cl)Cl>[I:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:10]([C@@H:6]2[C@H:7]3[C:1]4([CH2:3][CH2:2]4)[C@H:4]([CH2:9][CH2:8]3)[C@@H:5]2[C:13]([OH:12])=[O:14])=[O:11])=[CH:18][CH:17]=1
Reactant: O=C1OC(=O)C2C1C1CCC2C12CC2
Reactant: Nc1ccc(I)cc1
Solvent: ClC(Cl)Cl
Product: O=C(O)[C@@H]1[C@H](C(=O)Nc2ccc(I)cc2)[C@@H]2CC[C@H]1C21CC1

Procedure:
Following General Procedure A, Compound 2 (0.084 g, 0.44 mmol) and 4-iodoaniline (0.090 g, 0.44 mmol) in chloroform (6 mL) were converted into the title compound, which was isolated as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:21])=[C:4]([C:9]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][CH:15]=[N:14]3)=[O:10])[C:5]([F:8])=[CH:6][CH:7]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>C(Cl)Cl>[F:21][C:3]1[C:4]([C:9]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][CH:15]=[N:14]3)=[O:10])=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[NH:1][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[C:23]([F:22])[CH:24]=1
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: Nc1ccc(F)c(C(=O)c2ccc3nccnc3c2)c1F
Solvent: ClCCl
Product: O=C(Nc1ccc(F)c(C(=O)c2ccc3nccnc3c2)c1F)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
To a solution of (3-amino-2,6-difluorophenyl)(quinoxalin-6-yl)methanone (40 mg, 0.14 mmol, 1.0 eq.) in DCM (5 mL) were added TEA (31 mg, 0.28 mmol, 2.0 eq.) and 3-fluorobenzoyl chloride (22 mg, 0.14 mmol, 1.0 eq.). The resulting mixture was stirred at rt for 1 h, then concentrated. The residue was purified via flash column chromatography (PE/EA=2/1, v/v) to afford N-(2,4-difluoro-3-(quinoxaline-6-carbonyl)phenyl)-3-fluorobenzamide (26 mg, 45%). LRMS (M−H+) m/z calculated 406.1. found 406.1. 1H NMR (CDCl3, 400 MHz) δ 8.88-8.90 (dd, 2H), 8.55-8.60 (m, 1H), 8.43 (s, 1H), 8.33-8.35 (m, 1H), 8.19-8.21 (m, 1H), 7.88 (s, 1H), 7.54-7.57 (m, 2H), 7.40-7.45 (m, 1H), 7.22-7.24 (m, 1H), 7.04-7.09 (t, 1H).
Reaction SMILES: [NH:1]([C:8]1[C:13]([Cl:14])=[CH:12][N:11]=[C:10](Cl)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:16][CH:17]([CH2:27][NH:28][CH:29]([CH3:31])[CH3:30])[CH2:18][O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1.Cl>C(O)CCC.CO>[NH:1]([C:8]1[C:13]([Cl:14])=[CH:12][N:11]=[C:10]([NH:24][C:23]2[CH:25]=[CH:26][C:20]([O:19][CH2:18][CH:17]([OH:16])[CH2:27][NH:28][CH:29]([CH3:30])[CH3:31])=[CH:21][CH:22]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)NCC(O)COc1ccc(N)cc1
Reactant: Clc1ncc(Cl)c(Nc2ccccc2)n1
Agent: Cl
Solvent: CO
Solvent: CCCCO
Product: CC(C)NCC(O)COc1ccc(Nc2ncc(Cl)c(Nc3ccccc3)n2)cc1
Temperature: 100 °C
Yield: 41.3 %

Procedure:
4-Anilino-2,5-dichloropyrimidine (Method 7, 241 ma, 1.0 mmol) was dissolved in n-butanol (20 ml) and methanol (4 ml). 4-[2-Hydroxy-3-(isopropylamino)propoxy]aniline (obtained as described in Pharmazie 1980, 35, 278; 202 mg, 0.9 mmol) and ethereal hydrogen chloride (1.0M; 2 ml, 2.0 mmol) were added and the solution was heated at 100° C. for 20 hours, allowed to cool to ambient temperature and then concentrated to a volume of 5 ml. The solution was loaded on a Varian Mega Bond Elut column and the column was eluted with 0-4% 2.0M methanolic ammonia solution in DCM. Concentration of the appropriate fractions and recrystallization of the residue from acetonitrile gave the product as a white solid (159 mg, 41%). NMR: 1.0 (d, 6H), 2.5-2.6 (m, 1H), 2.65-2.75 (m, 2H), 3.8-3.95 (m, 3H), 4.9 (br s, 1H), 6.8 (d, 2H), 7.1 (t, 1H), 7.35 (t, 2H), 7.45 (d, 2H), 7.65 (d, 2H), 8.1 (s, 1H), 8.7 (s, 1H), 9.1 (s, 1H); MS (MH+): 428, 430.
Reaction SMILES: CON(C)[C:4](=[O:26])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH3:28][Mg]Cl>C1COCC1>[O:26]=[C:4]([CH3:28])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C[Mg]Cl
Reactant: CON(C)C(=O)CCCCCCCCCCNC(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)CCCCCCCCCCNC(=O)OCc1ccccc1
Reaction time: 6 h
Yield: 79.6 %

Procedure:
To a solution of 20 (1.11 g, 2.94 mmol) in THF (anhydrous, 10 mL) and cooled in an ice bath was added dropwise MeMgCl (3 M solution in diethyl ether, 3.92 mL, 11.75 mmol) over 10 min, and stirring continued at 0° C. for 6 h. The reaction was quenched by the slow addition of methanol (10 mL), and then concentrated under vacuum. The residue was chromatographed (silica gel, a gradient of 0:100 to 18:82 ethyl acetate/hexanes) to afford the desired product 21 (0.78 g, 80% yield) as a white solid: 1H NMR (300 MHz, CDCl3) δ 1.26 (m, 12H), 1.49-1.57 (m, 4H), 2.13 (s, 3H), 2.41 (m, 2H), 3.19 (m, 5H), 5.09 (s, 2H), 7.34 (m, 5H); m/z (ESI) 334 [M+H]+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([Br:20])=[CH:9][N:8]=1)(=O)=O.Cl.[OH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(CC)CC)C>CN(C)C=O>[CH2:13]([C:11]1[C:10]([Br:20])=[CH:9][N:8]=[C:7]([N:28]2[CH2:29][CH2:30][CH:25]([OH:24])[CH2:26][CH2:27]2)[CH:12]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OC1CCNCC1
Reactant: O=S(=O)(Oc1cc(Cc2ccccc2)c(Br)cn1)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OC1CCN(c2cc(Cc3ccccc3)c(Br)cn2)CC1
Reaction time: 3 h
Yield: 56 %

Procedure:
A mixture of 550 mg of 4-benzyl-5-bromo-2-pyridyl trifluoromethanesulfonate (Production Example 1), 600 mg of 4-hydroxypiperidine hydrochloride, 1 ml of triethylamine and 2 ml of N,N-dimethylformamide was heated under stirring for 3 hours in an oil bath kept at 100° C. in a nitrogen atmosphere. After cooling as it was, the reaction mixture was extracted with ethyl acetate/water. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to silica gel column chromatography and eluted with 50% ethyl acetate/hexane, to give 270 mg of the target compound.
Reaction SMILES: [CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:16][N:17]([CH3:32])[CH2:18][CH2:19][N:20]([CH3:31])[C:21]1[S:22][C:23]2[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:24]=2[N:25]=1>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:30][C:28]3[CH:27]=[CH:26][C:24]4[N:25]=[C:21]([N:20]([CH2:19][CH2:18][N:17]([CH3:16])[CH3:32])[CH3:31])[S:22][C:23]=4[CH:29]=3)=[O:13])=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)CCN(C)c1nc2ccc(N)cc2s1
Reactant: O=C(O)c1ccc(C2CCCCC2)cc1
Product: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(C4CCCCC4)cc3)cc2s1

Procedure:
The title compound is prepared by following General Method A, using 4-cyclohexyl-benzoic acid (0.16 g, 0.78 mmol), and N*2*-(2-Dimethylamino-ethyl)-N*2*-methyl-benzothiazole-2,6-diamine (0.15 g, 0.60 mmol) to afford a white solid (0.076 g, 29%). LC/MS: Retention time 5.00 min; (m/z): calcd for C25H32N4OS (M+H)+: 437.6; found: 437.0.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.Cl[S:17]([N:20]=C=O)(=[O:19])=[O:18]>C1(C)C=CC=CC=1>[C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][S:17](=[O:19])(=[O:18])[NH2:20])=[CH:15][CH:14]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1ccc(C(=O)c2ccccc2)cc1
Yield: 58.4 %

Procedure:
This compound was prepared according to the procedure used in Example 84. A mixture of 9.9 g (0.05 mole) of 4-hydroxybenzophenone, 7.1 g (0.0505 mole) of chlorosulfonyl isocyanate and 75 ml of toluene gave 8.1 g (58%) of the title compound as off-white flakes, mp 131°-133° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.FC1C(F)=CC=CC=1CSC1N=C(NS(N2CCC2)(=O)=O)C=C([O:43][CH:44](CO)[CH2:45][OH:46])N=1.C(O)CO.[H-].[Na+]>C1COCC1>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=[C:2]([O:43][CH2:44][CH2:45][OH:46])[CH:7]=1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Reactant: O=S(=O)(Nc1cc(OC(CO)CO)nc(SCc2cccc(F)c2F)n1)N1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: OCCO
Solvent: C1CCOC1
Product: OCCOc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4,6-dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine ((the product of example 1 step 5 g) and ethylene glycol (1.517 g) in THF (100 ml) was added NaH (1.3 g) slowly and the reaction was then allowed to stir overnight at RT. The reaction mixture was then partitioned between EtOAc (200 ml) and H2O (200 ml). The organics were separated and the aqueous layer was re-extracted with EtOAc (2×200 ml). Organics were combined, dried (MgSO4) and reduced in vacuo and the resulting residue was purified by column chromatography on silica gel 10% EtOAc/90% iso-Hex to give the subtitle compound as a clear oil. Yield: 2.4 g
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][OH:11])[CH2:4][CH2:3]1.[H-].[Na+].[O:14]=[C:15]1[N:20]([CH2:21][C:22]2[CH:31]=[CH:30][C:25]3[NH:26][C:27](=[O:29])[NH:28][C:24]=3[CH:23]=2)[N:19]=[C:18]([C:32]2[CH:37]=[C:36]([F:38])[C:35](F)=[C:34]([F:40])[CH:33]=2)[CH:17]=[CH:16]1>CN(C=O)C>[F:38][C:36]1[CH:37]=[C:32]([C:18]2[CH:17]=[CH:16][C:15](=[O:14])[N:20]([CH2:21][C:22]3[CH:31]=[CH:30][C:25]4[NH:26][C:27](=[O:29])[NH:28][C:24]=4[CH:23]=3)[N:19]=2)[CH:33]=[C:34]([F:40])[C:35]=1[O:11][CH2:10][CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: O=c1[nH]c2ccc(Cn3nc(-c4cc(F)c(F)c(F)c4)ccc3=O)cc2[nH]1
Reactant: CN1CCN(CCCO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(CCCOc2c(F)cc(-c3ccc(=O)n(Cc4ccc5[nH]c(=O)[nH]c5c4)n3)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
170 mg (1.08 mmol) of 3-(4-methylpiperazin-1-yl)propan-1-ol are dissolved in 20 ml of DMF, 64.5 mg (1.61 mmol) of NaH in paraffin oil (60%) are added under nitrogen, and the mixture is stirred at room temperature. After 10 min, 200 mg (0.54 mmol) of 5-[6-oxo-3-(3,4,5-tri-fluorophenyl)-6H-pyridazin-1-ylmethyl]-1,3-dihydrobenzimidazol-2-one are added, and the mixture is stirred at room temperature under a nitrogen atmosphere. The reaction is monitored by means of HPLC. After 3 h, the reaction is terminated. The mixture is neutralised using 1N HCl. The mixture is evaporated to dryness, the residue is dissolved in 100 ml of ethyl acetate and 30 ml of water, the aqueous phase is separated off and neutralised using sodium hydrogencarbonate and subsequently extracted. A precipitate deposits in the process and is separated off. The residue is stirred with methanol, filtered off with suction and dried in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH:13]=[CH:14][N:15](C)C)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl.[NH2:20]N>C(O)C>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][NH:15][N:20]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(C(=O)C=CN(C)C)cc1Cl
Reactant: NN
Agent: Cl
Solvent: CCO
Product: COC(=O)c1ccc(-c2cc[nH]n2)cc1Cl
Temperature: 77.5 °C
Yield: 99.3 %

Procedure:
To a suspension of 2-chloro-4-(3-dimethylamino-2-propen-1-on-1-yl)-benzoic acid, methyl ester (13.67g) in ethanol (53 ml) was added hydrazine monohydrochloride (7.0 g). The mixture was heated in an oil bath at 75-80° C. for one hour. The solvent was removed in vacuo. The resulting residue was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, and the solvent removed in vacuo to yield the tide compound as a crude solid (12 g). A purified sample had a melting point of 130-131° C.