Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18](O)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[CH:26]=[C:27]([CH:43]=[CH:44][C:45]=1[CH3:46])[C:28]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[CH:32]=1)=[O:29]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18]([NH:24][C:25]2[CH:26]=[C:27]([CH:43]=[CH:44][C:45]=2[CH3:46])[C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([N:37]3[CH2:38][CH2:39][O:40][CH2:41][CH2:42]3)[CH:32]=2)=[O:29])=[O:19])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C(=O)O)c2)CC1
Reactant: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1N
Product: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 42 %

Procedure:
Using an analogous procedure to that described in Example 18, 3-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoic acid was reacted with 3-amino-4-methyl-N-(3-morpholinophenyl)benzamide to give 3-[3-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzamido]-4-methyl-N-(3-morpholinophenyl)benzamide in 42% yield; NMR Spectrum: (DMSOd6) 1.38 (s, 9H), 1.54 (m, 2H), 1.91 (m, 2H), 2.27 (s, 3H), 3.06 (t, 4H), 3.2 (m, 2H), 3.64 (m, 2H), 3.72 (t, 4H), 5.01 (m, 1H), 6.66 (m, 1H), 7.18 (m, 2H), 7.28 (d, 1H), 7.4 (m, 3H), 7.56 (m, 2H), 7.77 (m, 1H), 7.92 (s, 1H), 9.98 (s, 1H), 10.01 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[CH3:14])[C:4](=[O:15])[C:3]=1[C:16]#[N:17].[Br:18]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:18][C:7]1[C:2]([Cl:1])=[C:3]([C:16]#[N:17])[C:4](=[O:15])[N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[CH3:14])[CH:6]=1
Reactant: CC1CCCCC1n1ccc(Cl)c(C#N)c1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CC1CCCCC1n1cc(Br)c(Cl)c(C#N)c1=O
Temperature: 50 °C
Yield: 86.1 %

Procedure:
To a solution of 4-chloro-1-(2-methylcyclohexyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step E (1.14 g) in N,N-dimethylformamide (9.0 mL) was added N-bromosuccinimide (993 mg) at room temperature. The reaction mixture was heated at 50° C. for 3 hr, and cooled to room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.29 g).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].C([O-])(=O)C.[Na+].Cl.Cl[CH:12]([C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)=[O:21])[C:13](=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl>O1CCCC1.O>[NH2:1][C:2]1[S:3][C:12]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[O:21])=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:4]=1
Reactant: CCOC(=O)C(=O)C(Cl)C(=O)c1ccccn1
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(N)sc1C(=O)c1ccccn1
Reaction time: 2 h
Yield: 20.7 %

Procedure:
To a solution of thiourea (4.5 g) and sodium acetate (5 g) in a mixture of tetrahydrofuran (50 ml) and water (15 ml) was added ethyl 3-chloro-4-(2-pyridyl)-2,4-dioxo-butyrate hydrochloride (5.6 g). After the mixture was stirred at 45° C. to 50° C. for 2 hours, water (50 ml) was added thereto. The resulting mixtures was acidified to pH 1.0 with 10% hydrochloric acid. The precipitate was collected by filtration. The precipitate was added to a mixture of water and ethyl acetate, and adjusted to pH 6.0 with 10% potassium carbonate. The separated ethyl acetate layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and tetrahydrofuran to give ethyl 2-amino-5-(2-pyridinecarbonyl)-4-thiazolecarboxylate (1.1 g).
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])C)=[O:4].[CH3:22][N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[CH2:28][O:29][C:30]1[CH:31]=[C:32](CN)[CH:33]=[CH:34][CH:35]=1>>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:7]2[S:6][C:5]3[C:3](=[O:4])[N:12]([CH2:14][C:34]4[CH:33]=[CH:32][CH:31]=[C:30]([O:29][CH2:28][C@@H:24]5[CH2:25][CH2:26][CH2:27][N:23]5[CH3:22])[CH:35]=4)[CH:11]=[N:10][C:9]=3[CH:8]=2)=[CH:20][CH:19]=1
Reactant: CN1CCC[C@H]1COc1cccc(CN)c1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N=CN(C)C
Product: CN1CCC[C@H]1COc1cccc(Cn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)c1

Procedure:
The title compound was synthesised using the same method as described for Example 20c using the reagents 5-(4-Chloro-phenyl)-3-(dimethylamino-methyleneamino)-thiophene-2-carboxylic acid methyl ester (0.176 g, 0.55 mmol) and 1-(3-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}phenyl)methanamine (0.10 g, 0.45 mmol). Purification by prep-HPLC gave the product as a solid. Yield: 0.22 g (41%). 1H NMR (400 MHz, CD3OD) δ 8.08 (s, 1H), 7.58-7.64 (m, 2H), 7.38-7.46 (m, 3H), 7.21-7.27 (m, 1H), 6.82-6.94 (m, 3H), 5.17 (s, 2H), 3.90-3.99 (m, 1H), 3.79-3.87 (m, 1H), 3.03-3.13 (m, 1H), 2.54-2.66 (m, 1H), 2.43 (s, 3H), 2.22-2.32 (m, 1H), 1.92-2.06 (m, 1H), 1.64-1.88 (m, 3H). MS (ESI+) 466.12 (M+1H+).
Reaction SMILES: Br[C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[OH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=1B(O)O>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:13]([C:3]1[C:2]([C:24]2[CH:25]=[C:26]([C:29]([F:32])([F:31])[F:30])[CH:27]=[CH:28][C:23]=2[OH:22])=[CH:6][N:5]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[N:4]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1nn(C2CCCCO2)cc1Br
Reactant: OB(O)c1cc(C(F)(F)F)ccc1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1nn(C2CCCCO2)cc1-c1cc(C(F)(F)F)ccc1O
Temperature: 75 °C
Yield: 53.8 %

Procedure:
To a solution of 4-bromo-3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (Preparation 869, 18.95 g, 0.06864 mol) in 1,2-dimethoxyethane (175 mL) was added aqueous potassium carbonate (2M in water, 68.0 mL, 0.123 mol) and tetrakis(triphenylphosphine)palladium(0) (6.34 g, 0.00549 mol). The reaction was sparged 3 times with Argon and heated to 75° C. To this, [2-hydroxy-5-(trifluoromethyl)phenyl]boronic acid (Preparation 871, 21.22 g, 0.103 mol) was added in four portions over six hours. The reaction solution was heated for an additional 12 hours and then allowed to cool. The mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. Purification by automated flash column chromatography using a 0-50% ethyl acetate/hexanes gradient and a 80 g column gave the title compound (13.2 g, 54%) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2([CH:17]=[CH2:18])[CH2:16][CH2:15]2)[CH2:11][O:10][C:9]1([CH3:20])[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH2:21].[OH-].[Na+].OO>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2([CH2:17][CH2:18][OH:21])[CH2:15][CH2:16]2)[CH2:11][O:10][C:9]1([CH3:20])[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC1(C[C@H]2COC(C)(C)N2C(=O)OC(C)(C)C)CC1
Reactant: O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](CC2(CCO)CC2)COC1(C)C
Reaction time: 3 h

Procedure:
2.5 ml of diborane-dimethylsulfide complex are added to 18.0 g of 3-tert-butoxycarbonyl-2,2-dimethyl-4(S)-[(1-vinylcyclopropyl)methyl]-1,3-oxazolidine, dissolved in 300 ml of tetrahydrofuran at 0° C. in the course of 3 minutes and the mixture is then stirred for 3 h, while cooling with ice. 5 ml of water, 16 ml of 2N sodium hydroxide solution and 8.5 ml of a 30% hydrogen peroxide solution are added in succession and the mixture is subsequently stirred at room temperature for 1 h. It is then diluted with ice-cold potassium carbonate solution and the aqueous phase is extracted with ethyl acetate. Purification of the crude product is carried out over 900 g of silica gel (mobile phase B): Rf (B)=0.25; anal. calc. for C16H35NO4 : C 64.18%, H 9.76%, N 4.68%; found C 64.05%, H 9.76%, N 4.73%.
Reaction SMILES: [CH3:1][C:2]1[C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][N:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[C:24]1[CH:25]=[C:26]([CH:41]=[CH:42][C:43]=1[N:44]1[CH2:48][C@H:47]([OH:49])[C@@H:46]([OH:50])[CH2:45]1)[C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]([Cl:40])([F:39])[F:38])=[CH:32][CH:31]=1)=[O:28]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:40][C:37]([F:38])([F:39])[O:36][C:33]1[CH:32]=[CH:31][C:30]([NH:29][C:27](=[O:28])[C:26]2[CH:25]=[CH:24][C:43]([N:44]3[CH2:45][C@H:46]([OH:50])[C@@H:47]([OH:49])[CH2:48]3)=[C:42]([C:7]3[C:2]([CH3:1])=[N:3][CH:4]=[N:5][CH:6]=3)[CH:41]=2)=[CH:35][CH:34]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(N2C[C@H](O)[C@@H](O)C2)c(Br)c1
Reactant: Cc1ncncc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ncncc1-c1cc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)ccc1N1C[C@H](O)[C@@H](O)C1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
4-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (Stage 297.1, 94 mg, 0.429 mmol), K2CO3 (118 mg, 0.857 mmol) and Pd(PPh3)4 (33.0 mg, 0.029 mmol) were added to a solution of 3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)benzamide (Stage 244.1, 150 mg, 0.286 mmol) in DMF (2.5 mL). at RT in a vial. The vial was evacuated/purged with argon, sealed and stirred at 130° C. for 2 h. The RM was diluted in EtOAc (80 mL), washed with water (3×30 mL), dried over Na2SO4, filtered, and the solvent was evaporated off under reduced pressure. The residue was dissolved in methanol (3 mL) and filtered through a SPE PL-Thiol cartridge (StratoSpheres™, 500 mg, nominal:1.5 mmol), the cartridge was washed with MeOH and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (Column 2-EP, from 20% to 25% in 6 min) and by preparative HPLC. The obtained residue was treated with a aq. solution of Na2CO3 (3 mL) and extracted twice with EtOAc (2×30 mL). The combined organic phases were washed with water (2×15 mL), dried over Na2SO4, filtered, and the solvent was evaporated off under reduced pressure to afford the title product as a beige solid. HPLC (Condition 10) tR=6.091 min, UPLC-MS (Condition 11) tR=0.93 min, m/z=491.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.19/2.40 (s, 3H) 2.65-2.78 (m, 2H) 3.06-3.22 (m, 2H) 3.80-3.90 (m, 2H) 5.01-5.12 (m, 2H) 6.93 (d, J=8.99 Hz, 1H) 7.32 (d, J=8.60 Hz, 2H) 7.70-7.80 (m, 1H) 7.83-7.89 (d, J=8.60 Hz, 2H) 7.91-7.98 (m, 1H) 8.82 (s, 1H) 9.05 (s, 1H) 10.01-10.12 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[F:21][C:22]([F:32])([F:31])[C:23](N1CCOCC1)=[O:24].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[C:5]([C:23](=[O:24])[C:22]([F:32])([F:31])[F:21])=[CH:4][CH:3]=1
Reactant: O=C(N1CCOCC1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cl)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1nc(Cl)ccc1C(=O)C(F)(F)F
Temperature: -50 °C
Reaction time: 2 h

Procedure:
8 g (35 mmol) of tert-butyl (6-chloropyridin-2-yl)carbamate (Example 1A) were initially charged in 100 ml of THF and cooled to −50° C. 55 ml (87 mmol) of butyllithium (1.6 N) were added dropwise. After the dropwise addition had ended, the reaction was warmed gradually to −10° C. and stirred at 0° C. for 2 h. Subsequently, the mixture was cooled again to −40° C., and 12.8 g (70 mmol) of 4-(trifluoroacetyl)morpholine (Example 6A), dissolved in 4 ml of THF, were added. The reaction solution was stirred at −40° C. for 1 h, then poured at −40° C. onto 1 l of ethyl acetate and 350 ml of ammonium chloride solution, and extracted. The organic phase was removed, dried over magnesium sulphate and concentrated on a rotary evaporator. The reaction mixture was chromatographed on silica gel (eluent: cyclohexane/ethyl acetate 10:1). 9 g (79% of theory) of the product were obtained as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=2)=[C:6]([C:17]([F:20])([F:19])[F:18])[CH:5]=[CH:4][N:3]=1.[OH-:21].[K+]>C(O)(C)(C)C>[Cl:16][C:11]1[CH:10]=[C:9]([CH:14]=[C:13]([Cl:15])[CH:12]=1)[O:8][C:7]1[C:2](=[O:21])[NH:3][CH:4]=[CH:5][C:6]=1[C:17]([F:20])([F:19])[F:18]
Reactant: [OH-]
Reactant: FC(F)(F)c1ccnc(Cl)c1Oc1cc(Cl)cc(Cl)c1
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=c1[nH]ccc(C(F)(F)F)c1Oc1cc(Cl)cc(Cl)c1
Temperature: 75 °C
Reaction time: 48 h

Procedure:
To 2-chloro-3-(3,5-dichlorophenoxy)-4-(trifluoromethyl)pyridine (2.10 g, 6.10 mmol) in tert-butanol (25 mL) was added potassium hydroxide (1.03 g, 18.4 mmol). The reaction mixture was placed in an oil bath and heated at 75° C. After 48 hours, the reaction mixture was allowed to cool to room temperature and was quenched with saturated aqueous ammonium chloride (25 mL) and diluted with water (25 mL). The mixture was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with water (2×50 mL) and the solvent was evaporated under reduced pressure to yield a solid. This was adsorbed onto silica and purified by column chromatography on a pre-packed silica gel Redi Sep 40 gram column, eluting with 0-5% methanol in CH2Cl2 to afford the title compound. 1H NMR (DMSO-d6) δ 12.69 (s, 1H), 7.58 (d, J=6.8 Hz, 1H), 7.32-7.30 (m, 1H), 7.10-7.08 (m, 2H), 6.48 (d, J=6.8 Hz, 1H). HRMS (M+1)=323.9800.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C@@H:10]([OH:29])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[C:18]=1[O:27][CH3:28])[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CN=C1.[C:42]([Si:46]([CH3:49])([CH3:48])Cl)([CH3:45])([CH3:44])[CH3:43]>CN(C=O)C>[C:1]([NH:8][C@@H:9]([CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C@@H:10]([O:29][Si:46]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:49])[CH3:48])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[C:18]=1[O:27][CH3:28])[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COc1ccc(C[C@H](C[C@H](O)[C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)C(=O)O)c(OC)c1OC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccc(C[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)C(=O)O)c(OC)c1OC
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 598 mg (1.175 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-[(2,3,4-trimethoxyphenyl)methyl]hexanoic acid in 6 ml of DMF is treated, while being stirred, with 653 mg (9.4 mmol) of imidazole and 822 mg (5.287 mmol) of t-butyldimethylchlorosilane. After it has been stirred for 17 h at RT, and under argon, the reaction solution is poured onto ice-water and the whole is extracted with ethyl acetate. The organic phase is washed with 10% citric acid solution and saline (cold). The combined aqueous phases are reextracted with ethyl acetate. The combined organic phases are dried with Na2SO4 and evaporated. The crude product is dried under HV for approximately 2 h and, after that, is dissolved in 15.6 ml of methanol and 5.3 ml of THF, and this solution is treated with 941 mg of potassium carbonate in 5.3 ml of water. This reaction mixture is stirred at RT for approximately 3 h, then concentrated down, at approximately 30° C., to half the volume and diluted with ethyl acetate; the organic phase is washed with 10% citric acid and saline (both being cold). The combined aqueous phases are reextracted with ethyl acetate. The combined organic phases are dried over Na2SO4 and evaporated. The crude product is chromatographed on silica gel (hexane:ethyl acetate, 2:1), and the title compound is obtained. IR(CH2Cl2) inter alia: 3436, 1708, 1603, 1494, 1166, 1100 and 837 cm-1. FAB-MS (M+H)+ =624. HPLC tRet =23.14 min (gradient II). 1H-NMR (CD3OD) inter alia: 6.76 (d, 1H); 6.59 (d, 1H); 6.07 and 5.50 (each d, in all 1H, rotamers of NH), 3.86, 3.82 and 3.81 (each s, each 3H); 3.75-3.57 (m, 2H); 2.93-2.75 (m, 2H); 2.70 (m, 1H); 1.42 (s, 9H); 0.87 (s, 6H); 0.11 and 0.08 (each s, each 3H).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][OH:10])[CH:4]=1.Br[C:12]1[C:13](=[O:32])[N:14]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[N:15]=[C:16]([C:19]2([CH3:24])[O:23][CH2:22][CH2:21][O:20]2)[C:17]=1[CH3:18].O>CN(C)C=O>[F:31][C:28]1[CH:27]=[CH:26][C:25]([N:14]2[C:13](=[O:32])[C:12]([O:10][CH2:9][C:5]3[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=3)=[C:17]([CH3:18])[C:16]([C:19]3([CH3:24])[O:23][CH2:22][CH2:21][O:20]3)=[N:15]2)=[CH:30][CH:29]=1
Reactant: OCc1cccnc1
Reactant: Cc1c(C2(C)OCCO2)nn(-c2ccc(F)cc2)c(=O)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C2(C)OCCO2)nn(-c2ccc(F)cc2)c(=O)c1OCc1cccnc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of 62.5% sodium hydride (92 mg) in N,N-dimethylformamide (8 ml) was added 3-pyridylcarbinol (0.25 ml) under ice cooling, followed by stirring at room temperature for 20 minutes. Then, 4-bromo-2-(4-fluorophenyl)-5-methyl-6-(2-methyl-1,3-dioxolan-2-yl)-3(2H)-pyridazinone (738 mg) was added, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After washing with water and a brine, the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, and the resulting residue was crystallized from ether to obtain 2-(4-fluorophenyl)-5-methyl-6-(2-methyl-1,3-dioxolan-2-yl)-4-(3-pyridylmethoxy)-3(2H)-pyridazinone (320 mg).
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH:17]([CH2:19][OH:20])[CH2:16][CH:15]([N:21]2[C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:31])[C:25]=3[C:24]3=[N:32][O:33][C:34]([CH3:35])=[C:23]3[C:22]2=[O:36])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH:17]([CH2:19][O:20][S:1]([CH3:4])(=[O:3])=[O:2])[CH2:16][CH:15]([N:21]2[C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:31])[C:25]=3[C:24]3=[N:32][O:33][C:34]([CH3:35])=[C:23]3[C:22]2=[O:36])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: Cc1onc2c1c(=O)n(C1CC(CO)CN(C(=O)OC(C)(C)C)C1)c1cccc(Cl)c21
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1onc2c1c(=O)n(C1CC(COS(C)(=O)=O)CN(C(=O)OC(C)(C)C)C1)c1cccc(Cl)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
Add DMAP (5 mg, cat.) and mesyl chloride (0.2 mL, 2.5 mmol) to a solution of 3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-5-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (0.95 g, 2.1 mmol) in pyridine (10 mL). Stir overnight at room temperature then concentrate to dryness. Partition between EtOAc, and water. Extract 2× with EtOAc. Wash the combined organics 3× with brine, dry over Na2SO4, filter and concentrate to dryness to afford the title compound (0.87 g, 79%) as a white solid as a mixture of cis isomers. MS(IS) 526.0 (M+); TLC (50% EtOAc/hexanes) Rf=0.65.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([C:17]2[S:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][CH:21]=2)[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.O>ClCCl>[C:22]1([C:19]2[S:18][C:17]([C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:16]=[C:7]([OH:6])[CH:8]=3)=[CH:21][CH:20]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1cc(-c2ccc(-c3ccccc3)s2)c2ccccc2c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Oc1cc(-c2ccc(-c3ccccc3)s2)c2ccccc2c1
Reaction time: 20 h
Yield: 90.4 %

Procedure:
Boron tribromide (1.04 ml, 10.76 mmol) was added slowly to a solution of 3-methoxy-1-(5-phenyl-2-thienyl)naphthalene (1.7 g, 5.38 mmol) in dichloromethane (50 ml) at 0° C. under nitrogen. After the addition was complete, the solution was allowed to stir for 20 h. The mixture was then poured into water (200 ml), extracted with Et2O (2×100 ml), washed with water (100 ml), dried (Na2SO4) and the solvent removed under reduced pressure. The resulting solid was washed with hexane and filtered to afford the title compound (1.47 g, 91%) as a red solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:30]1[CH2:29][CH2:28][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[F:20])[CH2:32][CH2:31]1)=[O:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(F)ccc2nc1OC
Reactant: Fc1ccccc1N1CCNCC1
Product: COc1nc2ccc(F)cc2nc1NC(=O)N1CCN(c2ccccc2F)CC1
Yield: 91 %

Procedure:
Ethyl N-(6-fluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(2-fluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound (yield, 91%). 1H NMR (200 MHz, CDCl3): δ 3.18 (s, 4H), 3.78 (s, 3H), 4.13 (s, 4H), 6.93-7.10 (m, 5H), 7.20-7.34 (m, 1H), 7.46-7.60 (m, 1H), 7.67-7.74 (m, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8][C:9](=[O:21])[NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:7]=1.[C:22](Cl)(=[O:26])[CH:23]([CH3:25])[CH3:24].O>N1C=CC=CC=1>[C:22]([N:2]([C:3]1[S:4][CH:5]=[C:6]([CH2:8][C:9](=[O:21])[NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:7]=1)[CH3:1])(=[O:26])[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)C(=O)Cl
Reactant: CNc1nc(CC(=O)Nc2cccc(C(F)(F)F)c2)cs1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)C(=O)N(C)c1nc(CC(=O)Nc2cccc(C(F)(F)F)c2)cs1
Yield: 60.2 %

Procedure:
A solution containing 7.6 g (0.025 mole) of 2-methylamino-4-(3-trifluoromethylphenylcarbamoylmethyl)thiazole and 2.9 g (0.027 mole) of isobutyryl chloride in 25 ml of pyridine was heated at about 45° for 24 hours. The mixture was poured into water. The thick oil failed to crystallize. The aqueous phase was decanted and the residue was dissolved in benzene. The organic phase was washed with water, dried over sodium sulfate and cooled. With stirring, hexane was added and a crystalline product precipitated. There was obtained 5.8 g of the desired amide, m.p. 122°-23°. N.M.R. (dimethyl-d6 sulfoxide) ∂ 1.1-1.3 (2 × CH3), 2.7-3.4 (CH, septet), 3.6 (NCH3), 3.7 (CH2), 6.9 (hetero-aromatic), 7.3-8.1 (aromatic), 10.4 (HNC=O).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:16][C:17]1[C:22]([NH2:23])=[C:21]([F:24])[C:20]([F:25])=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>ClCCl>[CH2:9]([O:16][C:17]1[C:22]([NH2:23])=[C:21]([F:24])[C:20]([F:25])=[C:19]([Br:1])[CH:18]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1c(OCc2ccccc2)ccc(F)c1F
Solvent: O
Solvent: ClCCl
Product: Nc1c(OCc2ccccc2)cc(Br)c(F)c1F

Procedure:
A round bottom flask containing N-bromosuccinimide (0.52 mg, 2.93 mmol), and dichloromethane (5 mL) is stirred in an ice bath. A solution of the 6-benzyloxy-2,3-difluoro-phenylamine (0.69 mg, 2.93 mmol) in 10 mL of dichloromethane is added quickly in one portion. The resulting mixture is stirred for 20 min then water is added and the resulting mixture is extracted twice with DCM. The organic portion is dried over MgSO4, filtered and concentrated to afford the title compound, which is used directly in the next step without purification.