Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19](Br)[N:20]=3)[N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].[CH3:32][N:33]1[C:41]2[CH2:40][CH2:39][C:38]([CH3:43])([CH3:42])[CH2:37][C:36]=2[C:35]([Sn](CCCC)(CCCC)CCCC)=[N:34]1>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.[Cu]I>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:35]4[C:36]5[CH2:37][C:38]([CH3:42])([CH3:43])[CH2:39][CH2:40][C:41]=5[N:33]([CH3:32])[N:34]=4)[N:20]=3)[N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2c1CC(C)(C)CC2
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CC(C#N)C1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4c3CC(C)(C)CC4)nc12)C(=O)N1CC(C#N)C1
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 73.6 %

Procedure:
In a round-bottomed flask, 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (130 mg, 0.26 mmol) and 1,5,5-trimethyl-3-(tributylstannyl)-4,5,6,7-tetrahydro-1H-indazole (375 mg, 0.41 mmol) were dissolved in DMF (2.4 ml). The flask was evacuated and backfilled with argon then tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol) and copper(I) iodide (10 mg, 0.053 mmol) were added. The reaction mixture was stirred at 90° C. in an oil bath for 2.5 h then cooled to room temperature, quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-5% MeOH) to afford 113 mg (75%) of 5-(2-trimethylsilanyl-ethoxymethyl)-2-(1,5,5-trimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a light yellow foam.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH:9]=[C:8]([CH3:11])[CH2:7]1)=[O:5])C.[OH-].[Na+]>CO>[CH3:11][C:8]1[CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:10][CH:9]=1
Reactant: CCOC(=O)C1CC=C(C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1=CCC(C(=O)O)C1
Temperature: 25 °C
Yield: 96.1 %

Procedure:
A solution of the 3-Methyl-cyclopent-3-enecarboxylic acid ethyl ester (255 mg, 1.65 mmol) in MeOH (4.0 mL) and 10% aq. NaOH (3.3 mL, 8.25 mmol) was heated at 50° C. for 16 h, reaction mixture was cooled to room temperature, solvent was evaporated, diluted with water. The aqueous solution was washed with ether, and acidified with aq. 1 N HCl, extracted with ether. The ethereal solution was washed with brine and dried. Evaporation of the solvent furnished the 3-Methyl-cyclopent-3-enecarboxylic acid (200 mg, 97% yield). 1H NMR (CDCl3, 400 MHz), 5.27 (brs, 1H), 3.26-3.17 (m, 1H), 2.7-2.55 (m, 4H), 1.74 (s; 3H).
Reaction SMILES: [Cl:1][C:2]1(Cl)[CH2:8][CH:7]([CH:9]([CH3:11])[CH3:10])[CH2:6][CH2:5][NH:4][C:3]1=[O:12].C([O-])(=O)C.[Na+]>C(O)(=O)C>[Cl:1][CH:2]1[CH2:8][CH:7]([CH:9]([CH3:10])[CH3:11])[CH2:6][CH2:5][NH:4][C:3]1=[O:12]
Reactant: CC(C)C1CCNC(=O)C(Cl)(Cl)C1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)C1CCNC(=O)C(Cl)C1
Reaction time: 1.5 h

Procedure:
3,3-Dichloro-5-isopropyl-azepan-2-one (5.00 g, 22.3 mmol) was dissolved in acetic acid (125 ml) and sodium acetate (anhydrous, 2.38 g, 29.0 mmol), 10% Pd-c catalyst (0.22 g) were added. The degassed mixture was hydrogenated at r.t. and atmospheric pressure for 90 min. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified over silica gel (ethyl acetate/n-heptane 1:1): 3.49 g (74%) 1H NMR (CDCl3) δ 0.88-0.90 (m, 6H), 1.26-1.29 (m, 1H), 1.63-1.67 (m, 2H), 1.76-1.94 (m, 2H), 2.16-2.21 (m, 1H), 3.19-3.23 (m, 1H), 3.30-3.36 (m, 1H), 4.64 & 4.67 (dd, 1H), 6.45 (br, 1H) MS: m/e=190.3 (MH+), 207.2 (MNH4+)
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[CH3:21][O:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][NH:26][CH2:27]2>CN(C=O)C>[CH3:21][O:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][N:26]([C:3]1[C:2]([F:1])=[CH:15][C:14]3[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11][N:6]4[CH:7]([CH3:10])[CH2:8][O:9][C:4]=1[C:5]=34)[CH2:27]2
Reactant: COc1cccc2c1CNC2
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CN(C)C=O
Product: COc1cccc2c1CN(c1c(F)cc3c(=O)c(C(=O)O)cn4c3c1OCC4C)C2
Yield: 51.8 %

Procedure:
131 mg of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid, 224 mg of 4-methoxyisoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 2 to produce 99 mg of the target compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11](=[O:14])[CH2:12]Br.[CH2:18]([NH:21][CH2:22][CH:23]=[CH2:24])[CH:19]=[CH2:20]>C(#N)C>[Br:7][C:8]1[CH:9]=[C:10]([C:11](=[O:14])[CH2:12][N:21]([CH2:22][CH:23]=[CH2:24])[CH2:18][CH:19]=[CH2:20])[CH:15]=[CH:16][CH:17]=1
Reactant: O=C(CBr)c1cccc(Br)c1
Reactant: C=CCNCC=C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCN(CC=C)CC(=O)c1cccc(Br)c1
Temperature: 0 °C
Yield: 97.6 %

Procedure:
Potassium carbonate (38.8 g, 281 mmol) is added to 3-bromophenacyl bromide (60 g 216 mmol) in acetonitrile (430 mL), and the mixture is cooled under nitrogen to 0° C. Diallylamine (34.6 mL, 280.63 mmol) is added drop wise over 1 hour and the reaction is allowed to warm to 22° C. overnight. The crude reaction mixture is concentrated and the residue is partitioned in water (300 mL) and MTBE (300 mL). The aqueous layer is discarded and the organic layer is washed with water (100 mL, 2×) and with brine (100 mL). The organic layer is dried over sodium sulfate, filtered, and the solvent evaporated to constant weight to give the title compound (62 g, 98%). ES/MS (m/e): 294 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:29](OCCC(C)C)=O>C(Cl)(Cl)Cl>[F:16][C:13]([F:14])([F:15])[C:9]1[CH:10]=[C:11]2[C:2](=[C:3]([C:4]([O:6][CH3:7])=[O:5])[CH:8]=1)[NH:1][N:29]=[CH:12]2
Reactant: COC(=O)c1cc(C(F)(F)F)cc(C)c1N
Reactant: CC(C)CCON=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(C(F)(F)F)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of compound 3, at 0° C. and under nitrogen atmosphere, in chloroform (0.3M) was added acetic anhydride (2.3 equiv.) drop wise and the resulting mixture was stirred for 1 h at r.t. Then potassium acetate (0.2 equiv.) was added followed by addition of isoamyl nitrite (2.2 equiv.) and the resulting mixture was heated at reflux for 16 h. After, the reaction was cooled down to r.t. While cooling, a solid precipitation was observed. The solid was filtrated and dried under vacuum to give the title compound 4. (0.324 g, 75%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][C:12]([NH2:15])=[N:13][CH:14]=2)O1.Cl[C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:21]=[C:20]([N:30]([CH3:37])[CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH:19]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:37][N:30]([CH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[C:20]1[N:21]=[C:22]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[N:23]=[C:18]([C:9]2[CH:14]=[N:13][C:12]([NH2:15])=[N:11][CH:10]=2)[CH:19]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CN(c1cc(Cl)nc(N2CCOCC2)n1)C1CCOCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CN(c1cc(-c2cnc(N)nc2)nc(N2CCOCC2)n1)C1CCOCC1
Temperature: 120 °C
Yield: 32.6 %

Procedure:
To an argon flushed mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (42 mg, 0.19 mmol), 6-chloro-N-methyl-2-morpholino-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine (12 mg, 0.038 mmol) in THF (0.8 mL), and aq. Na2CO3 (2M, 0.27 mL) in a pressure vessel, was added dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (8 mg, 0.0095 mmol) in one portion. The pressure vessel was sealed and the mixture was heated in a microwave at 120° C. for 600 seconds. The crude mixture was filtered, concentrated under reduced pressure and purified by reverse phase preparative HPLC to give N6-methyl-2-morpholino-N6-(tetrahydro-2H-pyran-4-yl)-4,5′-bipyrimidine-2′,6-diamine (4.6 mg, 32%). LC/MS (m/z): 372.2 (MH+), Rt 1.76 minutes.
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH:35]=[N:36][O:37][CH3:38])=[CH:29][CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:39][O:40]C(=O)C)(=O)C.O.[OH-].[Li+]>C1COCC1.CO.O>[CH3:38][O:37][N:36]=[CH:35][CH2:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][C:21]2[CH:20]=[C:19]([C@H:8]3[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:39][OH:40])[O:7]3)[CH:24]=[CH:23][C:22]=2[Cl:25])=[CH:28][CH:29]=1
Reactant: CON=CCOc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CON=CCOc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
To a solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(2-(methoxyimino)ethoxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (100 mg, 0.161 mmol) in THF (0.6 mL), methanol (0.8 mL) and water (0.3 mL) was added lithium hydroxide monohydrate (13.5 mg, 0.322 mmol) at 0° C. The reaction was stirred at r.t. for 1 h. Volatiles were evaporated in vacuo and the residue obtained was purified by column chromatography (silica gel, 1:9 MeOH:DCM) to provide the title compound (70 mg, 96.2%) as white solid.
Reaction SMILES: C([O:5][C:6](=[O:45])[C@@H:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]3[O:31][C:32]4[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([O:41][CH:42]([CH3:44])[CH3:43])[C:33]=4[C:34]=3[CH3:35])=[O:29])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O.ClCCl>>[Cl:40][C:37]1[CH:38]=[CH:39][C:32]2[O:31][C:30]([C:28]([NH:27][C:24]3[CH:23]=[CH:22][C:21]([C:18]4[CH:17]=[CH:16][C:15]([S:12]([NH:11][C@@H:7]([CH:8]([CH3:9])[CH3:10])[C:6]([OH:45])=[O:5])(=[O:13])=[O:14])=[CH:20][CH:19]=4)=[CH:26][CH:25]=3)=[O:29])=[C:34]([CH3:35])[C:33]=2[C:36]=1[O:41][CH:42]([CH3:44])[CH3:43]
Reactant: Cc1c(C(=O)Nc2ccc(-c3ccc(S(=O)(=O)N[C@H](C(=O)OC(C)(C)C)C(C)C)cc3)cc2)oc2ccc(Cl)c(OC(C)C)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(-c3ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc3)cc2)oc2ccc(Cl)c(OC(C)C)c12
Temperature: 25 °C
Reaction time: 9 h
Yield: 82 %

Procedure:
To 160 mg of (S)-2-{4′-[(5-chloro-4-isopropoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid tert-butyl ester was added 3 mL of TFA/dichloromethane (1:1) and the solution was stirred at room temperature for 9 h. When the reaction was done, the solvents were removed under vacuum and the residue was triturated with acetonitrile. The mixture was freeze-dried to yield 120 mg (77% yield) of (S)-2-{4′-[(5-chloro-4-isopropoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.8 (dd, J=12.4, 6.8 Hz, 6 H) 1.3 (d, J=6.1 Hz, 6 H) 1.9 (m, 1 H) 2.7 (s, 3 H) 3.6 (dd, J=9.3, 6.1 Hz, 1 H) 4.7 (m, 1 H) 7.5 (d, J=8.8 Hz, 1 H) 7.6 (m, 1 H) 7.8 (d, J=8.8 Hz, 2 H) 7.9 (m, 4 H) 8.0 (d, J=8.8 Hz, 2 H) 8.1 (d, J=9.3 Hz, 1 H) 10.6 (s, 1 H) 12.6 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25]#[N:26])=[C:4]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[C:5]2[C:10](=[O:11])[N:9]([CH3:12])[C:8](=[O:13])[N:7]([CH3:14])[C:6]=2[N:15]=1.Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]2[CH:39]=[CH:38][CH:37]=[N:36]2)=[CH:31][CH:30]=1>>[N:35]1([C:32]2[CH:33]=[CH:34][C:29]([CH2:28][NH:1][C:2]3[C:3]([CH2:25][NH2:26])=[C:4]([C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=4[O:23][CH3:24])[C:5]4[C:10](=[O:11])[N:9]([CH3:12])[C:8](=[O:13])[N:7]([CH3:14])[C:6]=4[N:15]=3)=[CH:30][CH:31]=2)[CH:39]=[CH:38][CH:37]=[N:36]1
Reactant: BrCc1ccc(-n2cccn2)cc1
Reactant: COc1ccc(F)cc1-c1c(C#N)c(N)nc2c1c(=O)n(C)c(=O)n2C
Product: COc1ccc(F)cc1-c1c(CN)c(NCc2ccc(-n3cccn3)cc2)nc2c1c(=O)n(C)c(=O)n2C

Procedure:
The synthesis of title compounds started from Compound 70a and 1-(4-(bromomethyl)phenyl)-1H-pyrazole, according to procedures described in the synthesis of Compound 56. MS [m+H] calc'd C27H27FN7O3 516; found 516.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([O:9][CH3:10])=[O:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.[O:18](C(OC(C)(C)C)=O)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[O:1]=[C:2]1[N:6]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[C@H:5]([C:7]([O:9][CH3:10])=[O:8])[CH2:4][CH2:3]1
Reactant: COC(=O)[C@@H]1CCC(=O)N1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a solution of commercially available (Aldrich) methyl 5-oxo-L-prolinate (20 g, 140 mmol) in DCM (200 ml) were added triethylamine (19.6 ml, 140 mmol), 4-(dimethylamino)pyridine (17.2 g, 140 mmol) and finally, dropwise, a solution of BOC2O (61 g, 280 mmol) in DCM (100 ml). The resulting red mixture was stirred at room temperature for 2 hours. Then the solvent was removed in vacuo and the crude material was purified by chromatography on silica gel eluting with cyclohexane/ethyl acetate (7:3 to 4:6) to afford (after trituration in hexane/diethylether 1:1) the title compound as a white solid (32.4 g, 96%); Rf (cyclohexanes:ethyl acetate=65:35): 0.21; 1H NMR (300 MHz, CDCl3) δ (ppm): 4.62 (dd, 1H), 3.78 (s, 3H), 2.68-2.58 (m, 1H), 2.52-2.45 (m, 1H), 2.37-2.27 (m, 1H), 2.08-1.97 (m, 1H), 1.48 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[C:14]([OH:15])=[CH:13][C:5]2[C:6]([CH3:12])([CH3:11])[O:7][C:8](=[O:10])[NH:9][C:4]=2[C:3]=1[Br:16].[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][CH2:25][CH2:26][CH2:27][CH2:28]Cl)=[CH:20][CH:19]=1>>[Br:1][C:2]1[C:14]([O:15][CH2:28][CH2:27][CH2:26][CH2:25][S:24][C:21]2[CH:20]=[CH:19][C:18]([CH3:17])=[CH:23][CH:22]=2)=[CH:13][C:5]2[C:6]([CH3:11])([CH3:12])[O:7][C:8](=[O:10])[NH:9][C:4]=2[C:3]=1[Br:16]
Reactant: CC1(C)OC(=O)Nc2c1cc(O)c(Br)c2Br
Reactant: Cc1ccc(SCCCCCl)cc1
Product: Cc1ccc(SCCCCOc2cc3c(c(Br)c2Br)NC(=O)OC3(C)C)cc1

Procedure:
Prepared analogously to Example 4 from 7,8-dibromo-6-hydroxy-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-(4-methylphenylmercapto)-butylchloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][C:10]([C:12]([F:15])([F:14])[F:13])=O>C(O)C>[F:13][C:12]([F:15])([F:14])[C:10]1[N:1]=[C:2]2[CH:7]=[N:6][CH:5]=[CH:4][N:3]2[CH:9]=1
Reactant: Nc1cnccn1
Reactant: O=C(CBr)C(F)(F)F
Solvent: CCO
Product: FC(F)(F)c1cn2ccncc2n1
Yield: 22.8 %

Procedure:
To a solution of 2-aminopyrazine (5.25 g, 55.2 mmol) in ethanol (120 mL) was added 1-bromo-3,3,3-trifluoroacetone (5.73 mL, 55.2 mmol). The reaction was stirred at reflux for 20 h. After evaporation of solvent, the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate (3×). The combined organic phase was washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography (silica gel, 1:1 ethyl acetate:hexane, then 100% ethyl acetate) to give 2.35 g of the title compound as a solid. 1H NMR (500 MHz, CDCl3) δ 8.02 (m, 2H), 8.13 (m, 1H), 9.22 (s, 1H). ESI-MS 188 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[O:23][C:24]([F:27])([F:26])[F:25])(=[O:14])=[O:13])[C:7](=[O:28])[C:6]2([C:40]1[CH:41]=[C:42]([CH2:48][CH2:49][N:50]2[CH2:55][CH2:54][N:53](C(OC(C)(C)C)=O)[CH2:52][CH2:51]2)[CH:43]=[CH:44][C:45]=1[O:46][CH3:47])[N:29]1[CH2:33][C@H:32]([OH:34])[CH2:31][C@H:30]1[C:35]([N:37]([CH3:39])[CH3:38])=[O:36].C([O-])(O)=O.[Na+]>CCOC(C)=O>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[O:23][C:24]([F:25])([F:27])[F:26])(=[O:13])=[O:14])[C:7](=[O:28])[C:6]2([N:29]1[CH2:33][C@H:32]([OH:34])[CH2:31][C@H:30]1[C:35]([N:37]([CH3:38])[CH3:39])=[O:36])[C:40]1[CH:41]=[C:42]([CH2:48][CH2:49][N:50]2[CH2:51][CH2:52][NH:53][CH2:54][CH2:55]2)[CH:43]=[CH:44][C:45]=1[O:46][CH3:47]
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CCN4CCN(C(=O)OC(C)(C)C)CC4)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CCN4CCNCC4)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.3 %

Procedure:
Concentrated hydrochloric acid (3.0 ml) was added to 120 mg of the compound obtained in Example 228, and the solution was stirred at room temperature for 30 minutes. The stirred solution was poured into a saturated aqueous solution of NaHCO3, and extraction was carried out with EtOAc. The extract was dried over Na2SO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by a preparative TLC plate (2 mm; mobile phase: CHCl3/8M ammonia MeOH solution=8/1; v/v) to obtain 60 mg of the title compound (colorless amorphous).
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[O:7])=[CH:4][CH:3]=1.CO[CH:38]1[CH2:42][CH2:41][CH:40](OC)O1>>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]4[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=4)[CH2:21][CH2:20]3)[C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=3)=[O:7])=[CH:34][CH:35]=2)[CH:38]=[CH:42][CH:41]=[CH:40]1
Reactant: COc1cccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(N)cc2)c1
Reactant: COC1CCC(OC)O1
Product: COc1cccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(-n3cccc3)cc2)c1
Yield: 78 %

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(3-methoxyphenyl)benzamide (238.1 mg, 0.50 mmol) and 2,5-dimethoxytetrahydrofuran (0.066 ml, 0.50 mmol), the procedure of Inventive Example 149 was repeated to obtain 205.0 mg (78.0%) of the title compound in a light brown amorphous form.
Reaction SMILES: C(O[Na])C.[OH:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.Br[C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH:10]([C:9]1[CH:12]=[CH:13][C:6]([O:5][C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7][CH:8]=1)=[O:11]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: CCO[Na]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(C=O)cc1
Yield: 41.9 %

Procedure:
In an ethanol solvent, 1 N ethoxy sodium (NaOEt) (1.1 eq.) was added dropwise to 4-hydroxybenzaldehyde (1.0 eq.) and ethyl α-bromoisobutyrate (1.1 eq.), and the reaction mixture was refluxed. After the ethanol was evaporated, the residual was distributed between ethyl acetate and water, and an organic layer was dried by using MgSO4, filtered, and evaporated. The residual was purified by silica gel column chromatography using hexane and ethyl acetate (8:1) to obtain Compound 97a.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([O:12][C:13](=[O:22])[C:14]1[CH:19]=[C:18](Cl)[N:17]=[C:16](Cl)[CH:15]=1)[CH3:11].C(=O)([O-])[O-].[Na+].[Na+]>CO.C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:10]([O:12][C:13](=[O:22])[C:14]1[CH:19]=[C:18]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:17]=[C:16]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:15]=1)[CH3:11]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1cc(Cl)nc(Cl)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOC(=O)c1cc(-c2ccccc2)nc(-c2ccccc2)c1
Temperature: 90 °C
Yield: 91 %

Procedure:
A solution of phenylboronic acid (915 mg, 7.50 mmol) in methanol (15 mL) was added to a stirred solution of ethyl-2,6-dichloro-isonicotinate (750 mg, 3.41 mmol) and tetrakis-(triphenylphosphine)-palladium(0) (197 mg, 5 mol %) in toluene (60 mL). 2N sodium carbonate (3.41 mL, 6.82 mmol) was added and the reaction was heated to 90° C. (oil bath temp.) for 2-3 hrs until complete (TLC control). The reaction mixture was cooled to room temperature and partitioned between water and diethyl ether. The phases were separated, the aqueous phase being further extracted with diethyl ether (3×30 mL). The combined extract was washed with water and brine. The ethereal solution was dried over anhydrous MgSO4, filtered and concentrated in vacuo to yield the title compound as a white solid (941 mg, 91%); Rf: 0.5 (30% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz) δ 8.18 (2H, s, ArH), 8.12 (4H, m, ArH), 7.42 (6H, m, ArH), 4.38 (2H, q, J=7 Hz, CH2O), 1.39 (2H, t, J=7 Hz, CH3)
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=2)[C:12]#[N:13])=[N:4][N:3]=1.[CH2:19]([C:21]1[C:26](/[CH:27]=[CH:28]/[O:29][CH3:30])=[CH:25][CH:24]=[CH:23][C:22]=1B1OC(C)(C)C(C)(C)O1)[CH3:20].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.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>[CH2:19]([C:21]1[C:26](/[CH:27]=[CH:28]/[O:29][CH3:30])=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=2)[C:12]#[N:13])=[N:4][N:3]=1)[CH3:20]
Reactant: CC(C)Cc1ccc(-c2nnc(Br)s2)cc1C#N
Reactant: CCc1c(/C=C/OC)cccc1B1OC(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=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(/C=C/OC)cccc1-c1nnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Temperature: 120 °C
Yield: 97.8 %

Procedure:
To a suspension of 5-(5-bromo-1,3,4-thiadiazol-2-yl)-2-(2-methylpropyl)benzonitrile (D26) (151 mg), 2-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (203 mg) and tripotassium phosphate (249 mg) in N,N-dimethylformamide (DMF) (6 mL) and water (1.5 mL) under nitrogen was added Pd(Ph3P)4 (54.2 mg). The reaction vessel was sealed and heated under microwave at 120° C. for 10 min. Water was added. The reaction mixture was extracted with EA for 3 times, the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, the dried solution was concentrated, and purified by column chromatography to afford 5-(5-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,3,4-thiadiazol-2-yl)-2-(2-methylpropyl)benzonitrile (D30) (185 mg) as a yellow oil. MS (ES): C24H25N3OS requires 403. found 404.2 (M+H+).