Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:10]1[N:11]=[C:12]([N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[S:13][CH:14]=1>C(OCC)(=O)C>[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:10]1[N:11]=[C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[S:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cccc(Cl)c3Cl)cs2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Clc1cccc(-c2csc(N3CCNCC3)n2)c1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 82.3 %

Procedure:
A 4 N solution (15 ml) of hydrogen chloride in ethyl acetate was added to a solution of tert-butyl 4-[4-(2,3-dichlorophenyl)-1,3-thiazol-2-yl]piperazine-1-carboxylate (370 mg, 0.893 mmol) in ethyl acetate (15 ml), the mixture was stirred at room temperature for 14 hours, and the solvent was distilled off under reduced pressure. The residue was dissolved in water, neutralized with a 1 N sodium hydroxide aqueous solution, and extracted with chloroform. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 231 mg (82.1%) of the desired product as a solid.
Reaction SMILES: [CH2:1]([C:4]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[C:11]([O:13][C:14](=[O:15])[CH:5]21)=[O:12])[CH:2]=[CH2:3].[CH2:16]([NH2:22])[CH2:17][O:18][CH2:19][CH2:20][OH:21]>>[OH:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][N:22]=[C:14]([CH:5]1[CH:6]([C:11]([OH:13])=[O:12])[CH:7]2[CH2:10][C:4]1([CH2:1][CH:2]=[CH2:3])[CH:9]=[CH:8]2)[OH:15]
Reactant: C=CCC12C=CC(C1)C1C(=O)OC(=O)C12
Reactant: NCCOCCO
Product: C=CCC12C=CC(C1)C(C(=O)O)C2C(O)=NCCOCCO
Temperature: 200 °C

Procedure:
120 g of allylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride (isomeric mixture) are reacted at 140° C. with 67.9 g of diglycolamine; the mixture is heated to 200° C. and the pressure lowerd to 10.6 Pa. The yield is 142.6 g of a yellow oil having a viscosity of 1.55 Pa.s at 25° C. and an n25D of 1.5230.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=2[O:31][CH3:32])=[CH:19][CH:18]=1)[NH:5][C:6](=O)[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1.O>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=2[O:31][CH3:32])=[CH:19][CH:18]=1)[NH:5][C:6](=[S:43])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Solvent: O
Solvent: Cc1ccccc1C
Product: COC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2OC)cc1)NC(=S)c1c(Cl)cccc1Cl
Temperature: 50 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
A mixture of N-(2,6-dichlorobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanine methyl ester (0.25 g) and Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disufide; 0.21 g) in xylene (10 mL) was refluxed overnight. The mixture was cooled to about 50° C. and water (15 mL) was added and refluxed for 2 h. The mixture was stirred at room temperature overnight and evaporated. The residue was partitioned between EtOAc and water. The EtOAc layer was washed with water, dried and evaporated to yield 0.25 g of N-(2,6-dichlorothiobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanine methyl ester. ESMS: m/z 504 (MH+).
Reaction SMILES: [CH2:1]([C:3]12[CH2:10][O:9][C:6]([C:11]3[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=3)([O:7][CH2:8]1)[O:5][CH2:4]2)[CH3:2].[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20]>C(NCC)C>[CH2:1]([C:3]12[CH2:10][O:9][C:6]([C:11]3[CH:16]=[CH:15][C:14]([C:23]#[C:22][Si:19]([CH3:21])([CH3:20])[CH3:18])=[CH:13][CH:12]=3)([O:7][CH2:8]1)[O:5][CH2:4]2)[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CCC12COC(c3ccc(I)cc3)(OC1)OC2
Solvent: CCNCC
Product: CCC12COC(c3ccc(C#C[Si](C)(C)C)cc3)(OC1)OC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Bis-triphenylphosphine palladium dichloride (60 mg) and cuprous iodide (10 mg) were added to a stirred solution of 4-ethyl-1-(4-iodophenyl)-2,6,7-trioxabicyclo[2,2,2]octane (1.5 gms) and trimethylsilylacetylene (0.92 ml) in dry diethylamine (40 ml) under nitrogen. The resulting mixture was stirred at room temperature for 16 hours. After this time the solvent was removed under vacuum and the residue extracted with diethylether. The ethereal solution was washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo. The residue was purified by column chromatography on alumina, eluting with 30% dichloromethane in hexane saturated with ammonia. 4-Ethyl-1-[4-(2-trimethylsilylethynyl)-phenyl]-2,6,7-trioxabicyclo[2,2,2]octane (1.2 gms) was obtained as an off-white solid (1.2 gms) after recrystallisation from hexane.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH3:10])[NH:7][C:6]=2[CH:11]=1.C([Li])(C)(C)C.[Cl:17][C:18]1[CH:29]=[CH:28][C:21]([C:22](N(OC)C)=[O:23])=[CH:20][C:19]=1[S:30](=[O:33])(=[O:32])[NH2:31]>O1CCCC1>[Cl:17][C:18]1[CH:29]=[CH:28][C:21]([C:22]([C:2]2[CH:3]=[CH:4][C:5]3[N:9]=[C:8]([CH3:10])[NH:7][C:6]=3[CH:11]=2)=[O:23])=[CH:20][C:19]=1[S:30]([NH2:31])(=[O:33])=[O:32]
Reactant: Cc1nc2ccc(Br)cc2[nH]1
Reactant: CON(C)C(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1nc2ccc(C(=O)c3ccc(Cl)c(S(N)(=O)=O)c3)cc2[nH]1

Procedure:
A solution of 0.303 g of 6-bromo-2-methyl-1H-benzoimidazole in tetrahydrofuran (20 mL) is cooled to −50° C. and treated with 2.7 mL of tert-butyllithium (1.5 M in pentane). After 2 h at −50° C. the reaction mixture is treated with 0.12 g of 4-chloro-N-methoxy-N-methyl-3-sulfamoyl-benzamide in tetrahydrofuran (10 mL). After 3 h the mixture is quenched with saturated aqueous ammonium chloride, taken up in ethyl acetate, and washed with saturated aqueous sodium chloride. The organics are dried (magnesium sulfate), concentrated and purified by silica gel chromatography (98:2 methylene chloride/methanol) to give 2-chloro-5-(2-methyl-3H-benzoimidazole-5-carbonyl)-benzenesulfonamide. MS (m/z): 348 (M−1); Rf 0.30 (9:1 methylene chloride/methanol).
Reaction SMILES: C([O:3][C:4](=[O:36])[C@H:5]([CH3:35])[CH2:6][C@H:7]([NH:21][C:22](=[O:34])[CH2:23][CH2:24][C:25]1[N:29](CCC#N)[N:28]=[N:27][N:26]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)C.C1CCN2C(=NCCC2)CC1>ClCCl>[C:12]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:14][C:9]([CH2:8][C@@H:7]([NH:21][C:22](=[O:34])[CH2:23][CH2:24][C:25]2[NH:29][N:28]=[N:27][N:26]=2)[CH2:6][C@@H:5]([CH3:35])[C:4]([OH:36])=[O:3])=[CH:10][CH:11]=1
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCc1nnnn1CCC#N
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCc1nnn[nH]1)C(=O)O
Reaction time: 3 h
Yield: 52.9 %

Procedure:
To a solution of (2R,4S)-5-Biphenyl-4-yl-4-{3-[1-(2-cyano-ethyl)-1H-tetrazol-5-yl]-propionylamino}-2-methyl-pentanoic acid ethyl ester (32 mg, 0.065 mmol) in dichloromethane (1 mL) is added DBU (24 mg, 0.164 mmol). After stirring for 3 hours, additional DBU (24 mg, 0.146 mmol) is added. After stirring for 2 hours, the reaction mixture is diluted with dichloromethane and washed with saturated aqueous NH4Cl. The organic layer is dried over Na2SO4 and concentrated. The residue is dissolved in MeOH and treated with aqueous 2M NaOH. After stirring for 1 hours, the reaction mixture is diluted with ethyl acetate and acidified with aqueous 1M HCl. The mixture is extracted with ethyl acetate and washed with brine. The organic layer is dried over Na2SO4 and concentrated. The residue is purified by reverse phase HPLC (0.1% TFA-H2O/MeCN) to give (2R,4S)-5-biphenyl-4-yl-2-methyl-4-(3-1H-tetrazol-5-yl-propionylamino)-pentanoic acid (14 mg). HPLC Retention time 1.17 minutes (condition C); MS 408.0 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 (d, J=7.07Hz, 3H), 1.34 (ddd, J=4.80, 10.11, 14.91Hz, 1H), 1.78 (ddd, J=4.04, 9.60, 13.64Hz, 1H), 2.31-2.42 (m, 1H), 2.52-2.59 (m, 2H), 2.68 (d, J=7.07Hz, 2H), 3.03 (dd, J=7.58, 7.58Hz, 2H), 3.90-4.01 (m, 1H), 7.20 (d, J=8.08Hz, 2H), 7.34 (t, J=9.09Hz, 1H), 7.45 (d, J=7.83Hz, 2H), 7.55 (d, J=8.34Hz, 2H), 7.64 (d, J=7.33Hz, 2H), 7.84 (d, J=8.34Hz, 1H), 11.99 (bs, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[N:11]12[CH2:12][CH2:13][CH:14]([CH2:15][CH2:16]1)[CH:9]([O:8][C:7]1[CH:17]=[CH:18][C:4]([NH2:1])=[CH:5][CH:6]=1)[CH2:10]2
Reactant: O=[N+]([O-])c1ccc(OC2CN3CCC2CC3)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(OC2CN3CCC2CC3)cc1
Yield: 102.8 %

Procedure:
The product of Example 22A (1.02 g, 4.1 mmol) in MeOH (25 mL) was treated with Pd/C (Aldrich, 10%, 150 mg) under H2 at room temperature for 1.5 hours. The mixture was filtered through a short column of diatomaceous earth and the filtrate was concentrated under reduced pressure to provide the title compound (0.92 g, yield, 100%). 1H NMR (MeOH-d4, 300 MHz) δ 1.40–1.56 (m, 1H), 1.65–1.90 (m, 2H), 1.96–2.13 (m, 2H), 2.70–3.00 (m, 5H), 3.10–3.20 (m, 1H), 4.35 (m, 1H), 6.65–6.78 (m, 4H) ppm. MS (DCl/NH3) m/z 219 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[CH2:32][C:33](=[O:39])[NH:34]2>>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[C:32](=[CH:20][C:3]1[NH:4][C:5]3[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]4[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]4)[C:7](=[O:19])[C:6]=3[C:2]=1[CH3:1])[C:33](=[O:39])[NH:34]2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Reactant: O=C1Cc2c(cccc2-c2c(F)cccc2F)N1
Product: Cc1c(C=C2C(=O)Nc3cccc(-c4c(F)cccc4F)c32)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Yield: 70.7 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(2,6-difluoro-phenyl)-1,3-dihydro-indol-2-one (prepared according to WO2002055517) as starting materials to give 2-[4-(2,6-difluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5-(2-piperidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (70 mg, 70.7%) as an orange solid.
Reaction SMILES: [NH3:1].C[O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1[CH2:14]Br>CO>[N+:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]2[C:6]=1[CH2:14][NH:1][C:4]2=[O:3])([O-:13])=[O:12]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1CBr
Reactant: N
Solvent: CO
Product: O=C1NCc2c1cccc2[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NH3 (2.0 M in MeOH, 50 ml) was slowly added to the solution of 2-bromomethyl-3-nitro-benzoic acid methyl ester (4.46 g, contaminated with a small amount of assumed starting material, 16.3 mmol) in 30 ml of MeOH at RT. The resulting mixture was stirred at RT overnight, to provide the title compound as a white solid. MS (ES+): 179.2 (M+H)+. Calc'd for C8H6N2O3—178.14.
Reaction SMILES: O.NN.[CH:4]1([C:7]2[CH:8]=[CH:9][C:10](/[C:15](/[C:30]3[CH:35]=[CH:34][C:33]([S:36][CH3:37])=[CH:32][CH:31]=3)=[CH:16]/[CH2:17][CH2:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)=[N:11][C:12]=2[O:13][CH3:14])[CH2:6][CH2:5]1.[OH-].[Na+]>C(O)C>[CH:4]1([C:7]2[CH:8]=[CH:9][C:10](/[C:15](/[C:30]3[CH:35]=[CH:34][C:33]([S:36][CH3:37])=[CH:32][CH:31]=3)=[CH:16]/[CH2:17][CH2:18][NH2:19])=[N:11][C:12]=2[O:13][CH3:14])[CH2:6][CH2:5]1
Reactant: COc1nc(/C(=C/CCN2C(=O)c3ccccc3C2=O)c2ccc(SC)cc2)ccc1C1CC1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1nc(/C(=C/CCN)c2ccc(SC)cc2)ccc1C1CC1
Temperature: 95 °C
Reaction time: 1 h

Procedure:
Hydrazine monohydrate (1 mL) was added to a solution of 2-{(3E)-4-(5-cyclopropyl-6-methoxypyridin-2-yl)-4-[4-(methylsulfanyl)phenyl]but-3-en-1-yl}-1H-isoindole-1,3(2H)-dione (320 mg) in ethanol (4 mL), and the mixture was stirred at 95° C. for one hour. The reaction solution was poured into a 3 M sodium hydroxide solution, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure to give (3E)-4-(5-cyclopropyl-6-methoxypyridin-2-yl)-4-[4-(methylsulfanyl)phenyl]but-3-en-1-amine as a colorless amorphous (225 mg, 97%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]=O)=[C:6]([N+:10]([O-:12])=O)[CH:5]=[CH:4][CH:3]=1>Cl.O>[CH3:1][C:2]1[C:7]2=[CH:8][O:12][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc([N+](=O)[O-])c1C=O
Agent: Cl
Solvent: O
Product: Cc1cccc2nocc12
Yield: 92.6 %

Procedure:
To a solution of 49.64 g (220 mmoles) stannous chloride dihydrate in 132 ml concentrated hydrochloric acid cooled to 15° was added 9.08 g (55.0 mmoles) of 6-methyl-2-nitrobenzaldehyde with rapid stirring. After 2 hours the mixture was diluted with 250 ml water and extracted with 3×150 ml ether. The extract was washed successively with dilute sodium bicarbonate solution, water, and brine, dried, and concentrated to give 6.78 g oil. The oil was flash chromatographed, eluting with chloroform to give 6.10 g (83%) (1) as an oil; nmr (deuteriochloroform): 2.5 (s, 3H), 6.7 (dd, 1H), 7.3 (m, 2H), 9.1 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:14]=1[C:15]1[N:16]=[N:17][C:18]([N:21]([CH3:32])[CH:22]2[CH2:27][C:26]([CH3:29])([CH3:28])[NH:25][C:24]([CH3:31])([CH3:30])[CH2:23]2)=[CH:19][CH:20]=1)[C:6]([NH:8][CH2:9][C:10]#[CH:11])=[O:7].[H-].[Na+]>O1CCOCC1.CCOC(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[O:7][C:10]([CH3:11])=[CH:9][N:8]=2)[CH:12]=[CH:13][C:14]=1[C:15]1[N:16]=[N:17][C:18]([N:21]([CH3:32])[CH:22]2[CH2:23][C:24]([CH3:31])([CH3:30])[NH:25][C:26]([CH3:28])([CH3:29])[CH2:27]2)=[CH:19][CH:20]=1
Reactant: C#CCNC(=O)c1ccc(-c2ccc(N(C)C3CC(C)(C)NC(C)(C)C3)nn2)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc(-c2ncc(C)o2)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Temperature: 25 °C
Yield: 55.3 %

Procedure:
To a solution of 3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-N-(prop-2-yn-1-yl)benzamide (190 mg, 0.44 mmol) in dioxane (8 mL) was added 60% wt NaH (52 mg, 1.31 mmol). The reaction was refluxed for 5 h, then cooled to RT and diluted in EtOAc and water. The organic layer was washed with water, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified via HPLC to give 6-(2-methoxy-4-(5-methyloxazol-2-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (106 mg). LCMS Rt=0.97 min (condition B); MS (M+1)=436.3. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.08 (d, J=8.1 Hz, 1H), 7.85 (d, J=9.6 Hz, 1H), 7.72 (dd, J=8.1, 1.5 Hz, 1H), 7.65 (d, J=1.3 Hz, 1H), 6.88 (s, 1H), 6.82 (d, J=9.6 Hz, 1H), 5.20-5.39 (m, 1H), 3.96 (s, 3H), 2.99 (s, 3H), 2.43 (s, 3H), 1.74 (dd, J=12.4, 3.3 Hz, 2H), 1.47-1.59 (m, 2H), 1.43 (s, 6H), 1.31 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:18]=[C:17]([Sn](C)(C)C)[CH:16]=[C:15]3[C:11]=2[CH:12]=[N:13][N:14]3S(C2C=CC=CC=2)(=O)=O)=[O:8])[N:6]=1.Br[C:33]1[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[CH:35][CH:34]=1.CC#N>CN(C=O)C.Cl[Pd]C1C=CC=CC=1C1C=CC=CC=1N(C)C.[C@H]12C[C@H](CC1)CC2PC1C[C@H]2C[C@@H]1CC2>[NH2:42][S:39]([C:36]1[CH:37]=[CH:38][C:33]([C:17]2[CH:16]=[C:15]3[C:11]([CH:12]=[N:13][NH:14]3)=[C:10]([NH:9][C:7]([C:5]3[N:6]=[C:2]([CH3:1])[S:3][CH:4]=3)=[O:8])[CH:18]=2)=[CH:34][CH:35]=1)(=[O:41])=[O:40]
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Reactant: Cc1nc(C(=O)Nc2cc([Sn](C)(C)C)cc3c2cnn3S(=O)(=O)c2ccccc2)cs1
Agent: CN(C)c1ccccc1-c1ccccc1[Pd]Cl
Agent: C1C[C@@H]2C[C@H]1CC2PC1C[C@@H]2CC[C@H]1C2
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1nc(C(=O)Nc2cc(-c3ccc(S(N)(=O)=O)cc3)cc3[nH]ncc23)cs1
Temperature: 135 °C
Reaction time: 18 h
Yield: 6.7 %

Procedure:
2-Methyl-N-[1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-yl]-1,3-thiazole-4-carboxamide (101 mg) was dissolved in DMF (0.4 ml) and added to 4-bromobenzenesulfonamide (42.5 mg) in DMF (0.4 ml). Chloro[2′-(dimethylamino)-2-biphenylyl]palladium-(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (1:1) (4 mg, heaped microspatula) was added to the reaction which was then heated under microwave irradiation at 135° C. for 20 min. The reaction was loaded onto a C18 SPE pre-conditioned with MeCN:0.1% TFA (aq), eluted with 3 ml MeCN:0.1% TFA (aq) then evaporated to dryness. The residue was dissolved in DMSO (0.5 ml) and purified by MDAP (method C). The residue was then dissolved in IPA (0.3 ml) and 2M NaOH (0.3 ml) was added. The reaction was stirred at RT for 18 h then diluted with DMSO (0.6 ml) and purified by MDAP (method D) to give the title compound (5 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[S:8])[NH:6][N:7]=1.[OH-].[Na+].[CH3:12]I>C(O)C>[CH3:1][C:2]1[C:3](=[O:9])[NH:4][C:5]([S:8][CH3:12])=[N:6][N:7]=1
Reactant: CI
Reactant: Cc1n[nH]c(=S)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1nnc(C)c(=O)[nH]1
Temperature: 40 °C
Yield: 47.9 %

Procedure:
To a solution of 6-methyl-3-thioxo-3,4-dihydro-1,2,4-triazin-5(2H)-one (4, 5.80 g, 40.6 mmol) in absolute ethanol (250 mL) was added NaOH (1.96 g, 49.1 mmol) followed by MeI (11.5 g, 81.2 mmol). The mixture was heated at 40° C. for 15 h. Most of the solvent was evaporated under reduced pressure. Water was added to the residue. The precipitated white solid was collected by filtration and washed with ethanol to give 5 (3.06 g). The aqueous phase was extracted with CH2Cl2 (80 mL×4). The combined extracts were dried over Na2SO4 and concentrated to give 3.34 g crude product. This was purified by column chromatography on silica gel, and eluted with 1:1 to 1:2 petroleum ether-ethyl acetate to provide 6-methyl-3-(methylthio)-1,2,4-triazin-5(4H)-one (5). MS: m/z, 158 (100%, M+1).
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([OH:5])=[O:4].Br[C:11]1[CH:12]=[C:13]([CH3:19])[C:14]([F:18])=[C:15]([CH3:17])[CH:16]=1.C([O-])([O-])=O.[K+].[K+].Cl>C(OCC)(=O)C.O.[Cu]I.CC(N(C)C)=O>[F:18][C:14]1[C:15]([CH3:17])=[CH:16][C:11]([NH:1][C@H:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([OH:5])=[O:4])=[CH:12][C:13]=1[CH3:19]
Reactant: Cc1cc(Br)cc(C)c1F
Reactant: CCCC[C@@H](N)C(=O)O
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCC[C@@H](Nc1cc(C)c(F)c(C)c1)C(=O)O
Temperature: 90 °C
Reaction time: 39 h

Procedure:
(R)-2-Amino-hexanoic acid (0.840 g, 6.4 mmol), 5-bromo-2-fluoro-1,3-dimethyl-benzene (1.292 g, 6.4 mmol), CuI (0.122 g, 0.64 mmol), and K2CO3 (1.326 g, 9.6 mmol) were weighed into a Schlenk flask. To this was added 8 mL of dimethylacetamide and the resulting mixture vacuum-pumped and nitrogen-filled alternatively three times. After heating to 90° C. with stirring for 39 h, the reaction mixture was cooled to room temperature, diluted with 20 mL of ethyl acetate and 10 mL of water, and then acidified with concentrated HCl to pH=3. The layers were separated and the aqueous layer extracted with ethyl acetate (20 mL×5). The organic layers were combined and dried over anhydrous Na2SO4. Removal of the solvent under reduced pressure gave the title product which was used directly in the next step with further purification. LC-MS: tR=8.5 min, m/z 254 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:6][CH2:5]1.[F:17][C:18]([F:32])([F:31])[C:19]1[CH:20]=[C:21]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>C(Cl)Cl>[N:12]1[CH:13]=[CH:14][CH:15]=[N:16][C:11]=1[NH:10][C@H:7]1[CH2:8][CH2:9][C@H:4]([CH2:3][CH2:2][N:28]2[CH2:27][CH2:26][N:25]([C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:31])([F:32])[F:17])[CH:20]=3)[CH2:30][CH2:29]2)[CH2:5][CH2:6]1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: BrCC[C@H]1CC[C@H](Nc2ncccn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: FC(F)(F)c1cccc(N2CCN(CC[C@H]3CC[C@H](Nc4ncccn4)CC3)CC2)c1

Procedure:
A mixture of trans-[4-(2-Bromoethyl)-cyclohexyl]-pyrimidin-2-yl-amine (0.26 g, 0.91 mmol), 1-(3-trifluoromethyl-phenyl)-piperazine (0.21 g, 0.91 mmol), and potassium carbonate (0.21 g, 1.5 mmol) was heated in 10 mL refluxing acetonitrile for 18 hours. The reaction was diluted with methylene chloride, filtered, and the solvents were removed under reduced pressure. The residue was partitioned between chloroform and aqueous 2N sodium carbonate solution. The organic layer was dried over sodium sulfate and evaporated. The resulting residue was recrystallized from acetonitrile to give the title compound; mp 167° C.
Reaction SMILES: Br[C:2]1[C:3]([Cl:19])=[C:4]([O:9][C:10]2[C:15]([F:16])=[C:14]([CH3:17])[CH:13]=[CH:12][C:11]=2[Cl:18])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:20]([Zn]C#N)#[N:21]>CCOC(C)=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>[Cl:19][C:3]1[C:4]([O:9][C:10]2[C:11]([Cl:18])=[CH:12][CH:13]=[C:14]([CH3:17])[C:15]=2[F:16])=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[C:20]#[N:21]
Reactant: Cc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2Cl)c1F
Reactant: N#C[Zn]C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: Cc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2Cl)c1F
Temperature: 120 °C
Yield: 117.7 %

Procedure:
2-[(3-bromo-2,5-dichlorophenyl)oxy]-1-chloro-3-fluoro-4-methylbenzene (2.0 g, 5.20 mmol) was combined with dicyanozinc (0.305 g, 2.60 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.601 g, 0.520 mmol) and heated at 120° C. for 60 min in a microwave reactor under an inert atmosphere. The reaction mixture was diluted with EtOAc, washed four times with water, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on 120 g silica eluted successively with 100% hexanes followed by 0 to 10% EtOAc/hexanes to give 2,5-dichloro-3-[(6-chloro-2-fluoro-3-methylphenyl)oxy]benzonitrile (1.01 g, 3.06 mmol, 58.7% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.00 (d, J=2.20 Hz, 1H), 7.31-7.47 (m, 2H), 7.24 (d, J=1.83 Hz, 1H), 2.29 (d, J=1.74 Hz, 3H).
Reaction SMILES: N1C=CC([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]2[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[S:28][CH:29]=[CH:30][N:31]=4)[CH:22]=3)[C:18](=[O:32])[CH2:17][CH2:16][CH2:15][CH2:14]2)=CC=1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35](B(O)O)[CH:34]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1COCC1.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.CCOC(C)=O>[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]2[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[S:28][CH:29]=[CH:30][N:31]=4)[CH:22]=3)[C:18](=[O:32])[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:34]=1
Reactant: O=C1CCCCC(c2ccccc2-c2ccncc2)N1Cc1cccc(-c2nccs2)c1
Reactant: OB(O)c1cccnc1
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: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1CCCCC(c2ccccc2-c2cccnc2)N1Cc1cccc(-c2nccs2)c1
Temperature: 80 °C

Procedure:
A mixture of 7-(2-bromophenyl)-1-(3-(thiazol-2-yl)benzyl)azepan-2-one (preparation described in example 450; 50 mg; 0.11 mmol), commercially available pyridin-3-ylboronic acid (14 mg; 0.11 mmol), and Pd(PPh3)4 (7 mg; 0.006 mmol) in THF (2 ml), and aq. 2 M Na2CO3 (0.2 ml) was heated to 80° C., under nitrogen, for 24 h. After cooling to rt, water and AcOEt were added. The separated aq. layer was further extracted with AcOEt. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.63 min.; [M+H]+: 440.15 g/mol.