Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([N:5](S(C)(=O)=O)[C:6]1[CH:35]=[CH:34][C:9]([C:10]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C@H:15]([N:22]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:23](=[O:25])[CH3:24])[CH2:14][C@@H:13]2[CH3:33])=[O:11])=[CH:8][CH:7]=1)(=[O:4])=[O:3].[OH-].[Na+].O.C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([N:22]([C@H:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]([C:10](=[O:11])[C:9]3[CH:34]=[CH:35][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][CH:8]=3)[C@@H:13]([CH3:33])[CH2:14]2)[C:23](=[O:25])[CH3:24])=[CH:27][CH:28]=1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(N(S(C)(=O)=O)S(C)(=O)=O)cc2)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(NS(C)(=O)=O)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.3 %

Procedure:
To a solution of N-((2S,4R)-1-{4-[bis(methylsulfonyl)amino]benzoyl}-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-N-(4-chlorophenyl)acetamide (259 mg, 0.44 mmol) in tetrahydrofuran (5.0 mL) at room temperature was added 1.0 M sodium hydroxide (0.880 mL, 0.88 mmol). The reaction was stirred at room temperature for 2 days. The resulting reaction mixture was poured into a 1:1 mixture of water and saturated sodium bicarbonate (25 mL) and extracted with ethyl acetate (1×25 mL). The aqueous layer was neutralized via addition of 1N HCl to pH ˜8 and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed once with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford N-(4-chlorophenyl)-N-((2S,4R)-2-methyl-1-{4-[(methylsulfonyl)amino]benzoyl}-1,2,3,4-tetrahydroquinolin-4-yl)acetamide (190 mg, 76%) as a light-yellow, foamy solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([S:9][C:10]1[CH:31]=[CH:30][C:13]2[N:14]([CH3:29])[C:15]3[CH:28]=[CH:27][CH:26]=[CH:25][C:16]=3[CH:17]=[C:18]([CH2:19][C:20](=O)[N:21]([CH3:23])[CH3:22])[C:12]=2[CH:11]=1)[CH3:8].C(OCC)(=O)C.[OH-].[Na+]>O1CCCC1>[CH2:7]([S:9][C:10]1[CH:31]=[CH:30][C:13]2[N:14]([CH3:29])[C:15]3[CH:28]=[CH:27][CH:26]=[CH:25][C:16]=3[CH:17]=[C:18]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[C:12]=2[CH:11]=1)[CH3:8]
Reactant: CCSc1ccc2c(c1)C(CC(=O)N(C)C)=Cc1ccccc1N2C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCSc1ccc2c(c1)C(CCN(C)C)=Cc1ccccc1N2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
2.2 g of lithium aluminum hydride were added in small fractions to a solution of 9 g of 2-ethylthio-5-methyl-11-dimethylcarbamoylmethyl [5H] dibenzo (b,f) azepine in 270 ml of tetrahydrofuran while keeping the temperature below 30°C and the mixture was stirred for 2 hours at room temperature and was cooled to 0°C. Ethyl acetate was added to the mixture followed by a 2N sodium hydroxide solution to dissociate the precipitate formed. The insolubles were removed by filtration and the organic phase was recovered by decanting. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with water, dried over magnesium sulfate and evaporated to dryness. The residue was chromatographed over silica gel with a 60-30-10 mixture of cyclohexane-chloroform-triethylamine as eluant which was evaporated to obtain 7.1 g of raw 2-ethylthio-5-methyl-11-(β-dimethylamino ethyl) [5H] dibenzo (b,f) azepine.
Reaction SMILES: Br.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[C:6](=[O:14])[N:5]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]1=[O:21].CS([C:26]1[C:31]2[CH:32]=[C:33]([O:38][CH3:39])[C:34]([O:36][CH3:37])=[CH:35][C:30]=2[N:29]=[N:28][N:27]=1)(=O)=O.CS(C)=O>CO>[CH3:39][O:38][C:33]1[C:34]([O:36][CH3:37])=[CH:35][C:30]2[N:29]=[N:28][N:27]=[C:26]([N:18]3[CH2:19][CH2:20][CH:15]([N:5]4[C:6](=[O:14])[C:7]5[C:12](=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=5)[N:3]([CH3:2])[C:4]4=[O:21])[CH2:16][CH2:17]3)[C:31]=2[CH:32]=1
Reactant: COc1cc2nnnc(S(C)(=O)=O)c2cc1OC
Reactant: Cc1ccc2c(c1)c(=O)n(C1CCNCC1)c(=O)n2C
Agent: Br
Solvent: CS(C)=O
Solvent: CO
Product: COc1cc2nnnc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1OC
Yield: 67 %

Procedure:
The procedure similar to that described in Example 40 was repeated, except that 354.0 mg (1.0 mmol) of 1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)-quinazoline hydrobromide (Compound v) obtained in Example 41 was used, 4-methanesulfonyl-6,7-dimethoxy-1,2,3-benzotriazine was used in place of 4-chloro-6,7-dimethoxyquinazoline, DMSO was used as a reaction solvent in place of methanol, and the reaction was conducted at room temperature. As a result, 307.6 mg (yield: 67%) of Compound 75 was obtained as white crystals.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.[CH2:25]([OH:28])[C:26]#[CH:27]>O1CCOCC1.ClCCl.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([C:27]#[C:26][CH2:25][OH:28])=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: C#CCO
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(C#CCO)ccc12
Temperature: 90 °C
Yield: 75.8 %

Procedure:
To a solution of 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (500 mg, 1.24 mmol, 1.00 eq) in degassed 1,4-dioxane (2.50 mL, 5.00 V), prop-2-yn-1-ol (0.09 mL, 1.49 mmol, 1.20 eq) Et3N (0.52 mL, 3.71 mmol, 3.00 eq), Bis(triphenylphosphine)palladium (II) dichloride (34.86 mg, 0.05 mmol, 0.04 eq) and copper (I) iodide (4.81 mg, 0.02 mmol, 0.02 eq) were added. The reaction mixture was heated at 90° C. for 1 h. The reaction mixture was diluted with dichloromethane and filtered through celite. The filtrate was concentrated and subjected to column chromatography to afford the title compound (0.38 g, 0.94 mmol, 75.7%) as a off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.87 (t, J=5.92 Hz, 1H), 8.09 (d, J=8.61 Hz, 1H), 8.01 (d, J=9.01 Hz, 1H), 7.86 (d, J=9.11 Hz, 1H), 7.68 (d, J=8.72 Hz, 1H), 5.53 (t, J=6.13 Hz, 1H), 4.39 (d, J=6.01 Hz, 2H), 3.27 (t, J=6.32 Hz, 2H), 1.98-2.04 (m, 2H), 1.74-1.86 (m, 5H), 1.24-1.33 (m, 2H). m/z: 393.2 [M+H]+
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH2:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[C:20]([C:31]([NH2:33])=[O:32])=[CH:19][N:18]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[O:34]([C:36]#[N:37])[K]>C(O)(=O)C>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH2:24][CH:25]4[CH2:30][CH2:29][N:28]([C:36](=[O:34])[NH2:37])[CH2:27][CH2:26]4)[C:20]([C:31]([NH2:33])=[O:32])=[CH:19][N:18]=3)=[CH:14][CH:15]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: N#CO[K]
Reactant: CC(=O)N1CCN(c2ccc(Nc3ncc(C(N)=O)c(NCC4CCNCC4)n3)cc2)CC1
Solvent: CC(=O)O
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(C(N)=O)c(NCC4CCN(C(N)=O)CC4)n3)cc2)CC1
Reaction time: 4 h
Yield: 29.4 %

Procedure:
A mixture of 2-(4-(4-acetylpiperazin-1-yl)phenylamino)-4-(piperidin-4-ylmethylamino)pyrimidine-5-carboxamide (25 mg, 0.055 mmol) and KOCN (20 mg, 0.25 mmol) in acetic acid (2 mL) was stirred at 100 C. for 4 h. The mixture was then purified by HPLC to give the titled compound (8 mg). MS 496.45 (M+H).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH3:4].[OH-].[K+].[C:8]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19])(=[O:10])[CH3:9]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O.C1(C)C=CC=CC=1>[CH2:1]([N:11]([C:8](=[O:10])[CH3:9])[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCBr
Reactant: CC(=O)Nc1ccc(F)cc1F
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCN(C(C)=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
0.9 g of triethylbenzylammonium chloride, 6.9 g of butyl bromide and a solution of 5.7 g of KOH in 6 ml of water are added to a stirred solution of 3.4 g of N-acetyl-2,4-difluoroaniline (Example 2) in 60 ml of toluene. The emulsion produced is warmed at 97° (reflux). After 1 h, the emulsion is cooled to room temperature and diluted with 20 ml of water. The two phases are separated, and the organic phase is dried over MgSO4 and evaporated in vacuo. The liquid crude product is purified by medium-pressure chromatography. 3.1 g of N-butyl-N-acetyl-2,4-difluoroaniline are obtained as a brownish oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[CH:14]([CH3:15])[CH2:13][CH:12]([C:16]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:11]2)[CH:3]=1.[C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][C:29]=1[F:37])#[N:27].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[C:26]([C:28]1[CH:33]=[CH:32][C:31]([C:2]2[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]3[C@H:14]([CH3:15])[CH2:13][C@H:12]([C:16]([NH:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[CH2:11]3)[CH:3]=2)=[CH:30][C:29]=1[F:37])#[N:27]
Reactant: CNc1nc(Cl)cc(N2CC(C(=O)NCc3ccccc3)CC2C)n1
Reactant: N#Cc1ccc(B(O)O)cc1F
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2C[C@@H](C(=O)NCc3ccccc3)C[C@H]2C)n1
Temperature: 100 °C
Yield: 114.1 %

Procedure:
Racemic (3S,5R)-1-[6-chloro-2-(methylamino)-4-pyrimidinyl]-5-methyl-N-(phenylmethyl)-3-pyrrolidinecarboxamide (100 mg, 0.28 mmol), (4-cyano-3-fluorophenyl)boronic acid (60 mg, 0.36 mmol, 1.3 equiv), tricyclohexylphosphine (12 mg, 0.043 mmol, 0.15 equiv), Pd2(dba)3 (20 mg, 0.022 mmol, 0.075 equiv) and K3PO4 (101 mg, 0.48 mmol, 1.7 equiv) were charged to a 20 mL microwave vial, followed by addition of 1,4-dioxane (3 mL) and water (1 mL). The mixture was bubbled with argon for 15 minutes, followed by capping and heating to 100° C. for 21 hours. This crude mixture was combined with another run starting with 300 mg of racemic (3S,5R)-1-[6-chloro-2-(methylamino)-4-pyrimidinyl]-5-methyl-N-(phenylmethyl)-3-pyrrolidinecarboxamide. The combined mixture was filtered through celite, and the cake was rinsed with EtOAc (100 mL). The filtrate was concentrated in vacuo, and the resulting residue was taken up in 25 mL of water, sonicated briefly, and filtered. The dark colored solids were washed with water, and dried under house vacuum for 1 hour. Attempt was made to dissolve these solids in CHCl3, EtOAc, and CH3OH, but there was always some residue left. The residue was checked by LCMS be the pure desired product. This dark colored residue was collected by filtration, and dissolved in CHCl3 with a small amount of MeOH (2% by volume, total solvent used about 100 mL) to give a dark solution, which was filterd through celite. The filtrate was concentrated in vacuo, and the resulting yellowish residue was dried under vacuum to give 142 mg of the title compound. The above organic filtrate (combined CHCl3, EtOAc and CH3OH wash) was concentrated in vacuo. Trituration in EtOAc (6 mL) and drying under vacuum gave another 220 mg of the title compound.
Reaction SMILES: O[C:2]1[N:7]=[CH:6][C:5]2=[CH:8][CH:9]=[C:10]([C:11]3[C:12]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[N:13][CH:14]=[CH:15][CH:16]=3)[N:4]2[N:3]=1.CN(C)C=O.C(N(CC)C(C)C)(C)C.C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.[NH2:58][C:59]1[CH:64]=[CH:63][C:62]([CH:65]2[CH2:70][CH2:69][N:68]([CH2:71][C:72]([NH2:74])=[O:73])[CH2:67][CH2:66]2)=[CH:61][CH:60]=1>>[CH3:21][S:18]([N:17]([CH3:22])[C:12]1[C:11]([C:10]2[N:4]3[C:5]([CH:6]=[N:7][C:2]([NH:58][C:59]4[CH:64]=[CH:63][C:62]([CH:65]5[CH2:66][CH2:67][N:68]([CH2:71][C:72]([NH2:74])=[O:73])[CH2:69][CH2:70]5)=[CH:61][CH:60]=4)=[N:3]3)=[CH:8][CH:9]=2)=[CH:16][CH:15]=[CH:14][N:13]=1)(=[O:20])=[O:19]
Reactant: NC(=O)CN1CCC(c2ccc(N)cc2)CC1
Reactant: CN(c1ncccc1-c1ccc2cnc(O)nn12)S(C)(=O)=O
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(c1ncccc1-c1ccc2cnc(Nc3ccc(C4CCN(CC(N)=O)CC4)cc3)nn12)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
Into a 8-dram vial, N-[3-(2-Hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-pyridin-2-yl]-N-methyl-methanesulfonamide (56 mg, 0.18 mmol), N,N-Dimethylformamide (0.50 mL, 6.4 mmol), N,N-Diisopropylethylamine (0.0672 mL, 0.386 mmol) and N-Phenylbis(trifluoromethanesulphonimide) (2.77 g, 7.75 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. 2-[4-(4-Amino-phenyl)-piperidin-1-yl]-acetamide (90.0 mg, 0.386 mmol) was added. The reaction was heated at 110° C. for 3 hours. The solvent was removed under vacuum overnight The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were combined and neutralized via polymer bound sulfonic acid column with 2N NH3 in methanol. The filtrate was concentrated to afford 2-[4-(4-{7-[2-(Methanesulfonyl-methyl-amino)-pyridin-3-yl]-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino}-phenyl)-piperidin-1-yl]-acetamide as a yellow solid (50 mg, 50%). LCMS (E/I+) 535.16 (M+H). NMR 1H (DMSO-d6)-9.42 (s, 1H), 9.01 (s, 1H), 8.56-8.61 (m, 2H), 7.64-7.69 (m, 1H), 7.56 (s, 1H), 7.54 (s, 1H), 7.19 (s, 1H), 7.07-7.14 (m, 2H), 6.98 (d, 2H, J=4.63 Hz), 3.13 (s, 3H), 3.00 (s, 3H), 2.84-2.96 (m, 4H), 2.32-2.44 (m, 1H), 2.08-2.19 (m, 2H), 1.64-176 (m, 4H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:40])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][C:23]([O:29]CC4C=CC(OC)=CC=4)=[C:24]([O:26][CH2:27][CH3:28])[CH:25]=3)=[CH:16][C:15]=2[F:39])=[CH:7][C:6]=1[C:41]([F:44])([F:43])[F:42])[CH3:3].[ClH:45]>C(Cl)Cl>[ClH:45].[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:40])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[C:24]([O:26][CH2:27][CH3:28])[C:23](=[O:29])[NH:22][CH:21]=3)=[CH:16][C:15]=2[F:39])=[CH:7][C:6]=1[C:41]([F:43])([F:42])[F:44])[CH3:3]
Reactant: CCOc1cc(-c2ccc(CC(=O)Nc3ccc(CN(C)C)c(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Agent: Cl
Solvent: ClCCl
Product: CCOc1cc(-c2ccc(CC(=O)Nc3ccc(CN(C)C)c(C(F)(F)F)c3)c(F)c2)c[nH]c1=O
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 38.1 %

Procedure:
To a solution of N-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (5.8 g, 7.30 mmol) in DCM (50 mL) was added HCl (1,4-dioxane, 5 mL, 20.00 mmol) at rt. The solution was stirred at 20° C. for 30 min. The solution was concentrated in vacuo to give the crude product. The crude material was purified by preparative HPLC (MeCN/H2O as eluants, acidic condition) to yield a off white solid of N-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide, hydrochloride (1.5 g, 2.78 mmol, 38.1% yield). TLC (DCM/MeOH=5:1, Rf=0.3): 1H NMR (400 MHz, CD3OD) δ 8.21 (d, J=1.4 Hz, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.36-7.53 (m, 5H), 4.50 (s, 2H), 4.20 (q, J=7.0 Hz, 2H), 3.87 (s, 2H), 2.95 (s, 6H), 1.50 (t, J=7.0 Hz, 3H); ES-LCMS m/z 492.2 (M+H).
Reaction SMILES: [CH:1]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:8][CH:9]=[C:10]([CH:14]=2)[C:11]([OH:13])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][N:22]=1>>[CH:1]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:8][CH:9]=[C:10]([CH:14]=2)[C:11]([NH:27][C:24]2[CH:25]=[CH:26][N:21]=[N:22][CH:23]=2)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Reactant: Nc1ccnnc1
Product: O=C(Nc1ccnnc1)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1

Procedure:
This compound was prepared following the same procedure as described in Example 11 using 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (Example 9c) (100 mg, 0.35 mmol) and 4-pyridazinamine (CAN 20744-39-2, 39.5 mg, 0.41 mmol) as starting materials; off white solid (12 mg, 9.5%). MS (ESI): 367.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:50]([C:52]([C:71]1[CH:84]=[CH:83][C:74]([O:75][CH2:76][C:77](=[O:82])[C:78]([CH3:81])([CH3:80])[CH3:79])=[C:73]([CH3:85])[CH:72]=1)([C:55]1[CH:60]=[CH:59][C:58](B2OC(C)(C)C(C)(C)O2)=[C:57]([CH3:70])[CH:56]=1)[CH2:53][CH3:54])[CH3:51].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:58]2[CH:59]=[CH:60][C:55]([C:52]([C:71]3[CH:84]=[CH:83][C:74]([O:75][CH2:76][C:77](=[O:82])[C:78]([CH3:80])([CH3:79])[CH3:81])=[C:73]([CH3:85])[CH:72]=3)([CH2:53][CH3:54])[CH2:50][CH3:51])=[CH:56][C:57]=2[CH3:70])=[CH:7][CH:6]=1
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: COC(=O)Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 96.6 %

Procedure:
(4-Bromo-phenyl)acetic acid methyl ester (Tetrahedron Letters 44 (2003) 331-334; 35 mg, 0.153 mmol), palladium acetate (2.2 mg, 0.010 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (8.2 mg, 0.020 mmol), potassium phosphate (62 mg, 0.306 mmol) and water (0.2 mL) were added to a solution of 1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-one (Example 30-(2); 50 mg, 0.102 mmol) in toluene (2 mL). After replacement with nitrogen, the mixture was stirred at 100° C. for 2.5 hours. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to give the target compound as a colorless oil (50.7 mg, 97%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:12][CH2:11][CH:10]([O:13][CH3:14])[CH2:9][CH:8]=1)(=O)=O.C(N(CC)CC)C.CN(C)C=O.[CH2:29]([O:36][C:37]1[N:38]=[N:39][C:40]([C:51]#[CH:52])=[CH:41][C:42]=1[O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1.[Cu]I.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>[CH2:29]([O:36][C:37]1[N:38]=[N:39][C:40]([C:51]#[C:52][C:7]2[CH2:12][CH2:11][CH:10]([O:13][CH3:14])[CH2:9][CH:8]=2)=[CH:41][C:42]=1[O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COC1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
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
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC1CC=C(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)CC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
A microwave reaction vial was charged with 4-methoxycyclohex-1-enyl trifluoromethanesulfonate (1069 mg, 4.11 mmol), copper(I) iodide (16.83 mg, 0.09 mmol), tetrakis(triphenylphosphine)palladium(0) (54.6 mg, 0.05 mmol), triethylamine (1432 μl, 10.27 mmol) and dry N,N-dimethylformamide (6849 μl). The reaction was evacuated and purged with nitrogen and a solution of 3,4-bis(benzyloxy)-6-ethynylpyridazine (Intermediate 5; 650 mg, 2.06 mmol) in dry tetrahydrofuran (3 ml) was added before the whole was then stirred in the microwave at 70° C. for 1 hour. Upon cooling, the resulting mixture was partitioned between ethyl acetate and water and the organic extracts were washed with water and brine, dried (MgSO4), filtered and concentrated to afford a brown oil. This was purified by chromatography on silica eluting with 0-75% ethyl acetate in petrol to give 3,4-bis(benzyloxy)-6-[(4-methoxycyclohex-1-en-1-yl)ethynyl]pyridazine (Intermediate 20) as a brown oil (860 mg, 85%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[N:3]=1.Cl[CH2:14][CH2:15][CH2:16][S:17](Cl)(=[O:19])=[O:18]>>[O:18]=[S:17]1(=[O:19])[CH2:16][CH2:15][CH2:14][N:1]1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[N:3]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COC(=O)c1ccc(N)nc1C
Product: COC(=O)c1ccc(N2CCCS2(=O)=O)nc1C

Procedure:
Using methyl 6-amino-2-methylnicotinate (170 mg) described in Preparation Example 36 and 3-chloropropane-1-sulfonyl chloride (0.25 mL) and by the reaction and treatment in the same manner as in Preparation Example 17, the title compound (220 mg) was obtained.
Reaction SMILES: COC1C=CC([C:9]2[C:13]([CH3:15])([CH3:14])[O:12][C:11](=[O:16])[C:10]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24]C3C=CC4C(=CC=CC=4)N=3)=[CH:19][CH:18]=2)=CC=1.[N:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>>[CH3:14][C:13]1([CH3:15])[O:12][C:11](=[O:16])[C:10]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:36]3[CH:37]=[CH:38][C:39]4[C:40](=[CH:13][CH:9]=[CH:10][CH:11]=4)[N:35]=3)=[CH:21][CH:22]=2)=[C:9]1[C:38]1[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=1
Reactant: OB(O)c1ccncc1
Reactant: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)OC2(C)C)cc1
Product: CC1(C)OC(=O)C(c2ccc(OCc3ccc4ccccc4n3)cc2)=C1c1ccncc1
Yield: 76 %

Procedure:
Following the procedure for the preparation of 4-(4-methoxyphenyl)-5,5-dimethyl-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (Example 33) using pyridine-4-yl boronic acid provided the title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[C:14]2[CH2:38][CH2:37][CH2:36][CH2:35][C:15]=2[S:16][C:17]=1[NH:18][C:19](=[O:34])[CH2:20][N:21]1[C:29]2[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=2[C:23]([C:30]([F:33])([F:32])[F:31])=[N:22]1)=[O:12])(C)(C)C.C(N(CC)CC)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:47][S:48]([NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[C:14]2[CH2:38][CH2:37][CH2:36][CH2:35][C:15]=2[S:16][C:17]=1[NH:18][C:19](=[O:34])[CH2:20][N:21]1[C:29]2[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=2[C:23]([C:30]([F:32])([F:33])[F:31])=[N:22]1)=[O:12])(=[O:50])=[O:49]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1c(NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)sc2c1CCCC2
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NCCNC(=O)c1c(NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)sc2c1CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
[2-({2-[2-(3-Trifluoromethyl-4,5,6,7-tetrahydroindazol-1-yl)-acetylamino]-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonyl}-amino)-ethyl]-carbamic acid tert-butyl ester was dissolved in a solution of DCM (1 mL) and TFA (1 mL) and stirred at RT for 1 h, before concentration in vacuo. The resulting colourless oil was redissolved in DCM (1 mL) and triethylamine (7.70 μL, 0.055 mmol) added, followed by methanesulfonyl chloride (2.20 μL, 0.028 mmol). The resulting mixture was stirred at RT overnight. The sample was concentrated in vacuo and the residue obtained purified by preparative reverse phase HPLC to yield the title compound as a white solid (4 mg, 0.007 mmol, 25%).