Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:33]=[CH:32][C:21]([CH2:22][NH:23][C:24](=[O:31])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)[C:11]3=[N:12][CH:13]=[C:14](Br)[CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=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>[NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:33]=[CH:32][C:21]([CH2:22][NH:23][C:24](=[O:31])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)[C:11]3=[N:12][CH:13]=[C:14]([C:39]4[CH:40]=[CH:41][C:36]([CH2:35][OH:34])=[CH:37][CH:38]=4)[CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ncccc1-c1nc2cc(Br)cnc2n1-c1ccc(CNC(=O)c2ccccc2)cc1
Reactant: OCc1ccc(B(O)O)cc1
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: Nc1ncccc1-c1nc2cc(-c3ccc(CO)cc3)cnc2n1-c1ccc(CNC(=O)c2ccccc2)cc1
Temperature: 150 °C

Procedure:
N-(4-(2-(2-aminopyridin-3-yl)-6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)benzamide (62.4 mg, 0.125 mmol), CsCO3 (40.6 mg, 0.125 mmol), Pd(PPh3)4 (14.4 mg, 0.013 mmol) and 4-(hydroxymethyl)phenylboronic acid (33.5 mg, 0.25 mmol) were dissolved in DMF (3 mL). The reaction mixture was heated to 150° C. for 15 min and after cooling to room temperature filtered through a Bakerbond filtration column. The reaction mixture was directly purified by reversed phase HPLC to give the desired product as the mono-TFA salt (21 mg, 25% yield). Mp. 171-174° C.; 400 M Hz 1H NMR (DMSO-d6) δ: 9.15 (t, J=6 Hz, 1H), 8.68-8.64 (m, 1H), 8.5-8.47 (m, 1H), 8.08-8.03 (m, 1H), 7.96-7.9 (m, 3H), 7.77-7.72 (m, 3H), 7.6-7.42 (m, 8H), 4.63-4.53 (m, 4H); LCMS [M+H]: 527.
Reaction SMILES: Cl.Br[C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:14][CH:13]=3)=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1.[CH3:28][O:29][C:30]1[CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:34][C:35]=1[O:36]CC1C=CC(OC)=CC=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+]>Cl[Pd-2](Cl)(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.ClCCl.C(#N)C>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([C:3]2[CH:4]=[C:5]3[C:11]([C:12]4[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)=[CH:14][CH:13]=4)=[CH:10][NH:9][C:6]3=[N:7][CH:8]=2)[CH:33]=[CH:34][C:35]=1[OH:36]
Reactant: Brc1cnc2[nH]cc(-c3ccc(OCCCN4CCCCC4)cc3)c2c1
Reactant: COc1ccc(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2OC)cc1
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Solvent: CC#N
Solvent: ClCCl
Product: COc1cc(-c2cnc3[nH]cc(-c4ccc(OCCCN5CCCCC5)cc4)c3c2)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.3 %

Procedure:
100 mg (0.24 mmol) of 5-bromo-3-[4-(3-piperidin-1-yl-propoxy)-phenyl]-1H-pyrrolo[2,3-b]pyridine hydrochloride, 120 mg (0.33 mmol) of 2-[3-Methoxy-4-(4-methoxy-benzyloxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 10 mg (5 mol %) of dichlorobis(triphenylphosphino)palladium(II) were placed in a vial and 1.5 ml of acetonitrile and 1.5 ml of a 2 M aqueous solution of sodium carbonate were added. The mixture was irradiated in a Personal Chemistry® microwave reactor to 165° C. for 1200 sec. The resulting mixture was distributed between dichloromethane and a saturated aqueous solution of sodium bicarbonate. The aqueous layer was extracted three times with dichloromethane and the combined organic phases were dried over sodium sulfate and evaporated. The crude product was purified by flash chromatography on amine functionalized silica gel (ISCO RediSep® amine column) using a gradient of ethyl acetate in hexanes. The resulting intermediate was dissolved in 30 ml of dichloromethane and 750 mg (1.06 mmol) of PS-thiophenol (Argonaut Technologies) was added. To this was added 1.5 ml of trifluoroacetic acid and the mixture was stirred at room temperature for 2 hours. The resin was filtered off and washed with dichloromethane. The filtrate was washed with a saturated aqueous solution of sodium bicarbonate, dried over sodium sulfate and evaporated. The residue was triturated with 20 ml of dichloromethane and dried by suction to afford 9 mg (20 μmol, 8% yield) of 2-methoxy-4-{3-[4-(3-piperidin-1-yl-propoxy)-phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-phenol as a beige powder. 1H-NMR (d6-DMSO) δ: 11.83 [1H] d, 9.06 [1H] s, 8.50 [1H] d, 8.28 [1H] d, 7.76 [1H], 7.67 [2H] d(m), 7.25 [1H] d, 7.12 [1H] dd, 7.01 [2H] d(m), 6.88 [1H] d, 4.02 [2H] t, 3.87 [3H] s, 2.39 [2H] t, 2.34 [4H] (m), br, 1.88 [2H] t, 1.50 [4H] qui, 1.38 [2H] (m). MS, m/z: 458 [MH+].
Reaction SMILES: [C:1]([NH:9][C:10]1[S:11][CH2:12][CH:13]2[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:16][C:14]2([C:29]2[S:33][C:32]([Si](C)(C)C)=[N:31][CH:30]=2)[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[C:1]([NH:9][C:10]1[S:11][CH2:12][CH:13]2[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:20])[CH2:16][C:14]2([C:29]2[S:33][CH:32]=[N:31][CH:30]=2)[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)c1ncc(C23CN(C(=O)OCc4ccccc4)CC2CSC(NC(=O)c2ccccc2)=N3)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC1=NC2(c3cncs3)CN(C(=O)OCc3ccccc3)CC2CS1)c1ccccc1
Reaction time: 1 h
Yield: 87.7 %

Procedure:
To a solution of racemic benzyl 2-benzamido-7a-(2-trimethylsilylthiazol-5-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazine-6-carboxylate (117 mg, 212 μmoles) in tetrahydrofuran (4 mL) is added 1 N tetrabutylammonium fluoride (1 N in tetrahydrofuran) (425 μL, 425 μmoles) and the mixture is stirred under nitrogen for one hour. The solution is diluted with water, extracted with ethyl acetate (3×), dried over sodium sulfate and concentrated. The crude product is purified over silica gel eluting with ethyl acetate/hexanes (5% to 100%) to give the title compound (89 mg, 88%). ES/MS (m/e): 479 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH:11]2[O:12][CH:10]2[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]#[N:14])[CH:8]=2)[O:3]1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20](=[O:23])[N:19]([CH3:24])[N:18]=1.[H-].[Na+]>CS(C)=O>[CH3:1][C:2]1([CH3:15])[CH:11]([OH:12])[CH:10]([NH:16][C:17]2[CH:22]=[CH:21][C:20](=[O:23])[N:19]([CH3:24])[N:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]#[N:14])[CH:8]=2)[O:3]1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: Cn1nc(N)ccc1=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cn1nc(NC2c3cc(C#N)ccc3OC(C)(C)C2O)ccc1=O
Reaction time: 4 h

Procedure:
2.0 g of 2,2-dimethyl-3,4-epoxy-6-cyanochroman ("IIa") are added to a mixture of 1.2 g of 3-amino-1-methyl-1,6-dihydropyridazin-6-one and 0.3 g of NaH (80% strength) in 50 ml of dimethyl sulfoxide (DMSO) at 25°, and the mixture is stirred for 4 hours. Customary working-up and purification by column chromatography (ethyl acetate/methanol) give 2,2-dimethyl-4-(1-methyl-1,6-dihydro-6-oxo-3-pyridazinyl-amino)-6-cyano-3chromanol, m.p. 117°-119°.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH:16]([C:18]2[C:19]([CH3:34])=[N:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)[CH3:17])=[CH:11][C:10]=1[CH3:35])(C)(C)C.[OH-].[Na+]>C1COCC1.CCO>[CH3:35][C:10]1[CH:11]=[C:12]([S:15][CH:16]([C:18]2[C:19]([CH3:34])=[N:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)[CH3:17])[CH:13]=[CH:14][C:9]=1[O:8][CH2:7][C:6]([OH:36])=[O:5]
Reactant: Cc1cc(SC(C)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OCC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(SC(C)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OCC(=O)O
Reaction time: 2 h

Procedure:
0.322 g (0.62 mmol) of the above prepared (2-methyl-4-{1-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethylsulfanyl}-phenoxy)-acetic acid tert-butyl ester, containing some methyl ester, was dissolved in 3.8 ml of THF/EtOH=1/1, treated with 1.87 ml (3 eq.) of 1N NaOH, and kept at ambient temperature for 2 h. The reaction mixture was then poured onto crashed ice/HCl dil., extracted twice with AcOEt, washed with water, dried over sodium sulfate, and evaporated to dryness to leave, after crystallization from AcOEt/hexane, 0.276 g of the title compound as off-white solid of mp. 115–117° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH2:7])=[N:4][N:3]=1.[CH2:8]([NH2:16])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.OP([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:7][C:5]1[S:6][C:2]([NH:16][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:3][N:4]=1
Reactant: Nc1nnc(Br)s1
Reactant: NCCc1ccccc1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nnc(NCCc2ccccc2)s1
Temperature: 100 °C

Procedure:
A mixture of 5-bromo-1,3,4-thiadiazol-2-ylamine (360 mg), phenethylamine (0.38 ml), and K2HPO4 (522 mg) in 2 ml of DMF is heated under nitrogen at 100° C. for two hours, then partitioned between water and ethyl acetate. The organic phase is washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. Flash chromatography of the residue on silica using 4-5% methanol in dichloromethane provides 261 mg of the title compound. Recrystallization of 238 mg of this from 10 ml of 1:1 acetonitrile toluene affords 205 mg of crystals.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:16])=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([C:12]([O:14]C)=[O:13])[CH2:6]2)#[N:2].[OH-].[Na+]>CO>[C:1]([C:3]1[C:4]([CH3:16])=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([C:12]([OH:14])=[O:13])[CH2:6]2)#[N:2]
Reactant: COC(=O)C1Cc2ccc(C#N)c(C)c2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C#N)ccc2c1CC(C(=O)O)C2
Reaction time: 8 h
Yield: 86.7 %

Procedure:
To a solution of methyl 5-cyano-4-methylindane-2-carboxylate (121 mg, 0.562 mmol) in methanol (2 mL), 1.0 N NaOH (1.69 mL, 1.69 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was acidified, extracted with EtOAc and the organic layer was washed with H2O, brine, dried (MgSO4), filtered and concentrated in vacuo to afford 98 mg of the title compound: 1H NMR (CDCl3) δ 2.48 (s, 3H), 3.26-3.48 (m, 5H), 7.16 (d, 1H, J=7.7 Hz), 7.47 (d, 1H, J=7.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:26])=[N:4][O:5][C:6]=1[N:7]([CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][CH:12]=1)(=[O:10])=[O:9].[Li]C(C)(C)C.[CH:32]1[C:37]([CH:38]=[O:39])=[CH:36][C:35]2[O:40][CH2:41][O:42][C:34]=2[CH:33]=1>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:26])=[N:4][O:5][C:6]=1[N:7]([CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH:38]([OH:39])[C:37]1[CH:32]=[CH:33][C:34]2[O:42][CH2:41][O:40][C:35]=2[CH:36]=1)(=[O:9])=[O:10]
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1csc2ncccc12
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(C(O)c2ccc3c(c2)OCO3)sc2ncccc12
Reaction time: 1 h
Yield: 43.3 %

Procedure:
To a solution of N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)thieno [2,3-b]pyridine-3-sulfonamide (0.25 g, 0.61 mmoles) in THF (10 ml) at −78° C. was added t-BuLi (1.7 M, 0.46 ml, 0.79 mmoles). Thirty minutes later piperonal (0.14 g, 0.91 mmoles) in THF (2 ml) was added via cannula, as a solution. The cooling bath was removed and the reaction was stirred 1 hr. at ambient temperature and then diluted with EtOAc (50 ml) and washed with H2O (2×75 ml). The organic layer was dried (MgSO4), filtered and concentrated. Flash chromatography (40% EtOAc/hexanes) provided 0.15 g (44%) of the title compound as a white foamy solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]=2)[CH2:2]1.Cl[C:16]1[N:17]=[C:18]2[C:23]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[N:22][CH:21]=[C:20]([C:30]3[CH:31]=[CH:32][C:33]([N:36]4[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]4)=[N:34][CH:35]=3)[N:19]2[CH:49]=1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>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:27]1[CH2:28][CH2:29][N:24]([C:23]2[C:18]3[N:19]([CH:49]=[C:16]([N:1]4[CH2:2][CH:3]([C:5]5[CH:14]=[CH:13][C:12]6[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=6)[N:6]=5)[CH2:4]4)[N:17]=3)[C:20]([C:30]3[CH:31]=[CH:32][C:33]([N:36]4[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:46])[CH3:47])=[O:43])[CH2:38][CH2:37]4)=[N:34][CH:35]=3)=[CH:21][N:22]=2)[CH2:25][CH2:26]1
Reactant: c1ccc2nc(C3CNC3)ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(N4CCOCC4)c4nc(Cl)cn34)cn2)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(N4CCOCC4)c4nc(N5CC(c6ccc7ccccc7n6)C5)cn34)cn2)CC1
Temperature: 120 °C

Procedure:
A microwave vial was charged with compound 24d (154 mg, 0.840 mmol), compound 24c (350 mg, 0.700 mmol), sodium tert-butoxide (94.1 mg, 0.980 mmol), Pd2(dba)3 (12.8 mg, 0.0140 mmol), and 2-(dicyclohexylphosphino)-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (26.6 mg, 0.0560 mmol) and purged with Argon gas. Toluene (3 mL) was then added and the resulting mixture was heated in a microwave at 120° C. for 1 h. The reaction mixture was allowed to cool to rt, diluted with water (20 mL) and EtOAc (20 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated. The residue obtained was purified by flash column chromatography on silica gel (1:0-1:4 heptane/EtOAc) to obtain compound 24e. Mass Spectrum (LCMS, ESI pos.) Calcd. for C36H41N9O3: 648.3 (M+H). Found 648.4.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[N:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]([O:27]CC)=O)=[O:22])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:32][NH2:33]>O1CCCC1.ClCCl.CO>[F:31][C:2]([F:30])([F:1])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[N:13][C:12]([N:15]3[CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:24][C:25]([NH:33][CH3:32])=[O:27])=[O:22])[CH2:19][CH2:20]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)COC(=O)N1CCN(c2ccc(-c3cccc(C(F)(F)F)c3)nn2)CC1
Reactant: CN
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CNC(=O)COC(=O)N1CCN(c2ccc(-c3cccc(C(F)(F)F)c3)nn2)CC1

Procedure:
The procedure described in Example 1 (step 1.4.) is used. Starting with 0.66 g (1.51 mmol) of 2-(ethyloxy)-2-oxo-ethyl 4-{6-[3-(trifluoromethyl)phenyl]-3-pyridazinyl}-1-piperazinecarboxylate, obtained in step 10.2., and 3 ml (6.02 mmol) of a solution of methylamine (2M) in tetrahydrofuran, and after chromatography on silica gel, eluting with a 96/4 mixture of dichloromethane and methanol, followed by washing with diisopropyl ether, 0.50 g of product is obtained in the form of a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])/[C:6](=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)/[CH2:5]2.[CH3:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:12][O:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5]/[C:6](=[CH:14]\[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)/[C:7]2=[O:13])=[CH:3][C:2]=1[N:29]1[CH2:30][CH2:31][CH:26]([CH3:25])[CH2:27][CH2:28]1
Reactant: CC1CCNCC1
Reactant: COc1cc2c(cc1Br)C/C(=C\c1cccc(C(F)(F)F)c1)C2=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1N1CCC(C)CC1)C/C(=C\c1cccc(C(F)(F)F)c1)C2=O
Temperature: 110 °C

Procedure:
To a solution of 152 (120 mg, 0.3007 mmol) and 4-methylpiperidine 129 (60.2 mg, 0.6015 mmol) in toluene was added cesium carbonate (197.2 mg, 0.6015 mmol). The reaction was degassed and purged with nitrogen for 10 min. Pd2(dba)3 (13.7 mg, 0.0150 mmol) and BINAP (28.1 mg, 0.0451 mmol) was added and again degassed and purged with nitrogen for another 10 min. The reaction was heated to 110° C. overnight under sealed conditions. The reaction was diluted with chloroform and filtered through celite bed. The organic layer was concentrated to get the crude compound 153 which was purified through flash chromatography by using 100-200 mesh silica gel eluting the compound (E)-6-methoxy-5-(4-methylpiperidin-1-yl)-2-(3-(trifluoromethyl)benzylidene)-2,3-dihydro-1H-inden-1-one 153 at 25% ethyl acetate in hexane as pale yellow coloured solid.
Reaction SMILES: [H-].[Na+].CCCCCC.[F:9][C:10]([F:18])=[CH:11][CH:12]1[CH2:16][NH:15][C:14](=[O:17])[CH2:13]1.Br[CH2:20][C:21]1[N:25]2[N:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:24]2=[N:23][C:22]=1[C:31]([F:34])([F:33])[F:32]>C1COCC1.O>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]2[N:25]([C:21]([CH2:20][N:15]3[CH2:16][CH:12]([CH:11]=[C:10]([F:18])[F:9])[CH2:13][C:14]3=[O:17])=[C:22]([C:31]([F:34])([F:33])[F:32])[N:23]=2)[N:26]=1
Reactant: O=C1CC(C=C(F)F)CN1
Reactant: FC(F)(F)c1nc2ccc(Cl)nn2c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1CC(C=C(F)F)CN1Cc1c(C(F)(F)F)nc2ccc(Cl)nn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
Sodium hydride (60% wt mineral oil dispersion, 0.82 g, 1.3 eq, 20.5 mmol) is washed three times by hexane (15 ml). THF (15 ml) is added at room temperature to this clean sodium hydride, a solution of 4-(2,2-difluorovinyl)pyrrolidin-2-one x98 (3.42 g, 23 mmol, 1.4 eq) and 3-(bromomethyl)-6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazine x36 (4.97 mg, 15.8 mmol, 1 eq) in THF (15 ml). After 3 hours of stirring at room temperature, a small amount of sodium hydride is added in order to complete the reaction and stirring is pursue overnight. Water (25 ml) is then added to the mixture and THF is removed evaporation under reduced pressure. The aqueous layer is extracted by ethyl acetate (2×50 ml), the resulting organic layer is dried over MgSO4, filtered and concentrated to dryness. The residue is purified by preparative chromatography (benzine/AcOEt:50/50) to afford 4.33 g of {[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluoro-vinyl)-pyrrolidin-2-one 33.
Reaction SMILES: Br[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[C:11]#[N:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[S:20]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21]1.C(=O)([O-])[O-].[K+].[K+]>[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.C1COCC1.CCO.O>[OH:19][C:16]1[CH:17]=[CH:18][C:13]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([C:11]#[N:12])=[C:2]2[C:22]2[CH:23]=[CH:24][S:20][CH:21]=2)=[CH:14][CH:15]=1
Reactant: OB(O)c1ccsc1
Reactant: N#Cc1c(Br)n(-c2ccc(O)cc2)c2ccccc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(-c2ccsc2)n(-c2ccc(O)cc2)c2ccccc12
Temperature: 100 °C
Reaction time: 48 h

Procedure:
To 2-bromo-1-(4-hydroxy-phenyl)-1H-indole-3-carbonitrile (Example 1) was added 2 eq 3-thiopheneboronic acid, 2.1 eq potassium carbonate and 10 mol % tetrakis(triphenylphosphine) palladium. THF:EtOH:H2O (4:1:0.5) was added and the vial was flushed with nitrogen, sealed and stirred at 100° C. for 48 hours. The reaction mixture was cooled to rt, diluted with H2O, extracted with EtOAc and filtered through silica. The organic phase was evaporated to dryness and the crude product was subjected to reversed phase preparative HPLC. Appropriate fractions were combined, evaporated, and identified by 1H-NMR and LC/MS. Purity was determined by analytical HPLC. ES/MS m/z: 317.9 (M+H), 314.8 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.73 (m, 1H), 7.62 (dd, 1H, J=1.3, 2.9 Hz), 7.54 (dd, 1H, J=2.9, 5.0 Hz), 7.37-7.30 (m, 2H), 7.26 (m, 2H), 7.18 (m, 1H), 7.15 (dd, 1H, J=1.3, 5.0 Hz) and 7.03 (m, 2H).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:36])[CH:21]([O:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:54])[C@@H:15]2[CH2:37][CH2:38][C@H:39]2[O:44][C:43](=[O:45])[CH2:42][C@H:41]([O:46][Si](C(C)(C)C)(C)C)[CH2:40]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:36])[CH:21]([O:28][C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:54])[C@@H:15]2[CH2:37][CH2:38][C@H:39]2[O:44][C:43](=[O:45])[CH2:42][C@H:41]([OH:46])[CH2:40]2)=[CH:10]1
Reactant: Cc1ccc(OC(C(=O)O[C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)C=C3C=C[C@H](C)[C@H](CC[C@@H]4C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O4)[C@H]32)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(OC(C(=O)O[C@H]2C[C@H](O)C=C3C=C[C@H](C)[C@H](CC[C@@H]4C[C@@H](O)CC(=O)O4)[C@H]32)c2ccccc2)cc1
Yield: 74.3 %

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 0.42 g of (4R,6R)-6-([1S,2S,6S,8S,8aR]-2-{1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-[(2RS)-2-(4-methylphenoxy)-2-phenylacetoxy]-2-methyl-1-naphthyl}ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 142, above] and 8.1 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 220 mg of the title compound as a white powder, melting at between 130° and 133° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][C:13]1[O:17][C:16]([CH2:18][CH2:19][OH:20])=[CH:15][CH:14]=1>N1C=CC=CC=1>[CH3:12][C:13]1[O:17][C:16]([CH2:18][CH2:19][OH:20])=[CH:15][CH:14]=1.[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:10])(=[O:17])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cc1ccc(CCO)o1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 152.9 %

Procedure:
4-Methylbenzenesulfonyl chloride (907 mg, 4.76 mmol) was added to a solution of compound 21A (500 mg, 3.96 mmol) in 6 mL of dry pyridine. The reaction was stirred at room temperature for 4 h and then quenched with ice. The reaction mixture was extracted with CH2Cl2 and the combined organic layers were washed with saturated aqueous sodium bicarbonate and water, dried and concentrated under reduced pressure to give 900 mg (81%) of compound 24A as a yellow oil.