Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([CH:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH3:9])=[CH:4][C:3]=1[C:16]1[N:24]=[C:23]([CH3:25])[N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][N:20]2[CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1.[NH2:32][C:33]1[CH:34]=[C:35]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[C:36]([Cl:39])=[N:37][CH:38]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[Cl:39][C:36]1[C:35]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])=[CH:34][C:33]([NH:32][C:2]2[C:3]([C:16]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:4][C:5]([CH:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[CH3:9])=[CH:6][N:7]=2)=[CH:38][N:37]=1
Reactant: CS(=O)(=O)Nc1cc(N)cnc1Cl
Reactant: Cc1nc(-c2cc(C(C)N3CCOCC3)cnc2F)c2ncn(C3CCCCO3)c2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(-c2cc(C(C)N3CCOCC3)cnc2Nc2cnc(Cl)c(NS(C)(=O)=O)c2)c2ncn(C3CCCCO3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
To a stirred solution of 4-(1-(6-fluoro-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethyl)morpholine (0.157 g, 0.368 mmol) and N-(5-amino-2-chloropyridin-3-yl)methanesulfonamide (Example 330 step 2, 0.103 g, 0.462 mmol) in THF (2 mL) in 20 mL microwave vial, NaHMDS(Aldrich, 1 M in THF, 1.47 mL, 1.47 mmol) was added dropwise at 0° C. The dark red mixture was stirred at 0° C. for 30 min. The mixture was partitioned between a mixture of saturated aqueous sodium chloride (10 mL)/buffer (pH 5.0, citric acid/NaOH) (10 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (2×20 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (50 g, eluent: iPrOH in CHCl3 0% to 10%) to afford N-(2-chloro-5-(3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)-5-(1-morpholinoethyl)pyridin-2-ylamino)pyridin-3-yl)methanesulfonamide (0.169 g, 73% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 13.18 (s, 1H) 9.78 (d, J=1.96 Hz, 1H) 8.83 (d, J=2.54 Hz, 1H) 8.63 (d, J=2.54 Hz, 1H) 8.36 (d, J=2.35 Hz, 1H) 8.31 (s, 1H) 6.76 (br. s., 1H) 5.85-5.90 (m, 1H) 4.17-4.24 (m, 1H) 3.79-3.88 (m, 1H) 3.73 (t, J=4.50 Hz, 4H) 3.51-3.59 (m, 1H) 3.14 (s, 3H) 2.94 (s, 3H) 2.45-2.62 (m, 4H) 2.01-2.22 (m, 3H) 1.66-1.93 (m, 3H) 1.48 (d, J=6.65 Hz, 3H). m/z (ESI, positive ion): 628.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6].NC(C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)C.[CH3:54][O:55][C:56](C1C=C(C=CC=1)C(O)=O)=[O:57].C(N(CC)CC)C>CN(C)C=O>[CH3:24][O:23][C:21]1[CH:22]=[C:17]([NH:16][C:13]2[N:14]=[N:15][C:10]([CH:8]([NH:7][C:5]([C:4]3[CH:3]=[C:2]([CH:31]=[CH:30][CH:29]=3)[C:56]([O:55][CH3:54])=[O:57])=[O:6])[CH3:9])=[CH:11][N:12]=2)[CH:18]=[C:19]([O:27][CH3:28])[C:20]=1[O:25][CH3:26]
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Agent: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C(=O)NC(C)c2cnc(Nc3cc(OC)c(OC)c(OC)c3)nn2)c1

Procedure:
In a similar manner as described for Intermediate 18, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (0.17 g, 0.56 mmol), 3-(methoxycarbonyl)benzoic acid (0.18 g, 0.62 mmol), O-(7-azabenzotriazol-1-yl-N,N,N′N′-tetramethyluronium hexafluorophospahte (0.24 g, 0.62 mmol) and triethylamine (0.17 mL, 1.2 mmol) in N,N-dimethylformamide (5 mL) gave methyl 3-{[(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)amino]carbonyl}benzoate (0.26 g) as a white solid. MS m/z 468 (M+1).
Reaction SMILES: [C:1]1([CH2:17]O)[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.P(Br)(Br)[Br:20].CCOCC.O>C1C=CC=CC=1>[Br:20][CH2:17][C:1]1[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccc2ccc3cccc4ccc1c2c34
Solvent: CCOCC
Solvent: O
Solvent: c1ccccc1
Product: BrCc1ccc2ccc3cccc4ccc1c2c34
Reaction time: 2 h
Yield: 236.4 %

Procedure:
A 10.00 g sample (43.1 mmol) of 1-Pyrenemethanol was dissolved in 250 mL of benzene with slight heating. The mixture was returned to room temperature and 1.63 mL (4.24 g, 17.24 mmol) of phosphorus tribromide were slowly added. The mixture was brought to reflux and stirred for 2 h. The mixture was returned to room temperature, and poured into a separatory funnel containing 500 mL 3:2 Et2O:H2O. The organic fraction was washed twice with 100 mL H2O and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure to yield 1-(bromomethyl)pyrene (12.030 g, 95.0%) as a dark yellow powder. TLC (SiO2, 1:1 Hexane:EtOAc) Rƒ=0.95. Mp=270° C. (dec) 1H NMR (CDCl3), δ 5.28 (s, 2H), 8.0-8.3 (m, 9H from pyrene). 13C NMR (CDCl3), δ32.643, 123.258-132.374 16 pks from pyrene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[I:12])[C:5](OC)=[O:6].CC(C[AlH]CC(C)C)C>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:9]=[CH:10][C:11]=1[I:12]
Reactant: COC(=O)c1ccc(I)c(Br)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: O
Product: OCc1ccc(I)c(Br)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 81.2 %

Procedure:
A solution of methyl 3-bromo-4-iodobenzoate (Preparation 23, 4.3 g, 12.6 mmol) in CH2Cl2 was cooled, under N2, to −78° C. DIBAL-H was added slowly to the solution, which was stirred at −78° C. for 45 minutes and then allowed to come to room temperature. Next, the reaction mixture was diluted with 1M HCL (40 mL) and stirred for 30 minutes. The reaction was further diluted with water and extracted with CH2Cl2. The organic phase was dried (Na2SO4) and concentrated under vacuum to afford the intermediate (3.2 g, 82%) as a solid. 1HNMR (CDCl3): 7.85 (1H), 7.67 (1H), 7.02 (1H), 4.65 (2H), 1.76 (1H, OH).
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12](Cl)=[O:13])=[C:10]([CH3:15])[C:9]2[C:4](=[CH:5][C:6]([C:16]([F:19])([F:18])[F:17])=[CH:7][CH:8]=2)[N:3]=1.[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH2:25].CCN(C(C)C)C(C)C>O1CCOCC1.O.CC(=O)OCC>[Cl:1][C:2]1[C:11]([C:12]([NH:25][CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[C:21]([F:20])[CH:22]=2)=[O:13])=[C:10]([CH3:15])[C:9]2[C:4](=[CH:5][C:6]([C:16]([F:19])([F:18])[F:17])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1c(C(=O)Cl)c(Cl)nc2cc(C(F)(F)F)ccc12
Reactant: NCc1cccc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(C(=O)NCc2cccc(F)c2)c(Cl)nc2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
A solution of 15.6 g (50.6 mmol) 2-chloro-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid chloride in 1,4-dioxane (85 ml) was added in drops to a solution of 7.6 g (60.8 mmol) 3-fluorobenzylamine and 10.3 ml (60.8 mmol) DIPEA in 1,4-dioxane (87 ml). The RS was subsequently stirred for 60 min at RT. The solution was then diluted with water and EA. The organic phase was separated, washed with a 4N aq. NH4Cl sol. and brine, dried over MgSO4 and concentrated in a vacuum. 19.4 g (48.9 mmol, 97%) 2-chloro-N-(3-fluorobenzyl)-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid amide was obtained as a residue. The raw product was further converted without additional purification.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4](P(=O)(OC)OC)[O:3]1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][C:20]=1[N+:27]([O-:29])=[O:28].C(N(CC)CC)C>O1CCCC1>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2](=[O:1])[O:3]2)=[CH:21][C:20]=1[N+:27]([O-:29])=[O:28]
Reactant: COc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: COP(=O)(OC)C1OC(=O)c2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C=C2OC(=O)c3ccccc32)cc1[N+](=O)[O-]
Temperature: 15 °C
Reaction time: 4 h

Procedure:
A stirred solution of dimethyl 3-oxo-1,3,-dihydroisobenzofuran-1-ylphosphonate (2.42 g, 0.01 mol; prepared in a manner similar to that described in Example 23) and 4-methoxy-3-nitrobenzaldehyde (1.81 g, 0.01 mol) in tetrahydrofuran (15 ml) was cooled to 15° C. and a solution of triethylamine (1.01 g, 0.01 mol) in tetrahydrofuran (1.5 ml) was added dropwise at <25° C. The mixture was stirred at ambient temperature for 4 hours, allowed to stand at this temperature for a further 16 hours and the resulting mixture was concentrated in vacuo. The residue was triturated with water (50 ml) and stirred at ambient temperature for 2 hours before the resulting solid was collected by filtration and dried in vacuo for 24 hours to give crude 3-(4-methoxy-3-nitrobenzylidene)-3H-isobenzofuran-1-one (2.53 g) as a yellow solid, m.pt. 173–181° C., which was used directly in the next stage.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[N:10]=[N:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si:14]([O:21][C@@H:22]1[C@@:39]2([CH3:40])[C:26](=[CH:27][CH:28]=[C:29]3[C@@H:38]2[CH2:37][CH2:36][C@@:34]2([CH3:35])[C@H:30]3[CH2:31][CH2:32][C@@H:33]2[CH2:41][O:42]CCC(N(C)C)=O)[CH2:25][C@@H:24]([O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52])[CH2:23]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].O1CCCC1.CC(C)([O-])C.[K+]>[Cl-].[Na+].O>[C:1]1([N:7]2[C:8](=[O:13])[N:9]=[N:10][C:11]2=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Si:14]([O:21][C@@H:22]1[C@@:39]2([CH3:40])[C:26](=[CH:27][CH:28]=[C:29]3[C@@H:38]2[CH2:37][CH2:36][C@@:34]2([CH3:35])[C@H:30]3[CH2:31][CH2:32][C@@H:33]2[CH2:41][OH:42])[CH2:25][C@@H:24]([O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:52])[CH3:53])[CH2:23]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CN(C)C(=O)CCOC[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)(C)[O-]
Agent: O=C1N=NC(=O)N1c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](CO)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Yield: 80.1 %

Procedure:
To 1α,3β-bis(tert-butyldimethylsilyloxy)-17β-(N,N-dimethylaminocarbonylethoxymethyl)androsta-5,7-diene 4-phenyl-1,2,4-triazoline-3,5-dione adduct (9 g), were added tetrahydrofuran (90 ml) and then potassium t-butoxide (10.5 g), followed by reaction at room temperature for 10 min. After stopping the reaction by adding saturated brine, the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, evaporated under reduced pressure to remove the solvent and the thus obtained residue was purified by column chromatography (hexane:ethyl acetate=2:1) to give the titled compound (6.34 g).
Reaction SMILES: [CH3:1][N:2]1[C:15]([C:16](OCCCC)=[O:17])=[C:14]([OH:23])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:25])=[O:24].[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>C1(C)C(C)=CC=CC=1>[CH3:1][N:2]1[C:15]([C:16]([NH:31][C:30]2[CH:32]=[CH:33][C:27]([F:26])=[CH:28][CH:29]=2)=[O:17])=[C:14]([OH:23])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:25])=[O:24]
Reactant: CCCCOC(=O)C1=C(O)c2c(c3ccccc3n2C)S(=O)(=O)N1C
Reactant: Nc1ccc(F)cc1
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2ccc(F)cc2)=C(O)c2c(c3ccccc3n2C)S1(=O)=O
Yield: 68 %

Procedure:
2,5-Dihydro-2,5-dimethyl-N-(4-fluoro-phenyl)-4-hydroxy-1,2-thiazino[5,6-b]indole-3-carboxamide-1,1-dioxide was prepared analogous to Example 9 from n-butyl 2,5-dihydro-2,5-dimethyl-4-hydroxy-1,2-thiazino[5,6-b]indole-3-carboxylate-1,1-dioxide and 4-fluoro-aniline in xylene; M.p.: 271°-272° C. (decomp.); Yield: 68% of theory;
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>CN1CCCC1=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[CH2:10][CH2:11][CH:12]([C:15]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[O:17])[CH2:13][CH2:14]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)NC1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NC1CCC(C(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.1 %

Procedure:
A mixture of 4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (10.0 g, 41 mmol), EDCI (23.64 g, 123 mmol) and HOBt (18.88 g, 123 mmol) in 1-methyl-2-pyrrolidinone (150 mL) was stirred at RT for 3 hours. Morpholine (10.75 mL, 123 mmol) was then added, and the resulting mixture was stirred at RT for 78 hours. The reaction was quenched by adding water and the resulting mixture was extracted with EtOAc. The organic layer was separated and washed twice with K2CO3 (sat'd aq) and an HCl (aq, 10%), again with once with a saturated K2CO3 (sat'd aq) and with brine. The organic layer was then dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was triturated with Et2O and filtered to give 5.9 g of [4-(morpholine-4-carbonyl)-cyclohexyl]-carbamic acid tert-butyl ester as a white powder.
Reaction SMILES: Br[CH2:2][C:3]1[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]2[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=2[CH:4]=1.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[CH:29]1[CH2:30][CH2:31][N:32]([CH2:2][C:3]2[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]3[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=3[CH:4]=2)[CH2:33][CH2:34]1
Reactant: COc1ccc(C2CCNCC2)c(OC)c1
Reactant: CC(C)(C)Cn1c(CBr)cc2cnc(C#N)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1ccc(C2CCN(Cc3cc4cnc(C#N)nc4n3CC(C)(C)C)CC2)c(OC)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
6-Bromomethyl-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (2.2 g) and 4-(2,4-Dimethoxy-phenyl)-piperidine (2.0 g) are dissolved in Acetone (30 ml) and potassium carbonate (3.6 g) is added to the solution. The reaction mixture is stirred for 6 h at room temperature. The mixture is diluted with ethyl acetate, washed with brine, dried over magnesium sulfate and filtrated. Ethyl acetate is evaporated and the residue is purified by column chromatography on silica gel using n-hexane:AcOEt=1:1 (v/v).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:43])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH3:2].[F:44][C:45]1[CH:46]=[C:47](B(O)O)[CH:48]=[CH:49][CH:50]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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]>[CH2:1]([O:3][C:4](=[O:43])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:49]3[CH:48]=[CH:47][CH:46]=[C:45]([F:44])[CH:50]=3)[CH:25]=[C:26]([O:28][CH2:29][CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:27]=2)[C:10]=1[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH3:2]
Reactant: OB(O)c1cccc(F)c1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(OCC3CCCC3)c2)c1CCC(=O)OCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OCC3CCCC3)cc(-c3cccc(F)c3)c2)c1CCC(=O)OCC
Yield: 73.2 %

Procedure:
A similar procedure as described in Example 43, step 4 was used, starting from 4-[3-[6-(3-bromo-5-cyclopentylmethoxy-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (152 mg, 0.23 mmol), 3-fluorophenylboronic acid (65 mg, 0.46 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (73 mg, 0.1 mmol), and cesium carbonate (150 mg, 0.46 mmol) to obtain 4-[3-[6-(5-cyclopentylmethoxy-3′-fluoro-biphenyl-3-yloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (114 mg, 74%) as a colorless viscous oil: ES(+)-HRMS m/e calcd for C41H53FO7 (M+H)+ 677.3848. found 677.3850.
Reaction SMILES: Cl.[Si]([O:9][C@@H:10]([CH2:20][C@H:21]([O:61][Si](C(C)(C)C)(C)C)/[CH:22]=[CH:23]\[C@H:24]([CH3:60])[C@H:25]([O:52][Si](C(C)(C)C)(C)C)[C@@H:26]([CH3:51])[CH2:27][C@@H:28]([CH3:50])[CH2:29][CH2:30][C@@H:31]([O:42][Si](C(C)(C)C)(C)C)[C@H:32]([CH3:41])[C@@H:33]([OH:40])[C@@H:34]([CH3:39])/[CH:35]=[CH:36]\[CH:37]=[CH2:38])[C@H:11]([CH3:19])/[CH:12]=[CH:13]/[CH:14]=C\C(O)=O)(C(C)(C)C)(C)C.C[CH2:70][O:71][C:72]([CH3:74])=[O:73]>C1COCC1.O>[CH3:70][O:71][C:72](=[O:73])/[CH:74]=[CH:14]\[CH:13]=[CH:12]\[C@@H:11]([CH3:19])[C@@H:10]([OH:9])[CH2:20][C@H:21]([OH:61])/[CH:22]=[CH:23]\[C@H:24]([CH3:60])[C@H:25]([OH:52])[C@@H:26]([CH3:51])[CH2:27][C@@H:28]([CH3:50])[CH2:29][CH2:30][C@@H:31]([OH:42])[C@H:32]([CH3:41])[C@@H:33]([OH:40])[C@@H:34]([CH3:39])/[CH:35]=[CH:36]\[CH:37]=[CH2:38]
Reactant: C=C/C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](CC[C@H](C)C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](C)/C=C/C=C\C(=O)O)O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C=C/C=C\[C@H](C)[C@H](O)[C@@H](C)[C@H](O)CC[C@H](C)C[C@H](C)[C@@H](O)[C@@H](C)/C=C\[C@@H](O)C[C@H](O)[C@H](C)/C=C/C=C\C(=O)OC
Reaction time: 24 h
Yield: 36 %

Procedure:
3N HCl (10 mL, prepared by adding 2.5 mL of conc. HCl to 7.5 mL MeOH) was added to a stirred solution of the macrolactonization precursor 48 (23 mg, 23 μmol) in THF (3 mL) at 0° C. After 24 h at room temperature, the reaction mixture was diluted with EtOAc (4 mL) and H2O (4 mL). The organic phase was retained and aqueous phase was extracted with EtOAc (2×4 mL). The combined organic phase was washed with saturated aqueous NaHCO3 (10 mL), dried with MgSO4, filtered and concentrated. The residue was purified by flash chromatography (EtOAc/hexane 3:2) to yield the product 50 (4.5 mg, 36%) as a colorless oil: IR (CHCl3) 3399, 2917, 2849, 1713, 1635, 1600, 1461, 1439, 1197, 1178, 970, 757 cm−1; 1H NMR (600 MHz, CD3OD) δ 7.36 (dd, J=15.3, 11.2 Hz, 1H), 6.67 (ddd, J=16.9, 11.1, 10.6 Hz, 1H), 6.63 (dd, J=11.3, 11.3 Hz, 1H), 6.14 (dd, J=15.4, 8.3 Hz, 1H), 6.03 (dd, J=11.0, 1.0 Hz, 1H), 5.59 (d, J=11.4 Hz, 1H), 5.43 (dd, J=10.7, 10.7 Hz, 1H), 5.42 (dd, J=10.8, 9.2 Hz, 1H), 5.32 (dd, J=10.4, 10.4 Hz, 1H), 5.17 (dd, J=16.8, 2.0 Hz, 1H), 5.08 (d, J=10.2 Hz, 1H), 4.61 (ddd, J=12.9, 8.5, 4.6 Hz, 1H), 3.80 (ddd, J=8.9, 4.4, 4.4 Hz, 1H), 3.69 (s, 3H), 3.63 (m, 1H), 3.46 (t, J=5.8 Hz, 1H), 3.13 (dd, J=8.0, 3.2 Hz, 1H), 2.93 (m, 1H), 2.71 (m, 1H), 2.38 (m, 1H), 1.73 (m, 1H), 1.56-1.53 (m, 3H), 1.52-1.46 (m, 2H), 1.44-1.36 (m, 3H), 1.09 (d, J=6.9 Hz, 3H), 0.98 (d, J=6.8 Hz, 3H), 0.96 (d, J=6.6 Hz, 3H), 0.95 (m, 2H), 0.94 (d, J=6.9 Hz, 3H), 0.87 (d, J=6.6 Hz, 3H), 0.86 (d, J=6.8 Hz, 3H); 13C NMR (150 MHz, CD3OD) δ 168.4, 148.5, 146.9, 135.7, 135.4, 133.85, 133.82, 130.6, 128.2, 117.7, 116.2, 79.2, 78.5, 74.8, 72.4, 65.8, 51.5, 45.1, 43.2, 43.0, 41.0, 37.2, 36.5, 34.0, 33.3, 33.1, 31.0, 20.7, 18.6, 18.4, 16.7, 13.8, 7.8; LRMS (ESI) 587.5 [M+Na]+, 559.2, 485.2, 413.3, 355.1, 212.1; HRMS (ESI) calcd for C33H56O7Na 587.3924 [M+Na]+, found 587.3953; [α]20D+8.7 (c 0.30, CDCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22]([C:24]3[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=3)=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:31]([F:34])([F:33])[F:32]>Cl.O1CCOCC1.O.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22]([C:24]3[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=3)=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:31]([F:34])([F:32])[F:33]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1ccc(C)nc1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(C(=O)c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)cn1
Temperature: 25 °C
Yield: 33.1 %

Procedure:
A mixture of 4-Chloro-N-[5-chloro-2-(6-methyl-pyridine-3-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (30 mg) in 3 mL of 4M HCl in dioxane and 1 mL of water was refluxed for 3 hours. After cooling to rt the mixture was diluted with water and sodium bicarbonate was added until pH was 9. The mixture was extracted with ethyl acetate, dried and concentrated. The residue was further purified via flash column (70% ethyl acetate in hexane) to afford 9.1 mg of title compound as an off white solid. 1H NMR: (400 MHz, CDCl3) δ 8.97 (m, 1 H), 8.35 (m, 1 H), 8.16-8.13 (m, 2 H), 8.08-8.05 (m, 1 H), 7.93-7.91 (m, 1 H), 7.59-7.57 (m, 1 H), 7.25-7.23 (1 H), 2.63 (s, 3 H). MS: (M+H)/z=490.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[NH2:21][C:22]1[C:23](=[O:35])[N:24]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH:25]=[CH:26][CH:27]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CC#N.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([NH:21][C:22]3[C:23](=[O:35])[N:24]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH:25]=[CH:26][CH:27]=3)=[O:18])=[CH:19][CH:20]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1
Reactant: Nc1cccn(-c2ccc(F)cc2)c1=O
Reactant: O=C(O)c1ccc(Nc2cc(Cl)nn3ccnc23)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C(Nc1cccn(-c2ccc(F)cc2)c1=O)c1ccc(Nc2cc(Cl)nn3ccnc23)cc1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
To a 2 dram vial was added 4-(6-chloroimidazo[1,2-b]pyridazin-8-ylamino)benzoic acid (0.050 g, 0.17 mmol, prepared as described in Example XIV, step 1b), 3-amino-1-(4-fluorophenyl)pyridin-2(1H)-one (0.053 g, 0.26) from 1a-1 and 1a-2 described below, EDCI (0.050 g, 0.26 mmol), HOBt (0.035 g, 0.26 mmol), TEA (0.07 ml, 0.51 mmol), DMF (0.8 ml) and CH3CN (0.8 ml). the reaction was allowed to stir at 50° C. for 12 hrs. Upon cooling, the solvent was removed in vacuo and diluted with methanol (2 ml). The solution was purified by HPLC (20-100% methanol gradient), which yielded 0.0.12 g of 4-(6-chloroimidazo[1,2-b]pyridazin-8-ylamino)-N-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridin-3-yl)benzamide.