Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:32]([CH3:33])=[CH:31][C:13]2[N:14]=[C:15]([N:17]3[CH2:22][CH2:21][O:20][C:19]([C:24]4[CH:29]=[CH:28][C:27](Cl)=[CH:26][CH:25]=4)([CH3:23])[CH2:18]3)[S:16][C:12]=2[C:11]=1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:41]C1C=CC(C2(C)OCCNC2)=CC=1>>[C:1]([O:5][C@@H:6]([C:10]1[C:32]([CH3:33])=[CH:31][C:13]2[N:14]=[C:15]([N:17]3[CH2:22][CH2:21][O:20][C:19]([CH3:23])([C:24]4[CH:29]=[CH:28][C:27]([CH3:41])=[CH:26][CH:25]=4)[CH2:18]3)[S:16][C:12]=2[C:11]=1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc2nc(N3CCOC(C)(c4ccc(Cl)cc4)C3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: Cc1ccc(C2(C)CNCCO2)cc1
Product: Cc1ccc(C2(C)CN(c3nc4cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(-c5ccc(Cl)cc5)c4s3)CCO2)cc1

Procedure:
(2S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-methyl-2-p-tolylmorpholino)benzo[d]thiazol-6-yl)acetic acid was prepared using the similar procedure as (2S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-(4-chlorophenyl)-2-methylmorpholino)-5-methylbenzo[d]thiazol-6-yl)acetic acid except 2-(4-methylphenyl)-2-methylmorpholine was used instead of 2-(4-chlorophenyl)-2-methylmorpholine. LCMS-ESI+: calc'd for C32H35ClN2O4S: 579.2, 581.2 (M+H+); found: 579.4, 581.3 (M+H+). 1H-NMR: 400 MHz, (CD3OD) δ: 7.62 (m, 1H), 7.47-7.54 (m, 3H), 7.32 (m, 3H), 7.14 (m, 2H), 5.14 (s, 1H), 4.31 (t, J=12.8 Hz, 1H), 3.80 (m, 1H), 3.64 (m, 1H), 3.40-3.51 (m, 3H), 2.50 (s, 3H), 2.28 (s, 3H), 1.44 (s, 3H), 0.95 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5](OC)=[CH:4][C:3]=1[N+]([O-])=O.C([O-])([O-])=O.[K+].[K+].[CH3:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(OCC)(=O)C>O1CCOCC1.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>[C:2]1([C:21]2[CH:20]=[CH:19][CH:24]=[CH:23][CH:22]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCC
Reactant: COc1ccc(Cl)c([N+](=O)[O-])c1
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: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: c1ccc(-c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
4,4,5,5-Tetramethyl-2-[4-(2-methylisoindolin-1-one)-yl]-[1,3,2]-dioxoborolane (0.97 g, 3.6 mmol) and 4-chloro-3-nitroanisole (0.67 g, 3.6 mmol) were dissolved in a mixture of dioxane (10 mL) and water (2 mL). K2CO3 (0.98 g, 7.2 mmol) and Pd(PPh3)4 (0.21 g, 0.2 mmol) were added. The reaction mixture was heated in a flow of argon to 80° C., kept at this temperature over a period of 24 h (TLC monitoring: hexane/ethyl acetate, 4:1), cooled, and filtered through Celite. The filtrate was evaporated. The residue was dissolved in CH2Cl2. An undissolved precipitate was filtered off. The filtrate was partially evaporated, and the product was purified in a short silica gel column (hexane/ethyl acetate) to give 0.76 g of a product containing PPh3O. The product was cyclized without additional purification.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26].O>CN(C=O)C>[C:1]1([O:11][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: Oc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cnccc1Oc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 50 ml of DMF was added 1-naphthol (11.25 g) and to this solution was added K2CO3 (20 g) portionwise. After stirring for 10 minutes at room temperature, 4-chloro-3-nitropyridine (11.2 g) in 60 ml of DMF was added dropwise. The reaction mixture was stirred for 4 hours at room temperature. The mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried (sat. NaCl, anhy. MgSO4).
Reaction SMILES: [NH2:1][C:2](=[N:15][OH:16])[C:3]1[CH:12]=[CH:11][C:6](C(OC)=O)=[CH:5][C:4]=1OC.[CH3:17][O:18][CH2:19][CH2:20][N:21]([CH2:23]C1C=C(C=CC=1)C#N)[CH3:22]>>[OH:16][NH:15][C:2](=[NH:1])[C:3]1[CH:4]=[CH:5][CH:6]=[C:11]([CH2:22][N:21]([CH2:20][CH2:19][O:18][CH3:17])[CH3:23])[CH:12]=1
Reactant: COCCN(C)Cc1cccc(C#N)c1
Reactant: COC(=O)c1ccc(C(N)=NO)c(OC)c1
Product: COCCN(C)Cc1cccc(C(=N)NO)c1
Yield: 93 %

Procedure:
The title compound was obtained following procedure and work up described for Intermediate 47 step 2 but starting from 3-{[(2-Methoxy-ethyl)-methyl-amino]-methyl}-benzonitrile obtained in step 1 (6.4 g, 31.3 mmol) to give the title compound as yellow viscous liquid (6.9 g, 93%). 1H NMR (DMSO-d6, 400 MHz) δ 9.57 (s, 1H), 7.59 (s, 1H), 7.50-7.53 (m, 1H), 7.28-7.29 (m, 2H), 5.75 (s, 2H), 3.48 (s, 2H), 3.41-3.44 (m, 2H), 3.21 (s, 3H), 2.48-2.52 (m, 2H), 2.13 (s, 3H). LC/MS (Method A): 238.1 (M+H)+.
Reaction SMILES: [C:1]([NH2:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:7][N:8]([CH:10](OC)OC)[CH3:9]>>[CH3:7][N:8]([CH3:10])/[CH:9]=[CH:3]/[CH:2]([CH3:4])[C:1]([NH2:6])=[O:5]
Reactant: CC(C)C(N)=O
Reactant: COC(OC)N(C)C
Product: CC(/C=C/N(C)C)C(N)=O

Procedure:
Following the procedure for 449, Step 3, isobutyramide was reacted with DMF-DMA to afford the title compound as a yellow oil. 1H NMR (CDCl3): 8.39 (1H, s), 3.10 (3H, m), 3.07 (3H, d, J=0.67 Hz), 2.68-2.56 (1H, m), 1.17 (3H, s), 1.18-1.11 (3H, s).
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:27])[C@:4]1([O:24]C=O)[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C:18](=[CH:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.O.C(=O)(O)[O-].[K+].[Cl-].[Na+]>CO>[Br:1][CH2:2][C:3](=[O:27])[C@:4]1([OH:24])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C:18](=[CH:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@@]2(C)[C@H]1CC[C@]2(OC=O)C(=O)CBr
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CBr
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 94.1 %

Procedure:
2.5 g of 21-bromo-17-formyloxy-4,9(11)-pregnadiene-3,20-dione is stirred at room temperature under argon in 100 ml of methanol and 18 ml of water with 1.3 g of potassium bicarbonate. After 45 minutes, the reaction mixture is introduced into ice water which contains sodium chloride, the thus-precipitated product is suctioned off, washed repeatedly with water, and dried under vacuum, thus obtaining 2.2 g of 21-bromo-17-hydroxy-4,9(11)-pregnadiene-3,20-dione [J. Org. Chem. 44 : 1582 (1979)]in the form of a crude product which is stirred in 50 ml of acetone and 2.7 g of potassium acetate at 50° C. After 2 hours, the reaction mixture is stirred into ice water, the thus-precipitated product is suctioned off, dissolved in ethyl acetate, washed with water, and dried over sodium sulfate, thus obtaining 1.9 g of 21-acetoxy-17-hydroxy-4,9(11)-pregnadiene-3,20-dione, mp 235.8° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[N:6]=1.[NH2:18][C:19]1[CH:20]=[C:21]([NH:26][C:27]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:30]=2)=[O:28])[CH:22]=[CH:23][C:24]=1[CH3:25]>>[CH3:25][C:24]1[CH:23]=[CH:22][C:21]([NH:26][C:27]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([N:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)[CH:30]=2)=[O:28])=[CH:20][C:19]=1[NH:18][C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:5]2[N:6]=[C:2]([CH3:1])[S:3][CH:4]=2)=[CH:17][CH:16]=1
Reactant: Cc1nc(COc2ccc(C(=O)O)cc2)cs1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1N
Product: Cc1nc(COc2ccc(C(=O)Nc3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3C)cc2)cs1

Procedure:
Using an analogous procedure to that described in the first paragraph of Example 26, 4-(2-methylthiazol4-ylmethoxy)benzoic acid was reacted with N-(3-amino4-methylphenyl)-2-morpholinopyridine-4-carboxamide. The reaction product was purified by column chromatography on silica using a 97:3 mixture of methylene chloride and methanol as eluent. There was thus obtained to give the title compound; NMR Spectrum: (DMSOd6) 2.2 (s, 3H), 2.44 (s, 3H), 3.5 (t, 4H), 3.7 (t, 4H), 5.19 (s, 2H), 7.11 (m, 3H), 7.23 (m, 2H), 7.4 (t, 2H), 7.54 (m, 3H), 7.68 (d, 1H), 7.78 (d, 1H), 7.96 (d, 2H), 8.24 (d, 1H), 9.73 (s, 1H), 10.27 (s, 1H); Mass Spectrum: M+H+ 544.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][C:8]1[CH:23]=[CH:22][C:11]([O:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[C:10]([CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[Cl:37][C:38]1[CH:39]=[C:40]([NH2:45])[CH:41]=[CH:42][C:43]=1[Cl:44]>C(Cl)Cl.CN(C=O)C>[Cl:37][C:38]1[CH:39]=[C:40]([NH:45][C:17]([C:16]2[CH:15]=[CH:14][C:13]([O:12][C:11]3[CH:22]=[CH:23][C:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:30])=[CH:9][C:10]=3[CH2:24][NH:25][S:26]([CH3:29])(=[O:27])=[O:28])=[CH:21][CH:20]=2)=[O:19])[CH:41]=[CH:42][C:43]=1[Cl:44]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)O)cc2)c(CNS(C)(=O)=O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)Nc3ccc(Cl)c(Cl)c3)cc2)c(CNS(C)(=O)=O)c1
Reaction time: 0.5 h
Yield: 37 %

Procedure:
The product of step D (62 mg, 0.14 mmol) was diluted with methylene chloride (1 mL) followed by the addition of oxalyl dichloride (0.093 mL, 0.19 mmol) and 1 drop of DMF. The reaction was stirred for 30 minutes followed by the addition of 3,4-dichlorobenzenamine (46 mg, 0.28 mmol). The reaction was allowed to stir for 1 hour. The reaction mixture was loaded directly onto a 12i sim and purified on the horizon eluting with methylene chloride:MeOH (99.5-0.5 to 95:5) to yield 30 mg of tert-butyl 2-(4-(4-((3,4-dichlorophenyl)carbamoyl)phenoxy)-3-(methylsulfonamidomethyl)phenyl)acetate as a clear oil.
Reaction SMILES: [C:1](=[O:33])([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([C:23]#[C:24][C:25]([CH3:32])([O:27][Si](C)(C)C)[CH3:26])[CH:9]=1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[C:1](=[O:33])([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([C:23]#[C:24][C:25]([OH:27])([CH3:32])[CH3:26])[CH:9]=1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: COc1ccc(F)c(-c2ccc(OC(=O)OC(C)(C)C)cc2C#CC(C)(C)O[Si](C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(F)c(-c2ccc(OC(=O)OC(C)(C)C)cc2C#CC(C)(C)O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a solution of tert-butyl 2′-fluoro-5′-methoxy-2-(3-methyl-3-((trimethylsilyl)oxy)but-1-yn-1-yl)biphenyl-4-yl carbonate (480 mg) in THF (3 mL) was added a solution (1 M, 2.0 mL) of tetrabutylammonium fluoride in THF, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (343 mg) as a colorless oil.
Reaction SMILES: [C:1]([N:5]([CH3:32])[C:6]([C:8]1[N:12]2[CH2:13][CH2:14][C:15]3[C:20]([C:11]2=[C:10]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[N:9]=1)=[CH:19][C:18]([O:21][CH2:22][CH2:23][NH2:24])=[C:17]([O:25][CH3:26])[CH:16]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:34]([O:36][CH3:37])=[O:35]>>[CH3:37][O:36][C:34](=[O:35])[NH:24][CH2:23][CH2:22][O:21][C:18]1[CH:19]=[C:20]2[C:15]([CH2:14][CH2:13][N:12]3[C:8]([C:6](=[O:7])[N:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[CH3:32])=[N:9][C:10]([C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)=[C:11]32)=[CH:16][C:17]=1[O:25][CH3:26]
Reactant: COc1cc2c(cc1OCCN)-c1c(-c3cccs3)nc(C(=O)N(C)C(C)(C)C)n1CC2
Reactant: COC(=O)Cl
Product: COC(=O)NCCOc1cc2c(cc1OC)CCn1c(C(=O)N(C)C(C)(C)C)nc(-c3cccs3)c1-2

Procedure:
Coupling of the product of example 31 (50 mg) with methyl chloroformate (11 μl) was performed according to the method described in example 32.
Reaction SMILES: [CH2:1]([C:3]1([C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=2)[O:8][CH2:7][CH2:6][CH2:5][O:4]1)[CH3:2].[H-].[Na+].Br[CH2:19][C:20]1[C:21]([Cl:30])=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2>O1CCCC1.[Cl-].[NH4+]>[Cl:30][C:21]1[C:20]([CH2:19][N:12]2[CH:13]=[CH:14][C:9]([C:3]3([CH2:1][CH3:2])[O:4][CH2:5][CH2:6][CH2:7][O:8]3)=[CH:10][C:11]2=[O:15])=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1
Reactant: CCC1(c2cc[nH]c(=O)c2)OCCCO1
Reactant: Clc1nc2ccccc2cc1CBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC1(c2ccn(Cc3cc4ccccc4nc3Cl)c(=O)c2)OCCCO1
Temperature: 0 °C
Yield: 69 %

Procedure:
A solution under argon of 4-(2-ethyl-1,3-dioxan-2-yl)-1,2-dihydro-2-pyridinone (obtained according to 4.e, 11 g, 52 mmol) in anhydrous tetrahydrofuran (370 ml) is treated at 0° C. with sodium hydride (80% in mineral oil, 1.68 g, 56 mmol). The resulting mixture is maintained under agitation at 0° C. for 15 min then treated with 3-bromomethyl-2-chloroquinoline (obtained according to 4.b, 13.4 g, 52 mmol) and the resulting mixture is maintained under agitation at ambient temperature for 24 hours. The reaction medium is then poured into an aqueous solution saturated in ammonium chloride (400 ml), the phases are separated, and the aqueous phase aqueuse is extracted with dichloromethane. The combined organic phases are washed with saturated aqueous sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue taken up in diethyl ether forms a precipitate which is collected by filtration and dried in order to produce 13.8 g (69%) of a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH:20]2[CH2:24][CH2:23][O:22][CH2:21]2)=[C:6]([C:8]2[C:9]3[CH:18]=[CH:17][NH:16][C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.C(N(CC)CC)C.[F:32][CH2:33][CH2:34][S:35](Cl)(=[O:37])=[O:36].[Cl-].[NH4+]>ClCCl>[F:32][CH2:33][CH2:34][S:35]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH:20]2[CH2:24][CH2:23][O:22][CH2:21]2)=[C:6]([C:8]2[C:9]3[CH:18]=[CH:17][NH:16][C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1)(=[O:37])=[O:36]
Reactant: Cn1cc(-c2cc(N)ccc2OC2CCOC2)c2cc[nH]c2c1=O
Reactant: O=S(=O)(Cl)CCF
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(-c2cc(NS(=O)(=O)CCF)ccc2OC2CCOC2)c2cc[nH]c2c1=O
Reaction time: 1 h
Yield: 6.5 %

Procedure:
To a mixture of Example 91b (80.0 mg, 0.246 mmol) and triethylamine (74.6 mg, 0.738 mmol) in dichloromethane (4 mL) was added dropwise 2-fluoroethanesulfonyl chloride (144 mg, 0.984 mmol), and the reaction mixture was stirred at about ambient temperature for about 1 hour. The reaction mixture was neutralized with saturated aqueous ammonium chloride solution (50 mL) and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried (anhydrous magnesium sulfate), filtered, and concentrated. The residue was purified by preparative HPLC (C18, 10-80% acetonitrile in 0.1% TFA/water) to provide the title compound (7.0 mg, 6.5% yield). 1H NMR (300 MHz, CDCl3) ppm 11.54 (bs, 1H), 7.45 (t, J=2.8 Hz, 1H), 7.19 (s, 1H), 6.88 (d, J=8.7 Hz, 1H), 6.73 (d, J=2.7 Hz, 1H) 6.67 (dd, J=3.1, 8.8 Hz, 1H), 6.40 (dd, J=2.0, 2.7 Hz, 1H), 4.76 (m, 1H), 3.82 (s, 3H), 3.85-3.62 (m, 8H), 2.97 (bs, 1H), 2.24-1.85 (m, 2H). MS (ESI+) m/z 436.2 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH2:17][N:18]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:19][CH:20]([OH:35])[CH2:21][NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:48]([CH:50]1[O:52][CH2:51]1)[Cl:49]>C1(C)C(C)=CC=CC=1>[OH:35][CH:20]([CH2:19][N:18]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:17][CH:2]([OH:1])[CH2:3][N:4]([CH2:51][CH:50]([OH:52])[CH2:48][Cl:49])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:21][N:22]([CH2:51][CH:50]([OH:52])[CH2:48][Cl:49])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCCCCNCC(O)CN(CCCCCCCCCCCC)CC(O)CNCCCCCCCCCCCC
Reactant: ClCC1CO1
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCCCN(CC(O)CCl)CC(O)CN(CCCCCCCCCCCC)CC(O)CN(CCCCCCCCCCCC)CC(O)CCl
Yield: 99.4 %

Procedure:
A reactor was charged with 16.6 g (0.025 mole) of 15,19-dihydroxy-17-dodecyl-13,17,21-triazatritriacontane obtained in Example 1 and 200 g of xylene, and the contents were kept at 50° C. To the contents, 6.9 g (0.075 mole) of epichlorohydrin was added dropwise over one hour and ten minutes, and the resultant mixture was aged for 36 hours. Thereafter, the solvent and unreacted epichlorohydrin were distilled off under reduced pressure at room temperature, thereby obtaining 21.2 g of 15,19-dihydroxy-13,21-bis(3-chloro-2-hydroxypropyl)-17-dodecyl-13,17,21-triazatritriacontane represented by the following formula. ##STR14##
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][C:26]1[O:30][N:29]=[CH:28][C:27]=1[C:31](Cl)=[O:32]>CN1CCCC1=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([F:24])=[C:2]([NH:1][C:31]([C:27]5[CH:28]=[N:29][O:30][C:26]=5[CH3:25])=[O:32])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: Cc1oncc1C(=O)Cl
Solvent: CN1CCCC1=O
Product: Cc1oncc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Yield: 51.3 %

Procedure:
Using N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (164 mg, 0.50 mmol), N-methylpyrrolidone (5 mL) and 5-methylisoxazole-4-carbonyl chloride (146 mg, 1.00 mmol), and in the same manner as in Example 162, the title compound (112 mg, yield 51%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[N:15]=[C:10]3[CH:9]=[C:8]2[C:20](=[S:22])[NH2:21])=[CH:4][CH:3]=1.CO[CH:27](OC)[CH2:28]Br.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([S:16]([CH3:19])(=[O:17])=[O:18])[N:15]=[C:10]3[CH:9]=[C:8]2[C:20]2[S:22][CH:27]=[CH:28][N:21]=2)=[CH:4][CH:3]=1
Reactant: COC(CBr)OC
Reactant: CS(=O)(=O)c1cnc2c(cc(C(N)=S)n2Cc2ccc(F)cc2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: CS(=O)(=O)c1cnc2c(cc(-c3nccs3)n2Cc2ccc(F)cc2)n1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of 5-(4-fluorobenzyl)-2-methanesulfonyl-5H-pyrrolo[2,3-b]pyrazine-6-thioamide (90 mg), bromoacetaldehyde dimethylacetal (0.06 ml), p-toluenesulfonic acid (4 mg) and acetic acid (1 ml) was stirred at 100° C. for 1.5 hours. The reaction solution was separated using silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain the desired product (30 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].[H-].[Na+].Br[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][N:14]=1.[OH-].[Na+]>CN1C(=O)CCC1.O>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([O:1][CH2:2][CH2:3][N:4]2[CH2:8][CH2:7][CH2:6][C:5]2=[O:9])=[N:14][CH:15]=1
Reactant: O=C1CCCN1CCO
Reactant: Brc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C1CCCN1CCOc1ccc(Br)cn1
Temperature: 80 °C

Procedure:
2.45 g (19 mmol) of 1-(2-hydroxyethyl)-pyrrolidin-2-one and 0.83 g (19 mmol) of sodium hydride (55% in mineral oil) in 10 ml of NMP were stirred at room temperature for 1 h. 3.0 g (12.7 mmol) of 2,5-dibromopyridine were added, and the mixture was heated to 80° C. for 2 h. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were dried and concentrated. The remaining oil was taken up in 200 ml of tert-butyl methyl ether and treated with a solution of hydrogen chloride in diethyl ether. The resulting greasy solid was isolated by decantation of the solvent and treated with a 25% aqueous sodium hydroxide solution. The product was extracted with ethyl acetate, and the combined organic phases were dried and concentrated. Yield: 2.75 g.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7](Br)=[CH:8][CH:9]=1)=[O:4].C(=O)([O-])O.[Na+].[CH2:16]([OH:19])[CH:17]=[CH2:18].O>CN(C=O)C.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[CH:16]([CH2:17][CH2:18][C:7]1[O:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:9][CH:8]=1)=[O:19]
Reactant: COC(=O)c1ccc(Br)o1
Reactant: C=CCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CCC=O)o1
Temperature: 60 °C
Reaction time: 20 h
Yield: 28.1 %

Procedure:
A solution of 5-bromo-2-furancarboxylic acid methyl ester (816 mg, MAYB) in DMF (3 ml) was added with tetra-n-butylammonium chloride (1.1 g, TCI), sodium hydrogencarbonate (688 mg), palladium acetate (10.4 mg, WAKO), and allyl alcohol (346 mg, TCI), and the mixture was stirred at 60° C. for 20 hours. The reaction solution was added with distilled water (30 ml), and ethyl acetate (20 ml), and the insoluble solid was removed by filtration. The filtrate was extracted with ethyl acetate (50 ml×2). The organic layers were combined, washed with saturated brine, and dried, and then the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (Flash, hexane:ethyl acetate=4:1) to obtain the title compound (Intermediate ih-01, 204 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH2:9][CH:10]=O)=[CH:6][N:5]=[C:4]2[N:12]([S:15]([C:18]3[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:13]=[CH:14][C:3]=12.[CH2:25]([C@H:27]1[C@@H:31]([N:32]=C=O)[CH2:30][C@@H:29]([NH:35][S:36]([CH:39]2[CH2:41][CH2:40]2)(=[O:38])=[O:37])[CH2:28]1)[CH3:26].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(Cl)Cl>[Cl:1][C:2]1[C:7]([CH2:8][CH2:9][CH2:10][NH:32][C@@H:31]2[C@H:27]([CH2:25][CH3:26])[CH2:28][C@H:29]([NH:35][S:36]([CH:39]3[CH2:41][CH2:40]3)(=[O:38])=[O:37])[CH2:30]2)=[CH:6][N:5]=[C:4]2[N:12]([S:15]([C:18]3[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:13]=[CH:14][C:3]=12
Reactant: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1N=C=O
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)c(CCC=O)cnc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1NCCCc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.8 %

Procedure:
To a mixture of 3-(4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)propanal (0.420 g, 1.04 mmol) and N-((1S,3S,4R)-3-amino-4-ethylcyclopentyl)cyclopropanesulfonamide (0.290 g, 1.25 mmol, prepared using OOO from Example #23 step E with NaOH) in DCE (4.00 mL) was added glacial acetic acid (0.089 mL, 1.6 mmol). The reaction mixture stirred for about 15 min at ambient temperature and sodium triacetoxyborohydride (0.331 g, 1.56 mmol) was added. The reaction was left stirring at ambient temperature for about 72 h. Saturated aqueous NaHCO3 (about 5 mL) was slowly added followed by DCM (5 mL). The layers were separated and the aqueous phase was extracted with DCM (2×5 mL). The combined organics were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The remaining yellow oil was purified by silica gel chromatography eluting with a gradient of 0-50% EtOAc in heptane to give N-((1S,3S,4R)-3-(3-(4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)propylamino)-4-ethylcyclopentyl)cyclo-propanesulfonamide (0.330 g, 55%) as a white foam: LC/MS (Table 1, Method b) Rt=2.10 min; MS m/z: 579 (M+H)+.