Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([O:11][C:12]2[CH:36]=[CH:35][C:15]([C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:19]=3)=[O:17])=[CH:14][CH:13]=2)[CH2:8][CH2:9]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:57].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:57][CH2:9][CH2:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:19]=2)=[O:17])=[CH:35][CH:36]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCOC(=O)CCCn1cc(C(=O)c2ccc(OC(CCO)c3ccccc3)cc2)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)CCCn1cc(C(=O)c2ccc(OC(CCBr)c3ccccc3)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
Ethyl 4-{3-[4-(1-phenyl-3-hydroxypropoxy) benzoyl]indol-1-yl}butanoate (4.00 g) obtained in Step 1 was dissolved in methylene chloride (40 ml). Triphenylphosphine (3.24 g) and carbon tetrabromide (3.24 g) were added to the resultant solution while cooling on ice bath and stirred for 30 minutes at room temperature. Saturated sodium bicarbonate solution was added to the reaction mixture to separate an organic layer. The organic layer was washed with brine and then dried. The solvent was distilled off. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), obtaining 3.97 g of ethyl 4-{3-[4-(3-bromo-1-phenylpropoxy)benzoyl]indol-1-yl}butanoate as colorless oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][O:13][CH:12]([CH2:17][NH:18]C(OCC(Cl)(Cl)Cl)=O)[C:11]=2[S:10][C:9]=1[NH2:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].P([O-])([O-])([O-])=O>O1CCCC1.[Zn]>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][O:13][CH:12]([CH2:17][NH2:18])[C:11]=2[S:10][C:9]=1[NH2:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CCOC2CNC(=O)OCC(Cl)(Cl)Cl
Agent: O=P([O-])([O-])[O-]
Agent: [Zn]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(N)sc2c1CCOC2CN
Temperature: 25 °C
Reaction time: 6 h
Yield: 66.8 %

Procedure:
The above 2-amino-7-((2,2,2-trichloro-ethoxycarbonylamino)methyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (4.0 g, 8.0 mmol) was dissolved in a mixture of tetrahydrofuran (15 ml) and a aqueous phosphate buffer (pH 3; 5 ml) followed by addition of zinc (16 g, 0.244 mol). The reaction mixture was stirred for 6 hours at room temperature at which time the solvent was removed in vacuo. To the residue was added diethyl ether (20 ml) and water (40 ml). Sodium carbonate was added to the aqueous phase until pH=8 and the aqueous phase extracted with dichloromethane (3×). The combined organic phases were dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified by flash chromatography on sillicagel (90 g) using a mixture of dichloromethane/ethanol/25% ammonia in water 100:10:0.7 as eluent. Pure fractions were collected and the solvent evaporated in vacuo affording 1.52 g (61%) of 2-amino-7-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][CH:16]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:33]1[CH:34]=[CH:35][C:36]2[S:40][CH:39]=[CH:38][C:37]=2[CH:41]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>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].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[S:40]1[C:36]2[CH:35]=[CH:34][C:33]([NH:1][C:2]3[CH:14]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][CH:16]=4)[CH:12]=[CH:11][C:3]=3[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[CH:41][C:37]=2[CH:38]=[CH:39]1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccc(NS(C)(=O)=O)cc2)cc1N
Reactant: Brc1ccc2sccc2c1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(-c2ccc(NS(C)(=O)=O)cc2)cc1Nc1ccc2sccc2c1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
To toluene 3.0 mL suspension of tert-butyl 2-amino-4-(4-(methanesulfonamido)phenyl)benzoate 0.12 g and cesium carbonate 0.27 g were added 5-bromobenzothiophene 0.14 g, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 7.9 mg, tris(dibenzylideneacetone)dipalladium(0) 3.0 mg and palladium acetate 1.5 mg at room temperature, and it was stirred at 110° C. for 24 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added to it, and insoluble matter was filtrated. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=2:1] to give tert-butyl 2-((benzothiophen-5-yl)amino)-4-(4-(methanesulfonamido)phenyl)benzoate.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][NH2:8])=[CH:4][CH:3]=1.[NH2:9][C:10]1[N:18]=[C:17]([CH2:19][O:20][CH3:21])[CH:16]=[CH:15][C:11]=1[C:12](O)=[O:13].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[NH2:9][C:10]1[N:18]=[C:17]([CH2:19][O:20][CH3:21])[CH:16]=[CH:15][C:11]=1[C:12]([NH:8][CH2:7][C:5]1[S:6][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:13]
Reactant: NCc1ccc(Br)s1
Reactant: COCc1ccc(C(=O)O)c(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COCc1ccc(C(=O)NCc2ccc(Br)s2)c(N)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.9 %

Procedure:
To a solution of C-(5-bromo-thiophen-2-yl)-methylamine (250 mg, 1.3 mmol) in N,N-dimethylformamide (5 mL) were added tiethylamine (0.54 mL, 3.9 mmol), 2-amino-6-methoxymethyl-nicotinic acid (240 mg, 1.3 mmol) described in Preparation Example A-11, and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (690 mg, 1.6 mmol) sequentially on an ice bath, then, the solution was stirred for 2 days at room temperature. The reaction solution was partitioned in water and ethyl acetate. The organic layer was separated, the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1), and the title compound (370 mg, 1.0 mmol, 79%) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3](B2OC(C)(C)C(C)(C)O2)=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:8]=[CH:7]2.[NH2:30][C:31]1[C:36]([F:37])=[C:35](Cl)[N:34]=[C:33]([C:39]([O:41][CH3:42])=[O:40])[C:32]=1[Cl:43].C(=O)([O-])[O-].[Na+].[Na+].C(#N)C.O>Cl[Pd](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.O.C(OCC)(=O)C>[NH2:30][C:31]1[C:36]([F:37])=[C:35]([C:3]2[C:2]([F:1])=[C:10]3[C:6]([CH:7]=[CH:8][N:9]3[Si:11]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:13])[CH3:14])[CH:18]([CH3:20])[CH3:19])=[CH:5][CH:4]=2)[N:34]=[C:33]([C:39]([O:41][CH3:42])=[O:40])[C:32]=1[Cl:43]
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1Cl
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: COC(=O)c1nc(-c2ccc3ccn([Si](C(C)C)(C(C)C)C(C)C)c3c2F)c(F)c(N)c1Cl
Temperature: 110 °C
Yield: 43.9 %

Procedure:
7-Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(triisopropylsilyl)-1H-indole (1.0 g, 2.4 mmol), methyl 4-amino-3,6-dichloro-5-fluoropicolinate (630 mg, 2.6 mmol), sodium carbonate (250 mg, 2.4 mmol) and with bis(triphenylphosphine)palladium(II) chloride (170 mg, 0.24 mmol) were combined in 10 mL of 1:1 v/v acetonitrile-water and heated at 110° C. for 30 min in a Biotage Initiator microwave reactor. The mixture was stirred with 30 mL ethyl acetate and 20 mL water and filtered through glass wool to remove dark solids. The organic phase was washed with sat. NaCl, dried (Na2SO4), and evaporated. Purification by flash chromatography (SiO2; eluting with 0-30% ethyl acetate in hexanes) provided 520 mg of the title compound as a white solid (520 mg; 42).
Reaction SMILES: [CH:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2].CS(O[CH2:19][CH:20]=[CH:21][CH3:22])(=O)=O>>[CH2:19]([N:5]1[C:6]([CH3:9])=[C:7]([CH3:8])[C:3]([CH:1]=[O:2])=[C:4]1[C:10]([O:12][CH3:13])=[O:11])[CH:20]=[CH:21][CH3:22]
Reactant: COC(=O)c1[nH]c(C)c(C)c1C=O
Reactant: CC=CCOS(C)(=O)=O
Product: CC=CCn1c(C)c(C)c(C=O)c1C(=O)OC

Procedure:
The title compound (cis/trans=93/7) was prepared as a pale brown oil in 33.4% yeild in a similar procedure to that described in Referential Example 9 by using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 2-butenyl methanesulfonate (cis/trans=96/4).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][C:3]=1OC.C(N(CC)CC)C.[C:33](Cl)(=[O:38])[CH2:34][CH:35]([CH3:37])[CH3:36]>C(Cl)Cl>[CH3:36][CH:35]([CH3:37])[CH2:34][C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:22][CH:23]=1)=[O:38]
Reactant: COc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1N
Reactant: CC(C)CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CC(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reaction time: 3 h
Yield: 129.1 %

Procedure:
To a stirred solution of 0.10 g of 10,11-dihydro-10-(4-amino-3-methoxybenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 1 ml of methylene chloride is added 0.06 g of triethylamine followed by 0.05 g of iso-valeryl chloride. The reaction mixture is stirred for 3 hours and then quenched with 1N NaOH. The organic layer is evaporated in vacuo to a residue which is stirred in 5 ml of tetrahydrofuran for 1 hour, then evaporated in vacuo to a residue. The residue is extracted with ethyl acetate-methylene chloride, washed with brine, dried (Na2SO4), filtered through hydrous magnesium silicate and evaporated in vacuo to give 0.15 g of residue which is stirred with ether-hexane to give 0.13 g of light yellow solid. MS(CI): 418(M+H).
Reaction SMILES: C(NCCNCCNCC1C=CC=CC=1)C1C=CC=CC=1.CNCCNCCNC.[CH2:31]([N:38]1[CH:45]2[N:41]([CH2:42][CH2:43][N:44]2[CH2:46]C2C=CC=CC=2)[CH2:40][CH2:39]1)C1C=CC=CC=1>>[CH3:46][N:44]1[CH:45]2[N:41]([CH2:40][CH2:39][N:38]2[CH3:31])[CH2:42][CH2:43]1
Reactant: c1ccc(CN2CCN3CCN(Cc4ccccc4)C32)cc1
Agent: CNCCNCCNC
Agent: c1ccc(CNCCNCCNCc2ccccc2)cc1
Product: CN1CCN2CCN(C)C12

Procedure:
If 1,7-dibenzyldiethylenetriamine were substituted for 1,7-dimethyldiethylenetriamine in essentially the procedure of part (A) above, the product would be 4,6-dibenzyl-1,4,6-triazabicyclo[3.3.0]octane, ##STR25##
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])[C:9]([C:11]1[CH:30]=[CH:29][C:14]2[N:15]([CH3:28])[C:16]([CH2:18][NH:19][C:20]3[S:21][C:22]([C:25](=[NH:27])[NH2:26])=[CH:23][N:24]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].[OH-].[Na+]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:9]([C:11]1[CH:30]=[CH:29][C:14]2[N:15]([CH3:28])[C:16]([CH2:18][NH:19][C:20]3[S:21][C:22]([C:25](=[NH:26])[NH2:27])=[CH:23][N:24]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ncc(C(=N)N)s1)n2C)c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: Cn1c(CNc2ncc(C(=N)N)s2)nc2cc(C(=O)N(CCC(=O)O)c3ccccn3)ccc21

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(5-amidino-thiazol-2-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. Yield: % of theory, C22H22N8O3S (478.5) Rf value: (silica gel; dichloromethane/methanol=4:1)
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[H-].[Na+].[Cl:16][C:17]1[C:22]([CH3:23])=[C:21](Cl)[CH:20]=[CH:19][N:18]=1>CC(N(C)C)=O.CCOCC>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([O:13][C:21]2[CH:20]=[CH:19][N:18]=[C:17]([Cl:16])[C:22]=2[CH3:23])[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(O)CC1
Reactant: Cc1c(Cl)ccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: Cc1c(OC2CCN(C(=O)OC(C)C)CC2)ccnc1Cl
Temperature: 23 °C
Reaction time: 0.75 h
Yield: 27 %

Procedure:
4-Hydroxy-piperidine-1-carboxylic acid isopropyl ester (0.496 mL, 2.90 mmol) was dissolved in anhydrous dimethylacetamide (DMA, 5 mL), NaH (60% oil dispersion, 116 mg, 2.90 mmol) was added and this mixture was stirred at 23° C. for 45 min, then this mixture was added dropwise to 2,4-dichloro-3-methyl-pyridine, which was dissolved in anhydrous DMA (4 mL). This mixture was stirred at 23° C. for 2 h then heated at 50° C. for 15 h, after which time the mixture was diluted with Et2O (140 mL), washed with water (14 mL), then brine twice (2×14 mL). The organic layer was separated, dried with MgSO4, and the solvent was evaporated in vacuo to give an oil which was purified by flash chromatography using hexanes-EtOAc, 75:25, v/v, then hexanes-EtOAc, 50:50, v/v, to give 4-(2-chloro-3-methyl-pyridin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester as a solid (223 mg, 27%). 1H NMR (CDCl3, 400 MHz) δ 8.09 (d, 1H), 6.69 (d, 1H), 4.91 (m, 1H), 4.60 (m, 1H), 3.61 (m, 2H), 3.52 (m, 2H), 2.24 (s, 3H), 1.91 (m, 2H), 1.80 (m, 2H), 1.24 d, 6H). LRMS calculated for C15H21ClN2O3: 312.12, Found: (MH)+ 313.4.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:23])[C:4]([C:6]1[C:10]2[CH2:11][CH2:12][CH2:13][C:14]3[C:15](=[N:16][C:17]([O:20]C)=[N:18][CH:19]=3)[C:9]=2[N:8]([CH3:22])[N:7]=1)=[O:5].[I-].[Na+].C[Si](Cl)(C)C>CC#N>[OH:20][C:17]1[N:16]=[C:15]2[C:9]3[N:8]([CH3:22])[N:7]=[C:6]([C:4]([N:3]([O:2][CH3:1])[CH3:23])=[O:5])[C:10]=3[CH2:11][CH2:12][CH2:13][C:14]2=[CH:19][N:18]=1
Reactant: COc1ncc2c(n1)-c1c(c(C(=O)N(C)OC)nn1C)CCC2
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CON(C)C(=O)c1nn(C)c2c1CCCc1cnc(O)nc1-2
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.8 %

Procedure:
To a solution of N,9-dimethoxy-N,1-dimethyl-1,4,5,6-tetrahydropyrazolo[4′,3′:6,7]cyclohepta[1,2-d]pyrimidine-3-carboxamide (583 mg, 1.8 mmol) in CH3CN (35 mL), sodium iodide (550 mg, 3.67 mmol) and trimethylsilylchloride (0.525 mL, 4.14 mmol) were added in sequence. Mixture was stirred for 24 h under argon atmosphere at room temperature then a second portion of sodium iodide (275 mg, 1.8 mmol) and trimethylsilylchloride (0.276 mL, 2.1 mmol) were added in sequence. After 24 h the solvent was evaporated, the residue dissolved with a mixture of DCM/MeOH (4/1) and washed with a saturated aqueous solution of Na2S2O3. The organic layer was dried over Na2SO4. The residue was crystallized from MeOH to give 452 mg (83% yield) of a white solid.
Reaction SMILES: Cl[CH2:2][CH:3]([CH3:19])[CH:4]([C:6]1[CH:18]=[CH:17][C:9]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:8][CH:7]=1)[OH:5].[C:20]([O-:23])(=[O:22])[CH3:21].[Na+].[Cl-].[Na+].C(OCC)(=O)C>CN(C)C=O>[C:20]([O:23][CH2:2][CH:3]([CH3:19])[CH:4]([C:6]1[CH:18]=[CH:17][C:9]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:8][CH:7]=1)[OH:5])(=[O:22])[CH3:21]
Reactant: CC(CCl)C(O)c1ccc(Cc2cccnc2)cc1
Reactant: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OCC(C)C(O)c1ccc(Cc2cccnc2)cc1
Yield: 36.7 %

Procedure:
In 11 ml of N,N-dimethylformamide was dissolved 2.29 g of 3-[p-(3-chloro-1-hydroxy-2-methylpropyl)benzyl]pyridine, and to the resulting solution was added 1.36 g of sodium acetate, after which the resulting mixture was subjected to reaction under reflux for 2 hours. The solvent was removed by distillation under reduced pressure, and to the residue thus obtained were added 20 ml of a saturated aqueous sodium chloride solution and 20 ml of ethyl acetate. The organic layer was separated, washed with 10 ml of water, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: chloroform] to obtain 910 mg (yield 36.7%) of colorless, oily 3-[p-(3-acetoxy-1-hydroxy-2-methylpropyl)benzyl]pyridine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[C:11]1[S:10][C:9]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:16]=3[C:26]([F:29])([F:28])[F:27])=[N:8][C:7]=1[CH2:6][CH2:5]2.[CH2:30]([Sn](CCCC)(CCCC)C=C)[CH2:31]CC>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:20]1([C:17]2[C:16]([C:26]([F:27])([F:28])[F:29])=[C:15]([C:9]3[S:10][C:11]4[C:12]5[C:4](=[CH:3][C:2]([CH:30]=[CH2:31])=[CH:14][CH:13]=5)[CH2:5][CH2:6][C:7]=4[N:8]=3)[O:19][N:18]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: FC(F)(F)c1c(-c2ccccc2)noc1-c1nc2c(s1)-c1ccc(Br)cc1CC2
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)sc1-2
Temperature: 110 °C

Procedure:
To 5-(7-bromo-4,5-dihydronaphtho[2,1-d]thiazol-2-yl)-3-phenyl-4-(trifluoromethyl)isoxazole (Preparation 82D), 0.4 g, 0.838 mmol) in toluene (2 mL) was added tributyl(vinyl)stannane (0.294 mL, 1.00 mmol), followed by bis(triphenylphosphine)palladium(II)chloride (0.029 g, 0.042 mmol) at room temperature. The reaction mixture was heated at 110° C. for 3 h. The reaction mixture was loaded onto a silica gel column and purified using hexane/EtOAc (9.25:0.75, 300 mL). The desired fractions were collected and concentrated to yield 0.35 mgs of a yellow solid. The solid was triturated with acetonitrile (5 mL), filtered and washed with acetonitrile (2×5 mL) to yield 200 mgs of a pale yellow solid (I crop). The mother liquor was concentrated to yield another 100 mgs of greenish-yellow solid (II crop). LC/MS M+1=425.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([O:20][CH3:21])=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:23][C:24]1[C:29]([NH2:30])=[CH:28][CH:27]=[C:26]([S:31]([CH3:34])(=[O:33])=[O:32])[N:25]=1.C(N1CCN2CCN(CC(C)C)P1N(CC(C)C)CC2)C(C)C.CC([O-])(C)C.[Na+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([O:20][CH3:21])=[C:18]([NH:30][C:29]3[C:24]([CH3:23])=[N:25][C:26]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:28]=3)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: COc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Reactant: Cc1nc(S(C)(=O)=O)ccc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: COc1c(Nc2ccc(S(C)(=O)=O)nc2C)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Temperature: 90 °C
Reaction time: 1 h
Yield: 21.8 %

Procedure:
A mixture of 4-(6-chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (14.7 g, 44.6 mmol), 2-methyl-6-(methylsulfonyl)pyridin-3-amine (8.20 g, 44.0 mmol), palladium acetate (0.50 g, 2.23 mmol), 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phospha-bicyclo[3.3.3]undecane (1.65 ml, 4.64 mmol), and sodium 2-methylpropan-2-olate (6.50 g, 67.6 mmol) in dioxane (300 mL) were stirred at 90° C. for 1 h and then at 60° C. overnight. The reaction mixture was cooled and filtered. The solid was washed with ethyl acetate. The filtrate was concentrated and the residue was purified by silica gel column chromatography using hexane/ethyl acetate (1:2). The fractions containing only the product were collected, and concentrated to give the title compound (4.6 g, 22%) that was crystallized from ethyl acetate/hexane as a white solid. The fractions containing the product contaminated with impurities were concentrated and the residue was further purified by recrystallization from ethanol to give the title compound (2.5 g, 12%) as a white solid. The two combined to give 7.1 g of the title compound in 34% yield. Exact mass calculated for C21H29N5O6S: 479.2. Found: LCMS m/z=480.4 (M+H+); 1H NMR (400 MHz, CDCl3) δ 1.27 (d, J=6.3 Hz, 6H), 1.80-1.85 (m, 2H), 2.02-2.07 (m, 2H), 2.66 (s, 3H), 3.19 (s, 3H), 3.38-3.45 (m, 2H), 3.78-3.83 (m, 2H), 4.01 (s, 3H), 4.91-4.97 (m, 1H), 5.38-5.42 (m, 1H), 7.30 (s, 1H), 7.97 (d, J=8.6 Hz, 1H), 8.20 (s, 1H), 9.01-9.04 (d, J=8.6 Hz, 1H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([N:28]([CH:38]3[CH2:40][CH2:39]3)CC3C=CC(OC)=CC=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:50][N:51]([CH3:56])[S:52](Cl)(=[O:54])=[O:53].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:38]1([NH:28][C:11]2[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=[C:9]([NH:8][C@H:5]3[CH2:6][CH2:7][C@H:2]([NH:1][S:52](=[O:54])(=[O:53])[N:51]([CH3:56])[CH3:50])[CH2:3][CH2:4]3)[CH:10]=2)[CH2:40][CH2:39]1
Reactant: COc1ccc(CN(c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccncc4F)cnc23)C2CC2)cc1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)S(=O)(=O)N[C@H]1CC[C@H](Nc2cc(NC3CC3)c3ncc(C(=O)Nc4ccncc4F)n3n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-((trans)-4-aminocyclohexylamino)-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide 8B (30 mg, 0.055 mmol) in CH2Cl2 (1 mL) was added DIEA (0.0062 mL, 0.035 mmol) and dimethylsulfamoyl chloride (1.5 mg, 10.45 μmol). The reaction mixture was stirred at room temperature for 2 hrs, concentrated, re-dissolved in TFA (0.849 mL, 11.02 mmol) and heated at 70° C. for 1 hr. The reaction mixture was concentrated and purified by HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 30% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA)) to isolate the title compound, 8-(cyclopropylamino)-6-((trans-4-((dimethylsulfamoyl)amino)cyclohexyl)amino)-N-(3-fluoro-4-pyridinyl)imidazo[1,2-b]pyridazine-3-carboxamide, as a white solid (13.0 mg, 44.4%). LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). Rt=1.61 (M+H=532.26). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.39 (1H, s), 8.71 (1H, d, J=2.52 Hz), 8.49 (1H, t, J=6.17 Hz), 8.43 (1H, d, J=5.29 Hz), 8.00 (1H, s), 7.61 (1H, s), 7.28 (1H, d, J=8.06 Hz), 6.92 (1H, d, J=8.31 Hz), 5.98 (1H, s), 3.78 (1H, br. s.), 3.00 (2H, br. s.), 2.58-2.73 (6H, m), 2.01 (2H, br. s.), 1.90 (2H, br. s.), 1.26 (4H, d, J=13.09 Hz), 0.68-0.85 (2H, m), 0.51-0.69 (2H, m).