Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[N:13][C:14]([C:25]3[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=3)=[N:15][C:16]([N:17]3[CH2:23][CH:22]4[O:24][CH:19]([CH2:20][CH2:21]4)[CH2:18]3)=[C:11]2[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.CN.C(N1C2=NC(C3C=C[C:73]([N:76]=[C:77]=[O:78])=CC=3)=NC(N3CC4OC(CC4)C3)=C2C=N1)C1C=CC=CC=1>ClCCl.O1CCCC1>[CH2:1]([N:8]1[C:12]2=[N:13][C:14]([C:25]3[CH:26]=[CH:27][C:28]([NH:29][C:77]([NH:76][CH3:73])=[O:78])=[CH:30][CH:31]=3)=[N:15][C:16]([N:17]3[CH2:18][CH:19]4[O:24][CH:22]([CH2:21][CH2:20]4)[CH2:23]3)=[C:11]2[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(Cc4ccccc4)c3n2)cc1
Reactant: O=C=Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(Cc4ccccc4)c3n2)cc1
Agent: CN
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(Cc4ccccc4)c3n2)cc1

Procedure:
A solution of 4-(1-benzyl-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline (22 mg, 0.05 mmol) in a mixture of dichloromethane (3 mL) and tetrahydrofuran (2 mL) was treated with triphosgene (8 mg, 0.03 mmol) as a solution in dichloromethane (1 mL). After the passage of 5 minutes, the appropriate nucleophile—in the case, 2.0 M methylamine solution in tetrahydrofuran (1 mL)—was added to the 3-(1-benzyl-6-(4-isocyanatophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (“isocyanate”) mixture. The reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 5% acetonitrile/95% of 0.1% aqueous trifluoroacetic acid to 100% acetonitrile to provide 1-{4-[1-benzyl-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}-3-methylurea. MS (ES+): 470.0 (M+H)+
Reaction SMILES: [CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH:22]1([NH2:25])[CH2:24][CH2:23]1>>[CH:22]1([NH:25][C:18]([C:14]2[S:13][C:12](/[CH:11]=[CH:10]/[C:9]3[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=3[CH3:21])=[N:16][C:15]=2[CH3:17])=[O:20])[CH2:24][CH2:23]1
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)O)s1
Reactant: NC1CC1
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)NC2CC2)s1
Yield: 44 %

Procedure:
As described for example 104, 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid (153 mg, 0.5 mmol) was converted, using cyclopropylamine instead of rac-2-amino-1-butanol, to the title compound (76 mg, 44%) which was obtained as a light yellow solid after purification by chromatography (silica, 50 to 100% ethyl acetate in heptane). MS: m/e=346.2 [M+H]+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]([CH:52]=[CH:53][CH:54]=2)[C:33]([NH:35][C:36]2[CH:51]=[CH:50][C:39]([C:40]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])=[CH:38][CH:37]=2)=[O:34])O1>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.C(OCC)(=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>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[CH:7]=[C:2]([C:30]3[CH:31]=[C:32]([CH:52]=[CH:53][CH:54]=3)[C:33]([NH:35][C:36]3[CH:51]=[CH:50][C:39]([C:40]([O:42][CH2:43][C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)=[O:41])=[CH:38][CH:37]=3)=[O:34])[N:3]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: COc1ccc(Nc2nc(Br)cn3ccnc23)cc1OC
Reactant: CC1(C)OB(c2cccc(C(=O)Nc3ccc(C(=O)OCc4ccccc4)cc3)c2)OC1(C)C
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: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(-c3cccc(C(=O)Nc4ccc(C(=O)OCc5ccccc5)cc4)c3)cn3ccnc23)cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 64.5 %

Procedure:
A mixture of 6-bromo-N-(3,4-dimethoxyphenyl)imidazo[1,2-a]pyrazin-8-amine (1.82 g, 5.22 mmol) and benzyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)benzoate (3.06 g, 5.22 mmol, 78% by mass) in 1 M aqueous sodium carbonate (8 mL) and 1,4-dioxane (24 mL) was sparged with nitrogen with stirring for 5 min. The resulting mixture was treated with tetrakis(triphenylphosphine)palladium(0) (1.20 g, 1.04 mmol) and stirred at reflux for 2.5 h. After this time, the reaction was cooled to ambient temperature, diluted with ethyl acetate (100 mL) and washed with brine (100 mL). The aqueous layer was extracted with ethyl acetate (100 mL) and the combined organic layers were dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, methylene chloride to 1:4 ethyl acetate/methylene chloride) to afford benzyl 4-(3-(8-(3,4-dimethoxyphenylamino)imidazo[1,2-a]pyrazin-6-yl)benzamido)benzoate (2.02 g, 65%) as an off-white solid: mp 154-160° C.; 1H NMR (300 MHz, CDCl3) δ 10.72 (s, 1H), 9.57 (s, 1H), 8.74 (s, 1H), 8.57 (s, 1H), 8.25 (d, J=7.8 Hz, 1H), 8.08-7.94 (m, 7H), 7.69-7.60 (m, 3H), 7.50-7.34 (m, 5H), 6.92 (d, J=8.7 Hz, 1H), 5.36 (s, 2H), 3.78 (s, 3H), 3.73 (s, 3H); ESI MS m/z 600 [M+H]+; HPLC, 8.93 min, 95.9% (AUC).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:23][C:24]([NH:26][CH2:27][CH2:28][CH3:29])=[O:25].[H-].[Na+].[CH3:32][O:33][CH2:34]Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[N:23]([CH2:32][O:33][CH3:34])[C:24]([NH:26][CH2:27][CH2:28][CH3:29])=[O:25]
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCNC(=O)N(COC)c1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 18 %

Procedure:
N-{2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-phenyl}-N′-propylurea (100 mg) was dissolved in anhydrous tetrahydrofuran (30 ml), and sodium hydride (60 wt %, 88 mg) was added to the solution. The mixture was stirred at room temperature for 15 min. Next, chloromethyl methyl ether (67 μl) was added to the reaction solution, and the mixture was stirred at room temperature for additional 30 min. The solvent was removed by distillation under the reduced pressure, and water was added to the residue. The mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC by development with chloroform/methanol to give 18 mg (yield 18%) of the title compound.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][CH2:20]3)[CH2:16][CH2:15]1)=[O:13])[CH2:8]2.CCN(C(C)C)C(C)C.[C:37](Cl)(=[O:39])[CH3:38]>C(Cl)Cl>[C:37]([N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17]2([CH2:16][CH2:15][N:14]([C:12]([NH:11][CH:2]3[CH:3]4[CH2:9][CH:7]5[CH2:6][CH:5]([CH2:10][CH:1]3[CH2:8]5)[CH2:4]4)=[O:13])[CH2:19][CH2:18]2)[CH2:20]1)(=[O:39])[CH3:38]
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)N1CCC2(CC1)CNc1ccccc12
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.8 %

Procedure:
To a solution N-(2-adamantyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide (50 mg, 0.108 mmol) and DIEA (27.86 g, 0.22 mmol) in dry CH2Cl2 (2-mL) at 0° C. under nitrogen was added dropwise a solution of acetyl chloride (9.28 mg, 0.12 mmol) in CH2Cl2 (0.5 mL). The mixture was stirred overnight at rt and evaporated to give a residue, which was purified by preparative HPLC to provide a white solid 1-acetyl-N-(2-adamantyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide (5.2 mg, 12%). 1H NMR (400 MHz, CD3OD): δ=1.61 (s, 1H), 1.653 (d, 2H), 1.72 (s, 1H), 1.88 (m, 10H), 2.015 (d, 5H), 2.286 (s, 3H), 3.027 (t, 2H), 3.867 (s, 1H), 4.088 (d, 4H), 7.044 (t, 1H), 7.191 (t, 2H), 8.082 (d, 1H); LC-MS (4 min) tR=1.59 min, m/z=408(M++1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[NH:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][CH2:13]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:12]1[CH2:13][CH2:14][CH:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:16][CH2:17]1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccccc2Br)CC1

Procedure:
A solution of 2-bromobenzene-1-sulfonyl chloride (50 mg, 0.20 mmol), tert-butyl piperidin-4-ylcarbamate (49 mg, 0.25 mmol), and diisopropylethyl amine (0.101 mL, 0.59 mmol) in CH2Cl2 was stirred for 90 min at rt. The reaction mixture was then concentrated to dryness to give the title compound in quantitative yield. The product was used without further purification.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][C:14]([NH:16][NH2:17])=[O:15])[CH:8]=2)[NH:3]1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[Cl:28])[C:22](O)=O.C(N(CC)CC)C.CCCP(=O)=O>CN(C=O)C>[Cl:18][C:19]1[CH:20]=[C:21]([C:22]2[O:15][C:14]([CH2:13][O:12][C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[NH:3][C:2](=[O:1])[CH:11]=[CH:10]4)=[N:16][N:17]=2)[CH:25]=[CH:26][C:27]=1[Cl:28]
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Reactant: NNC(=O)COc1ccc2[nH]c(=O)ccc2c1
Agent: CCCP(=O)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=c1ccc2cc(OCc3nnc(-c4ccc(Cl)c(Cl)c4)o3)ccc2[nH]1
Temperature: 100 °C
Yield: 4.8 %

Procedure:
To a stirred solution of 2-((2-oxo-1,2-dihydroquinolin-6-yl)oxy)acetohydrazide (0.2 g, 0.858 mmol) and 3,4-dichlorobenzoic acid (0.163 g, 0.858 mmol)) in DMF (8 mL) was added triethylamine (0.598 mL, 4.29 mmol) and propylphosphonic anhydride (T3P) (0.819 g, 2.57 mmol). The reaction mixture was heated at 100° C. overnight under N2 atm. The reaction mixture was concentrated to remove solvent and ice-cold water was added. The precipitate was filtered and washed with water to afford a brown solid. The crude product was purified by preparative HPLC on a C18 reverse phase column (ACN-NH4OAc method) to give 6-((5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl)methoxy)quinolin-2(1H)-one as a white solid (0.016 g, 4.81%). 1H NMR: 400 MHZ, DMSO-d6: δ 5.51 (s, 1H), 6.52 (d, J=9.60 Hz, 1H), 7.27-7.31 (m, 2H), 7.43 (d, J=2.40 Hz, 1H), 7.83-7.92 (m, 2H), 8.00 (dd, J=1.60, 8.40 Hz, 1H), 8.21 (d, J=1.60 Hz, 1H), 11.68 (s, 1H). LCMS: RT 1.92 min. LCMS (ES-API), m/z 390.0 (M+H).
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH2:11][O:12][C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[C:16]([C:22]([OH:24])=O)[NH:17]4)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[ClH:25].Cl.Cl.[C@H:28]1([CH2:38][N:39]2[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]2)[C@@H:37]2[N:32]([CH2:33][CH2:34][CH2:35][CH2:36]2)[CH2:31][CH2:30][CH2:29]1>>[ClH:25].[ClH:25].[C@H:28]1([CH2:38][N:39]2[CH2:44][CH2:43][CH:42]([NH:45][C:22]([C:16]3[NH:17][C:18]4[C:14]([CH:15]=3)=[C:13]([O:12][CH2:11][C:7]3[C:6]5[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:10]=5[O:9][CH:8]=3)[CH:21]=[CH:20][CH:19]=4)=[O:24])[CH2:41][CH2:40]2)[C@@H:37]2[N:32]([CH2:33][CH2:34][CH2:35][CH2:36]2)[CH2:31][CH2:30][CH2:29]1
Reactant: O=C(O)c1cc2c(OCc3coc4c(F)cccc34)cccc2[nH]1
Reactant: NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1
Agent: Cl
Product: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4c(F)cccc34)cccc2[nH]1

Procedure:
This compound is synthesized from 4-(7-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (114) (preparation see below) and amine 61 analogously to the method described in example 1.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:20]=[C:21]([CH3:23])[CH:22]=1)[O:7][C:8]1[C:9]([CH2:18][CH3:19])=[C:10]([CH:16]=[O:17])[NH:11][C:12](=[O:15])[C:13]=1[I:14].O>CO>[CH3:23][C:21]1[CH:20]=[C:6]([CH:5]=[C:4]([CH3:3])[CH:22]=1)[O:7][C:8]1[C:9]([CH2:18][CH3:19])=[C:10]([CH2:16][OH:17])[NH:11][C:12](=[O:15])[C:13]=1[I:14]
Reactant: CCc1c(C=O)[nH]c(=O)c(I)c1Oc1cc(C)cc(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCc1c(CO)[nH]c(=O)c(I)c1Oc1cc(C)cc(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaBH4 (0.047 g; 1.3 mmol) was added to a mixture of compound 159 (0.5 g; 0.013 mol) in methanol (3 ml). The mixture was stirred at room temperature for 1 hour. Water was added. The precipitate was filtered off, taken up in diisopropyl ether and dried to yield 0.26 g (52%), m.p.=70° C.).
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([CH3:19])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:20][CH2:21][O:22][CH3:23])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].[Li+].CC([N-]C(C)C)C.[I:32]I>C1COCC1.CCOC(C)=O>[CH2:1]([C:5]12[CH2:17][CH:16]([I:32])[C:15](=[O:18])[C:14]([CH3:19])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:20][CH2:21][O:22][CH3:23])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12CCC(=O)C(C)=C1c1ccc(OCOC)cc1C2
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCC12Cc3cc(OCOC)ccc3C1=C(C)C(=O)C(I)C2
Temperature: 25 °C

Procedure:
A solution of 9a-butyl-7-methoxymethoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (134 mg, 0.43 mmol) in anhydrous THF (2.5 mL) was cooled in an ice bath, stirred under a nitrogen atmosphere, and treated with 0.4M LDA in THF (1.2 mL, 0.48 mmol). After stirring at 0° C. for 30 minutes, the enolate solution was cooled to −78° C. and treated with a solution of iodine (540 mg, 2.13 mmol) in THF. The resulting mixture was allowed to gradually warm to room temperature, then stirred at room temperature overnight. The mixture was diluted with EtOAc (50 mL), washed with 1N HCl, saturated aqueous Na2SO3 (2×30 mL), water, 5% NaHCO3, and brine, dried over MgSO4, filtered, and evaporated under vacuum to provide crude (2SR,9aRS)-9a-butyl-2-iodo-7-methoxymethoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one as a gum.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:22][CH3:23])=[C:9]([CH2:11][N:12]3[CH:16]=[CH:15][N:14]=[C:13]3[C:17]3[S:18][CH:19]=[CH:20][N:21]=3)[N:10]=2)[N:7]=1.[CH2:24]([O:26]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:25].Cl.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[CH2:22]([C:8]1[N:6]2[N:7]=[C:2]([C:24](=[O:26])[CH3:25])[CH:3]=[CH:4][C:5]2=[N:10][C:9]=1[CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[C:17]1[S:18][CH:19]=[CH:20][N:21]=1)[CH3:23]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CCc1c(Cn2ccnc2-c2nccs2)nc2ccc(Cl)nn12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1c(Cn2ccnc2-c2nccs2)nc2ccc(C(C)=O)nn12
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of 6-chloro-3-ethyl-2-(2-thiazol-2-yl-imidazol-1-ylmethyl)-imidazo[1,2-b]pyridazine (100 mg, 0.26 mmol), 1-ethoxyvinyltributylstannane (142 mg, 0.39 mmol) and PdCl2(Ph3P)2 (10 mg) in anhydrous toluene (5 mL) is heated at 110° C. in a sealed tube for 5 hours. On cooling, water (2 mL), and concentrated HCl (2 mL) are added and the mixture is stirred at room temperature for 2 hours. The mixture is neutralized with sodium carbonate solution and extracted with methylene chloride (3×15 mL). The combined organic layers are dried (Na2SO4) and the solvent removed. The residue is purified by PTLC (5% methanol in methylene chloride) to give 1-[3-ethyl-2-(2-thiazol-2-yl-imidazol-1-ylmethyl)imidazo[1,2-b]pyridazin-6-yl]ethanone as a solid. 1H NMR (CDCl3): 7.95, d (1H); 7.86, d (1H0; 7.70, d (1H); 7.36, d (1H); 7.25, d (1H); 7.11, d (1H); 6.18, s (2H); 3.10, q (2H); 2.75, s (3H); 1.18, t (3H).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11])[OH:4].[C:23]1([CH2:29][CH2:30][C:31](Cl)=[O:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH:3]([OH:4])[CH:2]([NH:1][C:31](=[O:32])[CH2:30][CH2:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccccc1F
Reactant: O=C(Cl)CCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CCc1ccccc1)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(2-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in ethyl acetate (20 ml) were added 3-phenylpropionyl chloride (320 ml, 2.15 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (497 mg, 78%).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[C:12]2[CH:11]=[CH:10][S:9][C:8]=2[CH:7]=[CH:6][CH:5]=1.C([O-])(=O)C.[Na+]>ClCCl>[Br:1][C:11]1[C:12]2[C:4]([CH3:3])=[CH:5][CH:6]=[CH:7][C:8]=2[S:9][CH:10]=1
Reactant: Cc1cccc2sccc12
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccc2scc(Br)c12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of bromine (2.94 ml) in dichloromethane (30 ml) was added dropwise under nitrogen at −5° C. to a stirred mixture of 4-methylbenzo[b]thiophene (7.68 g), sodium acetate (6.38 g) and dichloromethane (100 ml). The mixture was stirred at ambient temperature for 6 hours, then it was filtered and the solvent was removed in vacuo. The residue was was distilled in vacuo to give 3-bromo-4-methylbenzo[b]thiophene (6.04 g) as a yellow oil, b.p. 100-120° C. @ 0.4 mmHg, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].S(Cl)([Cl:19])(=O)=O>C(OCC)C>[Cl:19][CH:9]([C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)CC(=O)c1ccccc1F
Solvent: CCOCC
Product: CCOC(=O)C(Cl)C(=O)c1ccccc1F
Yield: 97.2 %

Procedure:
Using ethyl 3-(2-fluorophenyl)-3-oxopropanoate (1.0 g, 4.75 mmol), sulfuryl chloride (771 mg, 5.7 mmol) and diethyl ether (50 mL) as starting materials and in the same manner as in Example 20-B (i), the title compound (1.13 g, 97%) was obtained as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.C(O[C:12](=[O:14])[CH3:13])(=O)C.[CH2:15]([NH:22][C:23](=[O:54])[NH:24][C:25]1[CH:52]=[CH:51][C:50]([NH2:53])=[CH:49][C:26]=1[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][N:33]([CH:36]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:32][CH2:31]1)=[O:28])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>ClCCl>[CH2:15]([NH:22][C:23](=[O:54])[NH:24][C:25]1[CH:52]=[CH:51][C:50]([NH:53][C:12](=[O:14])[CH3:13])=[CH:49][C:26]=1[C:27]([NH:29][CH:30]1[CH2:31][CH2:32][N:33]([CH:36]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:34][CH2:35]1)=[O:28])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCNC(=O)Nc1ccc(N)cc1C(=O)NC1CCN(C(c2ccccc2)c2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCNC(=O)Nc1ccc(NC(C)=O)cc1C(=O)NC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 24 h
Yield: 807.6 %

Procedure:
Triethylamine (0.098 ml, 0.65 mmol) and acetic anhydride (0.067 ml, 0.07 mmol) were added to a solution of the 2-(N'-n-heptylureido)-5-amino-N-(1-diphenylmethylpiperidin-4-yl)-benzamide (0.32 g, 0.59 mmol) in dichloromethane (3 ml) at room temperature. The mixture was stirred for 24 hours and then concentrated. The residue was purified by column chromatography on silica gel (50% ethyl acetate in cyclohexane) to give 2-(N'-n-heptylureido)-5acetylamino-N-(1-diphenylmethylpiperidin-4-yl)benzamide (0.33 g, 96.0%): mp 113°-115° C., 1H NMR (CDCl3)ppm: 0.86 (3H, t), 1.27 (8H, m), 1.49-1.69 (4H, m), 1.92-2.08 (4H, m), 2.17 (3H, s), 2.85 (2H, m), 3.22 (2H, q), 3.90 (1H, m), 4.28 (1H, s), 4.57 (1H, t), 6.40 (1H, d), 7.03 (1H, dd), 7.15-7.40 (11H, m), 8.06 (1H, d), 8.30 (1H, d), 10.10 (1H, s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([C:12]([S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:7][P:8](Cl)(Cl)=[O:9])[CH3:2].[CH2:23]([NH2:27])[CH2:24][CH2:25][CH3:26]>C(OCC)C>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([C:12]([S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:7][P:8]([NH:27][CH2:23][CH2:24][CH2:25][CH3:26])([NH:27][CH2:23][CH2:24][CH2:25][CH3:26])=[O:9])[CH3:2]
Reactant: CCCCN
Reactant: CCOC(=O)CN(CP(=O)(Cl)Cl)C(=O)SCc1ccccc1
Solvent: CCOCC
Product: CCCCNP(=O)(CN(CC(=O)OCC)C(=O)SCc1ccccc1)NCCCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.2 %

Procedure:
Freshly prepared ethyl-N-[(benzylthio)carbonyl]-N-[dichlorophosphinylmethyl]-glycinate (11.3 g.; 0.029 mol.) dissolved in 100 ml. of diethyl ether was added to a solution containing n-butylamine (8.6 g.; 0.118 mol.) in 100 ml. of diethyl ether. The reaction mixture was stirred for 16 hours at 25° C., then filtered. The filtrate was washed with water, dried over magnesium sulfate and concentrated in vacuo to yield ethyl-N-[(benzylthio)carbonyl]-N-[bis(n-butylamino)phosphinylmethyl]-glycinate (12.5 g.) as a solid having a melting point of 45°-48° C., and the following analysis:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Cl:13][CH2:14][CH2:15][N:16]=[C:17]=[O:18].C(N(CC)CC)C>C(C(C)=O)C>[Cl:13][CH2:14][CH2:15][NH:16][C:17](=[O:18])[O:12][C:9]1[CH:10]=[CH:11][C:2]([Cl:1])=[C:3]2[C:8]=1[N:7]=[CH:6][CH:5]=[CH:4]2
Reactant: O=C=NCCCl
Reactant: Oc1ccc(Cl)c2cccnc12
Solvent: CCC(C)=O
Solvent: CCN(CC)CC
Product: O=C(NCCCl)Oc1ccc(Cl)c2cccnc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Chloro-8-hydroxyquinoline (35.9 g), 2-chloroethyl isocyanate (21.1 g), and triethylamine (2.02 g) were mixed in 400 ml of methyl ethyl ketone and heted at reflux temperature with stirring for about one hour. The reaction mixture, upon cooling to room temperature, yielded the desired 5-chloro-8-quinolinyl N-(2chloroethyl)carbamate as glistening, cream colored cystals, m.p. 146° C.