Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[H-].[Na+].[C:14]([O:18][C:19](=[O:30])[NH:20][CH:21]([CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[CH:22]=O)([CH3:17])([CH3:16])[CH3:15].O>C1COCC1>[CH3:1][O:2][C:3](=[O:4])[CH:5]=[CH:22][CH:21]([NH:20][C:19]([O:18][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:30])[CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: CC(C)(C)OC(=O)NC(C=O)C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C=CC(NC(=O)OC(C)(C)C)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice cooled solution of trimethyl phosphonoacetate (19 mL, 0.11 mol) in THF (200 mL) was added 60% NaH (3.1 g, 0.08 mol) in portions. The ice bath was removed and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was then cooled to 0° C. before a solution of (1-cyclohexyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (9 g, 37 mmol) in THF (200 mL) was added. The reaction mixture was stirred at room temperature for another 20 min. Water (100 mL) was added, and then most of the THF was evaporated. The product was extracted with EtOAc (400 mL), and the organic layer was washed with aqueous NaCl solution and then dried with MgSO4. Evaporation yielded a residue which was purified by column chromatography (1:1 heptane:EtOAc) to yield 4-tert-butoxycarbonylamino-4-cyclohexyl-but-2-enoic acid methyl ester as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[OH-].[K+].Cl[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[Cl:23]>CS(C)=O.O.ClCCl>[F:1][C:2]1[CH:8]=[C:7]([O:9][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[Cl:23])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1
Reactant: Nc1ccc(O)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F
Reaction time: 20 h
Yield: 23.2 %

Procedure:
A solution of 2-fluoro-4-hydroxyaniline (7.1 g) and potassium hydroxide (3.7 g, 85% pure) in dimethylsulphoxide (25 ml) was heated to 80° C. and treated with a solution of 1,2-dichloro-4-(trifluoromethyl)benzene (10.9 g) in dimethylsulphoxide (10 ml). The mixture was stirred at 90°-95° C. for 20 hours, after which time it was diluted with a mixture of water and dichloromethane. The organic phase was dried over sodium sulphate and evaporated down to give 3.6 g of the crude desired product as a brown oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]([CH3:18])[NH:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Cl:19]N1C(=O)CCC1=O.O>CN(C)C=O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]([CH3:18])[NH:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:9][C:10]=1[Cl:19])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C2=NNC(=O)NC2C)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ccc(C2=NNC(=O)NC2C)cc1Cl
Yield: 58.1 %

Procedure:
A solution of 6-(4-acetamidophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.5 g) and N-chlorosuccinimide (0.41 g) in dimethylformamide (7 ml) was stirred at 40° C. for 3 hours and then poured into water. The thus-produced crsytals were collected by filtration, washed with water and dried to give 6-(4-acetamido-3-chlorophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.331 g).
Reaction SMILES: [CH2:1]([O:5][CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4].[N+:15]([CH3:18])([O-:17])=[O:16].C[O-].[Na+].Cl.[BH4-].[Na+]>CO.CS(C)=O.C(O)(=O)C>[CH2:1]([O:5][CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][CH2:18][N+:15]([O-:17])=[O:16])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCc1ccc(C=O)cc1
Reactant: C[N+](=O)[O-]
Agent: C[O-]
Agent: Cl
Agent: [BH4-]
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: CCCCOCc1ccc(CC[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 294.1 %

Procedure:
To a solution of 4-butoxymethyl-benzaldehyde (7.39 g, 3.84 mmol) described in Manufacturing Example 4-1-2 in methanol (140 mL) was added nitromethane (2.70 mL, 49.9 mmol) followed by sodium methoxide (1.49 M methanol solution, 9.41 mL, 46.1 mmol) at 0° C. The reaction solution was stirred for 30 minutes at room temperature, and 5 N aqueous hydrochloric acid solution (120 mL) was added thereto and stirred for further 25 minutes. This reaction solution was partitioned into saturated aqueous sodium chloride and ethyl acetate at 0° C. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. To a solution of the resulting residue in dimethyl sulfoxide (100 mL) and acetic acid (6 mL) was added sodium borohydride (1.84 g, 46.1 mmol) at room temperature while cooling appropriately. This solution was then stirred for 80 minutes at room temperature. The reaction solution was partitioned into water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1) to obtain the title compound (2.68 g, 29%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][NH:10][CH2:9][C:8]=3[C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[C:24](Cl)(=[O:33])[C:25]1[C:26]([O:31][CH3:32])=[CH:27][CH:28]=[CH:29][CH:30]=1.Cl.CCOCC>C1COCC1>[ClH:1].[Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][N:10]([C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[O:31][CH3:32])=[O:33])[CH2:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: COc1ccccc1C(=O)Cl
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Agent: Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)N1CCc2[nH]c3ncc(Cl)cc3c2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.7 %

Procedure:
3-Chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg, 0.24 mmol) and DIEA (0.05 mL, 0.29 mmol) were dissolved in THF (2 mL). o-Anisoyl chloride (0.04 mL, 0.29 mmol) was added dropwise, and the reaction solution was stirred at room temperature for 1 h. The crude reaction mixture was concentrated, and converted to the HCl salt by dissolving the crude material in MeOH (2 ml) and adding 1 M HCl/ether (2 equiv). The resulting solution was refrigerated overnight. The resulting precipitate was filtered and dried under vacuum to provide 24 (48 mg, 53% yield) as an off white solid. LC-MS (M+H=342, obsd.=342).
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[CH2:7][CH:8]([NH:13][C:14]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][N:17]1[C:22]([N:24]1[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[S:31][C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23])=[O:15])[CH:9]([OH:12])[CH2:10][F:11])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:38])[CH2:7][CH:8]([NH:13][C:14]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][N:17]1[C:22]([N:24]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=2[S:31][C:32]2[C:37]1=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:23])=[O:15])[C:9](=[O:12])[CH2:10][F:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(NC(=O)C1CCCCN1C(=O)N1c2ccccc2Sc2ccccc21)C(O)CF
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC(NC(=O)C1CCCCN1C(=O)N1c2ccccc2Sc2ccccc21)C(=O)CF
Temperature: 25 °C
Yield: 75.1 %

Procedure:
A stirred solution of [3S/R, 4S/R (2S)]-5-fluoro-4-hydroxy-3-{[1-(phenothiazine-10-carbonyl)piperidine-2-carbonyl]amino}-pentanoic acid tertbutyl ester (294 mg, 0.541 mmol) in anhydrous DCM (10 mL) was treated with 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (344 mg, 0.812 mmol) at 0° C. The resulting mixture was allowed to warm to room temperature over 2 h, diluted with ethyl acetate, then poured into a 1:1 mixture of saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium thiosulphate. The organic layer was removed and the aqueous layer re-extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (30% ethyl acetate in hexane) to afford the sub-title compound as a pale pink foam (220 mg, 75%): 1H NMR (400 MHz, CDCl3) δ 0.84-0.96 (1H, m), 1.20-1.40 (10H, m+2s), 1.51-1.56 (3H, m), 2.20-2.27 (1H, m), 2.70-2.98 (3H, m), 3.49-3.63 (1H, m), 4.74-5.24 (4H, m), 7.14-7.18 (2H, m), 7.28-7.38 (4H, m), 7.48-7.79 (3H, m); 13C (100 MHz, CDCl3) δ 20.8/21.0 (CH2), 23.7/23.9 (CH2), 25.8/25.9 (CH2), 28.2/28.3 (CH3), 36.8/36.9 (CH2), 46.0/46.1 (CH2), 52.9 (CH), 56.8 (CH), 82.6 (C), 84.4/84.5 (2d, J 184.0/183.3, CH2F), 123.7/123.8 (CH), 126.1 (CH), 128.0/128.1 (CH), 128.2/128.3 (CH), 130.4/130.5 (C), 141.4 (C), 160.0 (C), 170.0 (C), 171.7 (C), 202.9 (C); 19F (376 MHz, CDCl3) δ -231.9 (t), −232.2 (t).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[NH:4][CH2:5][CH:6]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[F:20])[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[C:22]([O:26][C:27]([N:29]1[CH:38]([C:39](=[O:53])[NH:40][CH:41]([C:50](O)=[O:51])[CH2:42][C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=2)[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[C:22]([O:26][C:27]([N:29]1[CH:38]([C:39](=[O:53])[NH:40][CH:41]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=2)[C:50]([N:10]2[CH2:11][CH2:12][N:7]([CH:6]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[CH2:5][NH:4][C:3]([O:2][CH3:1])=[O:21])[CH2:8][CH2:9]2)=[O:51])[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2CC1C(=O)NC(Cc1ccc(Cl)cc1)C(=O)O
Reactant: COC(=O)NCC(c1ccc(F)cc1F)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)NCC(c1ccc(F)cc1F)N1CCN(C(=O)C(Cc2ccc(Cl)cc2)NC(=O)C2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.7 %

Procedure:
To [2-(2,4-Difluoro-phenyl)-2-piperazin-1-yl-ethyl]-carbamic acid methyl ester (516) (0.14 g, 0.47 mmol), 3-[1-Carboxy-2-(4-chloro-phenyl)-ethylcarbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (0.22 g, 0.47 mmol) and O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.178 g, 0.47 mmol) was added MeCl2 (1.0 mL) and DMF (0.2 mL) followed by DIPEA (0.82 mL, 4.7 mmol). The reaction was allowed to stir at room temperature for 4 h. The reaction mixture was then concentrated to dryness. The resulting residue was taken up in EtOAc (30 mL) and washed with sat. NaHCO3 (30 mL) and brine (30 mL). The organic phase was concentrated to dryness. The crude material was purified by chromatography (silica gel 60 mesh, eluting with a gradient of 100% EtOAc to 5% TEA/5% MeOH in EtOAc) yielding 0.34 g (98%) pure product.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[F:17])(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=1[CH3:26]>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=1[CH3:26])=[CH:13][CH:12]=[CH:11][C:10]=2[F:17])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(F)cccc2c1Cl
Reactant: Cc1cc(O)ccc1N
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(F)cccc2c1Nc1ccc(O)cc1C
Yield: 50.7 %

Procedure:
3-butyryl-4-chloro-8-fluoroquinoline (1.75 g, 7 mmol), 4-amino-3-methylphenol (1.3 g, 10 mmol) and 1,4-dioxan (50 ml) were heated at reflux for 6.5 hours, then the solvent evaporated and the product converted to free base. Recrystallisation from methanol gave 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-8-fluoroquinoline (1.2 g), m.p. 205°-207°.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=NC=[CH:10][C:5]=2[S:4][CH:3]=1.S1C2=[CH:16][N:17]=CC=C2C=C1>>[Br:1][C:2]1[C:6]2[C:5](=[CH:10][N:17]=[CH:16][CH:7]=2)[S:4][CH:3]=1
Reactant: c1cc2ccsc2cn1
Reactant: Brc1csc2ccncc12
Product: Brc1csc2cnccc12

Procedure:
The title compounds is prepared essentially as described in synthesis of 3-bromothieno[3,2-c]pyridine using thieno[2,3-c]pyridine. mass spectrum (m/e): 215 (M+1).
Reaction SMILES: [OH:1][C@@H:2]([C:27]([CH3:35])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:28])[C:3]([NH:5][C@@H:6]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:7]([N:9]([CH3:22])[C@@H:10]([CH:19]([CH3:21])[CH3:20])/[CH:11]=[C:12](\[CH3:18])/[C:13]([O:15]CC)=[O:14])=[O:8])=[O:4].O[C@H](C(C)(C1C=CC=CC=1)C)C(N[C@@H](C(C)(C)C)C(N(C)[C@@H](C(C)C)/C=C(\C)/C(OCC)=O)=O)=O.O.O.[OH-].[Li+]>CO.O1CCCC1>[OH:1][C@@H:2]([C:27]([CH3:35])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH3:28])[C:3]([NH:5][C@H:6]([C:7]([N:9]([CH3:22])[C@@H:10]([CH:19]([CH3:21])[CH3:20])/[CH:11]=[C:12](\[CH3:18])/[C:13]([OH:15])=[O:14])=[O:8])[C:23]([CH3:24])([CH3:25])[CH3:26])=[O:4]
Reactant: CCOC(=O)/C(C)=C/[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@@H](O)C(C)(C)c1ccccc1)C(C)(C)C
Agent: CCOC(=O)/C(C)=C/[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@H](O)C(C)(C)c1ccccc1)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C/C(=C\[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@@H](O)C(C)(C)c1ccccc1)C(C)(C)C)C(=O)O
Temperature: 65 °C
Reaction time: 16 h

Procedure:
A 1:1 mixture of ethyl (E,4S)-4-[((2S)-2-{[(2S)-2-hydroxy-3-methyl-3-phenylbutanoyl]amino}-3,3-dimethylbutanoyl)(methyl)amino]-2,5-dimethyl-2-hexenoate and ethyl (E,4S)-4-[((2S)-2-{[(2R)-2-hydroxy-3-methyl-3-phenylbutanoyl]amino}-3,3-dimethylbutanoyl)(methyl)amino]-2,5-dimethyl-2-hexenoate (0.34 g, 0.70 mmol, from Reference Example 41) is dissolved in methanol (3.2 mL) and tetrahydrofuran (3.2 mL). To this solution is added water (1.6 mL) and lithium hydroxide monohydrate (64 mg, 1.5 mmol), and the resulting mixture is stirred at 65° C. for 16 hours. Solvents are removed in vacuo and the residue is then dissolved in water. The solution is acidified to pH 1 with 2 M aqueous hydrochloric acid solution and then extracted thrice with ethyl acetate. The combined extracts are washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, decanted, and concentrated under reduced pressure to afford a white foam. A sample of this crude material (200 mg) is subjected to HPLC purification (Prodigy OS3 column, acetonitrile/water/TFA) to give (E,4S)-4-[{N-[(2S)-2-hydroxy-3-methyl-3-phenylbutanoyl]-3-methyl-L-valyl}(methyl)amino]-2,5-dimethyl-2-hexenoic acid as a hard white foam, which is crushed into a powder (50 mg). MS (ES+): (M+H)=461.0
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]=[C:9]2S(C)(=O)=O)=[CH:4][CH:3]=1.O1CCCC1.O.[NH2:29][NH2:30]>[Cl-].[Na+].O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]=[C:9]2[NH:29][NH2:30])=[CH:4][CH:3]=1
Reactant: NN
Reactant: CS(=O)(=O)c1nc(C(F)(F)F)cc(=O)n1-c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: NNc1nc(C(F)(F)F)cc(=O)n1-c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A mixture of 3-(4-chlorophenyl)-3,4-dihydro-2-methanesulfonyl-6-trifluoromethylpyrimidin-4-one (2.0 g) and tetrahydrofuran (20 ml) was added with hydrazine monohydrate (NH2NH2. H2O) (0.5 g). After stirring for 30 minuets at room temperature, the mixture was added with saturated brine (30 ml) and then extracted with ethyl acetate. The extract layer was washed with water and then dried on anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the compound of interest (1.5 g) as a milk white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[C:4](=[O:32])[CH:5]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)[C:6]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])=[O:7])[CH3:2].[O:35]=[C:36]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:38]2(CCNCC2)[CH2:37]1>>[CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][C:12]=1[S:9]([NH:8][C:6](=[O:7])[CH:5]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=1)[C:4](=[O:32])[N:3]1[CH2:1][CH2:2][C:38]2([C:44]3[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:36](=[O:35])[CH2:37]2)[CH2:34][CH2:33]1)(=[O:10])=[O:11]
Reactant: CCN(CC)C(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Reactant: O=C1CC2(CCNCC2)c2ccccc21
Product: O=C1CC2(CCN(C(=O)C(Cc3ccc([N+](=O)[O-])cc3)C(=O)NS(=O)(=O)c3ccc4ccccc4c3)CC2)c2ccccc21
Yield: 23.7 %

Procedure:
In the same manner as in Example 1 (4), a crude product was obtained using the compound (300 mg) obtained in Example 6 (4) and 3-oxospiro[indane-1,4′-piperidine] (141 mg). This was purified by silica gel column chromatography to give the title compound (90 mg) as a white powder.
Reaction SMILES: [CH3:1][N:2]([CH3:38])[CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[S:18][C:17]3[C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:15][C:14]([Sn](CCCC)(CCCC)CCCC)=[N:13][C:12]=3[CH:11]=2)[CH2:5][CH2:4]1.[CH2:39]([O:46][C:47]1[C:48]2[N:49]([CH:54]=[CH:55][N:56]=2)[C:50](Br)=[CH:51][CH:52]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>O1CCOCC1.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.[Cu]I>[CH2:39]([O:46][C:47]1[C:48]2[N:49]([CH:54]=[CH:55][N:56]=2)[C:50]([C:14]2[N:15]=[C:16]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[C:17]3[S:18][C:10]([CH2:9][N:6]4[CH2:5][CH2:4][CH:3]([N:2]([CH3:38])[CH3:1])[CH2:8][CH2:7]4)=[CH:11][C:12]=3[N:13]=2)=[CH:51][CH:52]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: Brc1ccc(OCc2ccccc2)c2nccn12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCC(N(C)C)CC3)cc2n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CN(C)C1CCN(Cc2cc3nc(-c4ccc(OCc5ccccc5)c5nccn45)nc(N4CCOCC4)c3s2)CC1
Temperature: 140 °C
Yield: 92.5 %

Procedure:
A mixture of dimethyl-[1-(4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperidin-4-yl]amine (230 mg, 0.35 mmol), 8-benzyloxy-5-bromoimidazo[1,2-a]pyridine (127 mg, 0.42 mmol), Pd(PPh3)4 (40 mg, 0.035 mmol) and copper(I) iodide (66 mg, 0.35 mmol) in dioxane (3 mL) was purged with argon gas then heated at 140° C., for 20 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with MeOH then the desired product was eluted with 2 M NH3 in MeOH. The appropriate fractions were combined and evaporated. The resulting residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 20:80) to give {1-[2-(8-Benzyloxyimidazo[1,2-a]pyridin-5-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]piperidin-4-yl}dimethylamine as a white solid (189 mg, 92%). LCMS (Method H): RT 3.07 min; [M+H]+ 584
Reaction SMILES: [CH2:1]([C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]=1[C:14]([OH:16])=O)[CH3:2].Cl.[Cl:18][CH2:19][CH2:20][CH2:21][NH2:22].C(N(CC)CC)C.O>CN(C)C=O>[Cl:18][CH2:19][CH2:20][CH2:21][NH:22][C:14]([C:4]1[C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][O:7][C:3]=1[CH2:1][CH3:2])=[O:16]
Reactant: NCCCCl
Reactant: CCc1onc(-c2ccccc2)c1C(=O)O
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1onc(-c2ccccc2)c1C(=O)NCCCCl
Yield: 80.2 %

Procedure:
A solution of 3.1 g of 5-ethyl-3-phenylisoxazole-4-carboxylic acid (prepared as described in J. Org. Chem. 1985, 50, 5660-5666), 2.94 g of 3-chloropropylamine hydrochloride, 2.62 mL of 92% diethyl cianoposphonate and 4.38 mL of triethylamine in 50 mL of anhydrous dimethylformamide was stirred at room temperature for 3 hours, poured into 500 mL of water and extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with water, dried (sodium sulphate) and the solvent was evaporated under vacuum. The crude was purified by flash chromatography (ethyl acetate-petroleum ether 3:7) to give 3.35 g (73%) of the title compound. M.p. 75-76° C.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:16]([OH:19])([CH3:18])[CH3:17]>C(OCC)(=O)C>[CH:16]([O:19][C:8](=[N:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:18])[CH3:17]
Reactant: CC(C)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CC(C)OC(=NC1CCCCC1)NC1CCCCC1
Temperature: 55 °C
Reaction time: 6 h
Yield: 80.2 %

Procedure:
A mixture of 3.09 g of dicyclohexylcarbodiimide, 30 mg of cuprous chloride and 994 mg of isopropanol was stirred under an inert atmosphere at 55° C. for 6 hours and was then diluted with ethyl acetate. The organic phase was washed with water, then with N ammonium hydroxide solution, was dried and filtered. The filtrate was evaporated to dryness under reduced pressure to obtain 3.2 g of O-isopropyl-N,N'-dicyclohexyl-isourea which was used as is for the next step.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1.C(=O)([O-])[O-].[K+].[K+].CCOCC>CN(C)C=O>[N:16]1([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=2)[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: c1nc[nH]n1
Reactant: COC(=O)c1ccc(F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-n2cncn2)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
To a solution of methyl 4-fluoro-2-trifluoromethylbenzoate (4.95 g) in N,N-dimethylformamide was added 1,2,4-triazole (2.0 g) and potassium carbonate (4.0 g) at 20° C. and the mixture stirred for 4 hours at 60° C. The mixture was diluted (ether), washed (aqueous citric acid) and dried (magnesium sulfate). The residue was purified by chromatography to give methyl 4-(1,2,4-triazol-1-yl)-2-trifluoromethylbenzoate (5.07 g), NMR 3.98(s,3H),7.94-8.05(2H),8.15(2H),8.71 (s,1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]=[N+]=[N-])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCCCN=[N+]=[N-])cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1ccc(CCCCN)cc1OC
Yield: 0 %

Procedure:
Amine 26 was prepared as described in procedure A from azide 25 (11.0 g, 49 mol) and LAH (26 mL of 1 M solution in THF). Crude 26 was purified by flash chromatography (silica gel, 93:7:1 chloroform/ethanol/concentrated ammonium hydroxide) to give pure 26 (4.8 g, 42%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 1.42(m, 2H), 1.60 (m, 2H), 2.55 (m, 2H), 2.74 (m, 2H), 3.82 (s, 6H), 3.84 (s, 3H), 6.70 (m, 2H), 6.78 (m, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5](=[O:7])[CH3:6].C(=O)([O-])[O-].[K+].[K+].[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>O1CCCC1>[CH2:3]([O:4][C:5](=[O:7])[CH2:6][N:18]1[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]1)[CH3:2]
Reactant: CN1CCNCC1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22 %

Procedure:
To a solution of bromoethylacetate, 3.3 g (30.0 mmol) in 100 mL of tetrahydrofuran was added 4.14 g (30.0 mmol) of potassium carbonate and 3.3 mL (30.0 mmol) of 4-methylpiperazine. The reaction mixture stirred overnight at rt. and was concentrated to dryness. The residue was partitioned between 20% isopropanol/chloroform and saturated aqueous NaHCO3. The mixture was washed with saturated NaHCO3, washed with brine, dried over Na2SO4, filtered and concentrated to dryness to give 1.23 g (22%) of the desired product as a tan oil. MS (ion spray) 187.1 (M+).