Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:5]=[CH:6][CH:7]=1.[CH:32]1(CCCC(O)=O)CCCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:5]1([CH2:4][CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH2:6][CH2:7][CH2:2][CH2:3][CH2:32]1
Reactant: O=C(O)CCCC1CCCCC1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCCCC2CCCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 4-cyclohexyl-butyric acid and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C.O>CN1CCCC1=O>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:15][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=2)=[CH:12][CH:11]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: Fc1cccc(F)n1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cccc(NCc2ccc(Cl)cc2)n1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To 2,6-difluoropyridine (58, 9.85 g, 0.0856 mol) in N-methylpyrrolidinone (50.0 mL) were added p-chlorobenzylamine (61, 10.5 mL, 8.63 mmol) and N,N-diisopropylethylamine (30.0 mL, 0.172 mol). The reaction was stirred at 90° C. overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 25% ethyl acetate in hexane, then washed with ethyl acetate/hexane to give a white solid (536, 10 g, 50%).
Reaction SMILES: Cl.[CH:2]([C:5](C(C)C)([CH:8]([CH3:10])C)[CH2:6][NH2:7])([CH3:4])[CH3:3].[N:14](C1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1)=C=O>CN(C)C=O.O1CCCC1>[CH2:6]1[C:5]2[CH:8]=[CH:10][N:14]=[CH:4][C:2]=2[CH2:3][NH:7]1
Reactant: CC1(C)OB(c2ccc(N=C=O)cc2)OC1(C)C
Reactant: CC(C)C(CN)(C(C)C)C(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: c1cc2c(cn1)CNC2
Temperature: -15 °C
Reaction time: 0.33 h

Procedure:
HCl (1.55 g, 8.03 mmol) was suspended in dimethylformamide (30 ml) and treated with triisopropylethylamine (4.21 ml, 24.08 mmol). After stirring for 20 minutes, the mixture was cooled to −15° C. 2-(4-Isocyanatophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.028 g, 8.03 mmol) was dissolved in 10 ml tetrahydrofuran and added via syringe over 10 minutes. The mixture was allowed to warm to room temperature, and it was stirred for 3 hours and concentrated under a stream of nitrogen to minimal volume. The residue was diluted with cold water to give a turbid mixture which was filtered with water washes to provide the title compound after drying.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]3[NH:32][C:31]4[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=4[N:29]=3)[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].CN(C)C=O.[H-].[Na+].Br[CH2:52][CH2:53][CH2:54][CH2:55][C:56]#[N:57]>CO.ClCCl.ClCCl.O>[CH3:43][O:42][C:38]1[CH:37]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:39]=1[O:40][CH3:41])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]3[N:29]([CH2:52][CH2:53][CH2:54][CH2:55][C:56]#[N:57])[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[N:32]=3)[CH2:23][CH2:22]2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1)=[O:7]
Reactant: N#CCCCCBr
Reactant: COc1cc(C(=O)N2CCC(CCN3CCCN(c4nc5ccccc5[nH]4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)N2CCC(CCN3CCCN(c4nc5ccccc5n4CCCCC#N)CC3)(c3ccccc3)C2)cc(OC)c1OC
Reaction time: 12 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine (0.1 g, 0.17 mmol) and dimethylformamide (2 mL). Add sodium hydride (8 mg, 60% in oil, 0.34 mmol). After 12 hours, add 1-bromo-4-cyanobutane (27 mg, 0.17 mmol). After 1.5 hours, add water (5 mL) and dichloromethane (20 mL). Separate the layers and extract the aqueous layer twice with dichloromethane. Combine the organic layers, dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 5% methanol/dichloromethane/0.5% concentrated aqueous ammonia to give the title compound: Rf=0.26 (silica gel, 5% methanol/dichloromethane/0.5% concentrated aqueous ammonia).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[O:6]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=1)[S:3]([C:2]([F:15])([F:14])[F:1])(=[O:4])=[O:5]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: c1ccncc1
Product: O=S(=O)(Oc1ccccn1)C(F)(F)F
Yield: 68 %

Procedure:
In a modification to GP 2, reaction of 1.5 g Intermediate 1.4 (5.3 mmol, 1 eq.), and 2.69 ml trifluoromethanesulfonic acid anhydride (16 mmol, 3 eq.) in pure pyridine yielded 1.49 g 2-pyridyl triflate (3.6 mmol, 68% yield).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[OH-].[Na+].[F:8][C:9]([F:44])([F:43])[C:10]1[CH:11]=[C:12]([CH2:20][O:21][C@@H:22]2[CH2:28][CH2:27][C@@H:26]3[N:29]([CH2:30][CH2:31]OS(C)(=O)=O)[C@@:23]2([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:24][CH2:25]3)[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1.[ClH:45]>C(#N)C.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)C>[ClH:45].[F:18][C:16]([F:17])([F:19])[C:14]1[CH:13]=[C:12]([CH2:20][O:21][C@@H:22]2[CH2:28][CH2:27][C@@H:26]3[N:29]([CH2:30][CH2:31][N:1]4[CH:5]=[N:4][CH:3]=[N:2]4)[C@@:23]2([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:24][CH2:25]3)[CH:11]=[C:10]([C:9]([F:44])([F:8])[F:43])[CH:15]=1
Reactant: c1nc[nH]n1
Reactant: CS(=O)(=O)OCCN1[C@H]2CC[C@@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@]1(c1ccccc1)CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: CC#N
Solvent: CCOCC
Solvent: O
Product: FC(F)(F)c1cc(CO[C@@H]2CC[C@H]3CC[C@]2(c2ccccc2)N3CCn2cncn2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1,2,4-Triazole (25 mg, 0.37 mmol) was dissolved in acetonitrile (2 ml) and sodium hydroxide (44 mg, 1.11 mmol). This was stirred at room temperature for 30 minutes then tetrabutylammonium hydrogen sulphate and (1R*,2R*,5R*)-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-8-(2-mesyloxyethyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 68; 201 mg, 0.37 mmol) added. The reaction was heated to reflux for 2.5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (×3), dried (MgSO4), and concentrated in vacuo to give a brown oil. This was purified by flash column chromatography [5% methanol in dichloromethane] to give a brown oil and the hydrochloride salt was made by adding 1 equivalent of hydrogen chloride in diethyl ether (1N) and the title compound filtered off and dried in vacuo at 60° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12]Br)[CH:3]=1.[CH2:14]([SH:17])[CH:15]=[CH2:16].[O-]CC.[Na+].C(=O)(O)[O-].[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12][S:17][CH2:14][CH:15]=[CH2:16])[CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1CBr
Reactant: C=CCS
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CC[O-]
Agent: O=C([O-])O
Product: C=CCSCc1cc(Br)ccc1C(=O)OC
Yield: 10 %

Procedure:
Methyl 4-bromo-2-bromomethylbenzoate (24.6 g) was added to a stirred mixture of allylmercaptan (70%, 9 g), sodium ethoxide (5.77 g) and tetrabutylammonium iodide (0.4 g) for 15 minutes. Cold sodium bicarbonate solution was added and the mixture extracted with ether. The extract was washed with brine, dried (magnesium sulphate) and evaporated to give methyl 4-bromo-2-(2-propenylsulphenylmethyl)benzoate (2.41 g), NMR (CDCl3) 3.05 (d,2H), 3.9 (s,3H), 4.0 (s,2H), 5.1 (m,2H), 5.75 (m,1H), 7.4 (d,1H), 7.5 (s,1H), 7.75 (d,1H).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][C:9]([CH:12]=[O:13])=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[OH:13][CH:12]([C:9]1[CH:10]=[CH:11][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=Cc1ccn(-c2ccccc2)c1
Reactant: CCCCCBr
Agent: [Mg]
Product: CCCCCC(O)c1ccn(-c2ccccc2)c1
Yield: 95.9 %

Procedure:
This compound was synthesized according to the procedure described in Example 3. Thus, starting from 2.2 g of 1-phenylpyrrole-3-aldehyde, 1.2 g of magnesium and 3.8 g of 1-bromopentane, 3 g of pure product was obtained as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[NH:7][CH3:8].[CH3:13][C:14]([CH3:20])([CH3:19])[CH2:15][C:16](Cl)=[O:17].CN(C=O)C.[H-].[Na+]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([N:7]([CH3:8])[C:16](=[O:17])[CH2:15][C:14]([CH3:20])([CH3:19])[CH3:13])[CH:9]=1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CNc1cc(Br)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)CC(C)(C)C)c1cc(Br)ccc1[N+](=O)[O-]
Temperature: 70 °C

Procedure:
To a mixture of 5-bromo-N-methyl-2-nitroaniline (300 mg), 3,3-dimethylbutanoyl chloride (0.450 ml) and DMF (5 ml) was added NaH (40% oil dispersion, 57.1 mg), and the mixture was heated at 70° C. overnight. The mixture was poured into water, and extracted with EtOAc. The extract was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (214 mg) as a solid.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:19]([OH:21])=O)[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1.CN1CCOCC1>[CH2:22]([NH:29][C:19](=[O:21])[C@@H:9]([CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(=O)O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a cooled (−20° C.) solution of N-Boc-O-benzyl-D-serine (26 g) in tetrahydrofuran (208 mL), N-methylmorpholine (15 mL) was added and reaction mixture was stirred for 5 minutes. isobutylchloformate (18 mL) was added to the reaction mixture in 5 minutes at −20° C. The solution was further stirred for 5 minutes at −20° C. and benzyl amine (15.01 mL) was added to in it in 5 minutes at −20° C. The solution was stirred for 1 hr at −20° C. The solution was allowed to warm at room temperature and stirred for 1 hour. The precipitated hydrochloride salt of N-methylmorpholine was filtered. The filtrate was concentrated under vacuum to obtain solid 17 g N-benzyl-O-benzyl-N2-Boc-D-serinamide after crystallization from diisopropylether.
Reaction SMILES: [CH2:1]([NH:8][C:9]([N:11]1[C@H:16]2[CH2:17][N:18]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34](F)[N:33]=3)[C:19](=[O:30])[C@H:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=3[F:29])[N:15]2[C:14](=[O:39])[CH2:13][N:12]1[CH2:40][CH:41]=[CH2:42])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1C(=O)CCC1.[NH:50]1[CH2:53][CH:52]([N:54]2[CH2:59][CH2:58][N:57]([CH3:60])[C@H:56]([CH3:61])[CH2:55]2)[CH2:51]1.C(C1C=CC=CC=1)C1C=CC=CC=1>O>[CH2:1]([NH:8][C:9]([N:11]1[C@H:16]2[CH2:17][N:18]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([N:50]4[CH2:53][CH:52]([N:54]5[CH2:59][CH2:58][N:57]([CH3:60])[C@H:56]([CH3:61])[CH2:55]5)[CH2:51]4)[N:33]=3)[C:19](=[O:30])[C@H:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=3[F:29])[N:15]2[C:14](=[O:39])[CH2:13][N:12]1[CH2:40][CH:41]=[CH2:42])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1CN(C2CNC2)CCN1C
Reactant: C=CCN1CC(=O)N2[C@@H](Cc3ccc(O)cc3F)C(=O)N(Cc3cccc(F)n3)C[C@@H]2N1C(=O)NCc1ccccc1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: c1ccc(Cc2ccccc2)cc1
Product: C=CCN1CC(=O)N2[C@@H](Cc3ccc(O)cc3F)C(=O)N(Cc3cccc(N4CC(N5CCN(C)[C@H](C)C5)C4)n3)C[C@@H]2N1C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 42.9 %

Procedure:
To a mixed solution of (6S,9aS)-N-benzyl-6-((2-fluoro-4-hydroxyphenyl)methyl)-8-((6-fluoropyridin-2-yl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide (20.0 mg, 0.0347 mmol) described in Production Example 1-1-6 and NMP (2.0 mL) was added a mixture (59.0 mg) of (2R)-4-(azetidin-3-yl)-1,2-dimethylpiperazine and benzylbenzene described in Production Example 5-3 at room temperature. The resultant mixture was irradiated with a microwave at 140° C. for 12 hours. The reaction mixture was cooled to room temperature, and then water was added thereto, the resultant solution was extracted with ethyl acetate, and an organic layer was washed with water and then with saturated brine. An organic layer was dried over anhydrous magnesium sulfate and then filtrated. The solvent was evaporated under a reduced pressure, and the resultant residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=20:1) and then further purified by NH silica gel thin-layer chromatography (ethyl acetate) to give the title compound (10.8 mg, yield: 43%).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH2:6]([N:13]1[C:18](=[O:19])[C:17]2[C:20]3[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[C:21]=3[S:22][C:16]=2[N:15]=[C:14]1[C:28]1[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C[N+](C)=[CH:42][Cl:43].[Cl-].CC([O-])=O.[Na+]>ClCCCl.ClCCl.CN(C=O)C>[CH2:6]([N:13]1[C:18](=[O:19])[C:17]2[C:20]3[CH2:26][CH2:25][C:24]([CH:23]=[O:27])=[C:42]([Cl:43])[C:21]=3[S:22][C:16]=2[N:15]=[C:14]1[C:28]1[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COc1cc(-c2nc3sc4c(c3c(=O)n2Cc2ccccc2)CCCC4=O)cc(OC)c1OC
Reactant: C[N+](C)=CCl
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1cc(-c2nc3sc4c(c3c(=O)n2Cc2ccccc2)CCC(C=O)=C4Cl)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
POCl3 (3.5 ml) was added slowly to a cold, dry DMF (2.3 ml). 3-Benzyl-2-(3,4,5-trimethoxyphenyl)-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione (compound No. 2) (0.5 g, 1.1 mmol) in 1,2-dichloroethane was added slowly to the Vilsmeier reagent and stirred at room temperature for three hours after which the reaction mixture was refluxed for 15 minutes. After stirring overnight at room temperature the reaction mixture was diluted with dichloromethane and neutralized with NaOAc-solution (12 g/100 ml). The product was extracted with dichloromethane (3×30 ml). Organic phase was washed with water and dried. The crude product was purified by flash chromatography. The yield was 0.45 g (82%).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:12](OC)=[O:13])[C:8]2[CH:9]=[CH:10][S:11][C:7]=2[CH2:6][CH2:5][CH2:4]1.[H-].[Li+].[Al+3].[H-].[H-].[H-].[OH-].[Na+]>CCOCC>[CH3:1][N:2]([CH3:16])[C:3]1([CH2:12][OH:13])[C:8]2[CH:9]=[CH:10][S:11][C:7]=2[CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)C1(N(C)C)CCCc2sccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CN(C)C1(CO)CCCc2sccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
65 ml of ether solution containing 7.77 g of 4-dimethylamino-4-methoxycarbonyl-4,5,6,7-tetrahydro-1-benzothiophene obtained in Step 2 was added to an ice-cooled suspension of aluminum lithium hydride (1.23 g) in ether, then stirred for 20 minutes at room temperature. The reaction mixture was added with 5% NaOH solution, filtrated to remove the insoluble matters, followed by drying the organic phase.
Reaction SMILES: CN1C(=O)CCC1.C([O-])(=O)C.[Na+].[CH2:13]([O:15][C:16](=[O:35])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][O:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1Br)[CH3:14].C(OCC)(=O)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:13]([O:15][C:16](=[O:35])/[CH:17]=[C:18]1/[C:28]2[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:27]=2[O:26][CH2:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]/1=2)[CH3:14]
Reactant: CCOC(=O)C=Cc1ccccc1COc1cc(F)ccc1Br
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C1\c2ccccc2COc2cc(F)ccc21
Temperature: 55 °C
Yield: 56.4 %

Procedure:
To a clean, dry 100-gallon reactor with stirring under nitrogen add N-methyl pyrrolidinone (83.4 L), sodium acetate (2.706 kg, 32.98 mol), 3-[2-(2-bromo-5-fluoro-phenoxymethyl)-phenyl]-acrylic acid ethyl ester (9.256 kg, 21.99 mol) and tetrabutylammonium bromide (7.088 kg, 21.99). Initiate stirring and de-gas the reaction mixture under full vacuum for 30 min, purging with nitrogen. Allow the reactor to return to ambient pressure under nitrogen and repeat the degassing procedure. Add palladium (II) acetate (167 g, 2% weight) to the reaction mixture. Heat the reaction to between 100° C. and 125° C., stirring for a minimum of 3 to 5 h. Add ethyl acetate (100 L) and stir 30 min. Add water (100 L) and stir 30 min. Discontinue stirring and allow the layers to separate for a minimum of one hour. Collect the organic layer and extract the aqueous layer with ethyl acetate (50 L, then 25 L). Combine the organic portions and wash with water (40 L), a 20% aqueous sodium chloride solution (2×20 L), stirring for a minimum of 30 min each and allowing at least 30 min for layer separation. Dry the organic solution with magnesium sulfate (8.0 kg) and add activated carbon (2.0 kg) and silica gel 60 (2.0 kg), stirring for a minimum of one hour. Filter to remove the solids. Concentrate the filtrate to dryness under vacuum at <35° C. Add methanol (20 L) to the solid residue and heat the mixture to a clear solution at 50-60° C. Add heptane (40 L) and cool to between 20° C. and 25° C. Continue to further cool the reaction mixture to −10° C. over a minimum of 3 h. Stir at −10° C. for a minimum of 12 h. Filter to collect the resulting solid product, washing with a mixture of heptane:methanol, (75:25) (2×20 L). Dry the solids under vacuum at <40° C. to a constant weight to obtain the title compound (3.7 kg, 64%).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.Cl.[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[C:35]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)=[O:36].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:17][C:14]1[N:13]2[N:18]=[C:19]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[C:12]2[C:11]2[CH:10]=[CH:9][N:8]([CH2:7][CH2:6][N:40]3[CH2:39][CH2:38][N:37]([C:35]([C:29]4[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:28]=4[F:27])=[O:36])[CH2:42][CH2:41]3)[C:16]=2[N:15]=1
Reactant: O=C(c1ccc(F)cc1F)N1CCNCC1
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nc2c(ccn2CCN2CCN(C(=O)c3ccc(F)cc3F)CC2)c2nc(-c3ccco3)nn12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of the title D compound of Example 1, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (0.06 g, 0.165 mmol) in dry DMF (5 mL), the title B compound, (2,4-difluorophenyl)piperazin-1-yl-methanone hydrochloride (0.33 mmol) and 0.06 mL of DIEA are added, and the solution is stirred at 100° C. for 5 h. The reaction mixture is cooled to RT, and the solvent is removed under reduced pressure. To the residue, acetonitrile is added and the solution is stirred at 60° C. for 0.5 h. The solution is then cooled to RT, and the resulting solids are collected by filtration to give (4-(2-(5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl)ethyl)piperazin-1-yl)(2,4-difluorophenyl)methanone: LC/MS (M+1=493.1). 1H NMR (DMSO-d6, 400 MHz) δ 2.42 (m, 2H), 2.72 (t, 2H, J=6.0 Hz), 3.17 (m, 2H), 3.34 (m, 2H), 3.60 (m, 2H), 4.25 (t, 2H, J=6.0 Hz), 6.59 (d, 1H, J=3.2 Hz), 6.72 (m, 1H), 7.18 (m, 3H), 7.38 (m, 1H), 7.46 (m, 1H), 7.54 (brs, 2H, NH2), 7.93 (s, 1H). Anal. calculated for (C24H22F2N8O2+0.5H2O): C, 57.48; H, 4.62; F, 7.58; N, 22.34; 0, 7.98. Found C, 57.40; H, 4.46; N, 22.29.
Reaction SMILES: C(Cl)Cl.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[F:30])[C:15]2[C:20]([CH3:21])=[CH:19][N:18]=[C:17]([NH2:22])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1.N1C=CC=CC=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>CCCCCC.C(OCC)(=O)C>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[F:30])[C:15]2[C:20]([CH3:21])=[CH:19][N:18]=[C:17]([NH:22][S:38]([CH3:37])(=[O:40])=[O:39])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: Cc1cnc(N)cc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCCCCC
Solvent: c1ccncc1
Product: Cc1cnc(NS(C)(=O)=O)cc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 68.3 %

Procedure:
To a methylene chloride (5 ml) solution of [4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-methylpyridin-2-yl]amine (133 mg, 0.325 mmol) and pyridine (39 μl, 0.488 mmol) was added methanesulfonyl chloride (28 μl, 0.358 mmol) under ice cooling. The reaction mixture was stirred at room temperature for 2.5 hours. To the reaction mixture were added pyridine (26 μl, 0.325 mmol) and methanesulfonyl chloride (25 μl, 0.325 mmol). After the resulting mixture was stirred at room temperature for 16 hours, pyridine (26 μl, 0.325 mmol) and methanesulfonyl chloride (25 μl, 0.325 mmol) were added thereto. The resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure. To the residue thus obtained was added ethyl acetate. The resulting mixture was washed sequentially with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=3:2 eluate was concentrated under reduced pressure to give the title compound (108 mg, 0.222 mmol, 68%) as a white solid. The resulting white solid was washed with hexane-ether, and collected by filtration to give the title compound (67 mg) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:14][CH3:15])[C:12]=1[OH:13])[CH:6]=[CH:7][CH:8]=O.[C:16]([CH2:18][C:19]([N-:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:20])#[N:17]>>[C:25]1([CH2:24][CH2:23][CH2:22][NH:21][C:19](/[C:18](=[CH:8]/[CH:7]=[CH:6]/[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:12]([OH:13])=[C:11]([O:14][CH3:15])[CH:10]=2)/[C:16]#[N:17])=[O:20])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1cc(C=CC=O)cc(OC)c1O
Reactant: N#CCC(=O)[N-]CCCc1ccccc1
Product: COc1cc(/C=C/C=C(\C#N)C(=O)NCCCc2ccccc2)cc(OC)c1O
Yield: 90.2 %

Procedure:
The compound was prepared as described in Example 3 by adding 3,5-dimethoxy-4-hydroxycinnamaldehyde (0.10 g, 0.48 mmol) to N-(cyanoacetyl)phenylpropylamide (Example 19, 0.097 g, 0.48 mmol). After refluxing for 3 h the residue was purified by silica gel chromatography (CHCl3-hexane, 1:1) to give a brown solid (0.17 g, 90% yield). The product gave the following analytical data: