Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]2=[CH:8][S:9][CH:10]=[C:6]2[S:5](=[O:12])(=[O:11])[N:4]([CH3:13])[C:3]=1[C:14]([O:16]C)=O.[NH2:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:7]2=[CH:8][S:9][CH:10]=[C:6]2[S:5](=[O:11])(=[O:12])[N:4]([CH3:13])[C:3]=1[C:14]([NH:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1)=[O:16]
Reactant: Nc1nccs1
Reactant: COC(=O)C1=C(O)c2cscc2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2nccs2)=C(O)c2cscc2S1(=O)=O

Procedure:
0.9 G. of 4-hydroxy-3-methoxycarbonyl-2-methyl-2H-thieno[3,4-e]-1,2-thiazine 1,1-dioxide are suspended together with 0.4 g. of 2-aminothiazole in 100 ml. of absolute xylene and heated to reflux for 4 hours, 70 ml. of xylene being slowly distilled off. A crystalline precipitate separates from the cooled solution and is filtered off under suction. There is obtained 4-hydroxy-2-methyl-N-(2-thiazolyl)-2H-thieno[3,4-e]-1,2-thiazine-3-carboxamide 1,1-dioxide of melting point 243°-245° C. (decomposition).
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[CH:4][C:5](=[O:10])[C:6]([F:9])([F:8])[F:7].[Cl:13][C:14]1[N:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=1>C(O)C>[Cl:13][C:14]1[N:19]=[CH:18][C:17]([CH2:20][NH:21][C:3]([S:2][CH3:1])=[CH:4][C:5](=[O:10])[C:6]([F:9])([F:8])[F:7])=[CH:16][CH:15]=1
Reactant: NCc1ccc(Cl)nc1
Reactant: CSC(=CC(=O)C(F)(F)F)SC
Solvent: CCO
Product: CSC(=CC(=O)C(F)(F)F)NCc1ccc(Cl)nc1
Temperature: 20 °C

Procedure:
The product of Example 1, 1, 1-bismethylthio-4,4,4-trifluoro-1-buten-3-one, (4.32 g, 0.02 mol) and the product of Example 4, 6-chloro-3pyridylmethylamine (2.85 g, 0.02 mol) were dissolved in ethanol (50 ml). The resulting solution was heated under reflux for 2 hours under an atmosphere of nitrogen. The resulting mixture was cooled to ambient temperature (20° C.) and the solvent removed by evaporation under reduced pressure. The residue was chromatographically purified using a silica gel column eluted with dichloromethane/ether (19:1) to give the product, 1-(6-chloro-3- pyridylmethyl) amino-1-methylthio-4,4,4-trifluoro-1-buten-3-one, as a solid which recrystallized from ethanol, in a yield of 3.32 g (53%), melting point 112° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2.Br[CH2:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25].C(#N)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C>[C:24]([C:23]1[CH:22]=[C:21]([CH:28]=[CH:27][CH:26]=1)[CH2:20][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)#[N:25]
Reactant: CC(C)(C)OC(=O)N1CCc2c(O)cccc2C1
Reactant: N#Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCc2c(cccc2OCc2cccc(C#N)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.8 %

Procedure:
tert-Butyl 5-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.025 g, 0.10 mmol) was combined with 3-(bromomethyl)benzonitrile (Aldrich, 145610) (0.029 g, 0.15 mmol), acetonitrile (2.0 mL) and cesium carbonate (0.065 g, 0.20 mmol) and was stirred at r.t. overnight. This was diluted with ethyl acetate, filtered to remove the solids and concentrated under reduced pressure to give crude tert-butyl 5-(3-cyanobenzyloxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.040 g) as a semisolid. Analytical LCMS (M+Na)+: m/z=387.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[NH:12]1[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:9])=[C:6]([NH:7][C:8]([N:12]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13]2)=[O:10])[CH:11]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2o1
Reactant: O[C@H]1CCNC1
Product: O=C(Nc1cc(Cl)ccc1O)N1CC[C@H](O)C1
Yield: 880 %

Procedure:
5-chloro-1,3-benzoxazole-2(3H)-one (577 mg, 0.34 mmol) and (3S)-pyrrolidin-3-ol (0.6 mL, 0.74 mmol) was heated to 90° C. for 2 hrs. The resulting red solidified oil was purified on silica (dichloromethane/methanol) to give the titled compound (768 mg, 88%).
Reaction SMILES: [C:1]([C:6]1[O:7][C:8]2[CH:24]=[C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]4[CH:44]=[CH:43][C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[N:36]=4)=[CH:29][CH:28]=3)[CH:22]=[C:21]([OH:45])[C:9]=2[C:10](=[O:20])[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)([O:3]CC)=[O:2].C(=O)(O)[O-].[Na+].C(O)C>O>[C:1]([C:6]1[O:7][C:8]2[CH:24]=[C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]4[CH:44]=[CH:43][C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[N:36]=4)=[CH:29][CH:28]=3)[CH:22]=[C:21]([OH:45])[C:9]=2[C:10](=[O:20])[C:11]=1[C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)c1oc2cc(OCc3ccc(OCc4ccc5ccccc5n4)cc3)cc(O)c2c(=O)c1-c1ccc(OC)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2c(C(=O)O)oc3cc(OCc4ccc(OCc5ccc6ccccc6n5)cc4)cc(O)c3c2=O)cc1

Procedure:
0.14 g 2-carboethoxy-5-hydroxy-3-(4-methoxyphenyl)-7-(4-(quinolin-2-ylmethoxy)benzyloxy)-4-oxo-4H-1-benzopyran and 0.78 g sodium bicarbonate are combined in 7 ml of water and 7 ml of ethanol and refluxed overnight. The mixture is extracted with ether and the aqueous neutralized to pH6. The resulting solid is collected, dried to give 2-carboxy-5-hydroxy-3-(4-methoxyphenyl)-7-(4-(quinolin-2-ylmethoxy)benzyloxy)-4-oxo-4H-1H-benzopyran; m.p. 195°-96° C.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:6][C:3]=1[C:4]#[N:5].C1C(=O)N([Br:30])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:30][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]2[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[N:9]=2)=[CH:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2nc(Cl)c(C#N)cc2-c2ccccc2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: N#Cc1cc(-c2ccccc2)c(-c2ccc(CBr)cc2)nc1Cl

Procedure:
The solution of 2-chloro-6-(4-methylphenyl)-5-phenylnicotinonitrile (2-4; 0.066 g, 0.217 mmol), NBS (0.046 g, 0.26 mmol) and benzoylperoxide (0.010 g, 0.043 mmol) in CDCl3 (2 mL) was heated to reflux overnight. The mixture was concentrated to give 6-[4-(bromomethyl)phenyl]-2-chloro-5-phenylnicotinonitrile (2-5) and used without further purification. LRMS m/z (M+H) Calcd: 383.7, found: 383.1.
Reaction SMILES: C(OC([N:8]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14](=[O:21])[CH2:13][CH2:12][N:11]([C:22](=[O:31])[NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=2)[CH2:10][C:9]1=[O:32])=O)(C)(C)C.F[C:34](F)(F)[C:35]([OH:37])=[O:36]>C(Cl)(Cl)Cl>[C:35]([CH2:34][N:8]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14](=[O:21])[CH2:13][CH2:12][N:11]([C:22](=[O:31])[NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=2)[CH2:10][C:9]1=[O:32])([OH:37])=[O:36]
Reactant: Cc1cccc(NC(=O)N2CCC(=O)c3ccccc3N(C(=O)OC(C)(C)C)C(=O)C2)c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1cccc(NC(=O)N2CCC(=O)c3ccccc3N(CC(=O)O)C(=O)C2)c1

Procedure:
A solution of 1-tert-butyloxycarbonyl-4-(3-methylphenyl)carbamyl-2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine (452 mg, 1.0 mmol) in chloroform (4 ml) was stirred with trifluoroacetic acid (4 ml) at room temperature for 2 hours. The mixture was evapoarted to dryness and the residue dissolved in chloroform (50 ml), washed with brine (3×40 ml), and dried (MgSO4). Filtration and evaporation of the solvent gave the product. (393 mg, 99%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:49][CH2:50][C:51]1[C:52]([OH:59])=[N:53][C:54]([CH3:58])=[CH:55][C:56]=1[CH3:57]>ClCCl>[OH:59][C:52]1[C:51]([CH2:50][NH:49][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][C:2]=2[CH3:1])=[C:56]([CH3:57])[CH:55]=[C:54]([CH3:58])[N:53]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: Cc1cc(Oc2ccccc2)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(Oc3ccccc3)cc2C)c(O)n1
Reaction time: 0.5 h
Yield: 27.6 %

Procedure:
To a solution of 2-methyl-4-phenoxybenzoic acid (100 mg, 0.44 mmol) in dichloromethane (20 mL) were added o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (190 mg, 0.5 mmol), and triethylamine (77 mg, 0.7 mmol). The mixture was stirred for 0.5 hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (60 mg, 0.4 mmol) was added and the mixture was stirred at room temperature for 4 hours. The mixture was washed with water (50 mL) and the organic phase was separated, concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to afford N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-methyl-4-phenoxybenzamide (40 mg, 25%) as a white solid. LRMS (M+H+) m/z: calcd 362.16. found 362. HPLC purity (214 nm): 100%. 1H NMR (300 MHz, d6-DMSO): δ 7.40-7.31 (m, 3H), 7.18-7.13 (m, 1H), 7.02-6.99 (m, 2H), 6.83-6.76 (m, 2H), 6.12 (s, 2H), 4.47 (s, 2H), 2.43 (s, 3H), 2.41 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[N:8]=[C:7]([N:9]2[CH2:13][C@@H:12]3[C@@H:14]([NH2:17])[CH2:15][CH2:16][C@@H:11]3[CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[CH3:20][C:21]([CH3:23])=O.C(O)(=O)C.C([BH3-])#N>ClCCl>[CH:21]([NH:17][C@@H:14]1[C@@H:12]2[C@@H:11]([CH2:10][N:9]([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:18])[F:19])[N:8]=3)[CH2:13]2)[CH2:16][CH2:15]1)([CH3:23])[CH3:20]
Reactant: CC(C)=O
Reactant: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(3aR,4S,6aS)-2-(6-(Trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine from Example 264 Step A (44 mg, 0.162 mmol) and acetone (14.13 mg, 0.243 mmol) were combined in dichloromethane (0.5 mL). Acetic acid (0.5 mL) was added. The reaction mixture was stirred at ambient temperature for 30 minutes, then PS-cyanoborohydride (146 mg, 0.324 mmol) was added. After 18 hours, the reaction mixture was filtered and the solvent removed under a stream of nitrogen. The crude material was applied to a 4 g silica gel cartridge and purified with a gradient of 1-10% methanol in (2 N ammonia)/dichloromethane to give to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.57-7.52 (m, 1H), 6.99 (d, J=7.2, 1H), 6.55 (d, J=8.6, 1H), 3.62-3.54 (m, 1H), 3.54-3.45 (m, 2H), 3.25 (dd, J=10.7, 4.3, 1H), 3.03 (dd, J=11.8, 5.9, 1H), 2.83 (dt, J=12.4, 6.2, 1H), 2.76-2.67 (m, 1H), 2.49-2.41 (m, 1H), 2.02-1.92 (m, 2H), 1.45-1.29 (m, 3H), 1.06 (d, J=6.2, 3H), 1.03 (d, J=6.2, 3H); MS (ESI+) m/z 314 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:31])[C@H:10]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH:11][C:12](=[O:26])[C@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1C(=O)NOC(C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C:9](=[O:31])[C@H:10]([CH2:27][CH:28]([CH3:29])[CH3:30])[NH:11][C:12](=[O:26])[C@H:13]1[CH2:17][CH2:16][CH2:15][NH:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H]1CCCN1C(=O)NOC(C)(C)C)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](NC(=O)[C@H]1CCCN1)C(=O)OCc1ccccc1

Procedure:
N-(t-Butoxycarbamoyl)-(D)-proline N-hydroxysuccinimide ester (10) (1.25 g, 4.0 mmol) and (L)-leucine benzyl ester (0.885 g, 4.0 mmol) were stirred at ambient temperature in acetonitrile (10 mL) for 14 h. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was separated and washed with 1N HCl, saturated NaHCO3, and saturated NaCl. After drying over anhydrous MgSO4, evaporation of solvent gave N-(t-butyoxycarbamoyl)-(D)-prolylleucine benzyl ester as a colorless oil. N-(t-Butoxycarbamoyl)-(D)-prolylleucine benzyl ester (1.38 g, 3.3 mmol) was stirred for one hour at ambient temperature with a 30% (v/v) solution of trifluroacetic acid in dichloromethane (20 mL). The solvent was removed by rotary evaporation and the residue partitioned between ethyl acetate and a 50% (v/v) solution of saturated aq. NaHCO3 and saturated aq. Na2CO3. The organic phase was separated, washed with saturated aq. NaCl, and dried over anhydrous MgSO4. Filtration and solvent evaporation gave (D)-prolylleucine benzyl ester as a white semi-solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][C:3]2[N:7]=[CH:8][C:9]([C:11]#[N:12])=[CH:10][C:2]1=2.[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([Br:25])[C:22]=1[O:23][CH3:24])[C:17](Cl)=[O:18]>>[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([Br:25])[C:22]=1[O:23][CH3:24])[C:17]([N:1]1[CH2:6][CH2:5][O:4][C:3]2[N:7]=[CH:8][C:9]([C:11]#[N:12])=[CH:10][C:2]1=2)=[O:18]
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Reactant: N#Cc1cnc2c(c1)NCCO2
Product: COc1c(Br)cc(C(=O)N2CCOc3ncc(C#N)cc32)cc1Br
Yield: 73.9 %

Procedure:
By the same method as in the step d) of Example 2, 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-carbonitrile (7 mg, 0.043 mmol) was reacted with 3,5-dibromo-4-methoxy-benzoyl chloride (21 mg, 0.065 mmol) to obtain 1-(3,5-dibromo-4-methoxy-benzoyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-carbonitrile as white solid (14.4 mg, 74%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Cl.[CH3:25][C:26]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:31][C:26]5([CH3:25])[CH2:30][CH2:29][CH2:28][CH2:27]5)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CC1(N)CCCC1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(C)CCCC4)c3n2)c2ccc(F)cc21
Reaction time: 0.15 h
Yield: 22.9 %

Procedure:
A solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (62 mg, 0.20 mmol), 1-methylcyclopentanamine hydrochloride (35 mg, 0.26 mmol), HATU (98 mmol, 0.26 mmol) and DIEA (42 mg, 0.33 mmol) in 6 mL of DMF was stirred at room temperature for 16 hours. The solvent was evaporated at 70° C. under reduced pressure to give a crude product, which was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 55% acetonitrile/45% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 80% acetonitrile/20% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-N-(1-methylcyclopentyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (18 mg, 22.9%) as an off-white solid. MS: (M+H)+=393; 1H NMR (300 MHz, DMSO): δ 12.84 (s, 1H), 9.09 (s, 1H), 8.49-8.44 (m, 1H), 8.41 (s, 1H), 8.01 (s, 1H), 7.72 (d, 1H, J=7.8 Hz), 7.17 (t, 1H, J=8.1 Hz), 4.17 (s, 3H), 2.19 (brs, 2H), 1.79-1.76 (m, 6H), 1.57 (s, 3H).
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20]/[CH:21]=[CH:22]/[C@@H:23]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:24][CH:25]([CH3:27])[CH3:26])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:18][CH2:19][CH2:20]/[CH:21]=[CH:22]/[C@@H:23]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:24][CH:25]([CH3:26])[CH3:27]
Reactant: CC(C)C[C@@H](/C=C/CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)C[C@@H](/C=C/CCO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of the TBDPS-protected alcohol 8b (584 mg, 1.10 mmol, crude) in dry THF (9 mL) at 0° C. was added TBAF (1.0M/THF, 1.38 mL, 1.38 mmol), and the reaction mixture was allowed to warm to rt while stirring under argon for 3.5 h, then quenched with sat. aq. NH4Cl and diluted with EtOAc. The aqueous phase was separated and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography (SiO2, 5:5, hexanes/EtOAc) afforded 194 mg (60%, 2 steps) of the title compound as a colorless oil. [α]D23 −6.4 (c 1.0, DCM); 1H NMR (300 MHz, CDCl3) δ 7.20-7.40 (m, 5 H), 5.65-5.49 (m, 1 H), 5.44 (dd, 1 H, J=15.3, 6.6 Hz), 5.09 (s, 2 H), 4.67 (bs, 1 H), 4.16 (m, 1 H), 3.63 (bs, 2 H), 2.28 (q, 2 H, J=6.0 Hz), 1.82 (bs, 1 H), 1.65 (m, 1 H), 1.40-1.25 (m, 2 H), 0.80-1.00 (m, 6 H); HRMS (ESI) m/z calcd for C17H25NO3Na 314.1732, found 314.1739.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH2:11][C:12]1[CH:13]=[C:14]([CH:48]=[CH:49][CH:50]=1)[C:15]([NH:17][C:18]1[S:19][C:20]2[CH2:47][CH2:46][CH2:45][CH2:44][C:21]=2[C:22]=1[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]2[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=2)=[CH:28][CH:27]=1)=[O:24])=[O:16])[CH:6]([CH2:9][CH3:10])[CH2:7][CH3:8])=[O:4].[NH:51]1[CH2:61][CH2:60][CH:54]([C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:53][CH2:52]1>>[CH3:41][O:40][C:38]([C:37]1[CH:42]=[CH:43][C:34]([CH2:33][CH2:32][C:29]2[CH:30]=[CH:31][C:26]([NH:25][C:23]([C:22]3[C:21]4[CH2:44][CH2:45][CH2:46][CH2:47][C:20]=4[S:19][C:18]=3[NH:17][C:15]([C:14]3[CH:13]=[C:12]([CH:50]=[CH:49][CH:48]=3)[CH2:11][N:5]([CH:6]([CH2:9][CH3:10])[CH2:7][CH3:8])[C:3](=[O:4])[CH2:2][N:51]3[CH2:61][CH2:60][CH:54]([C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:53][CH2:52]3)=[O:16])=[O:24])=[CH:27][CH:28]=2)=[CH:35][CH:36]=1)=[O:39]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CCC(CC)N(Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1)C(=O)CCl
Product: CCOC(=O)C1CCN(CC(=O)N(Cc2cccc(C(=O)Nc3sc4c(c3C(=O)Nc3ccc(CCc5ccc(C(=O)OC)cc5)cc3)CCCC4)c2)C(CC)CC)CC1
Yield: 87.9 %

Procedure:
By using 370 mg of methyl 4-(2-{4-[({2-[(3-{[(chloroacetyl)(pentan-3-yl)amino]methyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoate and 400 mg of ethyl isonipecotate, the reaction similar to Preparation Example 30 was performed, thereby obtaining 380 mg of ethyl 1-(2-{[3-({3-[(4-{2-[4-(methoxycarbonyl)phenyl]ethyl}phenyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl}carbamoyl)benzyl](pentan-3-yl)amino}-2-oxoethyl)piperidine-4-carboxylate.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>Cl>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:29][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(CCCCOCCCCCCBr)cc1
Reactant: NCc1ccccc1
Agent: Cl
Product: O=[N+]([O-])c1ccc(CCCCOCCCCCCNCc2ccccc2)cc1

Procedure:
1-[4-[(6-Bromohexyl)oxy]butyl]-4-nitrobenzene (8.0 g) was added dropwise to benzylamine (30 ml) at 110°. The solution was heated at 110°-120° for 2 h, treated with hydrochloric acid (2M; 200 ml), and extracted with ethyl acetate (2×150 ml). The organic extract was washed with aqueous sodium carbonate (150 ml) and brine (150 ml), dried and evaporated. The residue was purified by FCC eluting with ether to give the title compound as a pale yellow oil (5.9 g). T.l.c. Ether Rf 0.15.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:10]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[N:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:19][CH:18]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCc1ccc(C=O)cc1
Reactant: N#Cc1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCCCCCc1ccc(C=Nc2ccc(C#N)cc2)cc1

Procedure:
A mixture of 5.9 g. of p-aminobenzonitrile and 10.2 g. of p-n-heptylbenzaldehyde in 100 ml. of benzene is treated with 150 mg. of p-toluenesulfonic acid and reacted as described in Example 1. After evaporation, there remain 15.4 g. of a yellow oil which crystallizes with cooling. Purification is carried out by several recrystallizations from isopropanol as described in Example 1. The p-[(p-n-heptylbenzyliden)amino]benzonitrile which is obtained has a melting point of 32.7°-33.0°C. and a clearing point of 72.3°C. UV (ethanol): ε281 = 24100 (shoulder at 310 nm). The nuclear magnetic resonance, mass spectrum, infrared and microanalysis data confirm the structure.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[NH:34][C:35](=[O:44])[C:36]3[N:37]([N:39]=[C:40]([CH2:42][OH:43])[CH:41]=3)[CH:38]=2)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>ClCCl.CN(C=O)C>[C:23]([C:27]1[CH:28]=[CH:29][C:30]([C:33]2[NH:34][C:35](=[O:44])[C:36]3[N:37]([N:39]=[C:40]([CH:42]=[O:43])[CH:41]=3)[CH:38]=2)=[CH:31][CH:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1ccc(-c2cn3nc(CO)cc3c(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)c1ccc(-c2cn3nc(C=O)cc3c(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
599 mg (1.41 mmol) Dess-Martin periodinane is added to a solution of 140 mg (0.471 mmol) 6-(4-tert-butyl-phenyl)-2-hydroxymethyl-5H-pyrazolo[1,5-a]pyrazin-4-one in 5 ml dichloromethane and 1 ml DMF. The reaction mixture is stirred at ambient temperature for 18 hours. The reaction mixture is filtered and the filtrate is washed with saturated sodium thiosulfate solution and with saturated sodium hydrogen carbonate solution. The organic phase is dried over sodium sulfate and evaporated. The residue is triturated with tert-butylmethylether, the solid is filtered off and dried under vacuum to give 6-(4-tert-butyl-phenyl)-4-oxo-4,5-dihydro-pyrazolo[1,5-a]pyrazine-2-carbaldehyde as light yellow crystals; HPLC/MS: 1.93 (C), [M+H] 296.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][C:10]2[CH:11]=[C:12]3[C:18]([C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)=[CH:17][N:16](OCC[Si](C)(C)C)[C:13]3=[N:14][CH:15]=2)[CH:4]=1.Cl>CCO>[CH3:1][N:2]([CH3:32])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][C:10]2[CH:11]=[C:12]3[C:18]([C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)=[CH:17][NH:16][C:13]3=[N:14][CH:15]=2)[CH:4]=1
Reactant: CN(C)c1cccc(Sc2cnc3c(c2)c(-c2cnn(C)c2)cn3OCC[Si](C)(C)C)c1
Agent: Cl
Solvent: CCO
Product: CN(C)c1cccc(Sc2cnc3[nH]cc(-c4cnn(C)c4)c3c2)c1
Temperature: 90 °C
Yield: 40 %

Procedure:
A mixture of 68 (78 mg, 0.163 mmol), 10% aq. HCl (1.0 mL), EtOH (1.0 mL) was heated at 90° C. for 14 h. Purification by PTLC using AcOEt as eluent gave 69 as a white solid (22.8 mg, 40%); 1H NMR (400 MHz, CDCl3) δ 2.70 (s, 6H), 3.79 (s, 3H), 7.26 (m, 1H), 6.34 (ddd, J=8.3, 2.5, 0.7 Hz, 1H), 6.44 (t, J=2.1 Hz, 1H), 6.91 (t, J=8.0 Hz, 1H), 7.26 (s, 1H), 7.45 (s, 1H), 7.55 (d, J=0.7 Hz, 1H), 8.10 (d, J=2.0 Hz, 1H), 8.28 (d, J=1.9 Hz, 1H).