Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH2:32][N:31]([C:33](=O)[CH2:34][C:35](=O)[CH:36]([CH3:38])[CH3:37])[CH2:30][CH2:29][C:5]=2[N:6]=[C:7]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[C:11]([CH3:28])=[CH:12][N:13]3[S:18]([C:21]2[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[N:8]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1.[CH3:63][NH:64][NH2:65]>C1COCC1.ClCCl.O>[CH:36]([C:35]1[CH:34]=[C:33]([N:31]2[CH2:30][CH2:29][C:5]3[N:6]=[C:7]([C:9]4[CH:17]=[CH:16][CH:15]=[C:14]5[C:10]=4[C:11]([CH3:28])=[CH:12][N:13]5[S:18]([C:21]4[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=4)(=[O:19])=[O:20])[N:8]=[C:3]([O:2][CH3:1])[C:4]=3[CH2:32]2)[N:64]([CH3:63])[N:65]=1)([CH3:37])[CH3:38]
Reactant: CNN
Reactant: COc1nc(-c2cccc3c2c(C)cn3S(=O)(=O)c2ccc(C)cc2)nc2c1CN(C(=O)CC(=O)C(C)C)CC2
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: COc1nc(-c2cccc3c2c(C)cn3S(=O)(=O)c2ccc(C)cc2)nc2c1CN(c1cc(C(C)C)nn1C)CC2
Temperature: 120 °C

Procedure:
To a solution of 1-(4-methoxy-2-(3-methyl-1-tosyl-1H-indol-4-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-methylpentane-1,3-dione (350 mg, 0.624 mmol) in THF (3.3 mL), in a 2-5 mL microwave vial, was added Lawesson's reagent (278 mg, 0.687 mmol) and methyl hydrazine (0.049 mL, 0.94 mmol). The vessel was immediately sealed and heated via microwave irradiation at 120° C. for 10 minutes. The reaction was then cooled to room temperature and diluted with dichloromethane and water. The layers were separated and the aqueous layer was extracted two additional times with dichloromethane. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified via silica gel flash chromatography (45-67% ethyl acetate/heptanes) to provide 6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-4-methoxy-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. MS (ESI+) m/z 571.4 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:16]=[C:17]([CH3:19])[CH:18]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4][C@H:3]1[O:20][CH3:21].[Cl:22][C:23]1[N:24]=[C:25]([C:30](O)=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CC(N(C)C)=O.ClCCl>[Cl:22][C:23]1[N:24]=[C:25]([C:30]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:9]=[C:10]([CH:16]=[C:17]([CH3:19])[CH:18]=3)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4][C@H:3]2[O:20][CH3:21])=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29]
Reactant: CCOC(=O)c1cc(C)cc(N2CC[C@H](N)[C@H](OC)C2)c1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cc(C)cc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)c1
Yield: 76.4 %

Procedure:
The same operation as in Example (1g) was performed using ethyl cis(±)-3-(4-amino-3-methoxypiperidin-1-yl)-5-methylbenzoate obtained in Example (259g) (about 0.24 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (37 mg, 0.21 mmol), WSC hydrochloride (134 mg, 0.70 mmol), HOBT (47 mg, 0.35 mmol), dichloromethane (1.5 mL) and DMA (1.5 mL), to obtain 72 mg of the title compound as a colorless oily substance (75%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](CBr)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[CH3:13][S-:14].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:14][CH3:13])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1CBr
Reactant: C[S-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1ccc(Br)cc1[N+](=O)[O-]
Reaction time: 60 h
Yield: 105.8 %

Procedure:
A suspension of 4-bromo-1-(bromomethyl)-2-nitrobenzene (1.0 g) and sodium methanethiolate (0.285 g) in tetrahydrofuran (20 ml) was stirred under nitrogen for 60 h. The solvent was evaporated, chloroform (50 ml) was added and the rsidual solid was removed by filtration. The filtrate was comncentrated under vacuum to give the title compound (0.89 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34](O)=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:68][O:69][C:70]1[CH:83]=[CH:82][C:73]([CH2:74][S:75][CH2:76][C@H:77]([C:79]([OH:81])=[O:80])[NH2:78])=[CH:72][CH:71]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[OH:16])[C@H:9]2[C:24]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([NH:78][C@@H:77]([C:79]([OH:81])=[O:80])[CH2:76][S:75][CH2:74][C:73]3[CH:72]=[CH:71][C:70]([O:69][CH3:68])=[CH:83][CH:82]=3)=[O:35])=[O:31])=[CH:37][CH:38]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Reactant: COc1ccc(CSC[C@@H](N)C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1ccc(CSC[C@@H](NC(=O)CNC(=O)COc2ccc([C@@H]3[C@@H](SCC(O)c4ccc(F)cc4)C(=O)N3c3ccc(F)cc3)cc2)C(=O)O)cc1
Temperature: 30 °C
Reaction time: 0.58 h

Procedure:
To a stirred solution of N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine, (21.3 mg, 0.039 mmol) in DMF (3 ml) was added N-methylmorpholine (20μl, 0.18 mmol). TBTU (15.1 mg, 0.047 mmol) was added and the mixture was stirred at 30° C. for 35 minutes. S-(4-methoxybenzyl)-D-cysteine (12.8 mg, 0.053 mmol) was added and the mixture was stirred 1 hour at 30° C. and 1.5 hours at ambient temperature. The formation of the ketone of the title compound was confirmed. M/z: 764.11 (M+1) and 762.06 (M−1). Methanol (3 ml) and sodium borohydride (15 mg, 0.40 mmol) were added and the mixture was stirred for 20 minutes. Ammonium acetate (25 mg) was added and the methanol was removed under reduced pressure. The remaining DMF-solution was purified with preparative HPLC on a C8 column, UV 240/260 nm. A gradient from 20 to 47% MeCN in 0.1M NH4OAc was used as eluent. The MeCN was removed from the collected fractions under reduced pressure. The remaining water solution was acidified to pH 1 with KHSO4 (2M) and extracted with DCM. The organic phase was concentrated under reduced pressure and the residue was dissolved in MeCN and water. After lyophilisation, the title compound was obtained as a white solid (10.7 mg, 36%). H-NMR (400 MHz, DMSO-d6): 2-60-2.80 (m, 2H), 2.83-2.97 (m, 2H), 3.63-3.66 (bd, 2H), 3.69 (s, 3H), 3.77-3.81 (bd, 2H), 4.24-4.33 (m, 2H), 4.52 (s, 2H), 4.67-4.76 (m, 1H), 5.03 (d, 0.5H), 5.06 (d, 0.5H), 5.60-5.90 (b, 1H), 6.82 (d, 2H), 6.98 (d, 2H), 7.05-7.25 (m, 8H), 7.30-7.38 (m, 4H), 8.00-8.10 (b, 1H), 8.30 (t, 1H). M/z: 764.07 (M−1).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([C:8]#N)=[N:6][CH:7]=1.N([O-])=[O:17].[Na+].[OH-:20].[Na+]>S(=O)(=O)(O)O>[Br:1][C:2]1[C:3]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([C:8]([OH:17])=[O:20])=[N:6][CH:7]=1
Reactant: O=N[O-]
Reactant: [OH-]
Reactant: N#Cc1cc(OCC(F)(F)F)c(Br)cn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)c1cc(OCC(F)(F)F)c(Br)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A solution of 5-Bromo-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carbonitrile (Example 78c, 1 g, 3.56 mmol) in sulfuric acid 97% (5 ml) was stirred at 120° C. for 2 h and a 6.0M aqueous solution of sodium nitrite (2.08 ml, 12.5 mmol, Eq: 3.5) was then slowly added to it at r.t. The resulting reaction mixture was stirred at room temperature for 30 minutes and stirred at 80° C. for 1 hour. The reaction was diluted by addition of 20 gr of ice and the pH was adjusted to 1-2 by addition of sodium hydroxide pellets by portions. A precipitate formed and was filtered off, dried under high vacuum to yield the title compound (1.02 g, 95%) as a white solid. MS (ESI, m/z): 300.2 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:26][CH2:25][C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)[C:5]([Cl:27])=[CH:4][N:3]=1.[CH:28]1([CH2:31][N:32]2[CH:36]=[C:35]([NH2:37])[CH:34]=[N:33]2)[CH2:30][CH2:29]1.FC(F)(F)C(O)=O>O1CCOCC1>[Cl:27][C:5]1[C:6]([NH:8][CH:9]2[CH2:10][CH2:11][C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][CH2:13]3)[CH2:25][CH2:26]2)=[N:7][C:2]([NH:37][C:35]2[CH:34]=[N:33][N:32]([CH2:31][CH:28]3[CH2:30][CH2:29]3)[CH:36]=2)=[N:3][CH:4]=1
Reactant: Nc1cnn(CC2CC2)c1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3nc(Cl)ncc3Cl)CC2)CC1
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3nc(Nc4cnn(CC5CC5)c4)ncc3Cl)CC2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
To a solution of tert-butyl 9-[(2,5-dichloropyrimidin-4-yl)amino]-3-azaspiro[5.5]undecane-3-carboxylate (500.5 mg, 1.21 mmol) and 1-(cyclopropylmethyl)-1H-pyrazol-4-amine (330.5 mg, 2.41 mmol) in 1,4-dioxane (50 mL) was added trifluoroacetic acid (686.5 mg, 6.02 mmol). The mixture was stirred at 100° C. overnight and concentrated in vacuo. The residue was purified with a silica gel column chromatography (PE/EtOAc (v/v)=1/1 to DCM/MeOH (v/v)=7/1) to give the product as a light yellow solid (550 mg, 88.45%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CN(C=O)C.N1C=CC=CC=1.[CH3:18][O:19][C:20]([C:22]1[CH:26]=[CH:25][N:24]([CH2:27][CH2:28][CH2:29][C@H:30]([NH:34][C:35](=[O:61])[C@H:36]([CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([CH3:60])[CH:55]=2)[NH:37][C:38](=[O:52])[CH:39]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:31]([NH2:33])=O)[N:23]=1)=[O:21]>CCOC(C)=O>[CH3:18][O:19][C:20]([C:22]1[CH:26]=[CH:25][N:24]([CH2:27][CH2:28][CH2:29][C@H:30]([NH:34][C:35](=[O:61])[C@H:36]([CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([CH3:60])[CH:55]=2)[NH:37][C:38](=[O:52])[CH:39]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:31]#[N:33])[N:23]=1)=[O:21]
Reactant: COC(=O)c1ccn(CCC[C@H](NC(=O)[C@H](Cc2cccc(C)c2)NC(=O)C(c2ccccc2)c2ccccc2)C(N)=O)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccn(CCC[C@@H](C#N)NC(=O)[C@H](Cc2cccc(C)c2)NC(=O)C(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Oxalyl chloride (0.082 mL, 0.94 mmol) is added dropwise to DMF (20 mL), and the resulting solution is cooled to 0° C. After the solution becomes clear, pyridine (0.15 mL, 1.88 mmol) is added, followed by N-[4-(3-methoxycarbonyl-1H-pyrazol-1-yl)-1(S)-(aminocarbonyl)butyl]-3-methyl-Nα-(2,2-diphenyl-acetyl)-L-phenylalaninamide (0.28 g, 0.47 mmol), in one portion. The yellow reaction solution is stirred at 0° C. for 1.5 hours, after which time it is diluted with EtOAc (50 mL), and washed with saturated NaHCO3 (1×50 mL), saturated LiCl (1×50 mL), dried over MgSO4, and evaporated. The residue is chromatographed (silica, 66% EtOAc/hexane) to yield N-[4-(3-methoxycarbonyl-1H-pyrazol-1-yl)-1(S)-cyanobutyl]-3-methyl-Nα-(2,2-diphenylacetyl)-L-phenylalaninamide as a white solid.
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)CO.CCOCC.[NH:26]1[C:30]2[CH:31]=[CH:32][C:33]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([Cl:46])[C:41]=4[Cl:47])[C:38]([CH3:48])=[C:37]([OH:49])[C:36]3=[O:50])=[CH:34][C:29]=2[N:28]=[CH:27]1>CO>[NH:28]1[C:29]2[CH:34]=[C:33]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([Cl:46])[C:41]=4[Cl:47])[C:38]([CH3:48])=[C:37]([O:49][CH3:3])[C:36]3=[O:50])[CH:32]=[CH:31][C:30]=2[N:26]=[CH:27]1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Reactant: CC1=C(O)C(=O)N(c2ccc3[nH]cnc3c2)C1c1cccc(Cl)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Solvent: OCCO
Product: COC1=C(C)C(c2cccc(Cl)c2Cl)N(c2ccc3nc[nH]c3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (9.0 g,160.71 mmol in water), diazald (24 g, 112.02 mmol), ethylene glycol/Et2O (2/1 v/v, 140 mL), 1-(1H-benzo[d]imidazol-5-yl)-5-(2,3-dichlorophenyl)-3-hydroxy-4-methyl-1H-pyrrol-2(5H)-one (3 g, 8.04 mmol, 1 eq) and MeOH (50 mL); yield: 1.2 g (38.46%); MS m/z: 388.1 [M+H]+; 1H-NMR: (400 MHz, DMSO-D6) δ: 12.44 (s, 1H), 8.16 (d, 1H), 7.64 (d, 1H), 7.54-7.40 (m, 2H), 7.32-7.18 (m, 3H), 7.08 (t, 1H), 6.31 (s, 1H), 3.96 (s, 3H), 1.73 (s, 3H); HPLC (METHOD [A]): rt 13.75 min (99.4%)
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][CH:21]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:35]([C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1)#[N:36]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][NH:27][C:41](=[O:42])[C:40]3[CH:44]=[CH:45][C:37]([C:35]#[N:36])=[CH:38][CH:39]=3)=[CH:22][CH:21]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(OCCCOc2ccc(CN)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1ccc(OCCCOc2ccc(CNC(=O)c3ccc(C#N)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.2 %

Procedure:
To a suspension of {4-[3-(4-aminomethyl-phenoxy)-propoxy]-benzyl}-carbamic acid tert-butyl ester prepared in Example 78 (3.00 g,7.76 mmol) in THF (30 mL) was added a 10% aqueous solution of potassium carbonate (53.90 mL, 38.81 mmol). 4-Cyanobenzoyl chloride (1.29 g, 7.76 mmol) was then added in one portion and the reaction mixture was stirred at room temperature for 16 hours. The mixture was then diluted with EtOAc (150 mL), washed with 1N aqueous HCl (2×150 mL), dried over MgSO4, and concentrated to provide the desired compound as a yellow solid (2.41 g, 60% yield) which did not require any further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]2[C:5](=[CH:6][C:7]([S:17]CC3C=CC(OC)=CC=3)=[CH:8][CH:9]=2)[N:4]=1.C(O)=O.O.S>C(Cl)Cl>[SH:17][C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:12]([C:13]([O:15][CH3:16])=[O:14])[C:3]([O:2][CH3:1])=[N:4]2)=[CH:9][CH:8]=1
Reactant: COC(=O)c1cc2ccc(SCc3ccc(OC)cc3)cc2nc1OC
Agent: S
Solvent: ClCCl
Solvent: O
Solvent: O=CO
Product: COC(=O)c1cc2ccc(S)cc2nc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of the ester from Step 4 (2.77 g), 90% formic acid (70 ml) and mercuric acetate (7.17 g) was stirred under an argon atmosphere at ambient temperature for 3 hours. The reaction mixture was poured into a mixture of water (350 ml) and CH2Cl2 (700 ml) and H2S gas was passed through the vigorously stirred mixture for 5 minutes. The organic phase was separated, filtered through celite, washed with water, dried (MgSO4) and reduced to dryness to provide the title compound, m.p. 103°-105°.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([F:11])[CH:9]=2)[NH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(OCC)(=O)C>CN(C=O)C.O>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([F:11])[CH:9]=2)[N:4]([C:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:19]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:3]=1
Reactant: Clc1ccccc1C(c1ccccc1)c1ccccc1
Reactant: Fc1cnc2[nH]nc(Br)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1cnc2c(c1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 3-bromo-5-fluoro-1H-pyrazolo[3,4-b]pyridine, 133a, (0.97 g, 4.49 mmol) and K2CO3 (1.86 g, 13.47 mmol) in DMF (9.7 mL) was cooled to 0° C. Chlorodiphenylmethylbenzene (1.38 g, 4.94 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was diluted into ethyl acetate (40 mL) and water (30 mL) and the layers were separated. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (40% ethyl acetate/hexanes) to afford 1.68 g of the desired product as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 8.45-8.38 (m, 1H), 8.04 (dd, J=8.0, 2.7 Hz, 1H), 7.35-7.16 (m, 15H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=3.03 minutes (M+H) 459.46.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C@H:6]([N:8]([C:13]([C:15]2[N:16]=[N:17][N:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:19]=2[CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:5][N:4]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:3]1.C(N(C(C)C)CC)(C)C.Br[CH2:49][CH2:50][CH2:51][CH2:52][C:53](Cl)=[O:54]>C1COCC1.O>[CH3:25][O:24][CH2:23][CH2:22][CH2:21][CH2:20][C:19]1[N:18]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:17]=[N:16][C:15]=1[C:13]([N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C@@H:6]1[CH2:5][N:4]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:3][C@H:2]([N:1]2[CH2:49][CH2:50][CH2:51][CH2:52][C:53]2=[O:54])[CH2:7]1)=[O:14]
Reactant: O=C(Cl)CCCCBr
Reactant: COCCCCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](N)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCCCCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](N3CCCCC3=O)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
tert-Butyl (3R,5S)-3-amino-5-[{[5-(4-methoxybutyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate (150 mg) was dissolved in THF (3 ml), diisopropylethylamine (74 μl) and 5-bromovaleryl chloride (42 μl) were added at 0° C. and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in THF (10 ml), potassium tert-butoxide (96 mg) was added at 0° C. and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, the residue was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography, and a fraction eluted with ethyl acetate-hexane (1:3-1:0) was concentrated under reduced pressure to give the object product (150 mg).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[C:19](=[O:26])[CH:20]=[C:21]([CH2:24][OH:25])[O:22][CH:23]=2)=[N:3][CH:2]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:34][S:35]([O:25][CH2:24][C:21]1[O:22][CH:23]=[C:18]([O:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][N:3]=2)[C:19](=[O:26])[CH:20]=1)(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: O=c1cc(CO)occ1OCCCCCOc1ncnc2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cc(=O)c(OCCCCCOc2ncnc3ccccc23)co1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of 5-(5-(quinazolin-4-yloxy)pentyloxy)-2-(hydroxymethyl)-4H-pyran-4-one 15 (0.53 g, 1.49 mmol) in CH2Cl2 (20 mL) was added at 0° C. triethylamine (252 μL, 1.78 mmol), methanesulfonyl chloride (138 μL, 1.78 mmol). The solution was stirred at RT for 1 h. Dichloromethane (50 mL) was added and the solution was washed with water (2×100 mL), dried over MgSO4, filtered and evaporated. (5-(5-(Quinazolin-4-yloxy)pentyloxy)-4-oxo-4H-pyran-2-yl)methyl methanesulfonate 20 was obtained (0.64 g, 99% yield) as a pale yellow oil.
Reaction SMILES: C[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[S:7])=[CH:4][CH:3]=1.[C:10]1([S:16]([NH2:19])(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O.[C:21]1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:21][S:7][C:6](=[N:19][S:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:18])=[O:17])[C:5]1[CH:4]=[CH:3][CH:2]=[CH:9][CH:8]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: Cc1ccc(C=S)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CSC(=NS(=O)(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
A stirred mixture consisting of 2.60 g (17.2 mmol) of 4-methylthiobenzaldehyde, 2.70 g (17.2 mmol) cf benzenesulfonamide and 20 mg of p-toluenesulfonic acid monohydrate in 150 mL of toluene was heated to reflux. The reaction vessel was equipped with a Soxhlet extractor containing 4A molecular sieves. After heating 8 hours, the mixture was allowed to cool to room temperature and was concentrated to afford 4.60 g (92%) of sulfonimine as light tan crystals: mp 1.50°-155° C.; 1H NMR (CDCl3, TMS ext std) δ9.15 (s, 1), 8.27-7.18 (m, 9), 2.53 (s, 3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([OH:24])[CH:22]=3)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:31](I)[CH3:32]>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH2:31][CH3:32])[CH:22]=3)[CH:17]=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc3ccc(O)cc23)CC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc2ccnc(N3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Yield: 89.5 %

Procedure:
To a solution of 105 mg of 1-(4-tert-butoxycarbonylpiperazin-1-yl)-7-hydroxyisoquinoline in 10 ml of acetone, 93 mg of potassium carbonate and 55 mg of ethyl iodide were added and heated under reflux for 2 hours. Further adding 55 mg of ethyl iodide, the solution was heated under reflux for 2 hours, followed by addition of 48 mg of potassium carbonate and 55 mg of ethyl iodide, and an overnight's refluxing. Cooling the system off, the residue was extracted with ethyl acetate after addition of water, washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified on silica gel column chromatography (ethyl acetate:n-hexane=1:4) to provide 102 mg (90%) of 1-(4-tert-butoxycarbonylpiperazin-1-yl)-7-ethoxyisoquinoline.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[O:15][CH3:16])=[O:4].[ClH:17].[F:18][C:19]1[CH:32]=[CH:31][C:22]([C:23]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])=[CH:21][CH:20]=1.C(N(CC)CC)C.Cl>C(O)C>[ClH:17].[F:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:2][C:3]([C:5]3[CH:14]=[CH:13][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:6]=3[O:15][CH3:16])=[O:4])[CH2:27][CH2:26]2)=[O:24])=[CH:31][CH:32]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: COc1c(C(=O)CBr)ccc2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1c(C(=O)CN2CCC(C(=O)c3ccc(F)cc3)CC2)ccc2ccccc12

Procedure:
1.5 g of 2-bromo-1'-methoxy-2'-acetonaphthone, 1.3 g of 4-(p-fluorobenzoyl)piperidine hydrochloride, and 1.6 g of triethylamine were added to 60 ml of ethanol. The mixture was refluxed for 15 min. The solvent was distilled off, and dichloromethane was added to the residue. The mixture was washed with water and dried. The dichloromethane was distilled off, and the residue was purified by column chromatography (silica gel) to prepare an oleaginous intended compound. The compound was converted into a hydrochloride by an ordinary method and then recrystallized to prepare 1.38 g of an intended hydrochloride.