Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:40])[C:5]([CH3:39])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:35]C(=O)C)=[C:17]([CH:34]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([C:30]([F:33])([F:32])[F:31])(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:40])[C:5]([CH3:39])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:35])=[C:17]([CH:34]=2)[C:18]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([S:27]([C:30]([F:31])([F:32])[F:33])(=[O:28])=[O:29])=[CH:25][CH:26]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(S(=O)(=O)C(F)(F)F)cc3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc(S(=O)(=O)C(F)(F)F)cc3)c2)=C(C)C1=O
Yield: 37.8 %

Procedure:
N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-(trifluoromethylsulfonyl)aniline (0.060 g, 0.103 mmol) was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (2 ml), the solution was stirred at room temperature for 2 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.021 g, 0.0389 mmol, 38%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[CH3:2]>C(O)C.[Pd]>[NH2:10][C:9]1[CH:8]=[CH:7][C:6]([N:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]2)=[CH:5][C:4]=1[O:3][CH2:1][CH3:2]
Reactant: CCOc1cc(N2CCN(C(C)=O)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCOc1cc(N2CCN(C(C)=O)CC2)ccc1N
Reaction time: 2 h

Procedure:
The compound prepared in Step 2 was dissolved in ethanol, added with 10% Pd/C and stirred under hydrogen atmosphere for 2 hours. Upon completion of the reaction, the Pd/C in the reaction mixture was removed using celite and the solvent was removed under reduced pressure. The thus obtained compound was used in the subsequent reaction without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][C:28]4[CH:37]=[C:36]5[C:31]([CH2:32][CH2:33][NH:34][CH2:35]5)=[CH:30][CH:29]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C:41]1(O[Si](C)(C)C)[CH2:43][CH2:42]1)C.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][C:28]4[CH:37]=[C:36]5[C:31]([CH2:32][CH2:33][N:34]([CH:41]6[CH2:43][CH2:42]6)[CH2:35]5)=[CH:30][CH:29]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: Nc1ncnn2c(Cc3ccc4c(c3)CNCC4)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ncnn2c(Cc3ccc4c(c3)CN(C3CC3)CC4)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 49.8 %

Procedure:
5-(2-Benzyl-2H-indazol-6-yl)-7-(1,2,3,4-tetrahydro-isoquinolin-7-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine (0.100 g, 0.21 mmol) was dissolved in MeOH (1 mL) and (1-ethoxy-cyclopropoxy)-trimethyl-silane (0.22 g, 1.24 mmol) was added followed by acetic acid (0.118 mL, 2.05 mmol) and sodium cyanoborohydride (0.058 g, 0.92 mmol). The resulting mixture was refluxed overnight and then allowed to cool. The mixture was filtered, concentrated and the residue was purified by preparative HPLC to give 55 mg (50%) of the title compound. 1H-NMR (CD3OD-d4) 8.36-8.23 (m, 1 H), 7.81 (s, 1 H), 7.78 (dd, 1H), 7.38-7.29 (m, 4 H), 7.19 (dd, 1 H), 7.10-6.99 (m, 2 H), 6.44 (s, 1 H), 5.63 (s, 2 H), 4.23 (s, 2 H), 3.72 (s, 2 H), 2.96-2.81 (m, 4 H), 1.86-1.79 (m, 1 H), 0.57-0.75 (m, 4 H); LC-MS [M+H]+=426.3, RT=2.32 min.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]([C@H:13]([CH2:39][O:40][CH2:41][CH2:42][O:43][CH3:44])[CH2:14][C:15]3([C:20]([NH:22][C@@H:23]4[CH2:28][CH2:27][C@H:26]([C:29]([O:31]CC5C=CC=CC=5)=[O:30])[CH2:25][CH2:24]4)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1>C(O)C.[Pd]>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]([C@H:13]([CH2:39][O:40][CH2:41][CH2:42][O:43][CH3:44])[CH2:14][C:15]3([C:20]([NH:22][C@@H:23]4[CH2:24][CH2:25][C@H:26]([C:29]([OH:31])=[O:30])[CH2:27][CH2:28]4)=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19]3)=[O:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COCCOC[C@H](CC1(C(=O)N[C@H]2CC[C@@H](C(=O)OCc3ccccc3)CC2)CCCC1)C(=O)Oc1ccc2c(c1)CCC2
Agent: [Pd]
Solvent: CCO
Product: COCCOC[C@H](CC1(C(=O)N[C@H]2CC[C@@H](C(=O)O)CC2)CCCC1)C(=O)Oc1ccc2c(c1)CCC2
Reaction time: 3.5 h
Yield: 76.7 %

Procedure:
A solution of (S)-benzyl cis-4-{1-[2-(5-indanyloxycarbonyl)-3-(2-methoxyethoxy)propyl]-1-cyclopentanecarboxamido}-1-cyclohexanecarboxylate (597 mg, 0.986 mmole) in 5% aqueous ethanol (10 ml) was hydrogenated over 10% palladium on charcoal catalyst (60 mg) at 60 p.s.i. (4.1 bar) and room temperature for 3.5 hours. The catalyst was removed by filtration and the filtrate evaporated under vacuum. The residue was dissolved in diethyl ether (50 ml) and the solution was clarified by filtration, and concentrated to low volume (about 5 ml) when crystallisation occurred. After granulation, filtration and drying gave the title ester (390 mg, 77%) as white crystals m.p. 107°-9° C., [α]D -5.8° (c=1, MeOH), Rf. 0.40 (silica; toluene, dioxan, acetic acid 90:24:5). Found: C,67.45; H,8.18; N,2.63. C29H41NO7 requires C,67.55; H,8.01; N,2.72%.
Reaction SMILES: FC(F)(F)C([O-])=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C@H:20]3[CH2:25][CH2:24][CH2:23][CH2:22][NH2+:21]3)[S:18][CH:19]=2)=[CH:11][CH:10]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[O:42]([CH2:49][C:50](Cl)=[O:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>ClCCl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:16]=[C:17]([C@H:20]3[CH2:25][CH2:24][CH2:23][CH2:22][N:21]3[C:50](=[O:51])[CH2:49][O:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[S:18][CH:19]=2)=[CH:13][CH:14]=1
Reactant: O=C(Cl)COc1ccccc1
Reactant: Clc1ccc(-c2csc([C@H]3CCCC[NH2+]3)n2)cc1
Agent: CN(C)c1ccccn1
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(COc1ccccc1)N1CCCC[C@@H]1c1nc(-c2ccc(Cl)cc2)cs1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (R)-2-[4-(4-chloro-phenyl)-thiazol-2-yl]-piperidinium trifluoroacetate (0.077 g, 0.20 mmol) in dry dichloromethane (2 mL) under argon was treated with triethylamine (0.079 g, 0.11 mL), dimethylaminopyridine (0.002 g, 0.020 mmol) and phenoxyacetyl chloride (0.033 g, 0.20 mmol). The mixture was stirred at room temperature for 16 h. The mixture was washed with water and saturated sodium chloride. The organic phase was dried over sodium sulphate and evaporated. The residual oil was purified by preparative HPLC: Column: YMC-Pack Pro C18 RS, 20×50 mm, S-5 um, 8 nm, No 200504707(W); Gradient: 0-0.4 min: 30% acetonitrile in (water+0.1% HCO2H), 0.4-2 min: increse of acetonitrile fraction from 30% to 95%, 2.4-3.7 min: 95% acetonitrile, 3.7-3.8 min: decrease of acetonitrile fraction from 95% to 30%; Program end at 4 min; Flow: 30 ml/min. 1-{(R)-2-[4-(4-Chloro-phenyl)-thiazol-2-yl]-piperidin-1-yl}-2-phenoxy-ethanone was obtained after lyophilization as a light yellow oil (0.037 g, 46%), MS (ISP): 413.1, 415.4 (M+H)+.. 1H-NMR (CDCl3, 300 MHz): 7.81 (2H, d), 7.38 (3H, m), 7.27 (2H, m), 6.98 (3H, m), 6.11+5.58 (1H, bs), 4.82 (2H, m), 4.56+3.91 (1H, bd), 3.36+2.86 (1H, bt), 2.59 (1H, m), 1.75 (5H, m).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]1([CH2:13][CH:14]=O)[CH2:12][CH2:11][CH2:10]1>C(Cl)Cl>[CH:9]1([CH2:13][CH:14]=[N:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: O=CCC1CCC1
Reactant: NCc1ccccc1
Solvent: ClCCl
Product: C(CC1CCC1)=NCc1ccccc1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 105.8 %

Procedure:
Benzylamine (2.95 g, 27.5 mmol) was added to a mixture of cyclobutylacetaldehyde (30.6 mmol) in CH2Cl2 (˜238 mL) and molecular sieves (5.0 g) and the mixture was stirred at room temperature for 5.5 hours. The mixture was filtered over Celite and the solvent was removed under vacuum to yield 5.45 g of crude N-(2-cyclobutylethylidene)-1-phenylmethanamine.
Reaction SMILES: N1C=CC=CC=1S[C:8](=[O:27])[CH2:9][C:10]1[N:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1.[CH2:28]([Mg]Br)[CH2:29][CH2:30][CH2:31][CH3:32]>>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]2[N:14]([C:10]([CH2:9][C:8](=[O:27])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:11]([C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)[N:12]=2)[CH:15]=1
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)Sc2ccccn2)cc1
Reactant: CCCCC[Mg]Br
Product: CCCCCC(=O)Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12

Procedure:
Prepared from (6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-thioacetic acid S-pyridin-2-yl ester 1c and pentylmagnesium bromide using a similar procedure described above. 1H NMR (400 MHz, CDCl3) δ 0.81 (t, 3H), 1.17 (m, 6H), 1.51 (m, 2H), 2.28 (s, 3H), 2.37 (s, 3H), 4.04 (s, 2H), 7.00 (d, J=8.4 Hz, 1H), 7.23 (d, J=7.3 Hz, 2H), 7.55 (m, 4H). Mass spectrum m/e 335 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([O:12][CH2:13][C@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)[C:5]([Br:19])=[CH:4][CH:3]=1.BrC1C(OC[C@@H]2CCCN2C(OC(C)(C)C)=O)=C(C(OC)=O)C(N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=CC=1>>[NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([O:12][CH2:13][C@@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)[C:5]([Br:19])=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(N)ccc(Br)c1OC[C@H]1CCCN1
Agent: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc(Br)c1OC[C@@H]1CCCN1C(=O)OC(C)(C)C
Product: COC(=O)c1c(N)ccc(Br)c1OC[C@@H]1CCCN1

Procedure:
Prepared by proceeding in a similar manner to Intermediate 7, starting from tert-butyl (S)-2-[6-bromo-3-bis-(tert-butoxycarbonyl)amino-2-methoxycarbonylphenoxy-methyl]pyrrolidine-1-carboxylate (Intermediate 15).
Reaction SMILES: [CH2:1]([Sn:5](Cl)([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([C:38]2[N:39]=[CH:40][N:41]3[CH:45]=[CH:44][S:43][C:42]=23)=[O:37])[CH:31]=1.[Cl-].[NH4+]>C1COCC1>[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([C:38]2[N:39]=[CH:40][N:41]3[CH:45]=[C:44]([Sn:5]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:1][CH2:2][CH2:3][CH3:4])[S:43][C:42]=23)=[O:37])[CH:31]=1
Reactant: O=C(c1cccnc1)c1ncn2ccsc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)c3cccnc3)c2s1
Temperature: -50 °C
Reaction time: 0.33 h

Procedure:
Tri-n-butylstannyl chloride (0.841 ml) and 2.95 ml of a 1.0 N lithium bis(trimethylsilyl)amide/THF solution were added to a solution of 520 mg of 7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazole in 25 ml of THF at −60° C. under an argon atmosphere, and the mixture was stirred for 20 min. The temperature of the mixture was raised to −50° C., 1.0 ml of a 1.0 N lithium bis(trimethylsilyl)amide/THF solution was added thereto, and the mixture was stirred for 30 min. The temperature of the mixture was raised to −40° C., 0.5 ml of a 1.0 N lithium bis(trimethylsilyl)amide/THF solution was added thereto, and the mixture was stirred for 30 min. An aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate, followed by washing with brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1→ethyl acetate only) to give 712 mg of the title compound.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][NH2+:16][CH2:17][C:18]1[O:19][CH:20]=[CH:21][CH:22]=1.[C:23]([O-])([O-])=O.[K+].[K+].CI>C1COCC1>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][N:16]([CH2:17][C:18]1[O:19][CH:20]=[CH:21][CH:22]=1)[CH3:23]
Reactant: O=C([O-])[O-]
Reactant: Clc1c(OCC[NH2+]Cc2ccco2)ccc2ccccc12
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CN(CCOc1ccc2ccccc2c1Cl)Cc1ccco1
Temperature: 25 °C
Reaction time: 14 h
Yield: 91 %

Procedure:
A solution (32 mg, 0.095 mmol) of 2-[(1-chloronaphthalen-2-yl)oxy]-N-(furan-2 ylmethyl)ethanaminium chloride (1) in 5 mL of THF was treated with 21 mg (0.15 mmol) of K2CO3 and 6 μL (0.100 mmol) of MeI. The resulting mixture was stirred for 14 h at room temperature. The solvent was distilled off under vacuum and the crude was triturated for 1 h in 5 mL of di-isopropyl ether. Pure 2-[(1-chloronaphthalen-2-yl)oxy]-N-(furan-2-ylmethyl)-N-methylethanamine was obtained after decantation of ether as a pale yellow oil in 91% yield.
Reaction SMILES: Br[CH2:2][O:3][C:4]1[C:5]([O:10][CH3:11])=[CH:6][CH:7]=[CH:8][CH:9]=1.[NH2-].[Na+].[CH2:14]([O:16][C:17]([O:19][CH2:20][CH3:21])=[CH2:18])[CH3:15].O>C1(C)C=CC=CC=1>[CH2:14]([O:16][C:17]1([O:19][CH2:20][CH3:21])[C:9]2[C:8](=[CH:7][CH:6]=[C:5]([O:10][CH3:11])[C:4]=2[O:3][CH3:2])[CH2:18]1)[CH3:15]
Reactant: COc1ccccc1OCBr
Reactant: C=C(OCC)OCC
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC1(OCC)Cc2ccc(OC)c(OC)c21
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
24 g (107 mmol) of bromoveratrol is poured onto 8.4 g (215 mmol)/2 eq.) of sodium amide in 10 mL of toluene, followed by 25 g (215 mmol/2 eq.) of 1,1diethoxyethylene. Heating is carried out at 80° C. for 4 hours 30 minutes; cooling to −10° C. is carried out and 50 mL of water and then 50 mL of toluene are poured in. The phases are separated and the aqueous phase is extracted again with toluene. The combined toluene phases are washed with water to neutral pH and are then concentrated. The residue is chromatographed over 600 g of silica (eluant: dichloromethane) to yield the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].C(N(CC)CC)C.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.O>ClCCl>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:9][C:3]2[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=2[NH2:1])(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(N)c(O)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2cc(C)ccc2N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
400 mg of 2-amino-5-methylphenol was dissolved in 6.5 ml of dichloromethane, and 476 μl of triethylamine and 619 mg of p-toluene sulfonylchloride were added and stirred at room temperature for 1 hour. To the reaction mixture, 60 ml of water was added, and extracted with 60 ml of ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and purified using silica gel column chromatography (hexane:ethyl acetate=3:1) to yield 730.1 mg of the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([C:22]([O:24]CC)=[O:23])[CH:14]=[C:15]([CH:21]=3)[C:16]([O:18]CC)=[O:17])[N:9]=2)[CH:4]=[CH:3][C:2]=1[C:27]1[CH:28]=[C:29]([C:38]([O:40]CC)=[O:39])[CH:30]=[C:31]([CH:37]=1)[C:32]([O:34]CC)=[O:33]>C1COCC1.CO.[OH-].[Na+]>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:21]=[C:15]([C:16]([OH:18])=[O:17])[CH:14]=[C:13]([CH:12]=3)[C:22]([OH:24])=[O:23])[N:9]=2)[CH:4]=[CH:3][C:2]=1[C:27]1[CH:37]=[C:31]([C:32]([OH:34])=[O:33])[CH:30]=[C:29]([CH:28]=1)[C:38]([OH:40])=[O:39]
Reactant: CCOC(=O)c1cc(C(=O)OCC)cc(-c2ccc3ccc(-c4cc(C(=O)OCC)cc(C(=O)OCC)c4)nc3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc(C(=O)O)cc(-c2ccc3ccc(-c4cc(C(=O)O)cc(C(=O)O)c4)nc3n2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.0 g of tetraethyl 5,5′-(1,8-naphthyridine-2,7-diyl)diisophthalate was dissolved in 60 mL of mixed solvent of THF and MeOH (v/v=1:1), 20 mL of 2N NaOH aqueous solution was added. The mixture was stirred at room temperature overnight. After the organic phase was removed, the aqueous phase was acidified with dilute hydrochloric acid to give white precipitate, which was filtered and washed with water several times. Yield: 1.5 g, 94%. 1H NMR (300 MHz, DMSO-d6): δ 8.44 (d, 2H), 8.62 (s, 2H), 8.68 (d, 2H), 9.10 (s, 4H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][S:5](=[O:8])(=[O:7])[N:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH2:3]1.[CH:18]1([C:21]2[CH:22]=[C:23]([CH3:33])[C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH2:20][CH2:19]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O1CCCC1.O>[CH:18]1([C:21]2[CH:22]=[C:23]([CH3:33])[C:24]([N:27]3[CH2:28][CH2:29][N:30]([C:13]([C:12]4[CH:11]=[CH:10][C:9]([N:4]5[CH2:3][CH:2]([CH3:1])[CH2:6][S:5]5(=[O:7])=[O:8])=[CH:17][CH:16]=4)=[O:15])[CH2:31][CH2:32]3)=[N:25][CH:26]=2)[CH2:20][CH2:19]1
Reactant: CC1CN(c2ccc(C(=O)O)cc2)S(=O)(=O)C1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CC(C)CS3(=O)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.7 %

Procedure:
4-(4-Methyl-1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoic acid (200 mg) described in Preparation Example 15 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (170 mg) described in Preparation Example 83 were dissolved in tetrahydrofuran (10 mL), 1-hydroxybenzotriazole 1 hydrate (139 mg) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (225 mg) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (120 mg).
Reaction SMILES: S(O)(=O)(=O)C.[NH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[N:10]=[C:9]([SH:14])[N:8]=1.[H-].[Na+].Cl[CH:18]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][N:21]=1)[CH3:19].O>CN(C)C=O>[NH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[N:10]=[C:9]([S:14][CH:18]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][N:21]=2)[CH3:19])[N:8]=1
Reactant: CC(Cl)c1nccc2ccccc12
Reactant: Nc1cc(Cl)nc(S)n1
Agent: CS(=O)(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(Sc1nc(N)cc(Cl)n1)c1nccc2ccccc12
Reaction time: 0.75 h
Yield: 53.5 %

Procedure:
4-Amino-6-chloro-2-mercapto-pyrimidine mesylate salt (1.29 g, 5 mmole) is dissolved in 8 ml dry dimethylformamide in a 50 ml one neck round bottom flask under nitrogen. The solution is treated with 60% sodium hydride (400 mg, 10 mmole) (exotherm) and the mixture is stirred 45 min. 1-(1-chloroethyl)-isoquinoline (958 mg, 5 mmole) in 2×2 ml dry dimethylformamide, is added to the reaction and the mixture is stirred overnight at room temperature. The reaction mixture is poured into 200 ml water and is extracted with 4×50 ml ethyl acetate. The combined organics are backwashed with 4×50 ml 50% saturated sodium chloride. The organics are dried over potassium carbonate and are concentrated in vacuo to a yellow oil. The crude material is chromatographed over 100 g silica gel (230-400 mesh), eluting with 25% acetone/hexane while collecting 22 ml fractions. Fractions 27-39 are combined and concentrated to given a pale yellow foam. Crystallization from diethyl ether afforded 847 mg (54%) of 4-Amino-6-chloro-2-(1-(1-isoquinolyl)ethyl)thio-pyrimidine (Cpd #232) as an off-white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH:3]1[CH:9]=[CH:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[CH2:5][CH2:4]1>C(O)C>[CH3:1][N:2]([CH3:14])[CH:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[CH2:5][CH2:4]1
Reactant: CN(C)C1C=Cc2ccccc2CC1
Solvent: CCO
Product: CN(C)C1CCc2ccccc2CC1
Reaction time: 0.5 h
Yield: 36.2 %

Procedure:
A mixture of 11.2 g of 7-dimethylamino-6,7-dihydro [5H] benzocycloheptene, 800 ml of ethanol and 11.2 g carbon containing 10% of Pd (OH)2 was held under a hydrogen atmosphere for 30 minutes and when the theoretical amount of hydrogen had been absorbed, the mixture was filtered. The filtrate was evaporated to dryness and the residue was chromatographed over silica gel. Elution with an 8-2-1 ethyl acetate-benzene-triethylamine mixture yielded 4.1 g of 7-dimethylamino-6,7,8,9-tetrahydro [5H] benzocycloheptene.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:5][CH:4]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[CH:25]=1.[H-].[Na+]>O1CCCC1>[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][N:31]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:5][CH:4]=2)[C:32](=[O:34])[CH3:33])[CH:25]=1
Reactant: CC(=O)NCc1cccnc1
Reactant: CCCCCCCCCCCCCCOc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(CN(Cc2cccnc2)C(C)=O)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 41.2 %

Procedure:
The title compound is prepared by the procedure of Example 27 using 1.1 g of product from Example 20, 0.431 g of product from Example 14, 0.145 g of washed 50% sodium hydride and 12 ml of tetrahydrofuran. The reaction is stirred at room temperature for 21 hours followed by heating at reflux temperature for 51/2 hours. The residue is purified by column chromatography (silica gel: 5% methyl alcohol/ethyl acetate) to give 0.535 g of the desired product. The spectral data indicates the presence of 2 rotomers.
Reaction SMILES: [OH:1][CH:2]1[CH:6]([OH:7])[CH:5]([N:8]2[C:12]3[N:13]=[C:14]([S:27][CH3:28])[N:15]=[C:16]([NH:17][CH:18]4[CH2:20][CH:19]4[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:11]=3[N:10]=[N:9]2)[CH2:4][CH:3]1[C:29]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34]C=1)=[O:30].C1(N)CCCC1>>[CH:32]1([NH:31][C:29]([CH:3]2[CH2:4][CH:5]([N:8]3[C:12]4[N:13]=[C:14]([S:27][CH3:28])[N:15]=[C:16]([NH:17][CH:18]5[CH2:20][CH:19]5[C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)[C:11]=4[N:10]=[N:9]3)[CH:6]([OH:7])[CH:2]2[OH:1])=[O:30])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: CSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C(=O)Nc4ccccc4)C(O)C3O)c2n1
Agent: NC1CCCC1
Product: CSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C(=O)NC4CCCC4)C(O)C3O)c2n1

Procedure:
The title compound was prepared according to the method of example 1, step d) using the product of Example 20, step b) and cyclopentylamine, followed by deprotection according to the method of example 1, step e).