Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.[NH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(CC)CC)C>O1CCCC1>[CH3:7][C:5]1[N:6]=[C:2]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[S:3][CH:4]=1
Reactant: Cc1csc(I)n1
Reactant: C1CNCCN1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1csc(N2CCNCC2)n1
Temperature: 160 °C
Yield: 65 %

Procedure:
A mixture of 1.33 mmol 2-iodo-4-methyl-thiazole, 4.00 mmol piperazine and 4.00 mmol triethylamine in 4 ml tetrahydrofuran in a sealed tube was heated at 160° C. for 2 h under microwave irradiation. The reaction mixture was concentrated and the residue was purified by chromatography (SiO2, methanol/dichloromethane) to afford the title compound as a yellow oil (yield 65%). MS (m/e): 184.3 (M+H+, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:9]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:8][C:3]=1[C:4]([O:6]C)=O.[Cl-].[NH2:23][C:24]([NH2:26])=[NH2+:25].C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[NH2:25][C:24]([NH2:26])=[N:23][C:4](=[O:6])[C:3]1[CH:8]=[C:9]([S:18]([CH3:21])(=[O:20])=[O:19])[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:11][C:2]=1[NH2:1]
Reactant: NC(N)=[NH2+]
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(-c2cccnc2)cc1N
Agent: [Cl-]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1cc(C(=O)N=C(N)N)c(N)cc1-c1cccnc1
Reaction time: 0.25 h

Procedure:
1.0 g of methyl 2-amino-4-(3-pyridyl)-5-methylsulfonylbenzoate [obtainable by reacting methyl 2-amino-4-bromo-5-methylsulfonylbenzoate with pyridine-3-boronic acid] is dissolved in 15 ml of 1-methylpyrrolidone and the solution is stirred for 15 min. Subsequently 0.9 g of guanidinium chloride and 2.6 ml of diisopropylethylamine are added and the mixture is stirred at room temperature for one hour. Customary workup gives N-diaminomethylene-2-amino-4-(3-pyridyl)-5-methylsulfonylbenzamide.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]([CH:28]1[CH2:31][CH2:30][CH2:29]1)([OH:27])[CH3:26])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[H-].[Na+].I[CH3:44]>O1CCCC1>[CH:28]1([C:25]([C:16]2[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:15]=2[CH2:14][N:7]([CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:39])[F:40])[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=2)[C:8]2[N:9]=[N:10][N:11]([CH3:13])[N:12]=2)([O:27][CH3:44])[CH3:26])[CH2:31][CH2:30][CH2:29]1
Reactant: CI
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(C)(O)C2CCC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C)(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCC1
Reaction time: 0.17 h
Yield: 79.5 %

Procedure:
To a solution of 1-(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)-1-cyclobutylethanol (22 mg; 0.038 mmol) in tetrahydrofuran (1.5 mL) was added sodium hydride (10 mg; 0.25 mmol; 60% dispersion in mineral oil). The reaction was stirred for 10 minutes. Iodomethane (0.05 mL; 0.80 mmol) was added. The reaction was stirred at room temperature for 16 hours. The reaction was quenched with water. The mixture was diluted with ethyl acetate and filtered over sodium sulfate and silica get column. After being concentrated under reduced pressure, the residue was taken up in ethyl acetate and washed with water (2×) and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified over a 4 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 10-50% ethyl acetate in hexanes) to give 18 mg (80% yield) of the title compound as a colorless gum. MS (ES+): Calc: 595.5, Found: 596.5 (M+H). 1H NMR (400 MHz, CDCl3) δ ppm 7.78 (s, 1H), 7.73 (s, 2H), 7.45 (d, J=8.3 Hz, 1H), 7.43 (s, 1H), 7.3 (d, J=8.3 Hz, 1H), 5.09 (s, 2H), 4.8 (q, J=16.18 Hz, 2H), 4.2 (s, 3H), 3.04 (s, 3H), 2.83 (m, 1H) 1.99 (m, 1H), 1.89-1.6 (m, 6H), 1.59 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:16][CH:17]=[C:18](Cl)[CH3:19])([CH2:13][CH2:14][CH3:15])[C:8]2=[O:12])=[CH:4][C:3]=1[CH2:21][CH2:22][C:23]([OH:25])=[O:24].S(=O)(=O)(O)[OH:27].O>C(Cl)Cl>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:16][CH2:17][C:18](=[O:27])[CH3:19])([CH2:13][CH2:14][CH3:15])[C:8]2=[O:12])=[CH:4][C:3]=1[CH2:21][CH2:22][C:23]([OH:25])=[O:24]
Reactant: CCCC1(CC=C(C)Cl)Cc2cc(CCC(=O)O)c(Cl)c(Cl)c2C1=O
Reactant: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: CCCC1(CCC(C)=O)Cc2cc(CCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 5 °C
Reaction time: 1 h

Procedure:
3-[6,7-Dichloro-2-(3-chloro-2-butenyl)-2,3-dihydro-1-oxo-2-propyl-1H-inden-5-yl]propionic acid (6.8 g, 0.0168 mole) dissolved in methylene chloride (65 ml) was added over 15 minutes to a mixture of sulfuric acid (75 ml) and methylene chloride (35 ml) at 5° C., stirred at 5° C. for 1 hour, poured over ice and water, and extracted with methylene chloride. The organic extracts were washed with water, dried over MgSO4 and concentrated under vacuum. The residue was recrystallized from butyl chloride to obtain the product mp 131°-3° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1)[CH3:2].[F:15][C:16]([F:30])([F:29])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26](O)=[O:27].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[F:15][C:16]([F:29])([F:30])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26]([N:12]1[CH2:11][CH2:10][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=2)[CH2:14][CH2:13]1)=[O:27]
Reactant: CCc1cccc(N2CCNCC2)c1
Reactant: O=C(O)Cc1ccccc1OCC(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCc1cccc(N2CCN(C(=O)Cc3ccccc3OCC(F)(F)F)CC2)c1
Reaction time: 48 h

Procedure:
1-(3-ethylphenyl)piperazine from the previous step was dissolved in 1 mL dry DMF, and to the solution was added 0.03 g (0.128 mmol) 2-(2,2,2-trifluoroethoxy)phenylacetic acid, 0.017 g (0.128 mmol) HOBT, and 0.024 g (0.128 mmol) EDC. The reaction was stirred for 2 days, after which time the solvent was removed in vacuo and the resulting residue partitioned between EtOAc/H2O. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with H2O, brine, dried over Na2SO4 and filtered. Removal of the solvent and subsequent purification via preparative TLC (2:1 Hexane/EtOAc) yielded the title compound as the free base. This was dissolved in 20 mL EtOAc and an excess of ethanolic HCl was added. The solvent was removed to give the Hcl salt of the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[CH:11][C:12]3[C:20]4[C:15](=[CH:16][C:17]([N:21]([CH3:31])[C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-])=O)[CH:23]=5)=[CH:18][CH:19]=4)[N:14](COCC[Si](C)(C)C)[N:13]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.O1C2C=CC(C=CC3C4C(=CC(N(C)C5C=CC=C([N+]([O-])=O)C=5)=CC=4)NN=3)=CC=2OC1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[CH:11][C:12]3[C:20]4[C:15](=[CH:16][C:17]([N:21]([CH3:31])[C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=5)=[CH:18][CH:19]=4)[NH:14][N:13]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CN(c1cccc([N+](=O)[O-])c1)c1ccc2c(C=Cc3ccc4c(c3)OCO4)nn(COCC[Si](C)(C)C)c2c1
Agent: CN(c1cccc([N+](=O)[O-])c1)c1ccc2c(C=Cc3ccc4c(c3)OCO4)n[nH]c2c1
Product: CN(c1cccc(N)c1)c1ccc2c(C=Cc3ccc4c(c3)OCO4)n[nH]c2c1

Procedure:
{3-(2-Benzo[1,3]dioxol-5-yl-vinyl)-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-methyl-(3-nitro-phenyl)-amine was converted to [3-(2-Benzo[1,3]dioxol-5-yl-vinyl)1H-indazol-6-yl]-methyl-(3-nitro-phenyl)-amine as described in Example 11. LCMS (EST) [M+H]/z Calc'd 415, found 415. Anal. Calc'd: C, 66.66; H, 4.38; N, 13.52. Found: C, 66.56; H, 4.48; N, 13.35.
Reaction SMILES: C([N:3](CC)CC)C.[Al+3].[Cl-].[Cl-].[Cl-].[N+]([C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][O:20][C:21]2=[O:22])=[CH:17][CH:16]=1)([O-])=O.CCOC(C)=O>ClCCCl>[OH:20][CH2:19][C:18]1[CH:17]=[CH:16][CH:15]=[CH:24][C:23]=1[C:21]([NH2:3])=[O:22]
Reactant: CCN(CC)CC
Reactant: O=C1OCc2ccc([N+](=O)[O-])cc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: NC(=O)c1ccccc1CO
Temperature: 17.5 °C
Yield: 30.6 %

Procedure:
A solution of triethylamine (TEA, 0.658 g, 0.91 ml, 6.50 mmol, 1.5 equiv.) in 1,2-dichloroethane (3 ml) was added dropwise under stirring and cooling with ice to a suspension of AlCl3 (0.635 g, 4.76 mmol, 1.1 equiv.) in 1,2-dichloroethane (7 ml). The temperature was maintained at 15-20° C. during the addition and the mixture was then allowed to warm up at room temperature. A solution of 1-dimethoxytrityl-6-amino-hexan-1-ol (16) (2.00 g, 4.76 mmol, 1.1 equiv., prepared as described by Woo and Fung (1996), International Pat. App. Pub. No. WO 96/05215) and 6-nitrophthalide (18) (0.766 g, 4.33 mmol, 1.0 equiv.) in 1,2-dichloroethane (3 ml) was added over a period of 20 min and the mixture was stirred at room temperature overnight. The completion of the reaction was confirmed by TLC analysis (EtOAc containing 1% TEA). The reaction mixture was then quenched with an ice-water mixture (30 ml) and stirred for an additional 30 min. The resulting suspension was filtered through a bed of Celite® and the filter cake was washed with 1,2-dichloroethane (10 ml). The organic phase of the combined filtrates was separated, washed with water (30 ml) and brine (20 ml), dried over MgSO4 and concentrated. The crude product was purified by flash chromatography (35-75% EtOAc in hexanes, gradient elution) yielding 0.20 g (8%) of compound (20) as a pale yellow oil. Rf=0.2 (hexanes/EtOAc 1:1, v/v, containing 1% TEA). 1H NMR (300 MHz, CD3CN) δ 8.32-8.27 (m, 2H), 7.76-7.73 (m, 1H), 7.47-7.44 (m, 2H), 7.33-7.20 (m, 8H), 6.87 (d, J=9.1 Hz, 4H), 4.69 (d, J=5.9 Hz, 2H), 4.14 (t, J=5.9 Hz, 1H), 3.77 (s, 6H), 3.35 (q, J=6.5 Hz, 2H), 3.03 (t, J=6.4 Hz, 2H), 1.64-1.55 (m, 4H), 1.43-1.28 (m, 4H). 13C NMR (75 MHz, CD3CN) δ 167.4, 158.8, 147.7, 145.9, 136.9, 130.1, 128.2, 128.0, 126.9, 125.1, 122.9, 113.2, 85.8, 63.3, 62.3, 55.1, 39.8, 29.8, 29.1, 26.7, 26.0.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10]([OH:20])(=O)[C:11]1[C:12](=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH:13]=[O:14]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:14])[O:20]2)=[CH:2]1
Reactant: O=Cc1ccccc1C(=O)O
Reactant: c1ccc2[nH]ccc2c1
Product: O=C1OC(c2c[nH]c3ccccc23)(c2c[nH]c3ccccc23)c2ccccc21

Procedure:
This reaction sequence is further illustrated below under the preferred anhydrous conditions using as specific reactants, indole and phthalaldehydic acid to produce 3,3-di-(indol-3-yl) phthalide. ##STR6##
Reaction SMILES: [CH:1]([CH:3]([NH:8][C:9](=[O:26])[C@H:10]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:4][CH2:5][CH2:6][CH3:7])=O.Cl.[NH2:28][CH2:29][CH2:30][SH:31].C(N(CC)CC)C.S(=O)(=O)(O)O>CO>[S:31]1[CH2:30][CH2:29][NH:28][CH:1]1[CH:3]([NH:8][C:9](=[O:26])[C@H:10]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCC(C=O)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Reactant: NCCS
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCCC(NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C1NCCS1
Yield: 103.2 %

Procedure:
In 20 ml of methanol was dissolved 1.0 g of N-benzyloxycarbonyl-L-leucine-(1-formyl)pentylamide obtained in the same manner as in Example 4-(b), and 400 mg of 2-aminoethanethiol hydrochloride, 0.4 ml of triethylamine, and a catalytic amount of concentrated sulfuric acid were added thereto. The mixture was allowed to react at room temperature for 12 hours. After completion of the reaction, the solvent was removed by distillation under redueed pressure. The residue was purified by medium-pressure column chromatography on silica gel to obtain 1.2 g of the titled compound as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:13]2[N:14]=[C:15]([CH3:19])[CH:16]=[C:17](O)[C:12]2=[CH:11][C:10]=1[CH3:20].P(Br)(Br)[Br:22].C([O-])(O)=O.[Na+]>BrC1C=CC=CC=1.C(Cl)(Cl)Cl>[Br:22][C:17]1[C:12]2[N:13]([C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[C:10]([CH3:20])[CH:11]=2)[N:14]=[C:15]([CH3:19])[CH:16]=1
Reactant: BrP(Br)Br
Reactant: Cc1cc(O)c2cc(C)c(-c3ccc(Cl)cc3Cl)n2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: Brc1ccccc1
Product: Cc1cc(Br)c2cc(C)c(-c3ccc(Cl)cc3Cl)n2n1
Temperature: 25 °C

Procedure:
A solution of 7-(2,4-dichlorophenyl)-2,6-dimethylpyrrolo[1,2-b]pyridazin-4-ol (34.2 g, 111.5 mmol) and phosphorus tribromide (50 mL, 142.5 g, 526.4 mmol) in bromobenzene (500 mL) is refluxed for 1 h. After cooling to room temperature, the mixture is diluted with CHCl3. Saturated NaHCO3 solution is added at 0° C. to neutralize and the mixture is separated immediately. The aqueous layer is extracted with CHCl3 (2×). The combined CHCl3 solution is dried over MgSO4 and filtered. The filtrate is concentrated in vacuo to dryness. The residue is subjected to column chromatography (silica gel, 1/10 EtOAc/heptane) to afford 38.8 g (93%) of light yellow solid as the title compound: 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J=1.5 Hz, 1H), 7.29 (m, 2H), 6.64 (s, 1H), 6.49 (s, 1H), 2.28 (s, 3H), 2.15 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 148.9, 136.8, 135.2, 134.3, 130.1, 129.3, 127.1, 125.6, 125.1, 124.2, 123.2, 114.8, 102.3, 22.0, 12.8; MS (EI) m/z 369 (M+), 371 (M+), 373 (M+); HRMS (FAB) calcd for C15H11BrCl2N2+H 368.9561, found 368.9572.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[CH:10]1([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:14][CH2:13][CH2:12][CH2:11]1>CN(C=O)C>[CH:10]1([N:15]2[CH2:16][CH2:17][N:18]([C:2]3[CH:7]=[C:6]([CH:5]=[CH:4][N:3]=3)[C:8]#[N:9])[CH2:19][CH2:20]2)[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: C1CCC(N2CCNCC2)C1
Reactant: N#Cc1ccnc(Cl)c1
Solvent: CN(C)C=O
Product: N#Cc1ccnc(N2CCN(C3CCCC3)CC2)c1
Temperature: 80 °C
Yield: 94.7 %

Procedure:
A mixture of 2 g (14 mmol) 2-chloro-4-cyanopyridine and 2.34 g (15 mmol) 1-cyclopentylpiperazine in 5 ml DMF was heated to 80° C. for 16 h. The mixture was evaporated under reduced pressure and the residue was treated with 100 ml 1M NaHCO3 aq. and extracted with two times 100 ml ethyl acetate. The combined organic phases were dried with MgSO4 and evaporated under reduced pressure to yield 3.4 g (92%) of the title compound as grey solid. (m/e): 257.3 (MH+; 100%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[CH:9]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[CH:7]=[CH:6][C:5]=2[CH2:4]1.[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1>S(=O)(=O)(O)O.C(OCC)C>[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[O:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[CH:9]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[CH:7]=[CH:6][C:5]=2[CH2:4]1
Reactant: C1=COCCC1
Reactant: COC(=O)c1ccc2c(c1)CCC(CO)C2
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: COC(=O)c1ccc2c(c1)CCC(COC1CCCCO1)C2
Reaction time: 1 h
Yield: 99.3 %

Procedure:
10.0 g of methyl 6-hydroxymethyl-5,6,7,8-tetrahydro-2-naphthalenecarboxylate was added to 3.82 g of 2,3-dihydropyrane. After further adding 5 drops of concentrated sulfuric acid, the resulting mixture was stirred for 1 hour. To this were further added 1.00 g of 2,3-dihydropyrane and 3 drops of concentrated sulfuric acid, followed by stirring for 5 hours. The resulting reaction mixture was mixed with 100 ml of diethyl ether, and the mixture was washed with saturated sodium bicarbonate aqueous solution, water and saturated sodium chloride aqueous solution in that order, followed by drying. By distilling off the solvent, 13.72 g of methyl 6-[(2-tetrahydropyranyl)oxymethyl]-5,6,7,8-tetrahydro-2-naphthalenecarboxylate was obtained in the form of yellow oil.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C@@H:11]3[CH2:16][CH2:15][C@H:14]([NH2:17])[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[CH:18]([N:21]1[C:30]2[N:29]=[C:28]([NH:31][C:32]3[CH:33]=[CH:34][C:35]([C:41](O)=[O:42])=[C:36]4[C:40]=3[O:39][CH2:38][CH2:37]4)[N:27]=[CH:26][C:25]=2[N:24]([CH3:44])[C:23](=[O:45])[C@@H:22]1[CH2:46][CH3:47])([CH3:20])[CH3:19].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.N>ClCCl>[CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C@@H:11]3[CH2:16][CH2:15][C@H:14]([NH:17][C:41]([C:35]4[CH:34]=[CH:33][C:32]([NH:31][C:28]5[N:27]=[CH:26][C:25]6[N:24]([CH3:44])[C:23](=[O:45])[C@H:22]([CH2:46][CH3:47])[N:21]([CH:18]([CH3:19])[CH3:20])[C:30]=6[N:29]=5)=[C:40]5[O:39][CH2:38][CH2:37][C:36]=45)=[O:42])[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[CH2:2][CH2:3]1
Reactant: N[C@H]1CC[C@@H](N2CCN(CC3CC3)CC2)CC1
Reactant: CC[C@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OCC4)nc2N1C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)N[C@H]4CC[C@@H](N5CCN(CC6CC6)CC5)CC4)c4c3OCC4)nc2N1C(C)C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
(cis)-4-[4-(Cyclopropylmethyl)piperazin-1-yl]cyclohexanamine 12e (577 mg, 2.43 mmol), the crude compound 7-[[(7S)-8-isopropyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylic acid 43e (1 g, 2.43 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium tetrafluoroborate (780 mg, 2.43 mmol) and diisopropylethylamine (690 mg, 5.35 mmol) were dissolved in 60 mL of dichloromethane. The reaction solution was stirred for 2 hours. The resulting mixture was added with 50 mL of aqueous ammonia and extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated brine (50 mL×3), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound N-[(cis)-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl]-7-[[(7S)-7-ethyl-8-isopropyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxamide 43 (1.12 g, yield: 74.6%) as a white solid.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.Cl.[CH3:13][O:14][C:15](=[O:30])[C@H:16]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:17][C:18](=[O:22])[C@H:19]([CH3:21])[NH2:20].C(N[C@H](C(O)=O)C)(OC(C)(C)C)=O.Cl.COC(=O)[C@H](CC1C=CC=CC=1)N>CO.C(Cl)(Cl)Cl>[CH3:13][O:14][C:15](=[O:30])[C@H:16]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:17][C:18](=[O:22])[C@H:19]([CH3:21])[NH:20][C:9](=[O:11])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)N
Reactant: O=C(O)Cc1ccccn1
Agent: COC(=O)[C@@H](N)Cc1ccccc1
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)Cc1ccccn1

Procedure:
Following General Procedure C and using 2-pyridylacetic acid hydrochloride (Aldrich) and N-(L-alaninyl)-L-phenylalanine methyl ester hydrochloride (prepared from N-BOC-L-alanine (Sigma) and L-phenylalanine methyl ester hydrochloride (Sigma) using General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp=137-139° C.). The reaction was monitored by tlc (Rf=0.4 in 8% MeOH/CHCl3) and the product was purified by silica gel chromatography using 8% MeOH/CHCl3 as the eluent, followed by recrystallization from 1-chlorobutane/acetonitrile.
Reaction SMILES: C1(S([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18]([OH:19])[C:13]=3[C:12]3[CH:22]=[C:23]([C:26]4[CH:31]=[CH:30][C:29]([CH2:32][N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[CH:28][CH:27]=4)[CH:24]=[N:25][C:11]2=3)(=O)=O)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[OH-].[K+].CO.O>[OH:19][C:18]1[C:13]2[C:12]3[CH:22]=[C:23]([C:26]4[CH:31]=[CH:30][C:29]([CH2:32][N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[CH:28][CH:27]=4)[CH:24]=[N:25][C:11]=3[NH:10][C:14]=2[CH:15]=[N:16][C:17]=1[C:20]#[N:21]
Reactant: N#Cc1ncc2c(c1O)c1cc(-c3ccc(CN4CCCCC4)cc3)cnc1n2S(=O)(=O)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#Cc1ncc2[nH]c3ncc(-c4ccc(CN5CCCCC5)cc4)cc3c2c1O
Reaction time: 2.5 h

Procedure:
9-Benzenesulfonyl-5-hydroxy-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (50 mg, 0.01 mmol) was dissolved in 0.15N potassium hydroxide solution in methanol (7 mL). The reaction mixture was stirred for 2.5 h then treated with a solution of monobasic potassium phosphate (136 mg, 1.0 mmol) in water (2 mL). The resultant mixture was concentrated in vacuo and the resultant residue was diluted with water (5 mL). The pH of the aqueous phase was adjusted to 7 by the addition of 1N hydrochloric acid. The aqueous phase was extracted with ethyl acetate, DCM and THF. The combined organic phase was concentrated in vacuo and the residue purified by flash chromatography (silica, 500 mg column, Si-SPE, 10-20% methanol in DCM) to afford the title compound as its hydrochloride salt (25 mg, 63%). 1H NMR (DMSO-D6, 400 MHz): 12.91 (s, 1H), 11.86 (br. s, 1H), 10.41 (s, 1H), 9.13 (d, J=2.2 Hz, 1H), 9.00 (d, J=2.2 Hz, 1H), 8.60 (s, 1H), 7.93 (d, J=8.1 Hz, 2H), 7.76 (d, J=8.1 Hz, 2H), 4.33 (d, J=5.2 Hz, 2H), 3.39-3.29 (m, 2H), 2.92-2.83 (m, 2H), 1.85-1.63 (m, 5H), 1.45-1.31 (m, 1H). LCMS (Method A): RT=5.32 min, M+H+=384.
Reaction SMILES: CN(C=O)C.[CH2:6]([C:9]1[C:17]2[O:16][N:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=2[CH:12]=[CH:11][C:10]=1[O:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31])[CH2:7][CH3:8].[H-].[Na+].Br[CH:35]([CH3:40])[C:36]([O:38][CH3:39])=[O:37]>C(OCC)(=O)C>[O:31]=[C:27]1[N:26]([CH2:25][CH2:24][CH2:23][O:22][C:10]2[CH:11]=[CH:12][C:13]3[C:14]([C:18]([F:21])([F:19])[F:20])=[N:15][O:16][C:17]=3[C:9]=2[CH2:6][CH2:7][CH3:8])[CH2:30][CH2:29][N:28]1[CH:35]([CH3:40])[C:36]([O:38][CH3:39])=[O:37]
Reactant: COC(=O)C(C)Br
Reactant: CCCc1c(OCCCN2CCNC2=O)ccc2c(C(F)(F)F)noc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCN2CCN(C(C)C(=O)OC)C2=O)ccc2c(C(F)(F)F)noc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a DMF solution (2 mL) of 1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-2-one as prepared in Example 39 (10 mg, 0.027 mmol), was added NaH (4.3 mg, 1.08 mmol) and stirred at room temperature for 30 minutes. Methyl 2-bromopropionate (27 mg, 0.16 mmol) was added and the mixture stirred for another 3 hour. After aqueous work-up and silica gel chromatography (hexanes:70% ethyl acetate), the title compound was obtained.
Reaction SMILES: [C:1](=[O:16])([O:9]C1C=CC=CC=1)[O:2]C1C=CC=CC=1.[OH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)([CH3:26])[CH3:25])=[CH:20][CH:19]=1>>[CH3:26][C:24]([C:21]1[CH:22]=[CH:23][C:18]([OH:17])=[CH:19][CH:20]=1)([C:27]1[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=1)[CH3:25].[C:1]([OH:16])([OH:9])=[O:2]
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Product: O=C(O)O
Temperature: 180 °C
Reaction time: 0.12 h

Procedure:
A 1-I glass melt polymerization reactor was passivated by acid washing, rinsing with deionized water and overnight drying at 70° C. It was charged with 130.4 g (608.6 mmol) of diphenyl carbonate and 120 g (525.6 mmol) of bisphenol A. A solid nickel stirrer was suspended in the mixture and the reactor was purged with nitrogen and heated to 180° C., whereupon the reaction mixture melted. Upon complete melting, it was allowed to equilibrate for 5-10 minutes, with stirring. There were then added, with stirring, 600 μl of a 0.221 M aqueous tetramethylammonium maleate solution and 500 μl of a 0.01 M aqueous sodium hydroxide solution. Heating at 180° C. and stirring were continued for 5 minutes, after which the temperature was raised to 210° C. and the pressure decreased to 180 torr, whereupon phenol began to distill. After 10 minutes, a bisphenol A polycarbonate oligomer had been produced.