Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.I[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]I>C(O)C>[NH:4]1[CH:5]=[N:6][C:2]([S:1][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:1][C:2]2[N:6]=[CH:5][NH:4][N:3]=2)=[N:3]1
Reactant: Sc1nc[nH]n1
Reactant: ICCCCCCCCI
Solvent: CCO
Product: c1nc(SCCCCCCCCSc2nc[nH]n2)n[nH]1
Yield: 35.2 %

Procedure:
20 mmole of 3-mercapto-1H-1,2,4-triazole (potassium salt) was dissolved in 20 ml of ethanol in stirring. 10 mmole of 1,8-diiodooctane was added dropwise to the solution of 3-mercapto-1H-1,2,4-triazole (potassium salt), and stirred overnight. After the solvent was evaporated in vacuum, the residual was washed with 50 ml pure H2O for three times, and then with 50 ml hexane for 3 times. At last, the residual was dried in oven at 60° C. for 24 hours. 1.1 g product was obtained as white solid. Yield: 30%. 1H NMR (DMSO): δ(ppm) 8.34 (2H, s), 3.04 (4H, t, JH-H=7.14), 1.61 (4H, m), and 1.23-1.32 (8H, m).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([CH:15]=[C:16](Br)Br)[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.Br[CH2:26][CH2:27][CH2:28][O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1.[NH4+].[Cl-]>C1COCC1.CN1C(=O)N(C)CCC1>[C:1]([O:5][C:6](=[O:19])[N:7]([CH3:8])[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]#[C:16][CH2:26][CH2:27][CH2:28][O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C=C(Br)Br)CC1
Reactant: BrCCCOC1CCCCO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C#CCCCOC2CCCCO2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3.97 g (10 mmol) of trans-[4-(2,2-Dibromo-vinyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester in 160 ml THF was treated at −78° C. with 13.13 ml (21 mmol) of BuLi (ca 1.6 M in hexane) and stirred for 2 h. 11 ml DMPU were added and 10 min later 4.60 g (20 mmol) of 1-bromo-3-tetrahydropyranyloxypropane in 15 ml THF were added over a period of 20 min. The reaction mixture was warmed up to RT for 16 h, cooled, poured into cooled aqueous saturated NH4Cl and extracted (Et2O 3×). The organic phase was washed with aqueous 10% NaCl, water, dried over Na2SO4, evaporated and purified by flash silica gel column (Hexane/EtOAc 98:2 to 90:10) to yield 1.61 g (42%) of trans-Methyl-{4-[5-(tetrahydro-pyran-2-yloxy)-pent-1-ynyl]-cyclohexyl}-carbamic acid tert-butyl ester, MS: 378 (M−H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH2:10][CH2:9][C:8]=2[CH:12]=1)([O-])=O.[H][H]>[Ni].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH2:10][CH2:9][C:8]=2[CH:12]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2c(c1)CCO2
Agent: [Ni]
Solvent: CO
Product: Nc1ccc2c(c1)CCO2
Yield: 97 %

Procedure:
The product (1 g, 6.1 mmol) obtained in Step 1, Raney Ni (0.1 g) and MeOH (10 mL) were used for hydrogenation at room temperature and hydrogen pressure of 50 PSI, until the reaction was finished. The catalyst was removed by filtration, the fitrate was concentrated under vacuum to obtain a product (800 mg, 97.2%).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[N:13]1[CH:18]=[CH:17][C:16]([CH:19]=[O:20])=[CH:15][CH:14]=1.[Cl-].[NH4+]>C1COCC1>[N:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:3]2[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=2)[OH:20])=[CH:15][CH:14]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: O=Cc1ccncc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(c1ccncc1)c1ccc(C(F)(F)F)cc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 111.6 %

Procedure:
Under a dry nitrogen atmosphere, an appropriate amount of freshly cut magnesium chips was suspended in 150 mL of THF. To this was added about 5% of a solution of 22.5 grams (0.100 mole) of 4-bromobenzotrifluoride in 75 mL of THF. The reaction mixture was then warmed to about 30° C. to initiate the reaction. Once the reaction was proceeding, the remainder of the solution of 4-bromobenzotrifluoride was added during a one hour period, at a rate to maintain the reaction mixture temperature at about 34° C. to about 38° C. Upon completion of addition, the reaction mixture was stirred during a one hour period, as it cooled to ambient temperature. After this time a solution of 8.5 grams (0.075 mole) of 4-pyridinecarboxaldehyde in 75 mL of THF was added portion wise while maintaining the reaction mixture temperature below 30° C. Upon completion of addition the reaction mixture was stirred at ambient temperature for about 18 hours. With vigorous stirring the reaction mixture was then poured into 600 mL of aqueous 10% ammonium chloride. The mixture was extracted with two 300 mL portions of ethyl acetate. The combined extracts were washed with 250 mL of an aqueous solution saturated with sodium chloride, then dried with magnesium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure, yielding 21.2 grams of the subject compound. The product was used without purification in the following reaction.
Reaction SMILES: O[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=C[C:6]([OH:12])=[CH:7][CH:8]=2)[CH:3]=1.CS(O)(=O)=[O:15]>C(OCC)C>[O:15]1[C:4]2[C:9](=[CH:10][CH:11]=[CH:2][CH:3]=2)[CH:8]=[CH:7][C:6]1=[O:12]
Reactant: CS(=O)(=O)O
Reactant: Oc1ccc2ccc(O)cc2c1
Solvent: CCOCC
Product: O=c1ccc2ccccc2o1
Yield: 5 %

Procedure:
To a mixture of 2,7-dihydroxynaphthalene (0.20 g, 1.3 mmol) and 1 (0.20 mg, 0.83 mmol) was added methanesulfonic acid (1.3 mL, 21 mmol) at 0° C. The clear brown solution gradually became dark orange within 4 h after which time the reaction mixture was diluted with cold (−30° C.) ethyl ether (10 mL), centrifuged (3000 rpm) at 4° C. for 20 minutes. After removing the ether by aspiration, the residual orange solid was dried under high vacuum, dissolved in H2O (3 mL), and purified by RP-HPLC using an appropriate linear gradient of acetonitrile containing 10% de-ionized water (A) and 0.1% (v/v) TFA/H2O (B) (3-50% A over 20 min. followed by a steep gradient to 100% A and equilibrium back to 3% A). The fractions containing the product were collected, concentrated, and lyophilized to give Mini401 as a white solid (5%). 1H NMR (DMSO-d6, 400 MHz): δ 10.21 (1H, s), 8.08 (1H, d, J=8.9 Hz), 7.94 (1H, d, J=8.8 Hz), 7.84 (3H, bs), 7.72 (1H, s), 7.33 (1H, d, J=8.8 Hz), 7.18 (1H, dd, J=8.8, 2.0 Hz), 6.44 (1H, s), 3.54 (2H, t, J=6.8 Hz), 3.32-3.29 (2H, m). 13C NMR (DMSO-d6, 75 MHz): δ 159.2, 157.6, 155.1, 153.0, 133.9, 131.5, 130.8, 125.3, 117.0, 115.2, 114.0, 111.9, 1079, 37.2, 33.9. LRMS (APCI+): Calc'd for C15H13NO3 255.1 m/z, measured 256.2 (MH+).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[C:12](\[CH2:27][O:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=[CH:31][CH:30]=2)/[CH2:13][NH:14][CH:15]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]2)=[CH:7][CH:6]=1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[OH:1][NH:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[C:12](/[CH2:13][NH:14][CH:15]2[CH2:19][CH2:18][NH:17][CH2:16]2)\[CH2:27][O:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=[CH:31][CH:30]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC/C(=C/c2ccc(C(=O)NO)cc2)COc2cccc3ccccc23)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NO)c1ccc(/C=C(/CNC2CCNC2)COc2cccc3ccccc23)cc1
Yield: 46.6 %

Procedure:
The compound of formula 4d (103 mg, 0.19 mmol) obtained in Example 4-4 was dissolved in dichloromethane (1.5 ml), and trifluoroacetic acid (0.07 ml, 0.95 mmol) was added dropwise thereto at room temperature. The resulting mixture was reacted at room temperature for 8 hours. After the completion of reaction, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was purified by a preparative HPLC, to obtain 37 mg of the title compound as pale orange foam, which was used in the subsequent analysis.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH2:10])=[O:4].[C:11]([N:19]=[C:20]=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CC(C)=O>[C:12]1([C:11]([NH:19][C:20](=[S:21])[NH:10][C:9]2[CH:8]=[CH:7][S:6][C:5]=2[C:3]([O:2][CH3:1])=[O:4])=[O:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1sccc1N
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: COC(=O)c1sccc1NC(=S)NC(=O)c1ccccc1

Procedure:
Methyl-3-amino-2-thiophene carboxylate (30 g, 1 equiv) and benzoyl isothiocyanate (46 ml, 1.8 equiv) in acetone (250 ml) were heated to 65° C. for 30 minutes. After cooling the solution was concentrated and the resulting solid filtered off and dried (40.54 g). 1H-NMR (CDCl3) δ 3.98 (3H, s), 7.54 (4H, m), 7.94 (2H, m), 8.81 (1H, d), 9.15 (1H, br s); MS (APCI+) found (M+1)=321; C14H12N2O3S2 requires 320.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[C:10]([C:11](=[O:21])[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=3[F:20])[C:5]2=[CH:4][CH:3]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.O.Cl>CN1C(=O)CCC1>[F:20][C:14]1[C:15]([F:19])=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][C:11]([C:10]1[C:5]2[C:6](=[N:7][C:2]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:3][CH:4]=2)[NH:8][CH:9]=1)=[O:21]
Reactant: C1CCNC1
Reactant: O=C(Cc1cccc(F)c1F)c1c[nH]c2nc(Cl)ccc12
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(Cc1cccc(F)c1F)c1c[nH]c2nc(N3CCCC3)ccc12

Procedure:
A solution of 1-(6-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(2,3-difluoro-phenyl)-ethanone (100 mg, 0.29 mmol) and pyrrolidine (1 mL) in NMP (2 mL) was heated in a sealed tube with microwave at 220° C. for 15 min. The solution was poured into water and 0.5N HCl was added to precipitate the product. The crude product was collected by filtration, washed with water, and dried on the pump for direct use (80 mg, 0.23 mmol, 79%). MS (ES+): m/e=342.2 (M+H); LC: 2.92 min.
Reaction SMILES: Br[C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[S:4][C:3]=1[CH3:11].[CH2:12]([CH:14]([C:17]1[C:18]2[N:19]([C:24](I)=[C:25]([CH3:27])[N:26]=2)[N:20]=[C:21]([CH3:23])[CH:22]=1)[CH2:15][CH3:16])[CH3:13]>C1COCC1.[Zn]>[CH2:12]([CH:14]([C:17]1[C:18]2[N:19]([C:24]([C:2]3[C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:5]4[S:4][C:3]=3[CH3:11])=[C:25]([CH3:27])[N:26]=2)[N:20]=[C:21]([CH3:23])[CH:22]=1)[CH2:15][CH3:16])[CH3:13]
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Reactant: Cc1sc2cccnc2c1Br
Agent: [Zn]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)sc4cccnc34)c(C)nc12
Yield: 9.2 %

Procedure:
380 mg of 3-Bromo-2-methyl-thieno[3,2-b]pyridine (1.66 mmol) is placed into the vial with 3.56 ml of Reiki Zn, suspension in THF (2.50 mmol) and capped and heated at 100C for 2 h. The excess Zinc is allowed to settle down and the solution is transferred to the vial containing 250 mg of 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.72 mmol) and 48 mg of PdCl2(pddf) (0.06 mmol) in 2 ml of dry THF. The vial is capped by Teflon cap and heated at 80C for overnight. The reaction mixture is quenched by sat.NH4Claq. and extracted by CH2Cl2, dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (Hexane: AcOEt: 2 M NH3 in MeOH=20:4:1) to give 24.2 mg of the title compound. Yield 9.2%. mass spectrum (m/e): 365 (M+1); 1H-NMR (CDCl3): 8.66 (dd, 1H, J=4.7 Hz, 1.4 Hz), 8.16 (dd, 1H, J=8.1 Hz, 1.4 Hz), 7.25 (dd, 1H, J=8.1 Hz, 4.7 Hz), 6.68 (s, 1H), 3.43 (m, 1H), 2.50 (s, 3H), 2.47 (s, 3H), 2.46 (s, 3H), 1.88 (m, 4H), 0.93 (m, 6H) ppm.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]1([CH3:28])[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[O:12][C:11]([NH:19]C(=O)C2C=CC=CC=2)=[N:10]1.N12CCCN=C1CCCCC2>CO>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]1([CH3:28])[CH2:14][C@@H:13]([C:15]([F:18])([F:16])[F:17])[O:12][C:11]([NH2:19])=[N:10]1
Reactant: C[C@@]1(c2cccc(F)c2F)C[C@@H](C(F)(F)F)OC(NC(=O)c2ccccc2)=N1
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@@]1(c2cccc(F)c2F)C[C@@H](C(F)(F)F)OC(N)=N1
Reaction time: 15 h
Yield: 95.6 %

Procedure:
To a solution of N-((4S,6S)-4-(2,3-difluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (7.0 g, 17.57 mmol) in MeOH (100 mL) was added 1,8-diazabicyclo-[5.4.0]undec-7-ene (3.15 mL, 21.09 mmol). The mixture was brought up to 60° C. for 15 h until the conversion was completed. The mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc and water. The separated organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel column (0-60% EtOAc/hexane) to afford (4S,6S)-4-(2,3-difluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (4.94 g, 16.79 mmol, 96% yield) as white crystalline solid. MS m/z=295.1 [M+H]+. Calculated for C12H11F5N2O: 294.2
Reaction SMILES: CS(C)=O.[C:5]([C:9]1[C:10](=[O:30])[CH2:11][CH:12]([C:16]2[CH:17]=[CH:18][C:19]3[O:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][C:27]#[N:28])[C:20]=3[CH:29]=2)[CH2:13][C:14]=1[OH:15])(=O)[CH2:6][CH3:7].Cl.[CH2:32]([O:34][NH2:35])[CH3:33].C([O-])(=O)C.[Na+]>Cl>[CH2:32]([O:34][N:35]=[C:5]([C:9]1[C:10](=[O:30])[CH2:11][CH:12]([C:16]2[CH:17]=[CH:18][C:19]3[O:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][C:27]#[N:28])[C:20]=3[CH:29]=2)[CH2:13][C:14]=1[OH:15])[CH2:6][CH3:7])[CH3:33]
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2ccc3c(c2)N(CC#N)C(=O)CO3)CC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: CCON=C(CC)C1=C(O)CC(c2ccc3c(c2)N(CC#N)C(=O)CO3)CC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 15 mL of methyl sulfoxide were added in sequence, 1.2 g (3.4 mmol) of 2-propionyl-3-hydroxy-5-(N-cyanomethyl-3-oxo-(2H)-1,4-benzoxazin-6-yl)cyclohex-2-en-1-one, 0.42 g (4.4 mmol) of ethoxyamine hydrochloride an d 0.36 g (4.4 mmol) of anhydrous sodium acetate. The resulting mixture was stirred at ambient temperature for 5 and 1/2 hours, becoming a clear amber solution. The reaction mixture was diluted with 100 mL of 0.1N HCl and extracted twice with 30 mL portions of ether. The extracts were combined, washed with water, then aqueous sodium chloride, dried over MgSO4 and filtered. Evaporation off of the solvent gave the crude product as a light amber oil which solidified upon standing. The crude solid was triturated in warm ether and the product isolated by filtration as a tan solid. The product was recovered in a yield of 1.1 g (81 percent of theoretical) and melted at 156°-159° C.; 1H NMR(CDCl3): d1.05-1.41 (m, 6H, both --CCH2CH3 's), 2.57-3.62 (m, 7H), 4.17 (q, J=7 Hz, 2H,--OCH2CH3), 4.70 (s, 2H, --OCH2C=O), 4.88 (s, 2H, --NCH2CN), 6.92-7.20 (m, 3H, aromatic H's), 15.10 (broad s, 1H, enol H); (Compound 4).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].Br[CH2:11][CH:12]1[CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH2:11][CH:12]1[CH2:14][CH2:13]1
Reactant: BrCC1CC1
Reactant: Oc1cc(F)ccc1Br
Product: Fc1ccc(Br)c(OCC2CC2)c1

Procedure:
Starting from commercially available 2-bromo-5-fluoro-phenol and bromomethyl-cyclopropane the title compound is prepared as colorless oil
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCCOC)[C:19](=[O:27])[C:18]3[C:17]4[CH2:28][CH2:29][CH2:30][CH2:31][C:16]=4[CH:15]=[CH:14][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])C.C(O)C>CCOCC>[O:27]=[C:19]1[C:18]2[C:17]3[CH2:28][CH2:29][CH2:30][CH2:31][C:16]=3[CH:15]=[CH:14][C:13]=2[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)[NH:20]1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc4c(c3c(=O)n2COCCOC)CCCC4)c1
Solvent: CCO
Solvent: CCOCC
Product: O=C(O)c1cnn(-c2nc3ccc4c(c3c(=O)[nH]2)CCCC4)c1
Yield: 53.1 %

Procedure:
Preparation of 1-(1-oxo-1,2,7,8,9,10-hexahydro-benzo[f]quinazolin-3-yl)-1H-pyrazole-4-carboxylic acid ethyl ester. HCl (4M in dioxane, 0.57 mL, 2.3 mmol) was added to a solution of 1-[2-(2-methoxy-ethoxymethyl)-1-oxo-1,2,7,8,9,10-hexahydro-benzo[f]quinazolin-3-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (70.0 mg, 0.164 mmol) and ethanol (0.57 mL). The reaction mixture was stirred at room temperature for 4 h, at which point ether (2 mL) was added and the precipitate was collected to yield the titled compound (27.0 mg, 49% yield). MS (ESI/Cl): mass calcd. for C18H18N4O3, 338.1; m/z found, 339.1 [M+H]+.
Reaction SMILES: [C:1]([C:6]1[CH:22]=[C:21]([C:23]([CH2:26][CH3:27])([CH3:25])[CH3:24])[CH:20]=[CH:19][C:7]=1[O:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13]C)=[O:12])([CH2:4][CH3:5])([CH3:3])[CH3:2].[OH-].[K+].C(O)C>C(OCC)C>[C:1]([C:6]1[CH:22]=[C:21]([C:23]([CH2:26][CH3:27])([CH3:25])[CH3:24])[CH:20]=[CH:19][C:7]=1[O:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([OH:13])=[O:12])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(C)(C)c1ccc(Oc2ccccc2C(=O)OC)c(C(C)(C)CC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: CCC(C)(C)c1ccc(Oc2ccccc2C(=O)O)c(C(C)(C)CC)c1

Procedure:
Next 2,4-di-(tert-amyl)phenoxybenzoic acid was prepared. A mixture of methyl 2,4-di-(tert-amyl)phenoxybenzoate (7.44 g, 20 mmol), potassium hydroxide (2.3 g, 40 mmol), and ethanol (60 mL) was heated at reflux for 4 h and then cooled to ambient. Diethyl ether (20 mL) was added, and the mixture was washed twice with 10% aqueous HCl. The organic layer was dried (Na2SO4) and the solvent was removed at reduced pressure to deposit a yellow solid. This crude product was purified by recrystallization from heptane to provide 5.0 g, 70% of theory) of 2,4-di-(tert-amyl)phenoxybenzoic acid as a tan solid. 1H NMR (CDCl3): δ 0.75 (t, 6H), 1.3 (s, 6H), 1.4 (s, 6H), 1.65 (q, 2H), 1.80 (q, 2H), 3.85 (s, 3H), 6.80 (d, 2H), 7.15 (m, 2H), 7.35(br s, 1H), 7.45 (t, 1H), 8.2 (d, 1H).
Reaction SMILES: Br.[CH2:2]([N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[C:13](Cl)[C:12]=2[N:11]=[C:10]1[NH2:23])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH3:24]>CO>[CH2:2]([N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[C:13]([NH2:24])[C:12]=2[N:11]=[C:10]1[NH2:23])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N
Reactant: Nc1nc2c(Cl)nc3ccccc3c2n1Cc1ccccc1
Agent: Br
Solvent: CO
Product: Nc1nc2ccccc2c2c1nc(N)n2Cc1ccccc1
Temperature: 170 °C

Procedure:
Crude 1-benzyl-4-chloro-1H-imidazo[4,5-c]quinoline-2-amine hydrobromide (0.500 g) and ammonia (20 mL of a 7 N solution in methanol) were added to a high-pressure vessel, which was sealed and heated in an oven at 170° C. for six days. The resulting solution was concentrated under reduced pressure, and the residue was purified by automated flash chromatography on silica gel (eluting with 0-10% methanol in dichloromethane with 1% ammonium hydroxide added) to provide 42 mg of 1-benzyl-1H-imidazo[4,5-c]quinoline-2,4-diamine as a brown powder, mp 254-256° C.
Reaction SMILES: CO[C:3]([C:5]1[C:6](=[O:17])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([Cl:16])[CH:9]=2)=[O:4].[NH2:18][CH2:19][C:20]([O-:22])=[O:21].[Na+].Cl>COCCO.O>[Cl:16][C:10]1[CH:9]=[C:8]2[C:13]([C:14]([OH:15])=[C:5]([C:3]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:4])[C:6](=[O:17])[O:7]2)=[CH:12][CH:11]=1
Reactant: COC(=O)c1c(O)c2ccc(Cl)cc2oc1=O
Reactant: NCC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: COCCO
Product: O=C(O)CNC(=O)c1c(O)c2ccc(Cl)cc2oc1=O

Procedure:
A suspension of 350 mg of 7-chloro-4-hydroxy-2-oxo-2H-chromene-3-carboxylic acid methyl ester (1.38 mmol) and 670 mg of sodium glycinate (6.9 mmol) in 13 mL of 2-methoxyethanol was heated at reflux temperature for 10 hours. The mixture was cooled acidified with 1N HCl and diluted with 10 mL water. The resultant white solid was collected on a glass fritted filter and washed twice with water and once with methanol. The solid was triturated with methanol to give 124 mg. MS: (+) m/z 298.03/300.02 (M+1, 35/37Cl)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][CH2:5]2.[OH-].[K+].Cl[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28].C(Cl)Cl>CS(C)=O>[N+:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][CH2:5]2)([O-:29])=[O:28]
Reactant: Oc1ccc2c(c1)CCC(c1ccccc1)O2
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccccc1Oc1ccc2c(c1)CCC(c1ccccc1)O2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
6-Hydroxyflavane (0.150 g) was dissolved in dry DMSO (5 ml) under nitrogen. KI (0.166 g) and KOH (0.074g) were added and solution was stirred at room temperature for 15 minutes. 2-Chloro-1-nitrobenzene (0.104 g) was added and the solution was stirred at +90° C. for 2.5 hours. Cooled solution was taken up with CH2Cl2 and washed with H2O and 2M NaOH. Phases were separated and water phase was washed CH2Cl2. All organic phases were combined and washed with 1M HCl and then H2O (until pH˜7) and brine. Solution was dried over Na2SO4 and purified with filtration through the small silica column in CH2Cl2:n-heptane (60:40). 1H-NMR (300 MHz; d6-DMSO): δ 8.01 (dd, 1H, J=8.1 Hz; J=1.7 Hz), 7.69 (m, 1H), 7.50-7.31 (m, 5H), 7.31-7.24 (m, 1H), 7.04 (dd, 1H, J=8.5 Hz; J=1.2 Hz), 6.92 (s, 1H), 6.90 (s, 2H), 5.12 (dd, 1H, J=10.1 Hz; J=2.3 Hz), 2.95 (ddd, 1H, J=16.9 Hz; J=11.2 Hz, J=5.8 Hz), 2.73 (ddd, 1H, J=16.9 Hz; J=3.2 Hz, J=1.7 Hz), 2.25-2.10 (m, 1H), 2.08-1.90 (m, 1H).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])=[N:5][N:4]=[C:3]1[S:13][CH3:14].[CH2:15](S)C.[OH-].[K+]>>[NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]([CH3:11])([CH3:10])[CH3:12])=[N:5][N:4]=[C:3]1[S:13][CH2:14][CH3:15]
Reactant: CCS
Reactant: CSc1nnc(C(C)(C)C)c(=O)n1N
Agent: [K+]
Agent: [OH-]
Product: CCSc1nnc(C(C)(C)C)c(=O)n1N
Temperature: 10 °C

Procedure:
A mixture of 230 g (1 mole of 93% active ingredient) of 4-amino-6-t-butyl-3-methylthio-1,2,4-triazin-5-one and 310 g (5 moles) of ethyl mercaptan and 0.5 g of crushed solid KOH was stirred and refluxed onto a 10° C. condenser. The vapors which pass through the condenser (methyl and ethyl mercaptans) were collected in a dry ice or caustic trap. The reaction was continued until thin layer chromotography indicated that the starting material was gone (usually 2-8 hours). The unreacted ethyl mercaptan was then distilled off while ~600 ml of warm (40° C.) water was added at such a rate that the water addition was complete when ~1/3 of the mercaptan had distilled. Distillation was continued until ~100 ml of water distilled at 100° C. The solution was then allowed to cool with rapid stirring. The product crystallized at 60°-70° C. and at 20° C. was filtered and washed with water, then dried. The final product, 4-amino-6-t-butyl-3-ethylthio-1,2,4-triazin-5-one, was obtained in nearly quantitative yield and contained less than 1% of the starting 3-methylthio compound.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[CH2:8][NH:9][C:10](=[O:12])[O-:11].Br[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:7]([O:12][C:10]([NH:9][CH2:8][C:7]1[CH:6]=[C:5]([CH:15]=[CH:14][CH:13]=1)[O:4][C:3]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:2]=1[NH:1][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:11])([CH3:13])([CH3:8])[CH3:6]
Reactant: CCOC(=O)CCCBr
Reactant: Nc1ccc(Cl)cc1Oc1cccc(CNC(=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCNc1ccc(Cl)cc1Oc1cccc(CNC(=O)OC(C)(C)C)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 118.4 %

Procedure:
A mixture of tert-butyl[3-(2-amino-5-chlorophenoxy)benzylcarbamate (3.5 g, 10 mmols), ethyl 4-bromobutyrate (2.9 ml, 20 mmols), potassium carbonate (1.4 g, 10 mmols) and N,N-dimethylformamide (30 ml) was stirred at 60° C. for 3 hours. The reaction mixture was cooled, poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography to give an oil of ethyl 4-[2-[3-(tert-butoxycarbonylaminomethyl)phenoxy]-4-chlorophenyl]aminobutyrate (2.74 g, 59.3%).