Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][B:5]([C:7]2[CH:8]=[N:9][NH:10][CH:11]=2)[O:4][C:3]1([CH3:13])[CH3:12].[H-].[Na+].[CH3:17][Si:18]([CH2:21][CH2:22][O:23][CH2:24]Cl)([CH3:20])[CH3:19]>O1CCCC1>[CH3:12][C:3]1([CH3:13])[C:2]([CH3:14])([CH3:1])[O:6][B:5]([C:7]2[CH:8]=[N:9][N:10]([CH2:24][O:23][CH2:22][CH2:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH:11]=2)[O:4]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnn(COCC[Si](C)(C)C)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
Into a 250-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.82 g, 30.0 mmol) in tetrahydrofuran (80 mL). This was followed by the addition of NaH (70%) (2.05 g, 85.4 mmol) in portions at 0° C. To this was added SEMCl (6.4 mL, 36.1 mmol) dropwise. The reaction mixture was stirred overnight at room temperature, then quenched with 50 mL of NH4Cl (sat). The aqueous phase was extracted with 2×100 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 7 g (72%) of the title compound as colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[NH:13][C:14]2[CH:15]=[C:16]([NH:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:17]=[CH:18][C:19]=2[CH3:20])[CH:3]=1.[CH:30]1([NH2:33])[CH2:32][CH2:31]1>CC(O)C>[CH:30]1([NH:33][C:2]2[N:7]=[CH:6][N:5]=[C:4]([N:8]3[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][C:14]3[CH:15]=[C:16]([NH:21][C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:17]=[CH:18][C:19]=3[CH3:20])[CH:3]=2)[CH2:32][CH2:31]1
Reactant: Cc1ccc(NC(=O)c2ccccc2)cc1Nc1nccn1-c1cc(Cl)ncn1
Reactant: NC1CC1
Solvent: CC(C)O
Product: Cc1ccc(NC(=O)c2ccccc2)cc1Nc1nccn1-c1cc(NC2CC2)ncn1
Temperature: 65 °C

Procedure:
A mixture of N-{3-[1-(6-chloro-pyrimidin-4-yl)-1H-imidazol-2-ylamino]-4-methyl-phenyl}-benzamide (2.65 g, 6.55 mmol), cyclopropylamine (8.8 mL, 124.43 mmol) in 2-propanol (30 mL) was heated at 65° C. for 16 h. The reaction mixture was then cooled down to room temperature and concentrated. The residue yellow solid was washed with water, dried under vacuum to afford the title compound. The obtained crude title compound was directly used for the next step reaction without any further purification. 1H NMR 600 MHz (DMSO-d6) δ 11.13 (bs, 1H), 10.24 (s, 1H), 8.77 (s, 1H), 8.48 (bs, 1H), 8.10 (bs, 1H), 7.98 (d, 2H, J=6.0 Hz), 7.71 (bs, 1H), 7.57 (s, 1H), 7.52 (s, 2H), 7.34 (d, 1H, J=6.6 Hz), 7.15 (d, 1H, J=6.6 Hz), 6.88 (s, 1H), 6.74 (bs, 1H), 2.61 (bs, 1H), 2.33 (s, 3H), 0.82 (s, 2H), 0.53 (s, 2H); MS m/z 426.5 (M+1).
Reaction SMILES: CN(C=O)C.S(Cl)([Cl:8])=O.[CH2:10]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:28]=1)[CH2:24]O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].N1C=CC=CC=1>ClCCl>[CH2:10]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:28]=1)[CH2:24][Cl:8])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCOc1cc(CO)cc(OCCCCCCCCCC)c1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCOc1cc(CCl)cc(OCCCCCCCCCC)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 94.5 %

Procedure:
Dry dichloromethane (5 mL), DMF (3.04 mL, 39.2 mmol), and a magnetic stir bar were placed into a 250 mL RBF and sealed with a rubber septum. N2 inlet and outlet needles were inserted into the septum. The flask was then cooled to 0° C. in an ice bath. Thionyl chloride (2.86 mL, 39.2 mmol) was added to the RBF via a syringe. The RBF was placed into an ice bath and cooled to 0° C. 3,5-didecoxybenzyl alcohol (15.0 g, 35.7 mmol) was dissolved in a solution of dichloromethane (60 mL) containing pyridine (2.88 mL, 35.7 mmol). This solution was then drawn into a syringe and added cautiously to RBF over 20 minutes. The solution gradually changed from a transparent yellow color to an opaque yellow color. Dichloromethane was used to rinse the beaker which was used to dissolve 3,5-didecoxybenzyl alcohol and then added to the RBF. The RBF was removed from the ice bath and allowed to stir overnight. The solution was then concentrated using a rotary evaporation. A solution of 50/50 ether/hexanes (100 mL) was added to the RBF, changing the solution from deep yellow to opaque white. The liquid was decanted off leaving behind any solid. The RBF was rinsed in this manner 2 more times, saving the decanted liquid. The decanted liquid was run through a silica gel baseline filtration apparatus. Filtrate was then concentrated using rotary evaporation. A compound solidified after approximately 2 hours under a high vacuum. There was a 14.8 g yield or a 94.5% yield of the derivative. The NMR characterization data for this derivative is as follows. 1NMR (300 MHz, CDCl3): 0.88 (t, J=6.6, 6H, CH2CH3), 1.27-1.43 (m, 28H, CH2(CH2)7), 1.76 (p, J=6.6, 4H, OCH2CH2), 3.92 (t, J=6.6, 4H, OCH2), 4.50 (s, 2H, ArCH2Cl), 6.39 (t, J=2.2, 1H, ArH), 6.50 (d, J=2.5, 2H, ArH). 13C NMR (75 MHZ, CDCl3): 14.23, 22.78, 26.12, 29.30, 29.42, 29.47, 29.70, 32.00, 46.56, 68.18, 101.332, 106.97, 139.38, 160.52.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[N:15]1([C:21]([O:23][CH2:24][CH:25]=[CH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CN(C)C=O>O>[Br:1][C:2]1[N:3]([CH2:10][C@:11]([OH:12])([CH3:14])[CH2:13][N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][CH2:24][CH:25]=[CH:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:29][CH:28]=3)=[O:22])[CH2:20][CH2:19]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Br)CO1
Reactant: O=C(OCC=Cc1ccc(C(F)(F)F)cc1)N1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@](O)(CN1CCN(C(=O)OCC=Cc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Br
Temperature: 50 °C
Reaction time: 20 h
Yield: 84 %

Procedure:
Mixture of (R)-2-bromo-4-nitro-1-(2-methyl-2-oxiranylmethyl)imidazole (2.04 g) prepared in example 6, 3-(4-trifluoromethylphenyl)-2-propenyl piperazin-1-carboxylate (2.69 g) and N,N-dimethylformamide (10 ml) was stirred at 50° C. for 20 hours. The reaction mixture was turned back to a room temperature, water (45 ml) was added, then extracted twice with ethyl acetate (15 ml). The organic layers were combined together, washed with water 3 times, dried over anhydrous sodium sulfate. Afer being filtrated under a reduced pressure, the residue thus obtained was purified by use of a silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/2), there was obtained 3-(4-trifluoromethylphenyl)-2-propenyl (S)-4-[3-(2-bromo-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]piperazin-1-carboxylate (3.77 g, yield: 84%)
Reaction SMILES: CN(C)CCN(C)C.[CH:9]([N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1)=[CH2:10].C([Li])CCC.[C:21]([C:25]1[CH:38]=[CH:37][CH:36]=[CH:35][C:26]=1[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28])([CH3:24])([CH3:23])[CH3:22].C(=O)=O>CCCCCC.O.O1CCCC1>[C:21]([C:25]1[CH:38]=[CH:37][CH:36]=[CH:35][C:26]=1[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:12]1[N:11]([CH:9]=[CH2:10])[CH:15]=[CH:14][N:13]=1)[OH:28])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1ccccc1C(=O)c1ccccc1
Reactant: C=Cn1ccnc1
Agent: CN(C)CCN(C)C
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: C=Cn1ccnc1C(O)(c1ccccc1)c1ccccc1C(C)(C)C
Temperature: -60 °C
Reaction time: 2 h

Procedure:
To a solution of 28.8 g. (0.25 mol) of N,N,N',N'-tetramethylethylenediamine and 17.6 g. (0.19 mol) of 1-vinylimidazole in 300 ml. of anhydrous tetrahydrofuran, 14 ml. (0.25 mol) of 20% butyllithium in n-hexane were added drop-wise with stirring at -60° C., and under a nitrogen atmosphere over the course of one hour. Stirring was continued for 2 hours under the same conditions, after which a solution of 48 g. (0.20 mol) of 2-tert.-butylbenzophenone in 300 ml. of anhydrous tetrahydrofuran was added drop-wise. The reaction mixture was stirred for 3.5 hours, after which the cooling means was removed and stirring was continued overnight under the nitrogen atmosphere. The lithium complex obtained was then decomposed with 15 ml. of water and a large excess of solid carbon dioxide. The precipitate was filtered off, the filtrate was dried over sodium sulphate and the solvent was distilled off. The solid residue was twice crystallised from ethyl acetate to which a small amount of ethanol had been added. α-(o-tert.-Butylphenyl)-α-phenyl-1-vinylimidazole-2-methanol was obtained. Melting point 152°-153° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[CH:14][CH:13]=2)=[N:10][C:9]([Br:24])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N([O-])=O.[Na+].[N-:29]=[N+:30]=[N-].[Na+].CCOCC>C(O)(C(F)(F)F)=O>[N:1]([C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20][CH:21]([CH3:22])[CH3:23])=[O:19])=[CH:14][CH:13]=2)=[N:10][C:9]([Br:24])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(Br)nc(-c2ccc(C(=O)OC(C)C)cc2)c1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Br)nc(-c2ccc(C(=O)OC(C)C)cc2)c1N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
Methyl 3-amino-6-bromo-2-(4-(isopropoxycarbonyl)phenyl)isonicotinate (1.0 g, 2.54 mmol) was dissolved in TFA (15 mL) and the yellow solution was cooled in an ice bath. Sodium nitrite (0.351 g, 5.09 mmol) was added with stirring to give a dark yellow mixture. After 30 min, sodium azide (1.65 g, 25.4 mmol) was added followed immediately by Et2O (15 mL). The light yellow mixture was stirred in the ice bath for 30 min. It was partitioned between EtOAc and sufficient sat. aq. NaHCO3 solution to neutralize the acid. The organic phase was washed with brine, dried with sodium sulfate, and the solvent removed to leave methyl 3-azido-6-bromo-2-(4-(isopropoxycarbonyl)phenyl)isonicotinate (1.0 gm, 2.3 mmole, 92% yield). 1H NMR (500 MHz, chloroform-d) δ ppm 8.13 (2H, d, J=8.24 Hz), 7.82 (2H, d, J=4.58 Hz), 7.80 (1H, s), 5.24-5.30 (1H, m), 4.01 (3H, s), 1.38 (6H, d, J=6.10 Hz).
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[NH:10][C:9](=[O:13])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]=[O:15].O>CO.C(Cl)Cl>[C:1]1([N:7]2[C:11](=[O:12])[N:10]([CH2:14][OH:15])[C:9](=[O:13])[O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=O
Reactant: O=c1[nH]c(=O)n(-c2ccccc2)o1
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: O=c1on(-c2ccccc2)c(=O)n1CO
Reaction time: 2 h

Procedure:
2-Phenyl-1,2,4-oxadiazolidin-3,5-dione (6.75 grams; 0.044 mole) dissolved in methanol (100 ml) and aqueous formaldehyde (5.67 ml of 37% conc.; 0.06 mole) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at reflux, with stirring for a period of about 2 hours. After this time the reaction mixture was stripped of methanol and water to yield a solid residue. The residue was then dissolved in methylene chloride, and the resulting solution was washed with water. The washed solution was dried over anhydrous magnesium sulfate and stripped of solvent to yield the desired product 2-phenyl-4-hydroxymethyl-1,2,4-oxadiazolidin-3,5-dione as a solid residue.
Reaction SMILES: ClCCCC(OCC)=O.CC1NC=NC=1C=O.[H-].[Na+].[CH2:20]([O:22][C:23]([CH2:25][CH2:26][CH2:27][N:28]1[C:32]([CH3:33])=[C:31]([CH:34]=O)[N:30]=[CH:29]1)=[O:24])[CH3:21].O(C(CCCN1C(C=O)=C(C)N=C1)=O)CC>CN(C)C=O>[CH3:34][C:31]1[N:30]=[CH:29][N:28]2[CH2:27][CH2:26][CH:25]([C:23]([O:22][CH2:20][CH3:21])=[O:24])[CH2:33][C:32]=12
Reactant: CCOC(=O)CCCn1cnc(C=O)c1C
Agent: CCOC(=O)CCCCl
Agent: CCOC(=O)CCCn1cnc(C)c1C=O
Agent: Cc1[nH]cnc1C=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCn2cnc(C)c2C1
Temperature: 70 °C

Procedure:
Ethyl 4-chlorobutyrate (7.0 g) was added at room temperature to a solution of 5-methyl-4-imidazole-carbaldehyde (4.17 g) and 60% oily sodium hydride (2.0 g) in 50 ml dimethylformamide (prepared by stirring at 50° C. for one hour). The resulting mixture was heated at 70° C. for four hours and then concentrated to dryness under reduced ressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer collected was washed with water and then with saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The dried solution was concentrated to dryness under reduced pressure, and the residue was subjected to column chromatography on silica gel (80 g). Elution with ethyl acetate gave 2.35 g (28%) of an about 1:1 mixture of 1-(3-ethoxycarbonylpropyl)-5-methyl-4-imidazole-carbaldehyde and 1-(3-ethoxylcarbonylpropyl)-4-methyl-5-imidazole-carbaldehyde.
Reaction SMILES: [OH-].[K+].[C:3]([C:7]1[C:8]([OH:16])=[CH:9][C:10]([CH3:15])=[C:11]([CH:14]=1)[CH:12]=[O:13])([CH3:6])([CH3:5])[CH3:4].[CH3:17][N:18]([CH3:22])[C:19](Cl)=[S:20].CN(C)C(Cl)=S.C1COCC1>O.C1COCC1>[C:3]([C:7]1[CH:14]=[C:11]([CH:12]=[O:13])[C:10]([CH3:15])=[CH:9][C:8]=1[O:16][C:19](=[S:20])[N:18]([CH3:22])[CH3:17])([CH3:6])([CH3:5])[CH3:4]
Reactant: CN(C)C(=S)Cl
Reactant: Cc1cc(O)c(C(C)(C)C)cc1C=O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OC(=S)N(C)C)c(C(C)(C)C)cc1C=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Potassium hydroxide (80 mL of a 10% aqueous solution) was added to a mixture of 5-tert-butyl-4-hydroxy-2-methylbenzaldehyde (99.0 g, 515 mmol) in water (180 mL) and THF (135 mL). This mixture was stirred at room temperature and a solution of dimethylthiocarbamoyl chloride (86.1 g) in THF (108 mL) added slowly over a 2 hour period with simultaneous addition of 10% KOH in order to hold the pH of the reaction mixture between 12.0 and 12.3. After approximately 70% of the dimethylthiocarbamoyl chloride-THF solution had been added, vacuum was applied to the reaction mixture to remove THF solvent and thus increase the rate of the bimolecular reaction. During the distillation, the simultaneous additions of 10% KOH and the dimethylthiocarbamoyl chloride-THF solution were continued while maintaining the pH range between 12.0 and 11.6 and the reaction temperature between 23-25° C. The distillation was continued for 10 minutes after all the dimethylthiocarbamoyl chloride-THF solution had been added and then stopped. Stirring at ambient pressure and temperature was continued for another 90 minutes. During this time the pH was stable between 11.6 and 11.75. A solution of ethyl acetate (150 mL) and heptane (150 mL) was added to the reaction mixture and after stirring and settling the layers were separated and the aqueous layer extracted with 1:1 heptane/ethyl acetate (150 mL). The combined organic extracts were extracted with 10% KOH (2×105 mL) and water (2×90 mL) and concentrated to an oil (210 gm). This was diluted with methanol (120 mL). The solution was warmed to 45° C. and water (20 mL) added. The solution was cooled to 25° C. and 50% NaOH (170 mg) was added. The resulting solution was concentrated to an oil (160 gm). This was redissolved in methanol (120 mL) at 50° C. and water (15 mL) added. The solution was cooled slowly with addition of dimethylthiocarbamic acid O-(2-tert-butyl-4-formyl-5-methylphenyl) ester seed crystals. Crystallization began at 43° C. The mixture was stirred and cooled over several hours to −5° C. The mixture was filtered and the solid washed with 4:1 methanol/water (75 mL) and vacuum dried at 40° C. overnight to give dimethylthiocarbamnic acid O-(2-tert-butyl-4-formyl-5-methylphenyl) ester (3a): 121.5 g (435 mmol, 84%): mp: 80-81° C.; assay (HPLC): 99.7 area %.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7](N)=[CH:6][CH:5]=1.Cl.N([O-])=O.[Na+].[I-:18].[K+].II>O>[F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([I:18])=[CH:6][CH:5]=1
Reactant: [I-]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: Cl
Agent: II
Agent: O=N[O-]
Solvent: O
Product: FC(F)(F)Oc1ccc(I)cc1
Temperature: -5 °C
Reaction time: 2 h

Procedure:
4-Trifluoromethoxyaniline (29.0 g.) was added at 0° C. to concentrated hydrochloric acid (160 mls.) and the thick white suspension so obtained was cooled to -5° C. The suspension was diazotised by adding a solution of sodium nitrite (13.0 g.) in water (20 ml.) over 20 minutes, keeping the temperature below 0° C. After 2 hours at 0° C., the suspension was added portionwise to a solution of potassium iodide (40 g.) and iodine (60 g.) in water (260 ml.) at 10° C. and the solution was allowed to stand at room temperature for 1 hour. The dark solution so obtained was extracted with diethyl ether three times, and the combined ether extracts were washed sequentially with sodium sulphite, water and brine, and on evaporation gave a golden oil which was distilled under water pump pressure to give 4-trifluoromethoxyiodobenzene as a pale pink liquid, b.p. 107°-8° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[N:8]=[CH:7][C:6]=1[NH2:15].[CH3:17][O:18][C:19]([NH:21][C:22](=NC(OC)=O)OC)=[O:20].C(O)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][CH:2]([CH3:16])[CH2:3][N:4]1[C:5]2[C:14]3[N:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=[C:22]1[NH:21][C:19](=[O:20])[O:18][CH3:17]
Reactant: CC(C)CNc1c(N)cnc2cccnc12
Reactant: COC(=O)N=C(NC(=O)OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)Nc1nc2cnc3cccnc3c2n1CC(C)C

Procedure:
A mixture of N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine (Gerster et al, U.S. Pat. No. 6,194,425, Example 30 Part A, 4.10 g, 19.0 mmol), 1,3-dimethoxycarbonyl-O-methylisourea (7.21 g, 37.9 mmol), acetic acid (5.69 g, 94.8 mmol), and p-toluenesulfonic acid (3.60 g, 19.0 mmol) in methanol (50 mL) was heated at reflux for 16 hours. The volatiles were removed under reduced pressure, and the residue was dissolved in chloroform (150 mL). The solution was washed sequentially with water (150 mL), aqueous sodium carbonate (150 mL of 4% w/w), water (150 mL), and brine (150 mL) and then concentrated under reduced pressure. The residue was purified by automated flash chromatography (40+M silica cartridge, eluting with 0% to 20% CMA in chloroform) followed by recrystallization from acetonitrile to provide 1.78 g of methyl [1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl]carbamate as a white solid, mp 195-197° C.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][NH:7][C:8]([NH2:10])=[NH:9].[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+].[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[N:28]([CH3:32])[C:29](Cl)=[O:30].[N+:33]([O-:36])([OH:35])=[O:34]>O1CCCC1>[N+:33]([O-:36])([OH:35])=[O:34].[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[N:28]([CH3:32])[C:29]([NH:10][C:8](=[NH:9])[NH:7][CH3:6])=[O:30]
Reactant: Cc1cccc(C)c1N(C)C(=O)Cl
Reactant: CNC(=N)N
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=[N+]([O-])O
Product: CNC(=N)NC(=O)N(C)c1c(C)cccc1C
Reaction time: 2 h

Procedure:
To a suspension of 12.21 g.(0.05 moles) of methyl guanidine sulfate in 110 ml. of tetrahydrofuran is added 8.0 g.(0.10 moles of sodium hydroxide) of 50% aqueous sodium hydroxide. After stirring for 11/2 hours, 4.5 g. of sodium sulfate is slowly added and the mixture stirred an additional 1/2 hour. To the solution is added a solution of 9.88 g. (0.05 moles) of 2,6-dimethylphenyl-N-methylcarbamoyl chloride in 30 ml. of tetrahydrofuran. After stirring for 24 hours, the THF is removed in vacuo and the residue partitioned with chloroform/water. The oily residue is triturated with 300 ml. of hexane and 20 ml. benzene to give a white solid. This is dissolved in 50 ml. of 1:4 HNO3 and warmed slightly over 1/2 hour, then cooled. The white solid which forms is filtered and air dried to obtain 1-(2',6'-dimethylphenyl)-1-methyl-3-methylamidinourea nitrate.
Reaction SMILES: [CH2:1]([C:4]1[S:5][C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:16])[C:7]=2[N:17]=1)[CH2:2][CH3:3].C(O)(=O)C.[Br:22]Br>O>[Br:22][C:13]1[CH:12]=[CH:11][C:10]2[N:9]=[C:8]([NH2:16])[C:7]3[N:17]=[C:4]([CH2:1][CH2:2][CH3:3])[S:5][C:6]=3[C:15]=2[CH:14]=1
Reactant: BrBr
Reactant: CCCc1nc2c(N)nc3ccccc3c2s1
Solvent: O
Solvent: CC(=O)O
Product: CCCc1nc2c(N)nc3ccc(Br)cc3c2s1
Temperature: 60 °C
Reaction time: 18 h
Yield: 189.2 %

Procedure:
2-Propylthiazolo[4,5-c]quinolin-4-amine (1.0 g, 0.41 mmol) was combined with acetic acid (15 mL) and heated to 60° C. Bromine (0.10 mL, 1.94 mmol) was added dropwise and the reaction mixture was stirred at 60° C. for 18 hours. The reaction mixture was diluted with water and the resulting precipitate was isolated by filtration to provide 0.25 g of 8-bromo-2-propylthiazolo[4,5-c]quinolin-4-amine as a yellow solid, m.p. 177-180° C. Analysis: Calculated for C13H12BrN3S: %C, 48.46; %H, 3.75; %N, 13.04; Found: %C, 47.98; %H, 3.95; %N, 12.70.
Reaction SMILES: O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[O:21][CH2:22][CH:23]2[O:28][CH2:27][C:26](=O)[N:25]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:24]2)[CH:14]=[CH:13]1.[OH-].[Na+]>O>[CH2:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[O:21][CH2:22][CH:23]2[O:28][CH2:27][CH2:26][N:25]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:24]2)[CH:14]=[CH:13]1
Reactant: O=C1COC(COc2cccc3c2CC=C3)CN1c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C1=Cc2cccc(OCC3CN(c4ccccc4)CCO3)c2C1

Procedure:
In 200 ml. of anhydrous tetrahydrofuran was suspended 3.0 g. of lithium aluminum hydride and after adding slowly to the suspension with stirring a solution prepared by dissolving 14.5 g. of 2-(7-indenyloxymethyl)-4-phenylmorpholin -5-one in 100 ml. of anhydrous tetrahydrofuran, the mixture was stirred overnight at room temperature. To the reaction mixture obtained were added successively 3 ml. of water, 3 ml. of a 15% sodium hydroxide aqueous solution, and then 9 ml. of water to decompose excessive lithium aluminum hydride. Then, by treating the solution in a similar manner as in Example 7-(b), 10.6 g. of oily 2-(7-indenyloxymethyl)-4-phenylmorpholine was obtained.
Reaction SMILES: Br[C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.B(O)O.[CH3:15][O:16][C:17]1[CH:18]=[C:19](O)[CH:20]=[CH:21][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+].CCO.O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH3:15][O:16][C:17]1[CH:22]=[C:21]([C:2]2[S:6][C:5]3[CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=3[CH:3]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc(O)c1
Reactant: O=C1CCCc2sc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: OBO
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: COc1cccc(-c2cc3c(s2)CCCC3=O)c1
Yield: 95 %

Procedure:
To 2-bromo-6,7-dihydro-5H-benzo[b]thiophen-4-one (5 g, 21.74 mmol) was successively added 3-methoxyphenol boronic acid (3.63 g, 23.92 mmol), 2M Na2CO3(aq) (43.5 mL, 86.98 mmol), Pd(PPh3)4 (251 mg, 0.22 mmol), 3:4 EtOH/H2O (37.5 mL) and DME (62.5 mL). The reaction mixture was degassed and heated to reflux for 12 hours. EtOAc (250 mL) was added and the crude reaction mixture was washed with water (2×100 mL). The organic layer was dried over magnesium sulphate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with EtOAc:hexanes (20:80) to give the title compound as an off-white solid in 95% yield. MS (ES+) 259. δH (d6 DMSO) 2.13 (2H, quint.), 2.50 (2H, m), 3.05 (2H, t), 3.81 (3H, s), 6.91 (1H, m), 7.20-7.22 (2H, m), 7.34 (1H, m), 7.67 (1H, s).