Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:20]([OH:22])=[O:21])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[CH:4][C:3]=1[F:24].FOBOF.[CH3:30][N:31]1[CH2:36][CH:35]2[CH2:37][CH:32]1[CH2:33][NH:34]2.C(N(CC)CC)C>FB(O)O.CS(C)=O.O>[F:24][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:34]1[CH2:33][CH:32]3[CH2:37][CH:35]1[CH2:36][N:31]3[CH3:30])[N:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19])[CH:8]=[C:7]([C:20]([OH:22])=[O:21])[C:6]2=[O:23]
Reactant: CN1CC2CC1CN2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2cc(Cl)c(F)cc2c1=O
Agent: FOBOF
Agent: OB(O)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN1CC2CC1CN2c1cc2c(cc1F)c(=O)c(C(=O)O)cn2-c1ccc(F)cc1F
Reaction time: 1 h
Yield: 18.8 %

Procedure:
15 g (37.36 m Mol) of the mixed anhydride of 7-chloro-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and difluoroboronic acid (obtained by heating 7-chloro-6-fluoro-1-(2.4-difluoro- phenyl)-1,4-dihycho-4-oxoquinoline-3-carboxylic acid in 60% aqueous fluoroboronic acid 15.36 g (56 m Mol) of the dihydrobromide of 2-methyl-2,5-diazabicyclo-(2.2.1)heptane and 31 ml (0.224 mol) triethylamine was stirred in 200 ml of dry DMSO at room temperature for 6 days. Then the reaction mixture was poured into 800 ml of cold water and the resultant precipitate collected by filtration washed with water and then heated to reflux with stirring in a mixture of 100 ml dioxane and 150 ml 3N NaOH for 1 hr. After cooling and with stirring, 500 ml of conc. HCl was added. After stirring for 1 hr., the undissolved material was removed by filtration, to give a clear solution which was extracted multiple times with methylene chloride. The aqueous phase was cooled in an ice bath and brought to pH 7.4 by the addition of dilute NaOH. The resultant was extracted with chloroform and the chloroform phase dried over sodium sulfate and the chloroform removed in vacuo, the resulting dark brown oil was recrystallized from 450 ml ethanol to give 3.15 g (18.8%) of the product as a hydrate, mp 215° C.-220° C. dec.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[C:5]([C:7]1[CH:23]=[CH:22][C:10]([C:11]([N:13]2[CH2:18][CH2:17][C:16]3[CH:19]=[CH:20][O:21][C:15]=3[CH2:14]2)=[O:12])=[CH:9][CH:8]=1)=[O:6].[CH3:27][NH:28][CH3:29].[CH2:30]=O>C(O)(=O)C>[CH3:27][N:28]([CH2:30][C:20]1[O:21][C:15]2[CH2:14][N:13]([C:11](=[O:12])[C:10]3[CH:22]=[CH:23][C:7]([C:5](=[O:6])[C:4]4[CH:24]=[CH:25][CH:26]=[C:2]([Cl:1])[CH:3]=4)=[CH:8][CH:9]=3)[CH2:18][CH2:17][C:16]=2[CH:19]=1)[CH3:29]
Reactant: C=O
Reactant: O=C(c1ccc(C(=O)N2CCc3ccoc3C2)cc1)c1cccc(Cl)c1
Reactant: CNC
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CN(C(=O)c1ccc(C(=O)c3cccc(Cl)c3)cc1)CC2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 0.240 g (0.656 mmol) of 6-[4-(3-chlorobenzoyl)benzoyl]-4,5,6,7-tetrahydrofuro[2,3-c]pyridine in 10 ml of acetic acid, 0.089 ml (0.984 mmol) of 50% aqueous dimethylamine and 0.080 ml (0.984 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 60 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with 5% aqueous sodium hydrogen carbonate and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform/methanol=50/1) to yield the desired product.
Reaction SMILES: C([O:3][C:4]([CH:6]1[N:10]2[C:11](=[S:21])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:13](=[O:14])[CH:9]2[CH2:8][CH2:7]1)=[O:5])C.CO.[OH-].[Na+]>O>[C:15]1([N:12]2[C:13](=[O:14])[CH:9]3[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[N:10]3[C:11]2=[S:21])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)C1CCC2C(=O)N(c3ccccc3)C(=S)N12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1CCC2C(=O)N(c3ccccc3)C(=S)N12
Reaction time: 3 h

Procedure:
To a solution of 1.5 g. of 2-phenyl-5,6,7,7a-tetra-hydro-1-oxo-3-thioxo-1H-pyrrolo[1,2-c]imidazole-5-carboxylic acid ethyl ester in 10 ml. of methanol, 5 ml. of 1 N sodium hydroxide in 10 ml. of water is added. The mixture is allowed to stand for 3 hours at room temperaure, then methanol is evaporated in vacuo. The residual solution is extracted with diethyl ether, then acidified and concentrated to a small volume. After standing overnight, 0.7 g. of the titular product crystallizes out, m.p. 230°C. (methanol).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.Cl>CCCCCC>[C:1]([C:5]1[CH:6]=[C:7]([O:12][CH3:13])[CH:8]=[C:9]([C:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=2)[C:10]=1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(O)c(C(C)(C)C)c1
Reactant: O=C1CCCCC1
Agent: Cl
Solvent: CCCCCC
Solvent: CC(=O)O
Product: COc1cc(C2=CCCCC2)c(O)c(C(C)(C)C)c1
Temperature: 40 °C
Reaction time: 64 h
Yield: 29 %

Procedure:
A mixture consisting of 36.1 g (0.20 mol) of 3-tert-butyl-4-hydroxyanisol, 19.6 g (0.20 mol) of cyclohexanone and 10 ml of acetic acid is placed in a reactor and saturated, with stirring, with hydrochloric acid gas at room temperature. After standing for 64 hours at room temperature, the mixture is again saturated with hydrochloric acid gas and stirred for another 5 hours at 40° C. The reaction mixture is diluted with hexane and washed with water, sodium chloride solution and sodium hydrogencarbonate solution. The organic phase is dried over magnesium sulfate and concentrated on a rotary evaporator. The residue is chromatographed over silica gel using the solvent system ethyl acetate/hexane=1:49, giving 15.1 g (29%) of 2-tert-butyl-6-cyclohexen-1-yl-4-methoxyphenol as a yellowish thick oil, 1H--NMR (CDCl3), δ(ppm): 3.75 (s, 3H, OCH3), 5.87 (m, 1H, cyclohexenyl--H), (compound (111), Table 1).
Reaction SMILES: C(=O)([O-])[O-:2].[Sr+2:5].[N+:6]([O-:9])([OH:8])=[O:7]>>[OH2:2].[OH2:7].[OH2:2].[OH2:2].[N+:6]([O-:9])([O-:8])=[O:7].[Sr+2:5].[N+:6]([O-:9])([O-:8])=[O:7]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])O
Agent: [Sr+2]
Product: O
Product: O=[N+]([O-])[O-]

Procedure:
The strontium carbonate (SrCO3) obtained by these methods is dissolved in dilute nitric acid, impurities are removed from the resulting strontium nitrate solution, and the product is then concentrated, cooled, and crystallized until a crystal film forms, yielding strontium nitrate tetrahydrate (Sr(NO3)2.4H2O).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH3:7][O:8][C:9]([C:11]1[CH:12]=[CH:13][N:14]2[C:19]=1[C:18](=[O:20])[N:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]([CH:28]=CN(C)C)=[N:15]2)=[O:10]>C1COCC1>[CH3:7][O:8][C:9]([C:11]1[CH:12]=[CH:13][N:14]2[C:19]=1[C:18](=[O:20])[N:17]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]([CH:28]=[O:2])=[N:15]2)=[O:10]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COC(=O)c1ccn2nc(C=CN(C)C)n(Cc3ccccc3)c(=O)c12
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccn2nc(C=O)n(Cc3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
Sodium periodate (0.52 g, 2.4 mmol) was added to pH 7 buffer solution (2.5 ml) of 3-benzyl-2-(2-dimethylamino-vinyl)-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-5-carboxylic acid methyl ester (0.17 g, 0.48 mmol) in THF (3.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was filtered through Celite® and the solids were washed with EtOAc (30 mL). The filtrate was washed with saturated NaCl (2×30 ml), dried (Na2SO4), filtered and concentrated in vacuo to afford the titled compound as a solid (0.15 g, 100%): 1H NMR (CDCl3) δ 9.41 (s, 1H), 7.16–7.40 (m, 7H), 5.68 (s, 2H), 3.88 (s, 3H); MS (ESI+) 312 (M++H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=O)[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=O.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>>[OH:1][C:2]1[CH:3]=[C:4]2[C:11](=[O:13])[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6](=[O:8])[C:5]2=[CH:9][CH:10]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ccc(O)cc1C(=O)O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Product: O=C1c2ccc(O)cc2C(=O)N1c1ccccc1

Procedure:
4-Hydroxy-N-phenylphthalimide was synthesized from 4-hydroxyphthalic acid and aniline in the same manner as in Example 1, a). By the reaction of the synthesized compound with trifluoromethanesulfonic anhydride, 4-(N-phenylphthalimide)-yl-triflate (NPhITf) was synthesized.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:18]1[N:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[C:19]=1[N+:35]([O-:37])=[O:36]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:18]2[C:19]([N+:35]([O-:37])=[O:36])=[C:20]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:29][CH:30]=3)[N:21]=[CH:22][N:23]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(Cl)c2[N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
4-Hydroxy-piperidine-1-carboxylic acid tert-butyl ester (3.03 mmol, 610 mg) and sodium hydride (10.6 mmol, 255 mg) were dissolved in dry THF (20 mL) and stirred for 30 minutes at room temperature. Then, (6-chloro-5-nitro-pyrimidin-4-yl)-(4-methanesulfonyl-phenyl)-amine (3.03 mmol, 1.0 g) was added. The reaction was stirred at room temperature for 30 minutes. Its progress was monitored by thin layer chromatography and LCMS. Sodium hydride was quenched with water and the desired compound was extracted in ethyl acetate. Organic solvents were evaporated in vacuo. Flash chromatography (Silica gel 60; 30/70 EtOAc/Hexanes) provided Compound A1 as a yellow solid (1.2 g, 68%). 1H NMR (400 MHz, CDCl3) δ (ppm): 10.10 (s, 1H), 8.33 (s, 1H), 7.90 (d, 2H), 7.79 (d, 2H), 5.51 (heptet, 1H), 3.58 (m, 2H), 3.46 (m, 2H), 2.97 (s, 3H), 1.84 (m, 4H), 1.36 (s, 9H). LCMS (ESI), m/z 494.4 (M+H+, 100%).
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[H-].[Na+].Cl[CH2:12][C:13]([CH3:15])=[CH2:14]>C1COCC1>[CH3:14][C:13](=[CH2:12])[CH2:15][O:8][CH2:7][C@@H:2]([NH2:1])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: C=C(C)CCl
Reactant: CC(C)C[C@H](N)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(C)COC[C@@H](N)CC(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
To a solution of L-leucinol (20.0 g, 0.17 mol) in an anhydrous THF (200 mL) was portionwise added 60% NaH (7.92 g, 0.198 mol). The resulting mixture was stirred for 30 min. at room temperature and further for 2 hours at 50° C. The mixture was then cooled to room temperature. To the resulting suspension was dropwise added a solution of 3-chloro-2-methylpropene (15.45 g, 0.17 mol) in an anhydrous THF (50 mL). The resulting mixture was stirred for 20 hours at room temperature. The THF was distilled off under reduced pressure. To the residue were successively added a mixture of ice and water and diethyl ether. The mixture was stirred for 5 min. at room temperature, and the organic portion was separated. The aqueous portion was subjected to extraction with diethyl ether. The extract was combined with the organic portion. The combined organic portion was washed with 1 mol/L aqueous hydrochloric acid (7 mL) and subjected to extraction with 1 mol/L aqueous hydrochloric acid (153 mL). The resulting hydrochloric acid extract was made to approx. pH 10 by addition of potassium carbonate and subjected to extraction with diethyl ether. The organic portion was washed with water, dried over sodium sulfate, and placed under reduced pressure to distill the solvent off. There was obtained the titled compound (20.22 g, 69.2%) as an oily product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=2)=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:29]=[O:30])C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:29]=[O:30])[N:11]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccc(F)cc2)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Product: C[Si](C)(C)CCOCn1cc(-c2ccc(F)cc2)nc1C=O

Procedure:
Reaction of 4(4-fluoro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (688 mg, 2.35 mmol), 1.5 M n-BuLi (2.0 mL, 3.0 mmol), and DMF (0.55 mL, 7.1 mmol) gave the title compound as a brown oil that was used without further purification in the next step. 1H NMR (CDCl3) 0.00 (s, 9H), 0.95 (m, 2H), 3.61 (m, 2H), 5.82 (s, 2H), 7.12 (m, 2H), 7.28 (s, 1H), 7.59 (s, 1H), 7.80. (m, 2H), 9.88 (s, 1H).
Reaction SMILES: C(OC([N:8]([CH3:51])[C@@H:9]([CH3:50])[C:10]([NH:12][C@H:13]1[C:19]2([CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[O:18][C:17]2[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=2[N:15]([CH2:29][C:30]2[C:39](OC)=[CH:38][CH:37]=[C:36]3[C:31]=2[CH:32]=[CH:33][C:34]([C:42]([NH:44][S:45]([CH3:48])(=[O:47])=[O:46])=[O:43])=[CH:35]3)[C:14]1=[O:49])=[O:11])=O)(C)(C)C.[C:52]([OH:58])([C:54]([F:57])([F:56])[F:55])=[O:53]>C(Cl)Cl>[F:55][C:54]([F:57])([F:56])[C:52]([OH:58])=[O:53].[CH2:52]([O:53][C:35]1[C:36]2[C:31](=[C:30]([CH2:29][N:15]3[C:14](=[O:49])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][CH3:51])[CH3:50])[C:19]4([CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)[O:18][C:17]4[CH:25]=[CH:26][CH:27]=[CH:28][C:16]3=4)[CH:39]=[CH:38][CH:37]=2)[CH:32]=[CH:33][C:34]=1[C:42]([NH:44][S:45]([CH3:48])(=[O:46])=[O:47])=[O:43])[CH3:54]
Reactant: COc1ccc2cc(C(=O)NS(C)(=O)=O)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C2(CCOCC2)Oc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1c(C(=O)NS(C)(=O)=O)ccc2c(CN3C(=O)[C@@H](NC(=O)[C@H](C)NC)C4(CCOCC4)Oc4ccccc43)cccc12
Yield: 67 %

Procedure:
5-(((S)-3-((S)-2-(tert-Butoxycarbonyl(methyl)amino)propanamido)-4-oxo-2′,3′,5′,6′-tetrahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-5 (4H)-yl)methyl)-6-methoxy-N-(methylsulfonyl)-2-naphthamide dissolved in DCM (1 mL) and 0.25 mL TFA was added. After 90 min the mixture was concentrated, the residue was dissolved in MeCN/H2O, and lyophilized to afford the title compound (45.4 mg, 67%) as a white solid. MS m/z 625.4 (MH+)
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=O)(C)(C)C.OC1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClC(Cl)C.CO.C(O)(=O)C>[N:8]1([CH:6]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:9][CH2:10][CH:11]([OH:14])[CH2:12][CH2:13]1
Reactant: OC1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: CO
Product: OC1CCN(C2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Oxo-piperidine-1-carboxylic acid tert-butyl ester (20 g) and 4-hydroxypiperidine (6.7 g) were stirred together in dichloroethane (200 ml) with acetic acid (4 ml) at RT for 30 minutes. Sodium triacetoxyborohydride (23 g) was then added and the mixture stirred at RT overnight. The mixture was evaporated to dryness and the residue taken into water, extracted with diethyl ether (3×200 ml), the aqueous was basified to pH 9-10 and extracted with dichloromethane (3×200 ml). The dichloromethane extracts were combined, dried (MgSO4) and evaporated to leave an oil (19 g; same compound as Example 9 step 1). The oil was dissolved in methanol (300 ml) and treated with concentrated hydrochloric acid (5 ml). The mixture was stirred overnight and then evaporated to dryness to leave the title compound as the hydrochloride salt (15 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:7](OC)=[O:8])([O-])=O.[NH2:18][NH2:19]>C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:7]([NH:18][NH2:19])=[O:8]
Reactant: NN
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Solvent: CCO
Product: NNC(=O)c1cc(N)cc(C(F)(F)F)c1
Yield: 77 %

Procedure:
Mix methyl 3-nitro-5-(trifluoromethyl)benzoate (1.8 g, 12 mmol), ethanol (6 mL) and 80% (w/w) hydrazine (10 mL), reflux overnight. Concentrate the mixture, partition the resulting residue between ethyl acetate and water, collect the organic layer, wash with sodium bicarbonate, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to give the crude product (1.23 g, 77%) which is used in next step without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][C@H:24]1[CH2:29][O:28][CH2:27][CH2:26][NH:25]1>>[CH3:23][C@H:24]1[CH2:29][O:28][CH2:27][CH2:26][N:25]1[C:18]([C:12]1[S:13][C:14]2[CH2:15][CH2:16][O:17][C:8]3[CH:7]=[C:6]([C:4]4[CH:5]=[N:1][NH:2][CH:3]=4)[CH:22]=[CH:21][C:9]=3[C:10]=2[N:11]=1)=[O:19]
Reactant: C[C@H]1COCCN1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: C[C@H]1COCCN1C(=O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (S)-3-methylmorpholine (1.2 equiv) to give 138 (14.9 mg, M+1 397.1)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N:9]([S:18]([CH3:17])(=[O:20])=[O:19])[S:18]([CH3:17])(=[O:20])=[O:19])=[CH:4][CH:3]=1
Reactant: Cc1nc(Cl)ccc1N
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(Cl)ccc1N(S(C)(=O)=O)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
In a dry flask, 6-chloro-2-methylpyridin-3-amine (160 mg, 1.12 mmol) and triethylamine (470 μl, 3.37 mmol) were taken up in dichloromethane (5.6 ml) under argon. The solution was cooled to 0° C. and stirred for 20 minutes. Methanesulfonyl chloride (131 μl, 1.68 mmol) was added dropwise over 15 minutes. The mixture was allowed to warm to room temperature and stirred as such for 16 hours. The reaction was quenched with aqueous sodium bicarbonate and washed three times with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated to afford the title compound.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[NH:8][CH:9]=[CH:10][N:11]=1.NC(N)=O.[N+:16]([O-])([OH:18])=[O:17]>O>[CH3:6][C:7]1[NH:8][CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[N:11]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ncc[nH]1
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1nc([N+](=O)[O-])c[nH]1
Yield: 81.5 %

Procedure:
A mixture of 2,730 parts of sulfuric acid (35 percent by weight), 835 parts of 2-methylimidazole, 410 parts of urea, 2,465 parts of nitric acid (32 percent by weight) and 1,350 parts of water is reacted continuously in a three-stage cascade (consisting of 3 reactors each with a distillation column and reflux condenser) for 6 hours at from 125° to 133° C. During the reaction, 1,130 parts of 14.4 percent strength by weight nitric acid distill off. The reaction mixture is then diluted with a 3.5-fold volume of water whilst cooling and is neutralized to pH 3-4 with ammonia solution. The 2-methyl-4-nitroimidazole which separates out is centrifuged off, washed, dried and recrystallized from water. 1,060 parts of 2-methyl-4-nitroimidazole (81.5% of theory) of melting point 145°-146° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH3:12])=[C:6]([NH2:13])[CH:5]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:31]=[CH:30][C:25]3[N:26]=[C:27]([NH2:29])[S:28][C:24]=3[CH:23]=2)[CH:16]=1.[C:32](N1C=CN=C1)(N1C=CN=C1)=S.C(Cl)CCl>CN(C=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([CH2:11][CH3:12])[C:32]([NH:29][C:27]3[S:28][C:24]4[CH:23]=[C:22]([O:21][C:17]5[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=5)[CH:31]=[CH:30][C:25]=4[N:26]=3)=[N:13][C:6]=2[CH:5]=1)=[O:14]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1nc2ccc(Oc3cccnc3)cc2s1
Reactant: CCNc1ccc(C(=O)OC)cc1N
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCn1c(Nc2nc3ccc(Oc4cccnc4)cc3s2)nc2cc(C(=O)OC)ccc21
Yield: 42.3 %

Procedure:
1-Ethyl-2-[6-(pyridin-3-yloxy)-benzothiazol-2-ylamino]-1H-benzoimidazole-5-carboxylic acid methyl ester (155.0 mg) was prepared by following General Procedure D starting from 3-amino-4-ethylamino-benzoic acid methyl ester (160.0 mg), 6-(pyridin-3-yloxy)-benzothiazol-2-ylamine (200.0 mg), 1,1′-thiocarbonyldiimidazole (200.0 mg), and EDC (200.0 mg) in DMF (2.0 mL).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][O:28][C:22]=3[CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][O:28][C:22]=4[CH:21]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CCc1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Reactant: c1nc[nH]n1
Product: CCc1cc2c(NCc3ccc4c(c3)OCO4)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-ethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-ethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl.[C:51]1([CH:57]([OH:61])[CH2:58][CH2:59][CH3:60])[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:40](=[O:42])[O:61][CH:57]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH2:58][CH2:59][CH3:60])=[C:18]([CH3:24])[CH:17]=1
Reactant: CCCC(O)c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCC(OC(=O)Nc1cc(C)c(Oc2ccnc3cc(OC)c(OC)cc23)cc1C)c1ccccc1
Temperature: 25 °C
Yield: 42.2 %

Procedure:
4-[(6,7Dimethoxy-4-quinolyl)oxy]2,5-dimethylaniline (89 mg) was added to toluene/triethylamine=10/1 (9 ml ) and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (126 mg), in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 1-phenyl-1-butanol (63 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (58 mg, yield 39%).