Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C:9]1([C:22](O)=[O:23])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)=[O:7])([CH3:4])[CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:58][N:59]([CH3:70])[C:60](=[O:69])[O:61][C:62]1[CH:67]=[CH:66][CH:65]=[C:64]([NH2:68])[CH:63]=1>C(OC(C)C)(=O)C.CCOC(C)=O>[C:2]([O:5][C:6]([NH:8][C:9]1([C:22](=[O:23])[NH:68][C:64]2[CH:65]=[CH:66][CH:67]=[C:62]([O:61][C:60](=[O:69])[N:59]([CH3:70])[CH3:58])[CH:63]=2)[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:1]
Reactant: CN(C)C(=O)Oc1cccc(N)c1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)OC(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(C)C(=O)Oc1cccc(NC(=O)C2(NC(=O)OC(C)(C)C)CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44.9 %

Procedure:
N-Boc-amino-(4-N-Boc-piperidinyl)carboxylic acid (0.114 g, 0.33 mmol), HATU (0.151 g, 0.40 mmol) and N,N-diisopropylethylamine (128 mg, 1.0 mmol) were combined in isopropyl acetate (2.3 mL) and stirred at room temperature for 15 minutes. 3-aminophenyl dimethylcarbamate (0.072 g, 0.40 mmol) was added, and the mixture heated at 80° C. for 1.5 hours. The reaction mixture was allowed to cool, diluted with EtOAc, washed with 2 N Na2CO3, 1 N HCl, and brine, and then dried over MgSO4 and concentrated. Purification by silica gel chromatography (60% EtOAc/hexanes) gave the title compound (0.075 g, 45%) as a white solid. MS (ES+) [M+NH4]+=524.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:7]([O:10][N:11]=[C:12]([C:16]1[N:20]=[C:19]([NH2:21])[S:18][N:17]=1)[C:13]([OH:15])=[O:14])[CH:8]=[CH2:9].[CH3:22]O.[OH-].[Na+]>C(Cl)Cl.N1C=CC=CC=1.O>[CH2:7]([O:10][N:11]=[C:12]([C:16]1[N:20]=[C:19]([NH2:21])[S:18][N:17]=1)[C:13]([O:15][CH3:22])=[O:14])[CH:8]=[CH2:9]
Reactant: CO
Reactant: C=CCON=C(C(=O)O)c1nsc(N)n1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: C=CCON=C(C(=O)OC)c1nsc(N)n1
Temperature: -20 °C
Reaction time: 0.83 h
Yield: 69.4 %

Procedure:
To solution of phosphorus pentachloride (10.92 g) in methylene chloride (110 ml) was added 2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) (11.4 g) under cooling at -20° C. and stirring, which was continued for 50 minutes at -15° to -5° C. To the mixture was dropped a solution of methanol (2.4 g) in pyridine (15.82 g) at -30° to -10° C. under stirring, which was continued for 20 minutes at -10° C. To the reaction mixture was dropped water (110 ml) and the mixture was adjusted to pH 2 with 1N aqueous sodium hydroxide and then stirred for 30 minutes at 0° C. The resulting precipitate was filtered, washed with water and dried to give methyl 2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetate (syn isomer) (8.40 g).
Reaction SMILES: N1N[N:3]=[N:4][C:5]=1[C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:22](Cl)(=[O:32])[C:23]1[CH:31]=[CH:30][CH:29]=[C:25]([C:26](Cl)=[O:27])[CH:24]=1.O>CCCCCC.C(Cl)(Cl)Cl>[N:16]1[C:21]2[C:20](=[CH:13][CH:8]=[CH:9][CH:10]=2)[CH:19]=[CH:18][C:17]=1[C:5]1[O:32][C:22]([C:23]2[CH:31]=[CH:30][CH:29]=[C:25]([C:26]3[O:27][C:5]([C:6]4[CH:15]=[CH:14][C:13]5[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=5)[N:7]=4)=[N:4][N:3]=3)[CH:24]=2)=[N:3][N:4]=1
Reactant: c1ccc2nc(-c3nn[nH]n3)ccc2c1
Reactant: c1ccncc1
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: c1cc(-c2nnc(-c3ccc4ccccc4n3)o2)cc(-c2nnc(-c3ccc4ccccc4n3)o2)c1
Temperature: 100 °C
Yield: 87 %

Procedure:
After dissolving 4.0 g of 2-(2H-tetrazole-5-yl)quinoline into 60 ml of dehydrated pyridine, 2.1 g of isophthaloylchloride was added. The mixture was heated to 100° C. and stirred under reflux for 4 hours. After cooling to a room temperature, the reaction solution was poured into water to collect a precipitated solid by suction filtration, and the solid was washed with water. The solid was dried under vacuum at 70° C. for 20 hours to obtain a brownish crude product. After dissolving the thus-obtained crude product into chloroform, hexane was added to allow purification by crystallization, thereby obtaining 4.12 g of 2QOXDm (14) (yield: 87%). NMR analysis (see FIG. 2) was performed for identification of the product. The results of the NMR analysis are as follows. 9.17 ppm (1H), 8.53 ppm (2H), 8.34-8.47 ppm (6H), 7.83-7.96 ppm (4H), 7.80 ppm (1H), 7.69 ppm (2H). Further, signals of all carbon atoms were confirmed (see FIG. 3). 164.7 ppm, 164.5 ppm, 147.9 ppm, 143.0 ppm, 137.4 ppm, ppm, 130.6 ppm, 130.1 ppm, 129.9 ppm, 128.7 ppm, ppm, 127.7 ppm, 125.9 ppm, 124.7 ppm, 119.9 ppm.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[O:17][CH3:18])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-:20].[Na+].[Na+]>O1CCOCC1.Cl>[CH3:18][O:17][C:9]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=1[C:7]1[C:2](=[O:20])[NH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc([N+](=O)[O-])ccc1-c1cccnc1F
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1cc([N+](=O)[O-])ccc1-c1ccc[nH]c1=O

Procedure:
1.50 g (6.04 mmol) of the product from example 54A are heated overnight in a mixture of 75 ml of dioxane and 75 ml of 4-molar hydrochloric acid. The mixture is then alkalized with sodium carbonate solution. The precipitate is filtered off with suction, washed with water and dried. This affords 1.43 g (96% of theory) of the desired compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[N:5]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:4]([CH3:20])([CH3:19])[CH2:3]1.[H-].[Na+].[N:23]1[C:30](Cl)=[N:29][C:27](Cl)=[N:26][C:24]=1Cl>O1CCOCC1>[CH2:11]([O:10][N:5]1[C:6]([CH3:8])([CH3:9])[CH2:7][CH:2]([O:1][C:24]2[N:26]=[C:27]([O:1][CH:2]3[CH2:7][C:6]([CH3:8])([CH3:9])[N:5]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:4]([CH3:19])([CH3:20])[CH2:3]3)[N:29]=[C:30]([O:1][CH:2]3[CH2:7][C:6]([CH3:8])([CH3:9])[N:5]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:4]([CH3:19])([CH3:20])[CH2:3]3)[N:23]=2)[CH2:3][C:4]1([CH3:19])[CH3:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCON1C(C)(C)CC(O)CC1(C)C
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCCCCCCCON1C(C)(C)CC(Oc2nc(OC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)nc(OC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)n2)CC1(C)C

Procedure:
The title compound is prepared by the reaction of 4-hydroxy-1-octyloxy-2,2,6,6-tetramethylpiperidine, sodium hydride, and cyanuric chloride in 1,4-dioxane solvent.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[OH-].[Na+].[CH2:14]([O:26][CH2:27][CH:28]1[O:30][CH2:29]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].Cl>O.C(O)(C)C>[ClH:1].[OH:30][CH:28]([CH2:27][O:26][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:29][NH:8][CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]([C:9]([OH:11])=[O:10])[NH2:2]
Reactant: CCCCCCCCCCCCOCC1CO1
Reactant: NCCCC[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCCCCCOCC(O)CNCCCC[C@H](N)C(=O)O
Yield: 23.8 %

Procedure:
L-lysine hydrochloride (18.3 g, 0.1 mols) and 2.0 g (0.2 mols) of sodium hydroxide were dissolved in 100 ml of water in a three-necked round flask, and 100 ml of i-propanol were added thereto. Then, 24.2 g (0.1 mols) of dodecylglycidyl ether were added dropwise thereto over a period of 30 minutes while being heat-refluxed and stirred. Further, the mixture was stirred under reflux for 3 hours. It was identified through TLC and gas chromatography that dodecylglycidyl ether disappeared. Thereafter, the resulting mixture was neutralized with 10.1 g (0.1 mols) of 36% hydrochloric acid. The reaction solution was concentrated under reduced pressure, and the residue was purified through silica-gel column chromatography (Kieselgel 60, eluent=mixture of chloroform, methanol and acetic acid at a ratio of 3:1:0.5) to give 10.1 g of Nε-(2-hydroxy-3-dodecyloxypropyl)-L-lysine hydrochloride (yield 23.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2C=CC3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[O:9]2)[CH:5]=[CH:6][CH:7]=1.C[N+]1([O-])CC[O:22]CC1.C[C:27]([OH:30])([CH3:29])[CH3:28]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:29]([OH:22])[C@@H:27]([OH:30])[C:28]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(C)(C)O
Reactant: Clc1cccc(C2C=Cc3ccccc3O2)c1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: C1CCOC1
Product: O[C@@H]1[C@@H](c2cccc(Cl)c2)Oc2ccccc2[C@@H]1O
Reaction time: 16 h
Yield: 91 %

Procedure:
To a solution of 2-(3-chlorophenyl)-2H-chromene (2i) (72.8 mg, 0.3 mmol) and 4-methylmorpholine N-oxide (52.7 mg, 0.45 mmol) in THF (3 mL) and water (0.116 mL) was added a 2.5 wt % solution of osmium tetraoxide in t-BuOH (0.118 mL). The mixture was stirred at 23 C for 16 h and was then quenched with a saturated solution of sodium thiosulfate. The mixture was extracted with EtOAc. The combined organics was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude was purified by flash chromatography using 20% EtOAc/hexanes to afford 9 as an off-white solid (76 mg, 91%). Analytical data for 9: 1H NMR (500 MHz, CDCl3) δ 7.53-7.48 (m, 1H), 7.39 (dd, J=7.6, 1.7 Hz, 1H), 7.37 (d, J=1.4 Hz, 3H), 7.30 (ddd, J=8.6, 7.3, 1.7 Hz, 1H), 7.02 (td, J=7.4, 1.2 Hz, 1H), 6.96 (dd, J=8.2, 1.1 Hz, 1H), 5.05 (d, J=9.5 Hz, 1H), 4.81 (t, J=3.7 Hz, 1H), 4.04 (ddd, J=9.5, 6.6, 3.7 Hz, 1H), 2.57 (d, J=3.7 Hz, 1H), 2.25 (d, J=6.6 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 154.0, 139.9, 134.8, 130.9, 130.7, 130.1, 129.0, 127.8, 125.9, 122.0, 121.7, 117.0, 76.2, 71.1, 66.2; IR (film): 3407, 2919, 2851, 1583, 1485, 1455, 1239, 1036, 1012, 754, 701, 511 cm−1; LRMS (ESI): Mass calculated for [M+H]+ C15H14ClO3: 277.1; found 277.1
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[C:5]([Cl:18])=[CH:4][N:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([NH2:27])[CH:24]=[CH:25][CH:26]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:18][C:5]1[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[N:7][C:2]([NH:27][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH3:19])[CH:22]=2)=[N:3][CH:4]=1
Reactant: COc1cccc(CNc2nc(Cl)ncc2Cl)c1
Reactant: COc1cccc(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(CNc2nc(Nc3cccc(OC)c3)ncc2Cl)c1
Temperature: 105 °C
Yield: 34.7 %

Procedure:
Into a reaction flask were added 2,5-dichloro-N-(3-methoxybenzyl)pyrimidin-4-amine (0.20 g, 0.70 mmol) (prepared according to Example 1, step A), 1,4-dioxane (20 mL), 3-methoxy-benzenamine (0.13 g, 1.0 mmol), and p-toluenesulfonic acid monohydrate (49 mg, 0.26 mmol). The mixture was heated at 105° C. for 2 days. To the mixture was added an aqueous solution of NaHCO3 (saturated, 0.5 mL) and the organic solvent was removed under vacuum. The aqueous layer was extracted with DCM twice. The combined organic layers were dried, filtered and concentrated. The crude product was purified by silica gel column chromatography to provide the desired product (90 mg, 30%). LCMS for C19H20ClN4O2 (M+H)+: m/z=371.1.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:7](=[O:13])[NH:8][N:9]=[CH:10][C:11]=1[Cl:12].[CH3:14][NH:15][CH2:16][CH2:17][C:18]1[CH:27]=[CH:26][C:23]([O:24][CH3:25])=[C:20]([O:21][CH3:22])[CH:19]=1.C(=O)([O-])O.[K+].C(OCC)(=O)C>CC(C)=O.C(N(CC)CC)C>[Cl:12][C:11]1[CH:10]=[N:9][NH:8][C:7](=[O:13])[C:6]=1[NH:5][CH2:4][CH2:3][CH2:2][N:15]([CH2:16][CH2:17][C:18]1[CH:27]=[CH:26][C:23]([O:24][CH3:25])=[C:20]([O:21][CH3:22])[CH:19]=1)[CH3:14]
Reactant: O=c1[nH]ncc(Cl)c1NCCCBr
Reactant: CNCCc1ccc(OC)c(OC)c1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(CCN(C)CCCNc2c(Cl)cn[nH]c2=O)cc1OC
Yield: 59.1 %

Procedure:
A mixture of 10.66 g (0.04 mole) of 4-(3-bromopropylamino)-5-chloro-3(2H)-pyridazinone (II), 10.0 g (0.05 mole) of N-methyl-homoveratryl amine (VI) and 8 g of potassium hydrogen carbonate is suspended in 80 cm3 of acetone. The reaction mixture is refluxed for 8 to 12 hours. The reaction is followed by TLC (eluent: ethyl acetate: acetone:triethylamine==10:10:0.5 (II Rf=0.76), (VI Rf=0.14), (I Rf=0.47)). The mixture is filtered while hot, washed with acetone and the mother liquor is evaporated in vacuo. To the residue 50 cm3 of ethyl acetate are added. The possibly separated inorganic substance is filtered off and the filtrate is evaporated again. The residual viscous, oily product (14 to 15 g) is triturated twice with 50 cm3 of hot water in order to remove the unreacted starting substance of the formula (VI). The warm aqueous solution is decanted. The oily residue is dissolved in methanol and dried over magnesium sulfate. Upon adding a small amount of diisopropyl ether and cooling the mixture white porous substance separates. Thus 9 g (59.0%) of crude product are obtained. M.p.: 89-90° C. After recrystallization from diisopropyl ether 7.0 g (46.0%) of the title compound are obtained.
Reaction SMILES: [CH:1]1([CH:4]([NH:10]S(C(C)(C)C)=O)[CH2:5][C:6]([OH:9])([CH3:8])[CH3:7])[CH2:3][CH2:2]1.[ClH:17].O1CCOCC1>CO>[Cl-:17].[CH:1]1([CH:4]([NH3+:10])[CH2:5][C:6]([OH:9])([CH3:8])[CH3:7])[CH2:3][CH2:2]1
Reactant: CC(C)(O)CC(NS(=O)C(C)(C)C)C1CC1
Reactant: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(O)CC([NH3+])C1CC1
Product: [Cl-]
Reaction time: 0.5 h

Procedure:
To a stirred solution of N-(1-cyclopropyl-3-hydroxy-3-methylbutyl)-2-methylpropane-2-sulfinamide (0.56 g, 2.26 mmol) in MeOH (1.2 mL) was added 4 N HCl in dioxane (1.1 mL, 4.4 mmol). The reaction mixture was left to stir for 30 min, concentrated, and dried under high-vacuum to give the title compound. 1H NMR (600 MHz, CD3SOCD3) δ 7.75 (br s, 3H); 2.54 (m, 1H); 1.77 (dd, 1H); 1.65 (dd, 1H); 1.19 (s, 3H); 1.14 (s, 3H); 0.96 (m, 1H); 0.53 (m, 3H); 0.26 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH2:4][CH2:5][C:6]=1[C:7](Cl)=[O:8].[F:10][C:11]1[CH:17]=[CH:16][C:14](N)=[C:13](C2CCCCCCC2)[CH:12]=1.C([N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])C.O>C1(C)C=CC=CC=1>[F:10][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:16][CH2:32][CH:31]([N:28]([C:7]([C:6]2[CH2:5][CH2:4][O:3][C:2]=2[CH3:1])=[O:8])[C:29]2[CH:30]=[CH:5][CH:6]=[CH:2][CH:1]=2)[CH2:17]1
Reactant: CCN(CC)CC
Reactant: CC1=C(C(=O)Cl)CCO1
Reactant: Nc1ccc(F)cc1C1CCCCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1=C(C(=O)N(c2ccccc2)C2CCCCCC(F)C2)CCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 132.8 %

Procedure:
At room temperature, a solution of 1.5 g (0.01 mol) of 2-methyl-4,5-dihydrofuran-3-carbonyl chloride in 10 ml of toluene is added dropwise with stirring to a mixture of 2.2 g (0.01 mol) of 4-fluoro-2-cyclooctylaniline, 1.0 g of triethylamine and 40 ml of toluene. After the addition has ended, the reaction mixture is stirred at room temperature for another 2 hours. The reaction mixture is subsequently admixed with water. The organic phase is separated off, dried over sodium sulphate and then concentrated under reduced pressure. The residue that remains is stirred with hexane. The resulting crystalline product is filtered off with suction and dried at 50° C. under reduced pressure. In this manner, 2.2 g (66.7% of theory) of N-(4-fluoro-2-cyclooctyl)-2-methyl-4,5-dihydrofuran-3-carboxanilide are obtained in the form of a solid substance of melting point 91° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[Cl:29][C:30]1[C:35](Cl)=[N:34][CH:33]=[CH:32][N:31]=1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[Cl:29][C:30]1[C:35]([N:20]2[CH2:21][CH2:22][C:16]3[C:15]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[N:14][C:13]([C:10]4[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=4)=[N:18][C:17]=3[CH2:19]2)=[N:34][CH:33]=[CH:32][N:31]=1
Reactant: Clc1nccnc1Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(c2nccnc2Cl)C3)cc1

Procedure:
1-Ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.0496 g, 0.130 mmol) and 2,3-Dichloropyrazine (0.0204 mL, 0.196 mmol) were combined then added dry N,N-Dimethylformamide (0.910 mL, 11.8 mmol) followed by N,N-Diisopropylethylamine (0.0456 mL, 0.262 mmol). The reaction was microwaved on 200 watts, 120° C. for 30 minutes on a CEM microwave. The reaction mixture was purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.64 (s, 1H), 8.30 (d, J=2.5, 1H), 8.21 (d, J=8.8, 2H), 8.01 (d, J=2.5, 1 H), 7.49 (d, J=8.8, 2H), 6.15 (t, J=5.6, 1H), 4.55 (d, J=15.7, 2H), 3.82-3.63 (m, 6H), 3.56-3.45 (m, 4H), 3.17-3.07 (m, 2H), 2.86 (s, 2H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+495.2 (M+H)+.
Reaction SMILES: C[C:2]1[C:3]([NH2:11])=[C:4]([C:8](O)=[O:9])[S:5][C:6]=1[CH3:7].[NH2:12][C:13](N)=[O:14].[OH-].[Na+]>C(O)(=O)C>[CH3:7][C:6]1[S:5][C:4]2[C:8]([OH:9])=[N:12][C:13]([OH:14])=[N:11][C:3]=2[CH:2]=1
Reactant: Cc1sc(C(=O)O)c(N)c1C
Reactant: NC(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1cc2nc(O)nc(O)c2s1
Temperature: 180 °C
Reaction time: 2.5 h
Yield: 60.3 %

Procedure:
A mixture of methyl 3-amino-5-methylthiophene-2-carboxylic acid (1.2 g) and urea (2.2 g) was stirred at 180° C. for 2.5 h. The mixture was left stand for cooling to room temperature, followed by 1 M aqueous sodium hydroxide (20 mL), the solids were dissolved, and the mixture was neutralized with acetic acid. The precipitated crystals were collected by filtration to obtain 6-methylthieno[3,2-d]pyrimidine-2,4-diol (0.77 g). (2) To a mixture of 6-methylthieno[3,2-d]pyrimidine-2,4-diol (0.77 g) and phosphorus oxychloride (8 mL) was added N,N-dimethylaniline (1.6 mL) at room temperature, and the mixture was stirred at 100° C. for 2 h. The reaction solution was added dropwise to water with ice cooling, and the aqueous layer was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel, chloroform) to obtain 2,4-dichloro-6-methylthieno[3,2-d]pyrimidine (0.50 g).
Reaction SMILES: C([NH:8][C:9]1[C:14]2=[N:15][O:16][N:17]=[C:13]2[CH:12]=[CH:11][C:10]=1[NH:18][C:19]([C:21]([O:23]CC)=O)=[O:20])(C(OCC)=O)=O>Cl>[OH:20][C:19]1[C:21]([OH:23])=[N:8][C:9]2[C:14]3=[N:15][O:16][N:17]=[C:13]3[CH:12]=[CH:11][C:10]=2[N:18]=1
Reactant: CCOC(=O)C(=O)Nc1ccc2nonc2c1NC(=O)C(=O)OCC
Agent: Cl
Product: Oc1nc2ccc3nonc3c2nc1O
Temperature: 0 °C
Yield: 96.6 %

Procedure:
A mixture of 2,5 g (7,1 mmol) 4,5-diethoxalylaminobenzofurazan and 20 ml lN hydrochloric acid was refluxed for 3 h. After cooling to 0° C., the precipitate was filtered off and washed with water to give 1,4 g (97%) 7,8-dihydroxy-1,2,5-oxadiazolo(3,4-f)quinoxaline, m.p.>300° C. NMR (DMSO-d6): 12,8 (lH, broad s), 12.3 (lH, broad s), 7.70 (lH,d), 7.37 (lH,d).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:23]([F:26])([F:25])[F:24])=[N:4][N:5]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.BrN1C(=[O:33])CCC1=O>C(Cl)(Cl)(Cl)Cl.C1C=CC=CC=1>[OH:33][CH2:1][C:2]1[C:3]([C:23]([F:26])([F:24])[F:25])=[N:4][N:5]([C:13]2[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1c(C(F)(F)F)nn(-c2ccc(S(N)(=O)=O)cc2)c1-c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(CO)c2-c2ccccc2)cc1

Procedure:
To a solution of 4-[4-methyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide prepared in Example 201 (500 mg, 1.3 mmol) in carbon tetrachloride (9 mL) and benzene (4 mL) was added N-bromosuccinimide (285 mg, 1.6 mmol). The mixture was irradiated with a sunlamp for 3.5 hours. The reaction mixture was partitioned between dichloromethane and water and the organic solution was dried and concentrated to give the desired product, 412 mg (69%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]([C:14]1[CH:15]=[CH:16][C:17]2[CH2:18][C@H:19]3[N:30]([C:31]([CH:33]4[CH2:35][CH2:34]4)=O)[CH2:29][CH2:28][C@@:25]4([C:26]=2[CH:27]=1)[C@H:20]3[CH2:21][CH2:22][CH2:23][CH2:24]4)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>O1CCCC1>[O:7]([C:14]1[CH:15]=[CH:16][C:17]2[CH2:18][C@H:19]3[N:30]([CH2:31][CH:33]4[CH2:35][CH2:34]4)[CH2:29][CH2:28][C@@:25]4([C:26]=2[CH:27]=1)[C@H:20]3[CH2:21][CH2:22][CH2:23][CH2:24]4)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(C1CC1)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(Oc2ccccc2)cc13
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(Oc2ccc3c(c2)[C@@]24CCCC[C@H]2[C@@H](C3)N(CC2CC2)CC4)cc1
Temperature: 25 °C
Yield: 63.3 %

Procedure:
To a suspension of 0.4 g of lithium aluminum hydride in 20 ml of anhydrous tetrahydrofuran was added dropwise, 4.6 g (0.011 mol) of (-)-3-phenoxy-N-cyclopropylcarbonylmorphinan in 30 ml of anhydrous tetrahydrofuran over a period of 15 minutes. After the mixture had been refluxed under nitrogen for 16 hours, it was cooled to room temperature and water was added dropwise. The resulting suspension was filtered and the filtrate was concentrated. The residue was partitioned between ether and 4 N hydrochloric acid. The acidic phase was made basic with concentrated ammonium hydroxide and the aqueous suspension was extracted with ether. The ether solution was washed with water and dried. Removal of the ether under reduced pressure afforded 2.6 g (59%) of the product (-)-3-phenoxy-N-cyclopropylmethylmorphinan. For analysis, a sample of this compound was distilled, bp 190°-200°/0.1 mmHg, [α]25D-89.07° (c 0.99, MeOH).
Reaction SMILES: [N:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:15]1[N:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:21][C:19]1[CH:18]=[CH:17][N:16]=[C:15]([N:4]2[CH2:3][CH2:2][N:1]([C@H:7]3[CH2:8][CH2:9][C@H:10]([OH:13])[CH2:11][CH2:12]3)[CH2:6][CH2:5]2)[N:20]=1
Reactant: Cc1ccnc(Cl)n1
Reactant: O[C@H]1CC[C@H](N2CCNCC2)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccnc(N2CCN([C@H]3CC[C@H](O)CC3)CC2)n1

Procedure:
The compound 10a (4.3 g, 23.3 mmol) is placed in 100 ml of toluene in the presence of 2-chloro-4-methylpyrimidine (3 g, 23.3 mmol) and of triethylamine (4.9 ml, 35.1 mmol) and then this mixture is heated at reflux for 16 h.