Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CI.[Br:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:7]=[CH:8][C:9]=1[OH:10].[C:16](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:7]=[CH:8][C:9]=1[O:10][CH3:16]
Reactant: COC(=O)Cc1ccc(O)c(Br)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)Cc1ccc(OC)c(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.4 %

Procedure:
Methyl iodide (2.05 mL, 4.68 g, 33 mmol) was added to a mixture of methyl 3-bromo-4-hydroxyphenylethanoate (Description 73, 7.35 g, 30 mmol) and potassium carbonate (8.29 g, 60 mmol) in dimethylformamide (30 mL) and the mixture was stirred at room temperature for 16 h. Water (100 mL) was added and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic fractions were washed with aqueous sodium hydroxide (1M, 2×100 mL), water (2×100 mL) and brine (100 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (7.65 g, 100%). 1H NMR (360 MHz, CDCl3) δ7.47 (1 H, d, J 2.1 Hz), 7.18 (1 H, dd, J 8.4, 2.1 Hz), 6.85 (1 H, d, J 8.4 Hz), 3.88 (3 H, s), 3.70 (3 H, s), and 3.49 (2 H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[N:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:20]([CH3:32])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:33][CH3:34])(=[O:10])=[O:9])=[C:4]([Cl:35])[CH:3]=1.[CH3:36][C:37]1[S:41][C:40](B(O)O)=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C(OCC)(=O)C>[Cl:35][C:4]1[CH:3]=[C:2]([C:40]2[S:41][C:37]([CH3:36])=[CH:38][CH:39]=2)[CH:7]=[CH:6][C:5]=1[S:8]([NH:11][C:12]1[N:17]=[C:16]([N:18]2[CH2:23][C@H:22]([CH3:24])[N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:20]([CH3:32])[CH2:19]2)[CH:15]=[CH:14][C:13]=1[O:33][CH3:34])(=[O:10])=[O:9]
Reactant: Cc1ccc(B(O)O)s1
Reactant: COc1ccc(N2C[C@@H](C)N(C(=O)OC(C)(C)C)[C@@H](C)C2)nc1NS(=O)(=O)c1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COc1ccc(N2C[C@@H](C)N(C(=O)OC(C)(C)C)[C@@H](C)C2)nc1NS(=O)(=O)c1ccc(-c2ccc(C)s2)cc1Cl
Yield: 85.8 %

Procedure:
1,1-Dimethylethyl (2R,6S)-4-[6-{[(4-bromo-2-chlorophenyl)sulfonyl]amino}-5-(methyloxy)-2-pyridinyl]-2,6-dimethyl-1-piperazinecarboxylate (D13) (0.10 g, 0.169 mmol), 5-methylthiophen-2-boronic acid (0.0739 g, 0.254 mmol), Palladium dichloride di-triphenylphosphine (5.9 mg, 0.0127 mmol), sodium carbonate (0.0359 g, 0.339 mmol) were heated in DME (1 mL) and water (0.5 mL) at 120° C. in the microwave for 20 minutes. The reaction was then diluted with ethyl acetate (50 mL) and washed with saturated sodium hydrogen carbonate (2×30 mL) and brine (30 mL). The organic layer was dried (MgSO4) and evaporated to give a yellow foam which was purified by chromatography [silica gel, eluting with 0 to 70% Ethyl acetate/pentane]. Product fractions evaporated to give a pale yellow oil (D16) (0.088 g) MS (ES+) m/e 607/609 [M+H]+.
Reaction SMILES: Cl[CH:2]([CH3:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)=[O:4].Cl.[CH3:17][NH:18][CH3:19].C([O-])([O-])=O.[K+].[K+].O>CC#N>[CH3:17][N:18]([CH3:19])[CH:2]([CH3:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)=[O:4]
Reactant: CNC
Reactant: CC(=O)Nc1ccc(C(=O)C(C)Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(=O)Nc1ccc(C(=O)C(C)N(C)C)cc1
Yield: 89.3 %

Procedure:
A mixture of N-[4-(2-chloro-1-oxopropyl)phenyl]acetamide (0.19 mol), N-methyl-methanamine hydrochloride (1:1)(0.38 mol) and K2CO3 (78.8 g) in CH3CN (1400 ml) was stirred and refluxed for 12 hours. The mixture was cooled, poured into water and extracted with CH2Cl2. The organic layer was dried, filtered and the solvent was evaporated, yielding 39.77 g (89%) of (±)—N-[4-[2-(dimethylamino)-1-oxopropyl]phenyl]-acetamide (interm. 9).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3](=[O:11])[C:2]1=[O:12].[S:13](=O)(=[O:16])([OH:15])[OH:14]>>[O:12]=[C:2]1[C:3](=[O:11])[NH:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([S:13]([OH:16])(=[O:15])=[O:14])[CH:6]=2)[NH:1]1
Reactant: O=c1[nH]c2ccccc2[nH]c1=O
Reactant: O=S(=O)(O)O
Product: O=c1[nH]c2ccc(S(=O)(=O)O)cc2[nH]c1=O
Reaction time: 0.5 h

Procedure:
2,3(1H, 4H)-Quinoxalinedione (10 g) was added portionwise to a stirred mixture of 65% fuming sulphuric acid (10 ml) and conc. sulphuric acid (40 ml) at room temperature. After stirring for 30 minutes at 55°-60°, the mixture was worked up as in example 1 to give the hydrated crystalline product (15.3 g, mp. >300°).
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)=[O:7])=[CH:4][CH:3]=1.[CH2:27]([C:31]1[CH:36]=[CH:35][C:34]([C@H:37](O)[CH2:38][CH2:39][CH3:40])=[CH:33][CH:32]=1)[CH:28]([CH3:30])[CH3:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C1(C)C=CC=CC=1.C(O)(=O)C>[CH2:27]([C:31]1[CH:32]=[CH:33][C:34]([C@@H:37]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([C:8]3[CH:9]=[C:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:11]4[C:16]=3[CH:15]=[CH:14][CH:13]=[CH:12]4)=[O:7])=[CH:25][CH:26]=2)[CH2:38][CH2:39][CH3:40])=[CH:35][CH:36]=1)[CH:28]([CH3:30])[CH3:29]
Reactant: CCOC(=O)CCCc1cc(C(=O)c2ccc(O)cc2)c2ccccn12
Reactant: CCC[C@@H](O)c1ccc(CC(C)C)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCC[C@H](Oc1ccc(C(=O)c2cc(CCCC(=O)OCC)n3ccccc23)cc1)c1ccc(CC(C)C)cc1
Temperature: -20 °C
Reaction time: 2.5 h
Yield: 49 %

Procedure:
To a mixture of ethyl 4-[1-(4-hydroxybenzoyl)indolizin- 3-yl]butyrate (392 mg), (R)-1-(4-isobutylphenyl)butan-1-ol (230 mg) and triphenylphosphine (292 mg) in tetrahydrofuran (3 ml) and toluene (15 ml) was added diethyl azodicarboxylate (0.178 ml) at -20° C. under nitrogen atmosphere. After the mixture was stirred at -20° C. under nitrogen for 2.5 hours, acetic acid (0.05 ml) was added and the mixture was warmed up to room temperature. The solvent was evaporated under reduced pressure and the residue was poured into a mixture of ethyl acetate and water. The organic phase was separated, washed with water and brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel column eluting with a mixture of n-hexane and ethyl acetate (4:1) to give ethyl 4-[1-[4-[(S)-1-(4-isobutylphenyl)butoxy]benzoyl]indolizin-3-yl]butyrate (295 mg) as an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]1(=[O:14])[O:13][C:11](=[O:12])[CH2:10][C:8]1=[CH2:9]>>[N:1]1([C:11](=[O:12])[CH2:10][C:8](=[CH2:9])[C:7]([OH:14])=[O:13])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: C=C1CC(=O)OC1=O
Product: C=C(CC(=O)N1CCOCC1)C(=O)O
Temperature: 25 °C

Procedure:
Morpholine (20 mL, 228.6 mmol) was slowly added to a stirring solution of itaconic anhydride (25.1 g, 228.6 mmol) suspended in dichloromethyl at 0° C. The reaction mixture was allowed to slowly warm to room temperature. Upon completion (LCMS), volatiles were removed by vacuum under reduced pressure. Crude yield: 44.96 g, 99%. Product was used without further purification.
Reaction SMILES: C[CH2:2][CH:3]([OH:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:20]CCC(O)CCCCCCCCCCCCCC.CCCCC(O)CCCCCCCCCCCCC>>[CH3:2][CH:3]([OH:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:20]
Reactant: CCCCCCCCCCCCCCCC(O)CC
Reactant: CCCCCCCCCCCCCCC(O)CCC
Agent: CCCCCCCCCCCCCC(O)CCCC
Product: CCCCCCCCCCCCCCCCC(C)O

Procedure:
3-octadecanol; 4-octadecanol; 5-octadecanol;
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:13][C:14]([CH3:16])=[O:15].[OH-:17].[Na+]>CCO>[C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[CH:13]/[C:14](=[O:15])/[CH:16]=[CH:9]/[C:8]2[CH:11]=[CH:12][C:5]([NH:4][C:1](=[O:17])[CH3:2])=[CH:6][CH:7]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C=O)cc1
Reactant: CC(C)=O
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)Nc1ccc(/C=C/C(=O)/C=C/c2ccc(NC(C)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53 %

Procedure:
A mixture of p-acetamidobenzaldehyde (8.15 g, 50 mmol) dissolved in 200 mL of hot EtOH) and acetone (1.8 mL, 25 mmol) was added dropwise to a solution of aq. NaOH solution (2 N, 25 mL) in EtOH (150 mL). The reaction mixture was stirred for 4 h at ambient temperature and the resulting orange precipitate was filtered, washed with water and dried in vacuo to afford NW270 as a bright yellow solid (4.6 g, 53%). mp: 253-255° C. 1H NMR (250 MHz, DMSO-d6) δ (ppm): 10.18 (s, 2H, NH), 7.81-7.58 (m, 10H, HAr, Hvin), 7.22 (d, 3J=16.0 Hz, 2H, Hvin), 2.08 (s, 6H, CH3). 13C NMR (75 MHz, DMSO-d6) δ (ppm): 188.2 (C), 168.6 (C), 142.1 (CH), 141.4 (C), 129.4 (CH), 124.1 (CH), 118.9 (CH), 24.1 (CH3). MS (EI) m/z: 348.2 (M+). Anal. calcd for C21H20N2O3: C, 72.40; H, 5.79; N, 8.04. Found: C, 72.14; H, 5.78; N, 7.97%.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:12]1([CH3:35])[CH:17]=[CH:16][C:15]([S:18](OCC2C([N+]([O-])=O)=CC=CC=2[N+]([O-])=O)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C1(S(C(S(C2CCCCC2)(=O)=O)=[N+]=[N-])(=O)=O)CCCCC1>>[CH3:3][C:2]([S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:35])=[CH:13][CH:14]=1)(=[O:20])=[O:19])([CH3:4])[C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: Cc1ccc(S(=O)(=O)OCc2c([N+](=O)[O-])cccc2[N+](=O)[O-])cc1
Reactant: CC(C)C(=O)c1ccccc1
Agent: [N-]=[N+]=C(S(=O)(=O)C1CCCCC1)S(=O)(=O)C1CCCCC1
Product: Cc1ccc(S(=O)(=O)C(C)(C)C(=O)c2ccccc2)cc1

Procedure:
Using isobutyrophenone, the reaction was carried out in the same manner as described in Synthesis Example 9, (2) and (3), the crude solid was recrystallized from methanol to afford 2-methyl-2-(p-toluenesulfonyl)propiophenone as a white needles.
Reaction SMILES: [C:1]1([S:7]([NH:10][CH2:11][CH2:12][N:13]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]3[CH2:22][CH2:23][N:24](C(OC(C)(C)C)=O)[CH2:25][CH2:26][C:14]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(C(O)=O)(F)(F)F.C(Cl)[Cl:42]>>[ClH:42].[CH2:22]1[C:15]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[N:13]([CH2:12][CH2:11][NH:10][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:8])=[O:9])[C:14]=2[CH2:26][CH2:25][NH:24][CH2:23]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCNS(=O)(=O)c3ccccc3)c3ccccc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=S(=O)(NCCn1c2c(c3ccccc31)CCNCC2)c1ccccc1
Reaction time: 2 h
Yield: 90 %

Procedure:
tert-Butyl 6-{2-[(phenylsulfonyl)amino]ethyl}-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.0430 g, 0.0916 mmol) was dissolved in CH2Cl2 (2 mL) at rt. CF3CO2H (1 mL) was added, then the reaction mixture was stirred for 2 h. The reaction mixture was concentrated and the residue was taken up in EtOAc (2 mL). HCl in Et2O (1N) (2 mL) was added and the precipitated salt was collected by filtration. N-[2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethyl]benzenesulfonamide hydrochloride (0.0335 g) was obtained in 90% yield. 1H NMR (300 MHz, CD3OD) δ 3.16, 3.19-3.23, 3.37-3.41, 3.44-3.47, 3.53-3.57, 4.34, 7.08, 7.15, 7.32, 7.49, 7.52, 7.61, 7.77; MS (ESI+) for C20H23N3O2S m/z 370.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[CH3:12]OC(OC)N(C)C.C(N)=O.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>C1(C)C=CC=CC=1>[F:10][C:8]([F:11])([F:9])[C:6]1[CH:5]=[CH:4][N:3]2[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:12][N:1]=[C:2]2[N:7]=1
Reactant: Nc1nccc(C(F)(F)F)n1
Reactant: CCOC(=O)CBr
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Solvent: NC=O
Product: CCOC(=O)c1cnc2nc(C(F)(F)F)ccn12
Yield: 63.6 %

Procedure:
A mixture of 2-amino-4-trifluoromethylpyrimidine (2.0 g, 12.2 mmol) and N,N-dimethylformamide dimethyl acetal (1.79 ml, 13.5 mmol) in toluene (50 ml) was heated at reflux for 1 h and then concentrated under reduced pressure. The resulting formamide was treated with ethyl bromoacetate (1.49 ml, 13.4 mmol) in toluene (60 ml) at reflux for 12 h and then concentrated under reduced pressure. The product was treated with saturated sodium hydrogencarbonate solution (50 ml) and extracted with EtOAc (3×50 ml). The combined organic extracts were washed with brine (50 ml), dried (MgSO4) and then concentrated while dry loading onto silica. Subsequent purification by column chromatography on silica using diethyl ether gave ethyl 7-trifluoromethylimidazo[1,2-α]pyrimidine-3-carboxylate (2.01 g, 64%): δH (360 MHz, CDCl3) δ 1.45 (3H, t, J 7.1), 4.47 (2H, q, J 7.1), 7.44 (1H, d, J 7.1), 8.60 (1H, s), 9.77 (1H, d, J 7.1); m/z (ES+) 347 (M++H).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[CH2:15]([O:22][CH:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:24][NH2:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:25][CH2:24][CH:23]([O:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)#[N:2]
Reactant: NCC(OCc1ccccc1)c1ccccc1
Reactant: CC(C)OC(=NC#N)c1cccnc1
Solvent: CO
Product: N#CNC(=NCC(OCc1ccccc1)c1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.6 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.20 g, 1.1 mmol) was dissolved in methanol (5 ml), and 2-benzyloxy-2-phenylethylamine (0.26 g, 1.1 mmol) was added. The mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate thus obtained was subjected to chromatography on a silica gel column (WAKO GEL C-200, 20 g) eluting with chloroform-methanol (100:1). The eluted fractions were concentrated under reduced pressure to give N-cyano N'-(2 benzyloxy-2-phenylethyl)-3-pyridinecarboximidamide (0.24 g, 0.7 mmol, yield: 64%) as colorless syrup. Next, to this syrup was added a 5% hydrogen chloride in methanol (2 ml). The solution was crystallized from methanol-diethyl ether to give N-cyano-N'-(2-benzyloxy-2-phenylethyl)-3-pyridinecarboximidamide hydrochloride as colorless powder.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[N:12]=[C:11]([C:13]#[N:14])[C:10]([OH:15])=[N:9][CH:8]=1.[OH-:16].[Na+]>O>[F:6][C:7]1[N:12]=[C:11]([C:13]([NH2:14])=[O:16])[C:10]([OH:15])=[N:9][CH:8]=1
Reactant: N#Cc1nc(F)cnc1O
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: NC(=O)c1nc(F)cnc1O
Temperature: 50 °C
Reaction time: 4 h
Yield: 92.3 %

Procedure:
14.39 g of concentrated sulfuric acid was added to 3.45 g of the oily 6-fluoro-3-hydroxypyrazine-2-carbonitrile, and the resulting mixture was stirred at 50° C. for 4 hours. The reaction mixture was then added dropwise over a period of 20 minutes to 44.5 ml of water that had been cooled to 3° C. Following completion of the dropwise addition, the resulting mixture was stirred for 20 minutes at a temperature of not more than 10° C. Subsequently, 10.17 g of a 28% aqueous solution of sodium hydroxide was added dropwise to the reaction mixture over a period of 15 minutes. Following completion of the dropwise addition, the mixture was stirred at the same temperature for 30 minutes. The solid product was then filtered off, and washed with 18 ml of water, yielding 2.22 g (yield: 92.3%) of 6-fluoro-3-hydroxypyrazine-2-carboxamide.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][S:8]2)[CH:2]=1.[OH:13]O>ClCCl.C(O)C.CC(O)=CC(C)=O.CC(O)=CC(C)=O.[Cu]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][S@:8]2=[O:13])[CH:2]=1
Reactant: OO
Reactant: c1cncc([C@@H]2CCCCS2)c1
Agent: [Cu]
Agent: CC(=O)C=C(C)O
Solvent: ClCCl
Solvent: CCO
Product: O=[S@@]1CCCC[C@H]1c1cccnc1
Reaction time: 7 h

Procedure:
A solution of (S)-2-(3-pyridyl)tetrahydro-2H-thiopyran (1.5 g) in dichloromethane (15 ml) is treated with ethanol (15 ml), followed by copper acetylacetonate (0.22 g). The green-blue solution is treated with a solution of hydrogen peroxide (2 ml; 27.5%) in ethanol (2 ml). After 2 hours the solution is treated with a further quantity of solution of hydrogen peroxide (1 ml; 27.5%) in ethanol (1 ml), followed by a similar further quantity each hour for seven hours. Thus, a total of 10 ml of 27.5% hydrogen peroxide is used. After a further period of four hours, the mixture is treated with dichloromethane (10 ml) and extracted with water (4×25 ml). The combined aqueous extract is treated with sodium ethylenediaminetetraacetate (0.5 g), followed by sufficient solid sodium chloride to form a saturated solution. This is then extracted with dichloromethane (4×50 ml), and the combined organic extract is dried over magnesium sulphate and evaporated, to give (1R,2S)-2-(3-pyridyl)tetrahydro-2H-thiopyran 1-oxide (1.1 g), in the form of a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][C:20](=[O:27])[N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:35][O:36][CH2:37][CH:38]([NH2:40])[CH3:39]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:40][CH:38]([CH3:39])[CH2:37][O:36][CH3:35])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][C:20](=[O:27])[N:21]3[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]3)=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: COCC(C)N
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCCC2)c1=O
Product: COCC(C)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCCC2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-oxo-2-(1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (±)-1-(methyloxy)-2-propanamine employing methods similar to those those described in Example 9 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as an off-white rigid foam: 1H NMR (CDCl3) δ 10.07 (1H, d, J=8 Hz), 8.55 (1H, s), 7.16 (2H, dd, J=9, 6 Hz), 7.03 (2H, t, J=9 Hz), 6.93 (1H, s), 4.97 (1H, d, J=17 Hz), 4.90 (1H, d, J=17 Hz), 4.34 (1H, m), 4.11 (2H, s), 3.50 (2H, m), 3.44 (4H, m), 3.38 (3H, s), 1.69 (2H, m), 1.57 (2H, m), 1.52 (2H, m), 1.28 (3H, d, J=7 Hz); HRMS calcd for C27H31FN4O5+H+: 511.2357. Found: 511.2162.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]([CH2:9][CH2:10][C:11]#[N:12])=[C:6]([NH2:8])[NH2:7])[CH3:2].[H-].[Na+]>O1CCCC1>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH2:9][CH2:10][C:11]([NH2:12])=[N:8][C:6]=1[NH2:7])[CH3:2]
Reactant: CCOC(=O)C(CCC#N)=C(N)N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(N)N=C(N)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 33.3 %

Procedure:
A tetrahydrofuran (7 mL) solution of 2-(2-cyanoethyl)3,3-diaminopropenoic acid ethyl ester (0.55 g, 3 mmol) described in Production Example 1-1-1 was dropped into a tetrahydrofuran (7 mL) suspension of sodium hydride (208 mg, 5.2 mmol, 60% in oil), which was refluxed while heating and stirring for 19 hours 20 minutes. Following completion of the reaction, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated to obtain the title compound (0.188 g, 1 mmol, 34%) as a crude product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH3:12][C:13]1[CH:14]=[N:15][NH:16][CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+].C(=NO)C1C(=CC=CC=1)O>ClCCl.C(#N)C>[CH3:12][C:13]1[CH:14]=[N:15][N:16]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=2)[CH:17]=1
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Reactant: Cc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cnn(-c2ccc(C)c([N+](=O)[O-])c2)c1
Temperature: 80 °C
Yield: 60 %

Procedure:
A dried flask under nitrogen was charged with 4-bromo-1-methyl-2-nitro-benzene (40 mmol), 4-methylpyrazole (20 mmol), Cs2CO3 (13 g), Cu2O (290 mg, 2 mmol), salicylaldoxime (1.1 g, 8 mmol) and 12 mL of acetonitrile. The mixture was heated at 80° C. for 24 h. The reaction mixture was cooled to room temperature, diluted with dichloromethane and filtered through celite. The filtrate was washed with water, dried and concentrated under reduced pressure. Column chromatography on silica gel (DCM/Hexane 30-100%) gave 4-methyl-1-(4-Methyl-3-nitro-phenyl)-1H-pyrazole as a yellow solid (60% yield).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[C:28]([Cl:29])=[C:27]([CH3:30])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)[N:19]=1>>[N:21]1[CH:22]=[CH:23][N:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:15]2[C:28]([Cl:29])=[C:27]([CH3:30])[S:26][C:16]=2[N:17]=1
Reactant: Cc1sc2nc(-c3cnccn3)nc(Cl)c2c1Cl
Reactant: NCCc1ccc2c(c1)OCO2
Product: Cc1sc2nc(-c3cnccn3)nc(NCCc3ccc4c(c3)OCO4)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyrazin-2-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-methylenedioxyphenethylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][OH:5].Cl[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]>O1CCOCC1>[CH2:13]([O:12][C:10]([NH:1][C@H:2]([CH2:3][CH2:4][OH:5])[C:6]([OH:8])=[O:7])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N[C@@H](CCO)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1COCCO1
Product: O=C(N[C@H](CCO)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice-cooled solution of H-Hse-OH (5 g) in dioxane/2M NaOH (168 mL/42 mL) was added benzyl chloroformate (6.7 mL) dropwise over 15 min. The reaction mixture was allowed to warm to RT and was stirred overnight at RT. The solvent was evaporated off and the aq. residue was extracted with Et2O and acidified with a 2M HCl solution. The aq. phase was extracted with DCM. The DCM layers were combined, washed with water, dried (Na2SO4) and evaporated off to give the desired product as a white powder (6.2 g).
Reaction SMILES: [CH:1]12[CH2:15][CH2:14][O:13][C:12]1([O:16]O)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2.C12CCOC=1CCCCCCCCCC2>>[C:12]1(=[O:16])[O:13][CH2:14][CH2:15][CH:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: OOC12CCCCCCCCCCC1CCO2
Agent: C1CCCCCC2=C(CCCC1)CCO2
Agent: O=C1CCCCCCCCC/C=C\CCO1
Product: O=C1CCCCCCCCCC=CCCO1

Procedure:
The 13-oxabicyclo[10.3.0]pentadecan-12-yl hydroperoxide used as stain product is a novel compound which was prepared from 13-oxabicyclo[10.3.0]pentadec-1(12)-ene having the following characteristics: