Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(#N)C>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:9])[CH:4]=1)[CH3:22]
Reactant: Oc1ccc(Cl)c(F)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)COc1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.2 %

Procedure:
To a solution of 4-chloro-3-fluoro-phenol (0.50 g, 3.34 mmol) in acetonitrile (8 ml) were added caesium carbonate (1.31 g, 4.01 mmol) and ethyl bromoacetate (0.40 ml, 3.51 mmol). The resulting suspension was stirred at room temperature for 1 hour and was then poured onto ice/aq. ammonium chloride solution (50 ml) and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (SiO2: heptane/ethyl acetate=gradient 100:0-70:30) to yield a colourless oil (0.81 g, 100%); 1H NMR (300 MHz, CDCl3): 7.30 (1H, d), 6.73 (1H, dd), 6.66 (1H, dd), 4.59 (2H, s), 4.28 (2H, q), 1.30 (3H, t).
Reaction SMILES: [Cl:1][C:2]1[N:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]([CH3:19])[CH2:17][C:16](=[O:20])[NH:15][N:14]=2)=[CH:9][C:8]=1[OH:21])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(=O)C>O>[Cl:1][C:2]1[C:3]([C:4]2[O:21][C:8]3[CH:9]=[C:10]([C:13]4[CH:18]([CH3:19])[CH2:17][C:16](=[O:20])[NH:15][N:14]=4)[CH:11]=[CH:12][C:7]=3[N:6]=2)=[CH:22][CH:23]=[C:24]([Cl:26])[N:25]=1
Reactant: CC1CC(=O)NN=C1c1ccc(NC(=O)c2ccc(Cl)nc2Cl)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(=O)O
Product: CC1CC(=O)NN=C1c1ccc2nc(-c3ccc(Cl)nc3Cl)oc2c1

Procedure:
5.8 g (0.015 mol) 2,6-dichloro-N-[2-hydroxy-4-(4-methyl-6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenyl]-nicotinamide, 0.6 g para-toluenesulphonic acid and 60 ml glacial acetic acid are refluxed together for 15 h, then 40 ml glacial acetic acid are eliminated in vacuo and the residue is mixed with water. The precipitate formed is filtered off, washed with ethanol and then recrystallised from dioxane/DMF.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[CH:16]=O)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[OH:18][C@@H:19]1[CH2:23][NH:22][C@H:21]([C:24](O)=O)[CH2:20]1.[CH3:27][N:28]1[C:32](=[O:33])C=[CH:30][C:29]1=[O:34]>CC#N>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[CH:16]3[N:22]4[CH:21]([CH2:20][CH:19]([OH:18])[CH2:23]4)[CH:24]4[C:32](=[O:33])[N:28]([CH3:27])[C:29](=[O:34])[C@H:30]34)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1C[C@H](O)CN1
Reactant: O=C/C=C/c1ccc(-c2cccc(F)c2)cn1
Reactant: CN1C(=O)C=CC1=O
Solvent: CC#N
Product: CN1C(=O)C2C3CC(O)CN3C(/C=C/c3ccc(-c4cccc(F)c4)cn3)[C@H]2C1=O

Procedure:
A mixture of 100 mg of (E)-3-[5-(3-fluorophenyl)pyridin-2-yl]propenal, 64 mg of (2S,4S)-4-hydroxypyrrolidine-2-carboxylic acid, 54 mg of N-methylmaleimide and 4 ml of MeCN is heated at the boil for 4 h. The volatile components are removed under reduced pressure and the residue is purified by column chromatography (silica gel, MeOH:DCM=5:95). In this manner, 4 pure fractions are isolated as racemic mixtures.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.I[CH2:30][CH:31]([CH3:33])[CH3:32]>C1(C)C=CC=CC=1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.[Ag-]=O>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][CH:19]([CH2:22][O:23][CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:20][OH:21])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)CI
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(CO)CO
Agent: O=[Ag-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: Cc1ccccc1
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(CO)COCC(C)C
Temperature: 40 °C
Reaction time: 8 h

Procedure:
250 mg (0.64 mmol) of 8-[(2,6-difluorobenzyl)oxy]-N-(1,3-dihydroxy-propan-2-yl)-2-methylimidazo[1,2-a]pyridine-3-carboxamide and 4.94 g (26.83 mmol) of 1-iodo-2-methylpropane were initially charged in dry toluene, 1.87 g (7.66 mmol) of silver(I) oxide and 118 mg (0.32 mmol) of tetra-n-butylammonium iodide were added and the mixture was stirred at 40° C. overnight. The reaction mixture was filtered through Celite, the filter cake was washed thoroughly, the filtrate was concentrated and the residue was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The crude product was then purified by preparative thick-layer chromatography (mobile phase: dichloromethane:methanol=20:1). This gave 13 mg of the target compound (4.5% of theory, purity 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Cl:9][C:10]1[S:11][C:12]([CH2:15]Cl)=[CH:13][CH:14]=1>C(#N)C>[ClH:9].[Cl:9][C:10]1[S:11][C:12]([CH2:15][N:3]2[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]2=[NH:1])=[CH:13][CH:14]=1
Reactant: Cc1ccc(N)nc1
Reactant: ClCc1ccc(Cl)s1
Solvent: CC#N
Product: Cc1ccc(=N)n(Cc2ccc(Cl)s2)c1
Product: Cl
Temperature: 60 °C
Reaction time: 18 h
Yield: 38.8 %

Procedure:
3.2 g (0.03 mol) of 2-amino-5-methylpyridine are dissolved in 100 ml of acetonitrile, and 5 g (0.03 mol) of 2-chloro-5-chloromethylthiophene are added. The mixture is stirred for 8 hours at 60° C. and for 18 hours at room temperature. The solid which has formed is filtered off with suction and dried. 1.6 g (20% of theory) of N-(5-chlorothien-2-yl-methyl)-5-methyl-2-iminopyridine hydrochloride of melting point 208° C. are obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[N:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH2:25])=[CH:20][CH:19]=1.O>CC(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:25][CH2:24][C:21]2[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=2)[CH:7]=1
Reactant: NCc1ccncc1
Reactant: Clc1cc(Cl)ncn1
Solvent: O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc(NCc2ccncc2)ncn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
To a solution of 4,6-dichloro-pyrimidine (1.5 g, 10.5 mmol) and DIPEA (1.62 g, 12.6 mmol) in iPrOH (40 mL) was added 4-pyridinylmethanamine (1.2 g, 11 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. Water was added and the mixture was extracted with DCM. The combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated to give the crude product, which was purified by flash chromatography on silica to obtain the title compound (1.8 g, yield: 80%). MS (ESI): 221 [M+H]+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C([O:13][C@H:14]1[CH2:17][C@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:15]1)(=O)C1C=CC=CC=1.S(=O)(=O)(O)O>C(OC(=O)C)(=O)C>[N+:1]([C:21]1[CH:22]=[CH:23][C:18]([C@H:16]2[CH2:15][C@H:14]([OH:13])[CH2:17]2)=[CH:19][CH:20]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: O=C(O[C@H]1C[C@H](c2ccccc2)C1)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1ccc([C@H]2C[C@H](O)C2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 56 %

Procedure:
To a mixture of nitric acid (fuming, 2.3 mL) and acetic anhydride (25 mL) was added dropwise a mixture of trans-3-phenylcyclobutyl benzoate (step 2, 3.7 g, 24.6 mmol) and sulfuric acid in acetic anhydride (25 mL) at −23° C. The resulting mixture was stirred in an ice-bath for 1.5 h. The mixture was poured into ice water (200 mL) and extracted with dichloromethane (2×100 mL). The organic layer was washed with water and brine (100 mL), then dried (Na2SO4), and concentrated. The oily residue was dissolved in methanol (100 mL), and 4N aqueous LiOH (50 mL) was added. The resulting mixture was stirred at room temperature for 10 min, then concentrated. The residue was dissolved in water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine, dried (Na2SO4), and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (2:1) to afford 2.7 g (56%) of the title compound as a pale yellow oil: MS (EI) m/z 193 (M+); 1H-NMR (CDCl3) δ 8.18 (2H, d, J=8.6 Hz), 7.38 (2H, d, J=8.6 Hz), 4.62–4.52 (1H, m), 3.81–3.71 (1H, m), 2.54–2.45 (4H, m).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:22][CH3:23])=[C:7]([O:20][CH3:21])[CH:8]=2)[N:3]=1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([CH2:37][CH2:38][CH2:39][NH2:40])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.CCOC(C)=O>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([CH2:37][CH2:38][CH2:39][NH:40][C:2]2[C:11]([CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][C:9]3[C:4](=[CH:5][C:6]([O:22][CH3:23])=[C:7]([O:20][CH3:21])[CH:8]=3)[N:3]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCN)CC1
Reactant: COc1cc2nc(Cl)c(C=Cc3ccccc3)nc2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1cc2nc(C=Cc3ccccc3)c(NCCCC3CCN(C(=O)OC(C)(C)C)CC3)nc2cc1OC
Temperature: 25 °C

Procedure:
A mixture 2-chloro-6,7-dimethoxy-3-styryl-quinoxaline (see Kadin, S. B., Ger Offen., DE 2357186; 255 mg, 0.78 mmol), 4-(3-amino-propyl)-piperidine-1-carboxylic acid tert-butyl ester (see Egbertson, M, U.S. Pat. No. 5494921; 392 mg, 1.6 mmol) and potassium carbonate (220 mg, 1.6 mmol) was heated at 120° C. in DMSO (2 mL) for 17 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with sat'd aq NaHCO3, sat'd aq NaCl, dried and concentrated under vacuum. The crude residue was chromatographed on SiO2-gel to give 150 mg of a yellow oil. API-MS: 533 (M+1). 1H NMR (300 MHz, CDCl3): d 7.75 (d, 1 H), 7.58 (d, 1 H), 7.35 (m), 7.15 (d, 1 H), 4.05 (m), 3.99 (s, 3 H), 3.97 (s, 3 H), 3.54 (bs, 1 H), 2.68 (t, 2 H),1.75 (m), 1.42 (s, 9 H), 1.1 (m).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17]([C:19]1[NH:20][C:21]2[CH2:22][CH2:23][CH2:24][CH2:25][C:26]=2[C:27]=1[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=O>N1CCCCC1.C(O)C>[O:16]=[C:12]1[C:11](=[CH:17][C:19]2[NH:20][C:21]3[CH2:22][CH2:23][CH2:24][CH2:25][C:26]=3[C:27]=2[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:10]2[C:14](=[CH:15][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)[NH:13]1
Reactant: O=Cc1[nH]c2c(c1CCC(=O)O)CCCC2
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C(O)CCc1c(C=C2C(=O)Nc3cc(-c4ccccc4)ccc32)[nH]c2c1CCCC2
Reaction time: 4 h
Yield: 33.3 %

Procedure:
A mixture of 90 mg 6-phenyl-2-oxindole, 95 mg 3-(2-formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid and piperidine ( 3 drops) in ethanol (2 mL) was held in a sealed tube at 90° C. for 4 hrs. The reaction mixture was concentrated and acidified with 6 N hydrochloric acid. The precipitate was collected by filtration and washed with water and hexane to give 59 mg of 3-[2-(2-oxo-6-phenyl-1,2-dihydro-indol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3yl]-propionic acid as a brown solid (31% yield).
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4]([CH3:6])=[O:5].O1CCCC1.[H-].[Na+].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1>O.C(Cl)Cl>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][CH:3]([S:4]([CH3:6])=[O:5])[S:2][CH3:1])=[CH:18][CH:17]=1
Reactant: COc1ccc(CBr)cc1
Reactant: CSCS(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(CC(SC)S(C)=O)cc1
Reaction time: 1 h
Yield: 50.3 %

Procedure:
1.175 g of methyl methylthiomethyl sulfoxide was dissolved in 5 ml. of tetrahydrofuran, and under cooling with ice, 0.965 g (one equivalent) of sodium hydride was added. The mixture was then stirred for 1 hour. 1.93 g of p-methoxybenzyl bromide (1 equivalent) was added, and the mixture was stirred for 22 hours at room temperature, followed by addition of 40 ml. of methylene chloride and 2 ml. of water. The reaction mixture was dried with sodium sulfate anhydride, and concentrated at reduced pressure. The residue was subjected to column chromatography (silica gel, methylene chloride) to give 1.163 g of methyl 2-(p-methoxyphenyl)-1-methylthioethyl sulfoxide in a conversion yield of 79.1%.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.C[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1C=NC1CCCCC1.Cl.[CH2:27]1COCC1>>[CH3:27][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH:12]=[O:11])=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:5][CH:4]=1
Reactant: COc1ccccc1C=NC1CCCCC1
Reactant: Cc1ccc(Br)cc1
Reactant: C1CCOC1
Agent: Cl
Agent: [Mg]
Product: Cc1ccc(-c2ccccc2C=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51 %

Procedure:
To a suspension of magnesium metal (1.1 g) in THF (3 ml) was added dropwise a solution of 4-bromotoluene (7.5 g) in THF (10 ml) under gentle reflux. The resulting solution of the Grignard reagent was added dropwise to an ice-cooled, stirred solution of N-(2-methoxyphenyl)methylidenecyclohexylamine (4.3 g) in THF (30 ml). The reaction mixture was stirred at room temperature for 1.5 hours, followed by heating under reflux for 7 hours. After addition of ice-water, the reaction mixture was acidified with conc. hydrochloric acid. The reaction mixture was extracted with ethyl acetate and the extract was washed with 1N-hydrochloric acid and water, dried and evaporated to dryness. The residue was purified by column chromatography on silica gel to give pale yellow syrup (2.0 g, 51%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]([CH3:26])[CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[O:17])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:27][C:28]([C:30]1([C:33]([OH:35])=O)[CH2:32][CH2:31]1)=[O:29].[NH2:36][C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]([CH3:26])[CH:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)=[O:17])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:27][C:28]([C:30]1([C:33]([NH:36][C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)=[O:35])[CH2:31][CH2:32]1)=[O:29]
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)O)CC4)c(F)c3)ccn2)CC1
Reactant: Nc1cccnc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5cccnc5)CC4)c(F)c3)ccn2)CC1
Reaction time: 30 h
Yield: 31.8 %

Procedure:
To a solution of 1-(2-fluoro-4-{2-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyridin-4-yloxy}phenyl)carbamoylcyclopropanecarboxylic acid (40 mg) in N,N-dimethylformamide (1.0 ml) were added 3-aminopyridine (15.5 mg), triethylamine (0.023 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (72.9 mg) at room temperature, followed by stirring for 30 hr. Liquid-liquid separation was carried out after addition of ethyl acetate and water to the reaction mixture. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solvent was removed under reduced pressure. The solid residue was dried under reduced pressure to provide the titled compound as white powder (14.7 mg, 32%).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH2:15])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3.C(N(CC)CC)C.[C:25](Cl)(=[O:27])[CH3:26]>C(Cl)Cl>[CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH:15][C:25](=[O:27])[CH3:26])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3
Reactant: CC(=O)Cl
Reactant: CC1(C)Oc2cc3nonc3cc2C(N)C1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC1c2cc3nonc3cc2OC(C)(C)C1O
Temperature: 0 °C
Yield: 88 %

Procedure:
To a mixture of 200 mg (0.850 m mol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole, 128 μl (0.917 m mol) of triethylamine and 17 ml of methylene chloride were added 128 μl (0.917 m mol) of acetyl chloride with stirring at 0° C., followed by stirring for 30 minutes. After the completion of the reaction, the precipitated crystals were filtered. The crystals were washed successively with methylene chloride and water and dried at 80° C. under reduced pressure to obtain 223 mg (yield: 88%) of the intended compound.
Reaction SMILES: O[C:2]1[NH:3][SH:4](=[O:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:2]1[NH:3][SH:4](=[O:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[SH]1(c2ccccc2)C=C(c2ccccc2)N=C(O)N1
Product: O=[SH]1(c2ccccc2)C=C(c2ccccc2)N=C(Cl)N1
Yield: 73 %

Procedure:
A solution of 13.84 g (0.049 mole) of 3-hydroxy-1,5-diphenyl-1H-1,2,4-thiadiazine-1-oxide of Example 7 in 50 ml of phosphorus oxychloride was refluxed for 30 minutes and then excess reagent was evaporated under vacuum. The residue was taken up in chloroform and the solution was washed once with water, dried over magnesium sulfate and evaporated to an oil. The residue crystallized on trituration with ethanol to obtain 10.8 g (73%) of 3-chloro-1,5-diphenyl-1H-1,2,4-thiadiazine-1-oxide melting at 117°-118° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]3[CH2:18][O:17][CH2:16][C@H:15]([CH3:19])[N:14]3[C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:20])[CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[N:27]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28]1.O>CN(C=O)C.C(Cl)(Cl)Cl>[N:27]1([C:32]([O:20][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([NH2:1])[C:11]2[N:12]=[C:13]4[CH2:18][O:17][CH2:16][C@H:15]([CH3:19])[N:14]4[C:10]3=2)=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: C[C@H]1COCc2nc3c(N)nc4ccc(O)cc4c3n21
Reactant: O=C(Cl)N1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H]1COCc2nc3c(N)nc4ccc(OC(=O)N5CCCC5)cc4c3n21
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.9 %

Procedure:
A solution of (11S)-6-amino-11-methyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-2-ol (500 mg, 1.85 mmol) dissolved in 15 mL of DMF was treated with cesium carbonate (1.80 g, 5.55 mmol) and pyrrolidinecarbonyl chloride (275 mg, 2.03 mmol). After stirring overnight at ambient temperature, the light brown mixture was poured into 150 mL of H2O and stirred for 30 minutes. The reaction mixture was extracted with CHCl3 (3×75 mL) and the combined extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give a brown solid. Chromatography (SiO2, 0-20% CMA/CHCl3) gave an off-white solid which was crystallized from acetonitrile to give 122 mg of the title compound as an off-white solid, mp 218-219° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4][CH2:3]1.[CH3:17][Mg]Br>O1CCCC1>[OH:1][C:2]1([CH3:17])[CH2:3][CH2:4][CH:5]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:6][CH2:7]1
Reactant: C[Mg]Br
Reactant: CC(C)(C)OC(=O)NCC1CCC(=O)CC1
Solvent: C1CCOC1
Product: CC1(O)CCC(CNC(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl (4-oxocyclohexyl)methylcarbamate (1.00 g) was dissolved in tetrahydrofuran (20 mL) and cooled to −78° C. Methylmagnesium bromide (4.40 mL) was added dropwise. The reaction was stirred for 2 hours at −78° C. then allowed to warm to 0° C. and stirred for 30 minutes. The resulting suspension was quenched with water (10 mL), diluted with ether (50 mL), washed with ammonium chloride (25 mL), washed with brine (25 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography (Reveleris 80 g) eluting using a gradient of 5% to 50% ethyl acetate/dichloromethane over 30 minutes (flow=60 mL/min) gave the title compound as a 2:1 mixture of cis and trans isomers.
Reaction SMILES: Br.[Br-].[CH3:3][N:4]([CH3:30])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:31]([C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=1)=O>O1CCCC1>[CH3:3][N:4]([CH3:30])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:31]\[C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=1
Reactant: CN(C)CCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: Br
Agent: [Br-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(/C=C\CCCCCN(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.8 %

Procedure:
2.47 g of potassium t-butylate were added to a suspension of 5.06 g of 6-(dimethylamino)hexyl-triphenylphosphonium bromide hydrobromide (see Example 1 a) in 50 ml of tetrahydrofuran at 0° under argon. To this suspension was added dropwise within 15 minutes a solution of 1.64 g of methyl p-formylbenzoate in 20 ml of tetrahydrofuran. The reaction mixture was stirred at room temperature for 18 hours and then evaporated. The residue was dissolved in 100 ml of 1N hydrochloric acid and the aqueous phase was washed three times with 100 ml of diethyl ether. The aqueous phase was made basic with solid potassium carbonate and extracted three times with 100 ml of ether. The ethereal phases were dried over magnesium sulphate and evaporated. The residue was chromatographed on 100 g of silica gel with methylene chloride/methanol/ammonium hydroxide 100:10:1. There were obtained 880 mg (32%) of methyl 4-[(Z)-7-(dimethylamino)-1-heptenyl]benzoate as a colourless oil.
Reaction SMILES: [C:1]([O-:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[NH4+:11].C([O-])([O-])OC.[CH3:17]O>>[N:4]1[C:3]2[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1](=[O:10])[NH:11][CH:17]=1
Reactant: [NH4+]
Reactant: Nc1ccccc1C(=O)[O-]
Reactant: CO
Agent: COC([O-])[O-]
Product: O=c1[nH]cnc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
In a 2-mL volume stainless steel pressure-resistant vessel were placed 280 mg (1.8 mmol) of ammonium anthranilate (prepared in the same manner as in Reference Example 1), 400 mg (3.6 mmol) of methyl orthoformate, and 1.5 mL of methanol. The reaction was carried out at 120° C. for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and analyzed (according to absolute quantitative analysis) by high performance liquid chromatography. There was produced 214 mg (reaction yield: 81%) of quinazolin-4-one.