Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[CH3:35][Si:36]([C:39]#[CH:40])([CH3:38])[CH3:37]>C1(C)C=CC=CC=1.[Cu](I)I.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:40]#[C:39][Si:36]([CH3:38])([CH3:37])[CH3:35]
Reactant: Clc1ccncc1I
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[Si](C)(C)C#Cc1cnccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
To a solution of 4-chloro-3-iodo pyridine (2.0 g, 8.3 mmol) in toluene (20 mL) add triphenyl phosphine (0.219 g, 0.83 mmol), copper iodide (0.079 g, 0.41 mmol) and palladium (II) acetate (0.093 g, 0.41 mmol), add triethylamine (3.49 mL, 25 mmol) dropwise at room temperature followed by the addition of trimethylsilylacetylene (1.65 mL, 11.69 mmol) at room temperature with continuous stirring. Stir the reaction mixture at room temperature for 2 hours. Concentrate the reaction mixture by evaporating the toluene under vacuum. Extract the compound (almost pure) by triturating with hexane and then decanting the hexane layer 4 to 5 times. Evaporate hexane under vacuum and dry it to obtain the pure compound (1.68 g, 96%). 1H NMR (400 MHz, CDCl3) δ 8.677 (s, 1H), 8.418 (s, 1H), 7.338 (d, J=2.6 Hz, 1H), 0.286 (s, 9H). MS (ES) m/z 210 [M+1]+.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[O:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:13]3[CH2:14][CH2:15][CH2:16][O:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: C1CNOC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Product: C1CON(C2CCC3(CC2)OCCO3)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1,4-dioxaspiro[4.5]decan-8-one (358.5 mg, 2.3 mmol), and isoxazolidine (168 mg, 2.3 mmol), and sodium triacetoxyborohydride (1.46 g, 6.9 mmol) were taken in acetonitrile and stirred for 18 h at room temperature. The mixture concentrated under vacuum and the residue basified with NaHCO3, saturated with solid NaCl and extracted with EtOAc/iPrOH (4:1) four times. Organic layer separated, dried over Na2SO4 and evaporated. Residue purified by silica column chromatography to give the title compound.
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]2[C@H:7]([O:15][C@@H:16]3[O:21][C@H:20]([CH2:22][OH:23])[C@@H:19]([OH:24])[C@H:18]([OH:25])[C@H:17]3[OH:26])[O:8][CH:9]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[C@H:5]2[CH2:4][C@@H:3]1[OH:27].[C:28](Cl)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>N1C=CC=CC=1>[CH3:1][C@@H:2]1[C@H:6]2[C@H:7]([O:15][C@@H:16]3[O:21][C@H:20]([CH2:22][O:23][C:28]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C@@H:19]([OH:24])[C@H:18]([OH:25])[C@H:17]3[OH:26])[O:8][CH:9]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[C@H:5]2[CH2:4][C@@H:3]1[OH:27]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C1=CO[C@@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H]2[C@@H](C)[C@@H](O)C[C@H]12
Solvent: c1ccncc1
Product: COC(=O)C1=CO[C@@H](O[C@@H]2O[C@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@@H](O)[C@H](O)[C@H]2O)[C@@H]2[C@@H](C)[C@@H](O)C[C@H]12
Temperature: 45 °C
Reaction time: 36 h
Yield: 65 %

Procedure:
The loganin was dissolved in pyridine and trityl chloride was added in 1.5 equivalents and stirred at 45° C. for 36 hrs to give the compound 6′-O-trityl loganin (2) in 65% yield.
Reaction SMILES: [O:1]([C:8]1[CH:12]=[CH:11][S:10][C:9]=1[CH:13]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[S:20]([CH2:23][C:24]#[N:25])(=[O:22])=[O:21]>>[O:1]([C:8]1[CH:12]=[CH:11][S:10][C:9]=1/[CH:13]=[C:23](/[S:20]([C:16]1[S:15][CH:19]=[CH:18][CH:17]=1)(=[O:22])=[O:21])\[C:24]#[N:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCS(=O)(=O)c1cccs1
Reactant: O=Cc1sccc1Oc1ccccc1
Product: N#C/C(=C\c1sccc1Oc1ccccc1)S(=O)(=O)c1cccs1

Procedure:
Reaction of 3-phenoxythiophen-2-carboxaldehyde and thien-2-ylsulfonylacetonitrile as in Example 1 gave (E)-3-(3-phenoxythien-2-yl)-2-(thien-2-ylsulfonyl)acrylonitrile
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[N:10]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]4[O:27][CH:26]=[N:25][CH:24]=4)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:9]=[CH:8]3)[CH2:2]1.Cl.N1CC(C2C=C3C(=CC=2)N(S(C2C=CC=CC=2)(=O)=O)CC3)C1>>[NH:1]1[CH2:2][CH:3]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[N:10]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([C:23]4[O:27][CH:26]=[N:25][CH:24]=4)=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH2:9][CH2:8]3)[CH2:4]1
Reactant: O=S(=O)(c1ccc(-c2cnco2)cc1)n1ccc2cc(C3CNC3)ccc21
Agent: Cl
Agent: O=S(=O)(c1ccccc1)N1CCc2cc(C3CNC3)ccc21
Product: O=S(=O)(c1ccc(-c2cnco2)cc1)N1CCc2cc(C3CNC3)ccc21

Procedure:
This compound was prepared from 5-azetidin-3-yl-1-(4-oxazol-5-yl-benzensulfonyl)-1H-indole by the method outlined for compound 7. ESI-MS [m/z]: 382.05 [M+H]+. 1H-NMR (400 MHz, d6-DMSO): δ=8.7 (bs, 1H), 8.55 (s, 1H), 7.9 (m, 5H), 7.45 (d, 1H), 7.25 (s, 1H), 7.2 (d, 1H), 4.2 (m, 2H), 4.1-3.9 (m, 5H), 2.95 ppm (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4](F)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][NH:18][CH3:19].C(O)C>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N:18]([CH3:19])[CH3:17])[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)c1cc(Br)ccc1C=O
Temperature: 110 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
To a suspension of 4-bromo-2-fluorobenzaldehyde (500 mg, 2.46 mmol) and potassium carbonate (340 mg, 2.46 mmol) in 5 mL of dry N,N-dimethylformamide was added dimethylamine/ethanol solution (0.67 mL, 5.6 M, 3.8 mmol) at room temperature. After being stirred at 110° C. overnight, the reaction mixture was diluted with ethyl acetate. The solution was washed with water, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5 to 80/20) to obtain the title compound as a yellow oil (458 mg, 81%).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[S:5])#[N:2].C[O-].[Na+].[CH3:10][N:11](C=NC=[N+](C)C)[CH3:12].[Cl-]>C(COC)OC>[C:1]([C:3]1[C:4]([SH:5])=[N:6][CH:10]=[N:11][CH:12]=1)#[N:2]
Reactant: CN(C)C=NC=[N+](C)C
Reactant: N#CCC(N)=S
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: COCCOC
Product: N#Cc1cncnc1S
Temperature: 25 °C
Reaction time: 5 h

Procedure:
At room temperature, 2-cyanothioacetamide (4.5 g, 0.045 mol) was added to an initial charge of sodium methoxide (24.3 g, 0.1.35 mol, 29% in methanol). 100 ml of dimethoxyethane were added. The Gold's reagent prepared as in Example 1 (8.1 g, 0.050 mol) was then added, and the reaction mixture was stirred at room temperature for about 5 hours. The mixture was then heated briefly to 50° C. and left to stand at room temperature overnight. The dimethoxyethane was stripped off on a rotary evaporator, 20 ml of water were added, and then the reaction mixture was cooled in an ice bath. 30 ml of 2N eq. HCl solution were used to adjust the pH to 5.5. After renewed cooling, the solid which had precipitated out was filtered off, then washed with a small amount of cold water and dried at 40° C. in a vacuum drying cabinet to give the title product in a yield of 5.57 g (90.4%) in the form of an orange solid.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[NH:1][C:2](=[O:11])[CH2:3][CH2:4]2)=[O:19]
Reactant: O=C1CCc2ccccc2N1
Reactant: O=C(Cl)CCCCCBr
Product: O=C1CCc2cc(C(=O)CCCCCBr)ccc2N1

Procedure:
Using 3,4-dihydroquinolin-2(1H)-one (2.94 g) and 6-bromohexanoyl chloride (5.1 g) according to the same method as that of Reference Example 1, the title compound was obtained as colorless crystals (1.62 g) having a melting point of 116 to 117° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:15]([O-])([OH:17])=[O:16]>CC(O)=O>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(Cc2ccccc2)cc1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(Cc2ccccc2)ccc1O
Reaction time: 3 h

Procedure:
To a solution of 4-benzylphenol (10.0 g, 54.3 mmol) in 300 mL AcOH at ambient temperature was added slowly dropwise a solution of nitric acid, red fuming (2.28 mL, 54.3 mmol) in 100 mL AcOH over 1-2 h. The reaction was allowed to stir for 3 h, poured onto ice, and the resulting solid was collected by filtration, rinsing with water to give 4-benzyl-2-nitrophenol as a yellow solid. MS (ESI) m/z: Calculated: 229.1; Observed: 227.8 (M++1).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][C:11]2[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O>CCOC(C)=O>[C:13]1([CH3:17])[CH:14]=[CH:15][CH:16]=[C:11]([NH:10][C:5]2[C:4]([NH2:1])=[CH:9][CH:8]=[CH:7][N:6]=2)[CH:12]=1
Reactant: Cc1cccc(Nc2ncccc2[N+](=O)[O-])c1
Solvent: CCOC(C)=O
Product: Cc1cccc(Nc2ncccc2N)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.4 %

Procedure:
A mixture of (3-nitropyridin-2-yl)-m-tolylamine (2.30 g, 10.0 mmol) in EtOAc (150 mL) was degassed with a stream of nitrogen prior to addition of 10% Pd/C (400 mg) and was stirred at RT under a hydrogen atmosphere for 16 h. The suspension was filtered and the filtrate was concentrated in vacuo to afford the title compound as a white solid (1.88 g, 94%). LCMS (Method C): RT 1.60 min [M+H]+ 200.1.
Reaction SMILES: [NH2:1][C:2]([CH3:11])([CH3:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:12]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[C:16]([F:22])[CH:15]=1)#[N:13].C([O-])(O)=O.[Na+].O>CN(C=O)C>[C:12]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:1][C:2]([CH3:11])([CH3:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[C:16]([F:22])[CH:15]=1)#[N:13]
Reactant: CC(C)(C)OC(=O)C(C)(C)N
Reactant: N#Cc1ccc(CBr)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)NCc1ccc(C#N)cc1F
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a stirred solution of tert-butyl 2-amino-2-methylpropanoate (Bachem, 7.9 g, 0.05 mol) in dry DMF (50 mL) under nitrogen, was added 4-cyano-2-fluoro benzyl bromide (10.6 g, 0.05 mol) and NaHCO3 (8.3 g, 0.099 mol) as a solid. The reaction mixture was stirred for 16 h at 70° C. Water (70 mL) was added and extracted with ethyl acetate (100 mL). The organic layer was washed with water (3×100 mL) and the solvent was dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography using silica gel (60-120 mesh) and petroleum ether/ethyl acetate as eluent, affording the title compound as colourless liquid. 1H NMR (DMSO-d6, 400 MHz) δ 7.78 (d, J=10.0 Hz, 1H), 7.71-7.65 (m, 2H), 3.69 (d, J=6.9 Hz, 2H), 2.55 (s, 1H), 1.44 (s, 9H), 1.19 (s, 6H).
Reaction SMILES: [Cl-].[NH2:2][P+:3]([N:10]([CH3:12])[CH3:11])([N:7]([CH3:9])[CH3:8])[N:4]([CH3:6])[CH3:5].[OH-].[Ba+2].[OH-].[Cl-]>O1CCCC1>[NH:2]=[P:3]([N:4]([CH3:6])[CH3:5])([N:10]([CH3:12])[CH3:11])[N:7]([CH3:9])[CH3:8]
Reactant: CN(C)[P+](N)(N(C)C)N(C)C
Agent: [Ba+2]
Agent: [Cl-]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C)P(=N)(N(C)C)N(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 5-l reactor fitted with a stirrer, a thermometer and a dropping funnel, 1.60 kg of tetrahydrofuran were weighed, followed by the addition of 250 g (1.16 mol) of aminotris(dimethylamino)phosphonium chloride. The contents were heated to 55° C., at which 2.29 kg of a 5.6 wt. % aqueous solution of barium hydroxide, said solution containing 0.83 mol (equivalent to 1.1 gram equivalents based on the chloride) of barium hydroxide, were added dropwise over 20 minutes. After completion of the dropwise addition, the resulting mixture was stirred at the same temperature for 30 minutes and was then allowed to cool down to room temperature in about 30 minutes. Iminotris(dimethylamino)phosphorane was formed with a reaction yield of 99 mol %.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[CH:3]=1.[S-:23][C:24]#[N:25].[K+].BrBr.C(=O)([O-])[O-].[Na+].[Na+]>CO>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[C:3]=1[S:23][C:24]#[N:25]
Reactant: Nc1cc(C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: N#C[S-]
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: N#CSc1c(C(F)(F)F)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N

Procedure:
A stirred mixture of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-trifluoromethylpyrazole (0.7 g) and potassium thiocyanate (0.55 g) in methanol (15 ml) was treated with a solution of bromine (0.3 g) in methanol (2 ml) at 0°-5° C. Stirring was maintained at this temperature for 1.5 hours, and the mixture was poured onto ice water, and brought to pH 9 by the addition of sodium carbonate. The product was filtered, washed with water and dried. Purification by chromatography on silica (Merck, 230-400 mesh, 0.7 kg cm-2) eluting with dichloromethane gave 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-thiocyanato-3-trifluoromethylpyrazole, in the form of a white solid, m.p. 49°-50° C.
Reaction SMILES: Br[CH2:2][CH2:3][S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C1(S)C=CC=CC=1.[OH:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1>[OH-].[Na+]>[CH2:26]([O:25][C:23]([C:22]1[CH:28]=[CH:29][C:19]([O:18][CH2:2][CH2:3][S:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:20][CH:21]=1)=[O:24])[CH3:27]
Reactant: BrCCSc1ccccc1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: Sc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1ccc(OCCSc2ccccc2)cc1

Procedure:
This compound was prepared by the condensation procedure 1A. The required intermediate 2-bromoethylphenyl sulphide may be prepared by condensing 1,2-bromoethane and thiophenol in sodium hydroxide solution, in a manner analogous to that used for preparation of the intermediates for compounds of Example Nos. 62-73, but in a method which gives better yields uses the scheme: ##STR25## Condensation with ethyl 4-hydroxybenzoate gave 1-(4-ethoxycarbonylphenoxy)-2-phenylthio ethane, m.p. 50°-51° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[N:12]([CH3:19])[C:13]1[CH:14]=[N:15][CH:16]=[N:17][CH:18]=1.[Li+].[OH-]>O1CCOCC1>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N:12]([CH3:19])[C:13]1[CH:18]=[N:17][CH:16]=[N:15][CH:14]=1
Reactant: COC(=O)c1ccc(F)c(N(C)c2cncnc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN(c1cncnc1)c1cc(C(=O)O)ccc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 70.3 %

Procedure:
Compound 20 (300 mg, 1.15 mmol, 1.00 eq) was dissolved in Dioxane (5.0 mL), and 1N LiOH (5.0 mL) was added. The reaction was stirred at rt for 45 minutes. The reaction was quenched with 1N HCl (5.0 mL) and extracted (3×) with ether. The combined organics were dried (MgSO4), filtered, and concentrated in vacuo to afford 200 mg (70%) of crude 4-fluoro-3-(methyl(pyrimidin-5-yl)amino)benzoic acid as a yellow solid. The product was confirmed by LCMS (>90% @ 220 nm and 254 nm) and carried forward without purification. 4-fluoro-3-(methyl(pyrimidin-5-yl)amino)benzoic acid (30 mg, 0.12 mmol, 1.0 eq), 6-methylpyridin-2-amine (15 mg, 0.14 mmol, 1.2 eq), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (91 mg, 0.24 mmol, 2.0 eq), and N,N-Diisopropylethylamine (85 mg, 0.66 mmol, 5.5 eq) were dissolved in DMF (0.98 mL) and stirred at rt overnight. The reaction was quenched with water, and the layers were separated via phase separation. The organic layer was dried on air concentrator and purified by mass directed preparatory HPLC to afford 15 mg (36%) of the title compound as a mono-TFA salt: 1H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.65 (s, 1H), 8.28 (s, 2H), 8.14 (dd, J=7.7, 2.2 Hz, 1H), 8.00-7.94 (m, 2H), 7.75 (t, J=7.9 Hz, 1H), 7.48 (dd, J=10.7, 8.7 Hz, 1H), 7.05 (dd, J=7.4, 1H), 3.39 (s, 3H), 2.45 (s, 3H); ES-MS [M+1]+:338.1.
Reaction SMILES: [I-].[CH2:2]([N+:5]1[C:14]2[C:13]3[O:15][CH2:16][CH2:17][O:18][C:12]=3[CH:11]=[CH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)[CH:3]=[CH2:4].[OH-:19].[K+].O>O1CCOCC1>[CH2:2]([N:5]1[C:14]2[C:13]3[O:15][CH2:16][CH2:17][O:18][C:12]=3[CH:11]=[CH:10][C:9]=2[CH:8]=[CH:7][C:6]1=[O:19])[CH:3]=[CH2:4]
Reactant: C=CC[n+]1cccc2ccc3c(c21)OCCO3
Reactant: [OH-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C=CCn1c(=O)ccc2ccc3c(c21)OCCO3
Yield: 64.2 %

Procedure:
10-(2-Propen-1-yl)-2,3-dihydro[1,4]dioxino[2,3-h]quinolin-10-ium iodide (5.91 g; 16.65 mmol), KOH (4.10 g; 73.26 mmol) and K3-[Fe(CN)6] (12.05 g; 36.63 mmol) were stirred in 50% aqueous 1,4-dioxane at RT for 1.5 h. Water (250 ml) was added and the aqueous layer was extracted with 10% MeOH/DCM (150 ml) and the organics were washed with water (250 ml). The organics were dried with MgSO4 and the solvents removed. The crude residues were purified by column chromatography on silica gel using a 0-7% MeOH/DCM gradient to give the desired product (2.6 g; 65%). MS (ES+) m/z 244 (MH+).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1.F[C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=[O:22]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:19]2[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=2[CH:21]=[O:22])[CH2:13]1
Reactant: O=Cc1ccccc1F
Reactant: c1ccc2sc(OCC3CCCNC3)nc2c1
Product: O=Cc1ccccc1N1CCCC(COc2nc3ccccc3s2)C1
Yield: 12.2 %

Procedure:
Using 3-[(benzothiazol-2-yl)oxymethyl]piperidine (58.0 mg, 0.234 mmol) and 2-fluorobenzaldehyde (0.0381 mL, 0.351 mmol), the same procedure was followed as in Step 1c of Example 1 to give 10.1 mg (12%) of the desired compound as a colorless oil.
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:5])[O-:4].C[NH3+].Cl[CH:9]([C:13](=[O:15])[CH3:14])[C:10](=O)[CH3:11].CCOCC>CO>[C:13]([C:9]1[S:5][C:3](=[O:4])[N:2]([CH3:1])[C:10]=1[CH3:11])(=[O:15])[CH3:14]
Reactant: CC(=O)C(Cl)C(C)=O
Reactant: CNC([O-])=S
Agent: C[NH3+]
Solvent: CCOCC
Solvent: CO
Product: CC(=O)c1sc(=O)n(C)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methylammonium N-methylthio-carbamate (13.1 g, 0.105 mol; prepared from methylamine and carbonyl sulfide as described, Y. Gelernt et al. 1974, J. Chem. Soc. Perkin Trans. 1, 2610) was partially dissolved in MeOH (150 mL). 3-Chloro-pentane-2,4-dione (14.9 mL, 0.125 mol) was added drop-wise at room temperature, producing a gradual exotherm to 40° C. After stirring at room temperature for 1 h, the solvent was removed in vacuo. The residue was treated with H2O (50 mL) and was extracted with CH2Cl2 (3×50 mL). The combined organic fractions were washed (brine), dried (Na2SO4), filtered, and evaporated in vacuo to an amber-coloured oil. This was purified by chromatography (300 g SiO2, eluting with 1:1 heptane/Et2O to obtain non-cyclized adduct, then Et2O to obtain 5-acetyl-3,4-dimethyl-3H-thiazol-2-one, which was recrystallized from EtOH as colourless needles (14.2 g). 1H-NMR (CDCl3): δ 2.34 (s, 3H), 2.59 (s, 3H), 3.33 (s, 3H). IR (ATR): 1655 and 1621 cm−1 (CO str).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[N:12][C:11]([NH:14][NH2:15])=[N:10][CH:9]=1.[C:16]([O-])([O-])(OCC)[CH3:17]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[N:12]([C:16]([CH3:17])=[N:15][N:14]=2)[N:13]=1
Reactant: CCOC(C)([O-])[O-]
Reactant: NNc1ncc(-c2ccccc2F)nn1
Product: Cc1nnc2ncc(-c3ccccc3F)nn12

Procedure:
A mixture of 3.8 g. of 6-(o-fluorophenyl)-3-hydrazino-1,2,4-triazine and 40 ml. of ethyl orthoacetate is refluxed for 4 hours, cooled and the solid is collected by filtration and washed with hexane, giving the desired product as a yellow solid, m.p. 199.5°-203.5° C.
Reaction SMILES: [C:1]([Cl:4])(Cl)=O.C1(C)C=CC=CC=1.[CH3:12][O:13][C:14]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:15]=1[CH2:16][N:17]1[C:26]2[C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[CH:23]=[CH:22][C:21]=2[NH:20]C(=O)[C:18]1=[O:32]>CN(C)C=O>[Cl:4][C:1]1[C:18](=[O:32])[N:17]([CH2:16][C:15]2[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[CH:36][C:14]=2[O:13][CH3:12])[C:26]2[C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: COc1ccc(Cn2c(=O)c(=O)[nH]c3ccc4ccccc4c32)c(OC)c1
Reactant: O=C(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2c(=O)c(Cl)nc3ccc4ccccc4c32)c(OC)c1
Temperature: 0 °C
Yield: 90 %

Procedure:
A solution of 20% phosgene in toluene (10 ml, 19 mmol) was added to a solution of 1-(2,4-dimethoxybenzyl)benzo[f]quinoxaline-2,3(1H, 4H)-dione (950 mg; 2.6 mmol) in dry N,N-dimethylformamide (100 ml) with stirring at 0° C. The mixture was stirred at room temperature overnight, and evaporated to dryness. The residue was triturated with ice/water, filtered and dried in vacuo to give 900 mg (90%) of the title compound, m.p. 186° C. 1H-NMR (DMSO-d6): δ 3.80 (s, 3H), 3.82 (s, 3H), 5.65 (s, 2H), 6.45 (dd, 1H), 6.55 (d, 1H), 7.00 (d, 1H), 7.35 (m, 1H), 7.55 (m, 1H), 7.75 (m, 2H), 7.90 (m, 1H), 8.22 (d, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[NH:14][C:13](=[O:17])[CH:12]=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:19][CH2:20][CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:19]([N:14]1[C:13](=[O:17])[CH:12]=[N:11][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[C:15]1=[O:16])[CH2:20][CH2:21][CH3:22]
Reactant: O=c1cnn(-c2ccc([N+](=O)[O-])cc2)c(=O)[nH]1
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCn1c(=O)cnn(-c2ccc([N+](=O)[O-])cc2)c1=O
Temperature: 45 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
A mixture of 40 parts of 2-(4-nitrophenyl)-1,2,4-triazine-3,5-(2H,4H)-dione, 25.7 parts of 1-bromobutane, 26.25 parts of potassium carbonate and 720 parts of N,N-dimethylformamide was stirred overnight at 45° C. The reaction mixture was poured into 2000 parts of ice water. The precipitated product was filtered off, washed with water and 2,2'-oxybispropane and stirred in methanol. The product was filtered off and dried in vacuo at 70° C., yielding 33.9 parts (68.6%) of 4-butyl-2-(4-nitrophenyl)-1,2,4-triazine-3,5(2H,4H)-dione (int. 27).
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([CH2:9][NH2:10])=[O:8].C(=O)(O)[O-].[Na+].[C:16](Cl)(=[O:20])[CH:17]([CH3:19])[CH3:18]>>[C:16]([NH:10][CH2:9][C:7]([C:3]1[O:2][CH:6]=[CH:5][CH:4]=1)=[O:8])(=[O:20])[CH:17]([CH3:19])[CH3:18]
Reactant: NCC(=O)c1ccco1
Reactant: CC(C)C(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)C(=O)NCC(=O)c1ccco1
Yield: 67.3 %

Procedure:
16.0 g of (2-furylcarbonyl)methylamine hydrochloride, 20.5 g of sodium bicarbonate and 11.4 g of isobutyryl chloride are treated in the same manner as described in Preparation 1-(1). 13.0 g of N-isobutyryl-(2-furylcarbonyl)methylamine are thereby obtained. Yield: 67.0%