Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:3][CH:2]=1.CS[C:16](SC)=[N:17][C:18]#[N:19].O.[NH2:23][NH2:24]>C(O)C>[NH2:19][C:18]1[NH:17][C:16]([N:11]2[CH2:12][CH2:13][N:8]([CH2:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:9][CH2:10]2)=[N:23][N:24]=1
Reactant: NN
Reactant: CSC(=NC#N)SC
Reactant: c1cc(CN2CCNCC2)ccn1
Solvent: CCO
Solvent: O
Product: Nc1nnc(N2CCN(Cc3ccncc3)CC2)[nH]1

Procedure:
A 17.7 g (0.1 mole) amount of 1-(4-pyridylmethyl)piperazine (prepared as described above) was dissolved in 25 ml of ethanol and then added dropwise over 30 minutes to a stirred solution of 14.6 g (0.1 mole) of dimethyl cyanodithioiminocarbonate in 125 ml of ethanol. The mixture was refluxed for 20 hours, the evolved gas being led into a sodium hypochlorite trap, for the first 3 hours. Then 6.0 ml (0.12 mole) of hydrazine hydrate was added into the refluxing reaction mixture through the condenser and the mixture was refluxed for 6 hours longer. The mixture was evaporated to a solid residue which was recrystallized with ether and gave 25.8 g of the product of the Example as pale yellow crystals, mp 191°-193° C.
Reaction SMILES: B(Cl)(Cl)Cl.[F:5][C:6]1[C:11]([CH:12]=[O:13])=[C:10]([O:14]C)[C:9]([O:16][CH3:17])=[CH:8][CH:7]=1.O>ClCCl>[F:5][C:6]1[C:11]([CH:12]=[O:13])=[C:10]([OH:14])[C:9]([O:16][CH3:17])=[CH:8][CH:7]=1
Reactant: COc1ccc(F)c(C=O)c1OC
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccc(F)c(C=O)c1O
Yield: 95.1 %

Procedure:
1M boron trichloride in dichloromethane (25 ml; 25 mmol) was added to a solution of 6-fluoro-2,3-dimethoxy-benzaldehyde [Cantrell, Amanda S.; Engelhardt, Per; Hoegberg, Marita; Jaskunas, S. Richard; Johansson, Nils Gunnar; et al.; J. Med. Chem.; 39; 21; 1996; 4261-4274] (4.26 g; 23 mmol) in dichloromethane (30 ml) keeping the reaction temperature at −70 C. The reaction mixture stirred at room temperature overnight and hydrolyzed with water. The organic phase was separated, washed with water and evaporated in vacuc. The residue was chromatographed (silica gel, EA:Hex, 5:1) to give 3.72 g (94%) of 6-fluoro-2-hydroxy-3-methoxy-benzaldehyde as yellow crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1.[H][H].[CH2:14]=O>[Pd].O>[CH3:14][N:4]([CH2:3][CH2:2][OH:1])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1
Reactant: Cc1ccc(NCCO)cc1
Reactant: C=O
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Product: Cc1ccc(N(C)CCO)cc1
Temperature: 120 °C

Procedure:
N-(2-hydroxyethyl)-p-toluidine, 50 g, was combined with 1 g 5% palladium on carbon catalyst and charged to a pressure reactor. The pressure reactor was heated to 120° C. and fed hydrogen gas to maintain 120 psig pressure. Formaldehyde, 178 g 37% solution in water, was fed to the pressure reactor over 10 hours. After hydrogen uptake ceased, the reaction mass was filtered to remove catalyst and decanted to separate the aqueous phase.
Reaction SMILES: Br[C:2]1[C:3](=[O:17])[C:4]([CH3:16])([CH3:15])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.[Pd]>[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[C:3](=[O:17])[C:4]([CH3:16])([CH3:15])[O:5][C:6]=2[C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(C2=C(Br)C(=O)C(C)(C)O2)cc1
Reactant: CC1(C)OB(c2ccc(OCc3ccccc3)cc2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C2=C(c3ccc(OCc4ccccc4)cc3)C(=O)C(C)(C)O2)cc1
Yield: 85.7 %

Procedure:
4-Bromo-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (2 g, 6.7 mol), 2-(4-(benzyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.43 g, 0.0067 mol), and Cs2CO3 (11 g, 0.034 mol) in toluene (25 mL) and water (8 mL) was degassed, Pd (dppf) Cl2 (1.1 g, 0.0013 mol) was added under an inert atmosphere and the mixture degassed once again. The reaction was heated at reflux for 3 h, upon which the reaction mixture was filtered through a pad of Celite® and the filtrate was diluted with EtOAc (100 mL), washed with water (50 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified by flash column chromatography using 30% ethyl acetate in hexane and silica gel (230-400 Mesh), Rf=0.30 to afford 4-(4-(benzyloxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (2.3 g, 73%) as solid. 1H NMR (500 MHz, d6-DMSO): δ 8.42 (d, J=7.6 Hz, 1H), 8.06-7.99 (m, 2H), 7.95 (t, J=7.2 Hz, 1H), 7.72 (t, J=7.2 Hz, 1H), 7.63 (t, J=7.8 Hz, 1H), 7.56 (d, J=7.2 Hz, 2H); 7.18 (d, J=7.4 Hz, 2H), 7.12 (d, J=7.2 Hz, 2H), 6.89 (d, J=7.2 Hz, 2H), 5.38 (s, 2H), 3.79 (s, 3H). 1.42 (s, 6H). MS: [M+H]+: m/z=452.1; [M+Na]+: m/z=474.2.
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3](OCC)=O.[H-].[Na+].ClC[C:16]1[CH:17]=[N:18][O:19][C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[CH:23][CH:22]=1.Cl>O1CCCC1.O>[CH3:28][S:27][C:24]1[CH:23]=[CH:22][C:21]([C:20]2[O:19][N:18]=[CH:17][C:16]=2[CH2:3][CH2:2][C:1]([OH:9])=[O:8])=[CH:26][CH:25]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CSc1ccc(-c2oncc2CCl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CSc1ccc(-c2oncc2CCC(=O)O)cc1
Reaction time: 0.17 h
Yield: 60.9 %

Procedure:
To a solution of diethyl malonate (10.3 g) in tetrahydrofuran (80 ml) was gradually added sodium hydride (60%, oil, 2.34 g) at 0° C. The mixture was stirred for 10 min and a solution of 4-chloromethyl-5-(4-methylthiophenyl)isoxazole (7.00 g) in tetrahydrofuran (70 ml) was added dropwise at 0° C. The mixture was stirred at room temperature for 8 hr. The reaction mixture was poured into water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was dissolved in a mixture of 6N hydrochloric acid (50 ml) and acetic acid (100 ml), and heated under reflux for 5 hr. The reaction mixture was concentrated, and water was added to the residue to give colorless crystals (4.68 g, yield 61%) of 3-[5-(4-methylthiophenyl)-4-isoxazolyl]propionic acid. The crystals were recrystallized from ethyl acetate-isopropyl ether to give a colorless prism. melting point: 124–125° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.Cl.Cl[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]Cl.C(=O)([O-])[O-].[K+].[K+].O>CC(O)CC>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:5][CH:4]=1
Reactant: ClCCNCCCl
Reactant: COc1ccc(N)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)O
Product: COc1ccc(N2CCNCC2)cn1
Yield: 98.3 %

Procedure:
A mixture of 6-methoxy-3-pyridinamine (0.2 mol) and 2-chloro-N-(2-chloroethyl)-ethanamine hydrochloride (0.3 mol) in 2-butanol (500 ml) was stirred and refluxed. Potassium carbonate (0.7 mol) was added portionwise (20 g/h), the mixture was refluxed for 48 hours, an additional amount of potassium carbonate (30 g) was added and the mixture was stirred for 48 hours. The mixture was poured into water, extracted with CH2Cl2 and separated. The organic layer was dried, filtered and evaporated, yielding 38 g (98%) of 1-(6-methoxy-3-pyridinyl)piperazine (interm. 29).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([OH:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].F[C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=1[C:25]([F:28])([F:27])[F:26].Cl>CN(C)C=O.O>[CH2:7]([O:14][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=1[C:25]([F:26])([F:28])[F:27])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCO
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(C(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of potassium t-butoxide (20.7 g) in N,N-dimethylformamide (120 ml) was added n-heptanol (15.6 ml), and the mixture was stirred at room temperature for 30 min. A solution of 4-fluoro-3-trifluoromethylbenzoic acid (16.7 g) in N,N-dimethylformamide (60 ml) was added dropwise to the reaction mixture at 0° C., and the mixture was stirred at 70° C. for 1 hr. The reaction mixture was ice-cooled, water (320 ml) was added, and 6M-hydrochloric acid (40 ml) was added at room temperature. The mixture was stirred at room temperature for 30 min and precipitated crystals were collected by filtration. The crystals were dissolved in ethanol (60 ml) at 70° C., water (96 ml) was added dropwise at the same temperature and the mixture was stirred for 30 min. The mixture was allowed to cool to room temperature, and stirred for 30 min under ice-cooling. The precipitated crystals were collected by filtration to give the object product (24.1 g) as pale-brown crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[CH:5]=[N:6][C:7]=1[O:8][CH3:9].F[C:12]1[C:17]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[N:19]=2)=[CH:16][C:15]([CH2:44][N:45]2[CH2:50][CH2:49][N:48]([S:51]([CH3:54])(=[O:53])=[O:52])[CH2:47][C@@H:46]2[CH3:55])=[CH:14][N:13]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:12]2[C:17]([C:18]3[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:26][C:27]4[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)[CH2:35][C:36]4[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=4)[N:19]=3)=[CH:16][C:15]([CH2:44][N:45]3[CH2:50][CH2:49][N:48]([S:51]([CH3:54])(=[O:52])=[O:53])[CH2:47][C@@H:46]3[CH3:55])=[CH:14][N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ncc(N)cc1F
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)C[C@@H]4C)cnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)C[C@@H]4C)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
A mixture of 5-fluoro-6-methoxypyridin-3-amine (3.34 g, 23.53 mmol) and (S)-4-(2-fluoro-5-((2-methyl-4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (13.6 g crude from previous step) in THF (150 mL) at −10° C. was treated dropwise with LiHMDS (1.0 M in THF, Aldrich; 64.2 mL, 64.2 mmol) and the mixture was stirred for 30 min. The reaction was quenched with water and saturated NH4Cl(aq) (100 mL each) and diluted with EtOAc (50 mL). The organic layer was separated, and precipitated solids were collected by filtration. The filtered organic layer was then concentrated to minimal volume, and the precipitated brownish-yellow solid was collected by filtration and washed with a minimal amount of EtOAc. All collected solids were then combined, slurried in isopropanol, collected by filtration, and dried in vacuo to give (S)-4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-((2-methyl-4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (9.678 g, 81% over 2 steps) as a yellow solid. m/z (ESI, +ve ion) 758 (M+H)−.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([Cl:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH3:28][NH:29][CH2:30][CH3:31]>C(#N)C>[Cl:23][C:22]1[C:16]2[O:15][CH2:14][C@H:13]([CH2:12][N:29]([CH3:28])[CH2:30][CH3:31])[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=1
Reactant: CCNC
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(Cl)cc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CCN(C)C[C@H]1COc2c(Cl)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 57 using [(2R)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol), N-methylethanamine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 319 (M+, 0.3), 85 (3), 84 (3), 73 (5), 72 (bp), 63 (2).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][N:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[Cl:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>O1CCOCC1>[N:21]1[CH:20]=[CH:19][N:11]2[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:29](=[O:30])[C:28]4[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:27]=4[Cl:26])=[CH:23][CH:22]=3)=[O:7])[CH2:9][C:10]=12
Reactant: Nc1ccc(C(=O)N2Cc3nccn3Cc3ccccc32)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(Nc1ccc(C(=O)N2Cc3nccn3Cc3ccccc32)cc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A slurry of 0.330 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-imidazo[2,1-c][1,4]benzodiazepine in 15 ml of dioxane is stirred and warmed slightly to obtain a nearly complete solution. The reaction mixture is cooled to room temperature and 43 mg of sodium hydride in oil added. The mixture is warmed slightly. Gas evolution stops in a few minutes. The reaction mixture is cooled to room temperature and 153 μl of 2,4-dichlorobenzoyl chloride in 2,5 ml of dioxane added. An additional 3.5 ml of dioxane is added and the reaction mixture stirred at room temperature for 2 days. The volatiles are evaporated in vacuo to a residue which is partitioned between water and chloroform. The organic layer is separated and the aqueous phase extracted with chloroform two more times. The combined organic layers are trated with activated carbon and filtered through MgSO4. The filtrate is evaporated in vacuo to a tan foam which is purified by flash chromatography on silica gel by elution with CHCl3 and 3-7% CH3OH in chloroform to give 310 mg of tan foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]=[CH:6][C:5]2=O.S(O)(O)(=O)=O.[CH3:18][NH:19][NH2:20].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([OH:8])=[C:4]([C:5]2[N:19]([CH3:18])[N:20]=[CH:7][CH:6]=2)[CH:3]=1
Reactant: O=c1ccoc2ccc(Cl)cc12
Reactant: CNN
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cn1nccc1-c1cc(Cl)ccc1O
Temperature: 25 °C

Procedure:
To a suspension of 6-chlorochromone (2.00 g, 0.011 mol) in ethanol (35 mL) was added methylhydrazine sulfate (1.85 g, 0.013 mol) and triethylamine (2.0 mL, 0.014 mol) and the mixture was heated at reflux for 18 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo and the resulting residue purified by silica gel chromatography eluting with 0 to 100% EtOAc in hexane to yield two regioisomeric products in a 1:4 ratio, the title compound being the minor regiosiomer.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:13])[N:12]=2)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].[C:22]1([OH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:19]([C:3]1[CH:4]=[C:5]([C:8]2[S:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:13])[N:12]=2)[CH:6]=[CH:7][C:2]=1[O:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([O-:21])=[O:20]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)c1sc(-c2ccc(F)c([N+](=O)[O-])c2)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1sc(-c2ccc(Oc3ccccc3)c([N+](=O)[O-])c2)nc1C
Temperature: 100 °C
Yield: 98.8 %

Procedure:
A reaction mixture solution prepared by suspending 931 mg of ethyl 2-(4-fluoro-3-nitrophenyl)-4-methyl-1,3-thiazole-5-carboxylate, 339 mg of phenol and 622 mg of potassium carbonate in 15 mL of dimethylformamide was heated at 100° C. for 14 hours under a nitrogen atmosphere. The reaction mixture solution was cooled to room temperature, water was added and extraction was performed using ethyl acetate. The organic layer was washed with saline and then dried and concentrated under reduced pressure. The resulting crude product was separated and purified by silica gel column chromatography to obtain 1.14 g of ethyl 2-(3-nitro-4-phenoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH3:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1CO.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[CH3:37])=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: Cc1ccccc1CO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCc4ccccc4C)cc3C)c2cc1OC
Yield: 83.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (140 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, (2-methylphenyl)methanol (57 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (122 mg, yield 77%).
Reaction SMILES: Cl.[CH2:2]([NH:4][CH2:5][NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:3].[OH-].[Na+].[C:17](Cl)(Cl)=[O:18].N1C=CC=CC=1>O.O1CCCC1>[C:8]1([C:7]2[O:14][C:17](=[O:18])[N:4]([CH2:2][CH3:3])[CH2:5][N:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)Cl
Reactant: CCNCNC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCN1CN=C(c2ccccc2)OC1=O
Reaction time: 2 h

Procedure:
A suspension of 21.5 g of N-(ethylaminomethyl)-benzamide hydrochloride (0.1 mole) in 300 ml of water is neutralised at 0°-25°C with 50 ml of 2 normal sodium hydroxide solution (0.1 mole). Extraction is performed with ethyl acetate, the organic phase is dried over magnesium sulphate and the solvent is evaporated off. The residue is taken up in 150 ml of tetrahydrofuran and the solution is treated dropwise with 9.9 g of phosgene (0.1 mole) in 150 ml of tetrahydrofuran. The addition is effected at 0°-25°C over the course of 1 hour. Then a solution of 15.8 g (0.2 mole) of pyridine in 150 ml of tetrahydrofuran is added over the course of a further hour. Stirring of the reaction mixture is continued for 2 hours and it is then refluxed for 3 hours. After the reaction mixture has cooled, the precipitate which has formed is filtered off and the filtrate is evaporated to dryness. The residue is taken up in chloroform and washed first with sodium bicarbonate solution and then with water. The solvent is evaporated off and crystallisation of the residue from ethyl acetate/n-hexane yields 6-phenyl-3-ethyl-3,4-dihydro-2H-1,3,5-oxadiazin-2-one with a melting point of 96°-98°C (compound 1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[NH2:12][C:13]([CH3:20])=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].[F:21][C:22]([F:32])([F:31])[C:23](=[O:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(O)C>[OH:30][C:23]1([C:22]([F:31])([F:32])[F:21])[CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12]1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: CCOC(=O)C=C(C)N
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(O)(C(F)(F)F)C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Yield: 21.3 %

Procedure:
3-Nitrobenzaldehyde (3.0 g, 20 mmoles), ethyl 3-amino-2-butenoate (2.6 g, 20 mmoles) and ethyl 4,4,4-trifluoro-3-oxobutanoate (2.92 ml, 20 mmoles) were heated at reflux in ethanol (25 ml) for 6 hours. The solvent was removed in vacuo and the residue crystallised by the addition of ether/petroleum ether (60°-80°). The resulting solid was recrystallised from ether/petroleum ether (60°-80°) to give the title compound as colourless crystals (1.9 g) mp 120°-1°.
Reaction SMILES: [CH2:1]([C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].Cl[CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21]>CS(C)=O>[CH3:19][Si:20]([CH2:23][NH:15][CH2:14][C:13]1[CH:12]=[CH:11][C:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:17][CH:16]=1)([CH3:22])[CH3:21]
Reactant: CCCCCCCCCc1ccc(CN)cc1
Reactant: C[Si](C)(C)CCl
Solvent: CS(C)=O
Product: CCCCCCCCCc1ccc(CNC[Si](C)(C)C)cc1
Reaction time: 16 h
Yield: 36.5 %

Procedure:
A solution of 1.3 g (6 mmol) of 4-(nonyl)benzylamine (from Step A) and 700 mg (6 mmol) of chloromethyltrimethylsilane in 5 mL of DMSO was stirred at 90° C. for 3 h, then at rt for 16 h. The mixture was partitioned between MTBE and 1N NaOH. The organic layer was separated, washed with sat'd NaCl, dried and concentrated. Flash chromatography using 9:1 v/v hexane/EtOAc as the eluant afforded 700 mg of N-(trimethylsilylmethyl)-4-(nonyl)benzylamine.
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][CH3:5].O[CH:8]([CH3:12])[C:9](=O)[CH3:10]>C(O)CCCCC>[CH3:1][N:2]1[C:9]([CH3:10])=[C:8]([CH3:12])[N:4]([CH3:5])[C:3]1=[S:6]
Reactant: CNC(=S)NC
Reactant: CC(=O)C(C)O
Solvent: CCCCCCO
Product: Cc1c(C)n(C)c(=S)n1C
Temperature: 155 °C
Reaction time: 24 h

Procedure:
1,3-dimethyl-4,5-dimethylimidazole-2-thione was synthesized according to a method obtained by modifying a method suggested by N. Kuhn, et al. (N. Kuhn and T. Kratz, Synthesis, June 1993, p.561), and a procedure of synthesizing the same is described below. 100 mmol of dimethylthiourea and 100 mmol of 3-hydroxyl-2-butanone were added to 250 ml of 1-hexanol in order, and then subjected to a reflux reaction for about 12 hours while increasing a reaction temperature to 150 to 160° C. At this time, white solid reactants were dissolved in 1-hexanol to be partly converted into yellow solid reactants according to an increase in the reaction temperature. After a completion of the reflux reaction, the resulting solution was left in a freezer at about −30° C. for about one day to separate into a white solid component and a yellow liquid component. The yellow liquid component was removed by use of a syringe, and the remaining white solid component was rinsed with water and ether and dried to produce 1,3-dimethyl-4,5-dimethylimidazole-2-thione. 1,3-dimethyl-4,5-dimethylimidazole-2-thione thus produced was analyzed by a 1H-NMR analyzer and the results are as follows:
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.F[C:21]1[CH:22]=[CH:23][C:24]([N+:29]([O-:31])=[O:30])=[C:25]([CH:28]=1)[NH:26][CH3:27]>O>[CH2:1]([O:8][C:21]1[CH:22]=[CH:23][C:24]([N+:29]([O-:31])=[O:30])=[C:25]([CH:28]=1)[NH:26][CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNc1cc(F)ccc1[N+](=O)[O-]
Reactant: OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
Benzyl alcohol (0.93 mL, 9 mmol) and potassium carbonate (1.24 g, 9 mmol) were added to a N,N-dimethyl formamide solution (5 mL) of 5-fluoro-N-methyl-2-nitroaniline (510 mg, 3 mmol). The mixture was stirred at 60-70° C. for 8 hours. The reaction solution was cooled, then water was added thereto, and precipitated crystals were collected by filtration. The resulting crystals were washed with water, and dried at 50° C., thereby obtaining 680 mg of orange, powdery 5-benzyloxy-N-methyl-2-nitroaniline (yield: 88%).