Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[C:16]([O:18]COC)=[C:15]([OH:22])[CH:14]=[CH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:25]I>CN(C)C=O>[CH2:1]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[C:16]([OH:18])=[C:15]([O:22][CH3:25])[CH:14]=[CH:13]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: COCOc1c(O)ccc2cccc(Cc3ccccc3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2cccc(Cc3ccccc3)c2c1O
Reaction time: 0.5 h

Procedure:
82.7 g of 8-benzyl-1-methoxymethoxy-2-naphthol was dissolved in 300 ml of N,N-dimethylformamide to give a solution. 12.3 g of sodium hydride (55% suspension in oil) was added to the solution at room temperature. The obtained mixture was stirred for 30 minutes, followed by the dropwise addition of 17.5 ml of methyl iodide. The obtained mixture was stirred for one hour and poured onto ice-water. The obtained mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated in a vacuum. The obtained residue was purified by silica gel column chromatography (developer: 3 to 9% ethyl acetate/hexane) to give 79.5 g of the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][C:7]2[N:11]=[CH:10][NH:9][N:8]=2)=[CH:4][CH:3]=1.[Mn]([O-])(=O)(=O)=[O:15].[K+]>O>[F:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([C:7]2[N:11]=[CH:10][NH:9][N:8]=2)=[O:15])=[CH:4][CH:3]=1
Reactant: Fc1ccc(Cc2nc[nH]n2)cc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: O=C(c1ccc(F)cc1)c1nc[nH]n1

Procedure:
3-(4-Fluorobenzyl)-1,2,4-triazole (9 g.) and potassium permanganate (13.5 g.) were heated in water at 80° for 1 hour. The reaction mixture was filtered, and the residue was washed twice each with water and chloroform. The combined filtrate and washings were adjusted to pH 3 and filtered. The solid residue was dissolved, as far as possible, in hot methanol, the solution was filtered and evaporated to dryness to give 3-(4-fluorobenzoyl)-1,2,4-triazole as a cream-colored solid, m.p. 225°-230°.
Reaction SMILES: [C:1](C1C=CC(C(Cl)=O)=CC=1)#[N:2].Cl[C:13]1[CH:18]=[C:17](Cl)[CH:16]=[CH:15][C:14]=1[C:20]1[C:25]([C:26]2[NH:27][CH:28]=[CH:29][N:30]=2)=[CH:24][N:23]=[C:22]([NH:31][CH2:32][CH2:33][NH:34][C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][N:36]=2)[N:21]=1>>[NH:30]1[CH:29]=[CH:28][N:27]=[C:26]1[C:25]1[C:20]([C:14]2[CH:15]=[CH:16][C:17]([C:1]#[N:2])=[CH:18][CH:13]=2)=[N:21][C:22]([NH:31][CH2:32][CH2:33][NH:34][C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][N:36]=2)=[N:23][CH:24]=1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Product: N#Cc1ccc(-c2nc(NCCNc3ccc([N+](=O)[O-])cn3)ncc2-c2ncc[nH]2)cc1

Procedure:
4-[5-imidazol-2-yl-2-({2-[(5-nitro(2-pyridyl))amino]ethyl}amino)pyrimidin-4-yl]benzenecarbonitrile was prepared from 4-cyanobenzoyl chloride using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [C:1]12[C:10](=[O:11])[O:9][C:7](=O)[C:2]=1[CH2:3][CH2:4][CH2:5][CH2:6]2.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:28])=[C:17]([CH:27]=1)[O:18][CH:19]([CH2:24][CH2:25][CH3:26])[C:20](=[N:22][OH:23])[CH3:21]>C(O)(=O)C>[Cl:28][C:16]1[CH:15]=[CH:14][C:13]([N:12]2[C:10](=[O:11])[C:1]3[CH2:6][CH2:5][CH2:4][CH2:3][C:2]=3[C:7]2=[O:9])=[CH:27][C:17]=1[O:18][CH:19]([CH2:24][CH2:25][CH3:26])[C:20](=[N:22][OH:23])[CH3:21]
Reactant: CCCC(Oc1cc(N)ccc1Cl)C(C)=NO
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Product: CCCC(Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Cl)C(C)=NO
Temperature: 25 °C

Procedure:
A mixture of 1.52 g. of cyclohexene-1,2-dicarboxylic anhydride, 2.57 g. of 3-(5-amino-2-chlorophenoxy)-hexan-2-one oxime (nD25 =1.5506) and 8 ml. of acetic acid was refluxed for 2.5 hours and the reaction mixture was cooled to room temperature and the product was extracted with ethyl acetate and was washed with water and was dehydrated over sodium sulfate. The product was purified by a chromatography on a column of silica gel (developing solvent: ethyl acetate:n-hexane of 1:3) to obtain 3.53 g. of Compound No. 68 shown in Table 1.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[O:17][C@@H:16]([CH2:18][OH:19])[C@H:14]([OH:15])[C@@H:12]2[OH:13])=[C:4]([S:20][NH2:21])[N:3]=1.O.C1C=C(Cl)C=C(C(OO)=[O:31])C=1>C(O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[O:17][C@@H:16]([CH2:18][OH:19])[C@H:14]([OH:15])[C@@H:12]2[OH:13])=[C:4]([S:20]([NH2:21])=[O:31])[N:3]=1
Reactant: NSc1nc(N)nc2c1ncn2[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: CCO
Product: Nc1nc(S(N)=O)c2ncn([C@H]3O[C@@H](CO)[C@H](O)[C@@H]3O)c2n1
Temperature: -10 °C
Yield: 86.5 %

Procedure:
A mixture of 2-amino-9-(β-L-ribofiiranosyl)purine-6-sulfenamide 17 (200 mg, 0.637 mmol), ethanol (90 mL) and water (6.4 mL) was vigorously stirred at −10° C. in a salt-ice bath. A solution of MCPBA (80%, 137.0 mg, 0.637 mmol) in ethanol 5.5 mL was added dropwise over a period of 15 minutes. The mixture was allowed to stir and warm as the ice melt (8 h), and stirred at ambient temperature for addition 14 h. A small amount of precipitate was filtered out and the filtrate evaporated at 23° C. to dryness. The residue was triturated with ethyl ether (30 mL) and the solid was collected by filtration, washed with ethyl ether (10 mL). The solid was again suspended in ethyl ether (25 mL), filtered, and dried to give 182 mg (87%) of 2-amino-9-(β-L-ribofuranosyl)purine-6-sulfinamide 18 as a colorless solid.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[OH:26][C@H:27]([CH3:31])[C:28](O)=[O:29]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:28](=[O:29])[C@H:27]([OH:26])[CH3:31])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: C[C@@H](O)C(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: C[C@@H](O)C(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (17.7 mg, 53.8%), MS (ISP) m/z=403.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (30 mg, 0.0818 mmol) and (R)-2-hydroxypropanoic acid.
Reaction SMILES: OS(O)(=O)=O.[C:6]1([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N+:18]([O-])([OH:20])=[O:19].[OH-].[Na+]>>[N+:18]([C:9]1[CH:8]=[CH:7][C:6]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:11][CH:10]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])O
Reactant: c1ccc(-c2cccnc2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc(-c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 99 %

Procedure:
To a solution of H2SO4 (6 mL) cooled in an ice bath to 0° C. was added 3-phenylpyridine (1.0 g, 6.4 mmol). The orange-red solution was vigorously stirred while HNO3 (1 mL) was slowly added dropwise to give a cloudy light yellow solution. After stirring at room temperature for 20 min the solution was carefully poured into a beaker filled with ice (200 g). The solution was neutralized with 20% NaOH to give a cloudy white suspension which was extracted with EtOAc (3×150 mL). The organic layers were combined, washed with brine (2×50 mL), dried (NaSO4) and concentrated in vacuo to give the desired product (1.2 g, 99%) as a light yellow solid. Data for 3-(4-nitrophenyl)pyridine: Rf =0.47 (silica gel, methanol/CHCl3, 5/95); 1H NMR (400 MHz, acetone-d6) 8.99 (s, 1H), 8.67 (s, 1H), 8.37 (d, J=7.0, 2H), 8.18 (m, 1H), 8.02 (d, J=7.0, 2H), 7.53 (m, 1H).
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[NH:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:23]([O:22][C:21]([NH:20][CH2:19][CH2:18][N:10]1[C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:12][C:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:9]1)=[O:27])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: COC(=O)c1cc(-c2ccccc2)n[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(-c2ccccc2)nn1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 86.2 %

Procedure:
The compound prepared in Example 120 (0.500 g), tert-butyl 2-bromoethylcarbamate (0.704 g) and potassium carbonate (1.16 g) were suspended in acetonitrile (20 mL) and heated at reflux overnight. Another 0.5 equivalents of tert-butyl 2-bromoethylcarbamate was added and the reaction mixture heated at reflux overnight again. The reaction mixture was cooled to room temperature and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organics were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography to furnish the title compound (0.624 g) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:12]=[C:13]([C:30]3[CH:35]=[CH:34][C:33]([S:36][CH3:37])=[CH:32][CH:31]=3)[N:14]([CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.I([O-])(=O)(=O)=[O:39].[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[C:11]2[N:12]=[C:13]([C:30]3[CH:35]=[CH:34][C:33]([S:36]([CH3:37])=[O:39])=[CH:32][CH:31]=3)[N:14]([CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CSc1ccc(-c2nc3c(Cl)nc4ccccc4c3n2CCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)c1ccc(-c2nc3c(Cl)nc4ccccc4c3n2CCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 50 °C
Reaction time: 13 h
Yield: 72.4 %

Procedure:
To a suspension of 0.63 g of tert-butyl 4-[2-[4-chloro-2-(4-methylthio-phenyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl]-1-piperidinecarboxylate in 18 ml of 1,4-dioxane, a solution of 0.38 g of sodium periodate in 6 ml of water was added dropwise, and the mixture was stirred at 50° C. for 13 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography using 1,2-dichloroethane—methanol (10:1) as an eluting solvent to give 0.47 g of a colorless solid. Recrystallization from a mixture of isopropanol and water gave colorless crystals having the melting point of from 183 to 186° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:20])=[C:4]([S:8]([NH:11][C:12]2[S:13][CH:14]=[C:15]([CH2:17][CH2:18]O)[N:16]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:41].O>CN(C=O)C>[Br:41][CH2:18][CH2:17][C:15]1[N:16]=[C:12]([NH:11][S:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[CH3:20])(=[O:10])=[O:9])[S:13][CH:14]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCO)cs1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCBr)cs1
Temperature: 0 °C
Yield: 41 %

Procedure:
An ice-cold mixture of EXAMPLE 181A (2.03 g, 6.10 mmol), triphenylphosphine (4.80 g, 18.31 mmol) and carbontetrabromide (6.07 g, 18.31 mmol) in DMF (30 mL) was stirred for 1.5 h, and was then poured into water. The mixture was extracted with DCM, dried (sodium sulfate) and the solvent was evaporated. The crude material was twice purified by flash chromatography on silica gel gradient eluting with 0-4% acetone in DCM giving N-[4-(2-bromoethyl)-1,3-thiazol-2-yl]-3-chloro-2-methylbenzenesulfonamide as a solid (990 mg, 41%). MS (Ionspray, [M+H]+) m/z 394; Anal. Calcd. (found) for C12H12BrClN2O2S2: C, 36.4 (36.6)%; H, 3.1 (3.3)%; N ,7.1 (7.2)%.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:10]=[CH:11][CH:12]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CCCCCC.O1CCCC1>[CH2:26]([O:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:10]=[CH:11][CH:12]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCCCCCOCc1ccccc1
Reactant: CCCCC=Cc1cccc(Br)c1
Agent: [Li]C(C)(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCC=Cc1cccc(CCCCCOCc2ccccc2)c1
Reaction time: 0.17 h

Procedure:
At -78° C., 27.8 ml of t-butyl lithium (1.7M) in hexane are added to 5.30 gm of 3-bromo-(1-hexenyl)benzene in 75 mls of tetrahydrofuran. The reaction is stirred for 10 minutes, and then 1.1 ml of Li2CuCl3 (0.20M/THF) is added followed dropwise by 5.78 grams of 1-bromo-5-benzyloxy pentane. After allowing the reaction mixture to come to ambient temperature over 5 hours and stirring for an additional 24 hours, silica gel is added; and the mixture is concentrated and then chromatographed (HPLC) to yield pure 3-(5-benzyloxypentyl)-1-(1-hexenyl)benzene.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])([O-:3])=[O:2].C(N(CC)CC)C.[P:19]([O-:24])([O:22][CH3:23])[O:20][CH3:21]>C(OCC)(=O)C>[CH3:21][O:20][P:19]([CH:7]([OH:8])[C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:24])[O:22][CH3:23]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: COP([O-])OC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COP(=O)(OC)C(O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 77 %

Procedure:
3-Nitrobenzaldehyde (20 g, 0.132 mol) was dissolved in 100 mL of ethyl acetate. Triethylamine (22 mL, 0.158 mol, 1.2 eq) was added, followed by dimethyl phosphite (15.7 mL, 0.171 mmol, 1.3 eq) and the mixture was stirred at room temperature. After 2 hours the mixture was diluted with 150 mL of ethyl acetate and washed with saturated aqueous ammonium chloride (2×50 mL) and water (50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was treated with ethyl ether to obtain a beige solid, which was filtered and dried under vacuum at 40° C. for 1 h (26.7 g, 77% yield).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[CH:16]1([NH:22][C:23]([NH:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[S:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[ClH:1].[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2([OH:4])[CH2:2][S:24][C:23](=[N:22][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[N:25]2[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:6][C:7]=1[S:12](=[O:15])(=[O:14])[NH2:13]
Reactant: NS(=O)(=O)c1cc(C(=O)CCl)ccc1Cl
Reactant: S=C(NC1CCCCC1)NC1CCCCC1
Product: Cl
Product: NS(=O)(=O)c1cc(C2(O)CSC(=NC3CCCCC3)N2C2CCCCC2)ccc1Cl

Procedure:
5.2 g of 2,4'-dichloro-3'-sulfamoylacetophenone and 4.8 g of 1,3-dicyclohexylthiourea were reacted according to the prescription made in Example 12, the end product was precipitated with 200 ml of diethyl ether and the oil was crystallized after decanting the solvent with diethyl ether. Colorless, crystalline solid body: melting point: 177° C (from acrylonitrile).
Reaction SMILES: [CH2:1]([N:5]([CH2:13][CH2:14][CH2:15][CH3:16])[C:6]1[S:10][C:9]([CH:11]=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH2:17]([N:21]1[C:26]([OH:27])=[CH:25][C:24]([CH3:28])=[C:23]([C:29]#[N:30])[C:22]1=[O:31])[CH2:18][CH2:19][CH3:20]>C(OC(=O)C)(=O)C>[CH2:17]([N:21]1[C:26](=[O:27])/[C:25](=[CH:11]/[C:9]2[S:10][C:6]([N:5]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][CH:8]=2)/[C:24]([CH3:28])=[C:23]([C:29]#[N:30])[C:22]1=[O:31])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCn1c(O)cc(C)c(C#N)c1=O
Reactant: CCCCN(CCCC)c1ccc(C=O)s1
Solvent: CC(=O)OC(C)=O
Product: CCCCN1C(=O)C(C#N)=C(C)/C(=C\c2ccc(N(CCCC)CCCC)s2)C1=O

Procedure:
To a 100 ml flask, 3.0 g of 5-(dibutylamino)thiophene-2-carbaldehyde, 2.59 g of 1-butyl-6-hydroxy-4-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile and 10 ml of acetic anhydride are added, followed by heating while refluxing. After completion of the reaction, the resulting material is cooled and the solvent is removed to obtain (E)-1-butyl-5-((5-(dibutylamino)thiophen-2-yl)methylene)-4-methyl-2,6-dioxo-1,2,5,6-tetrahydropyridine-3-carbonitrile in solid phase.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=[O:4].[O-]CC.[Mg+2:13].[O-]CC>C1COCC1>[C:1]([O-:7])(=[O:6])[CH2:2][C:3]([O-:5])=[O:4].[CH2:8]([Mg+2:13])[CH3:9]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: [Mg+2]
Agent: CC[O-]
Solvent: C1CCOC1
Product: CC[Mg+2]
Product: O=C([O-])CC(=O)[O-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of monoethyl malonate 1(1.65 g, 12.5 mmol) in THF (25 mL) was added the magnesium ethoxide (0.61 g, 6.25 mmol). The reaction mixture was allowed to stir at rt for 5 h (until the solution become clear). The result solution was used for next step without any treatment.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH:22]([CH3:24])[CH3:23]>CN(C=O)C>[CH:22]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1)([CH3:24])[CH3:23]
Reactant: O=C1CCC(c2ccc(O)cc2)CC1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C2CCC(=O)CC2)cc1
Temperature: 100 °C
Yield: 95.6 %

Procedure:
A solution of 4-(4-hydroxyphenyl)cyclohexanone (6.0 g, 31.6 mmol) in DMF (90 mL) was treated with K2CO3 (21 g, 158 mmol, 5 equiv) and 2-iodopropane (15 mL, 26.8 g, 158 mmol, 5 equiv.). The reaction was heated at 100° C. overnight. After the solvent was removed, the residue was treated with H2O and extracted with EtOAc. The organic extracts were combined and washed with brine, dried over Na2SO4 and concentrated in vacuum to give the spectroscopically pure 4-(4-isopropoxyphenyl)cyclohexanone (7.02 g, 95%). 1H NMR (CDCl3): 7.14 (dt, 2H), 6.84 (dt, 2H), 4.3 (septet, 1H), 2.97 (tt, 1H), 2.46-2.52 (m, 4H), 2.16-2.24 (m, 2H), 1.83-1.98 (m, 2H) and 1.33 (d, 6H). Step 2:
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)=[N:5][CH:4]=1.Cl.[F:19][C:20]1[CH:33]=[CH:32][C:23]([CH2:24][C:25]2([OH:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[F:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:24][C:25]2([OH:31])[CH2:26][CH2:27][N:28]([C:11]([C:10]3[C:9]([C:6]4[CH:7]=[CH:8][N:3]=[CH:4][N:5]=4)=[N:17][CH:16]=[CH:15][CH:14]=3)=[O:13])[CH2:29][CH2:30]2)=[CH:32][CH:33]=1
Reactant: OC1(Cc2ccc(F)cc2)CCNCC1
Reactant: O=C(O)c1cccnc1-c1ccncn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1cccnc1-c1ccncn1)N1CCC(O)(Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.2 %

Procedure:
A suspension of 2-(pyrimidin-4-yl)nicotinic acid dihydrochloride (0.25 g), 4-(4-fluorobenzyl)-4-hydroxypiperidine hydrochloride (0.22 g), HATU (0.52 g) and triethylamine (0.76 mL) in DMF (3 mL) was stirred overnight at room temperature. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and recrystallized from ethyl acetate/hexane to give the title compound (0.050 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[C:28]=1[C:29](Cl)=[O:30].O=C1CC(=O)N(C2C=CC(C(O)=O)=CC=2)C2C=CC3C(C=2N1)=CC=CC=3>>[CH3:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[C:28]=1[C:29]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:30]
Reactant: COc1cccc(C(F)(F)F)c1C(=O)Cl
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C1CC(=O)N(c2ccc(C(=O)O)cc2)c2ccc3ccccc3c2N1
Product: COc1cccc(C(F)(F)F)c1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 74 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3), and 2-methoxy-6-(trifluoromethyl)benzoyl chloride, the title compound (yield 74%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5][CH2:4][C@@H:3]2[CH2:7][NH:8][CH2:9][C@H:2]12.CCN(C(C)C)C(C)C.[NH2:26][C:27]1[N:32]=[C:31](Cl)[CH:30]=[C:29]([Cl:34])[N:28]=1>CCO.O>[NH2:26][C:27]1[N:32]=[C:31]([N:8]2[CH2:7][C@@H:3]3[C@@H:2]([N:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5][CH2:4]3)[CH2:9]2)[CH:30]=[C:29]([Cl:34])[N:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]2CNC[C@@H]21
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]2CN(c3cc(Cl)nc(N)n3)C[C@@H]21
Yield: 77.7 %

Procedure:
To a solution of racemic tert-butyl (4aR*,7aR*)-octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate (460 mg, 2.03 mmol) in EtOH (1 mL) containing DIPEA (590 μL, 3.39 mmol) was added a solution of 2-amino-4,6-dichloropyrimidine (277 mg, 169 mmol) in EtOH (9 mL) with stirring and the solution was heated to reflux for 24 hours. The solution was cooled and diluted with water (10 mL) and the resulting solid was collected by filtration, washed with water (20 mL) and dried in vacuo at 60° C. to yield the title compound as a white solid (558 mg, 93%).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C(O[CH:15]=[CH:16][C:17](=O)[C:18](F)([F:20])[F:19])C.C(N(CC)CC)C>C(#N)C>[CH2:9]([O:8][C:6](=[O:7])[C:5]1[CH:15]=[CH:16][C:17]([CH:18]([F:20])[F:19])=[C:3]([S:2][CH3:1])[C:4]=1[OH:11])[CH3:10]
Reactant: CCOC=CC(=O)C(F)(F)F
Reactant: CCOC(=O)CC(=O)CSC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C(F)F)c(SC)c1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
60 g of ethyl 4-(methylsulphanyl)-3-oxobutanoate and 61.3 g of 4-ethoxy-1,1,1-trifluorobut-3-en-2-one were initially charged in 312 g of acetonitrile and cooled to 0° C. under nitrogen. Within 30 minutes, 17.2 g of triethylamine were added dropwise at 0° C. and then stirring of the mixture at 0° C. continued for 2 hours. The reaction was stirred at 20° C. overnight, concentrated and admixed with 265 g of 10% sodium hydroxide solution, the mixture was stirred for 1 h, and the solids were filtered off with suction, washed 3 times with 50 ml of 3.5% NaOH and dried by suction. The solids were then admixed with 250 ml of water and 250 ml of toluene, and adjusted to pH 1 with 10% HCl, and further HCl was metered in with continued stirring until the pH remains below 3. Finally, the filtered phases were separated and the water phase was extracted once more with toluene. The combined toluene phases were dried and concentrated: Yield 53.7 g (60.1% of theory). 1H NMR (CDCl3, 400 MHz): δ=11.73 ppm (1H, s), 7.95 ppm (1H, d), 7.22 ppm (1H, d), 7.11-7.25-7.39 ppm (1H, t, CHF2), 4.46 ppm (2H, q), 2.41 ppm (3H, s), 1.44 ppm (3H, t).