Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[CH2:2][CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.[CH3:25]S(C)=O>>[CH3:2][C:3]([C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)([C:4]([O:6][CH2:7][CH3:25])=[O:5])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(CC)C(=O)OC
Reactant: CS(C)=O
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C)(C(=O)OCC)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
Diethyl methyl malonate (6.17 g, 35.4 mmol) was added to a stirred solution of sodium hydride (1.63 g, 42.5 mmol, 60%) in DMSO (50 ml) and stirred for 1 h at room temperature. 1-Fluoro-4-nitrobenzene (5.00 g, 35.4 mmol) was added dropwise to the reaction mixture and stirred for 6 h at room temperature. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with diethyl ether. The separated organic layer was washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the crude product. Purified by column chromatography over silica gel (60-120 mesh) using 20% ethyl acetate in petroleum ether as eluent afford 8.20 g (78.8%) of diethyl 2-methyl-2-(4-nitrophenyl)malonate as an oil.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][N:15]([C:19]([N:21]4[CH2:26][CH2:25][CH:24]([C:27]([F:30])([F:29])[F:28])[CH2:23][CH2:22]4)=[O:20])[CH2:14][C:13]=3[CH:31]=2)O1.Br[C:34]1[CH:39]=[CH:38][C:37]([C:40]2[N:41](C(OCC(C)C)=O)[CH:42]=[CH:43][N:44]=2)=[CH:36][CH:35]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1.O>[NH:41]1[CH:42]=[CH:43][N:44]=[C:40]1[C:37]1[CH:38]=[CH:39][C:34]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][N:15]([C:19]([N:21]4[CH2:22][CH2:23][CH:24]([C:27]([F:28])([F:30])[F:29])[CH2:25][CH2:26]4)=[O:20])[CH2:14][C:13]=3[CH:31]=2)=[CH:35][CH:36]=1
Reactant: CC(C)COC(=O)n1ccnc1-c1ccc(Br)cc1
Reactant: CC1(C)OB(c2ccc3c(c2)CN(C(=O)N2CCC(C(F)(F)F)CC2)CCO3)OC1(C)C
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N1CCC(C(F)(F)F)CC1)N1CCOc2ccc(-c3ccc(-c4ncc[nH]4)cc3)cc2C1
Temperature: 120 °C
Yield: 14 %

Procedure:
To a solution of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-{[4-(trifluoromethyl)piperidin-1-yl]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepine (0.4 g, 0.88 mmol) and isobutyl 2-(4-bromophenyl)-1H-imidazole-1-carboxylate (0.6 g, 1.86 mmol) in dioxane (4 mL) and water (0.5 ml) was added diisopropylethylamine (0.34 g, 2.64 mmol). The solution was sparged with N2(g) for ten minutes before the addition of dichloro[1,1-bis-(diphenylphosphino]ferrocenepalladium (II) dichloromethane adduct (0.072 g, 10 mol %). The resulting suspension was heated at 120° C. for 2 hours in a sealed tube on a CEM Explorer microwave synthesizer. On cooling to room temperature the mixture was diluted with ethyl acetate (100 mL), washed with saturated sodium bicarbonate (70 mL), brine (50 mL) then dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel chromatography (97:3 dichloromethane/methanol) then preparative reverse phase HPLC of the combined product containing fractions (0.1% aqueous ammonium acetate-acetonitrile) to afford 7-[4-(1H-imidazol-2-yl)phenyl]-4-{[4-(trifluoromethyl)piperidin-1-yl]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepine (0.058 g, 12% yield) as a white solid. 1H NMR (400 MHz, methanol-d4): 7.92 (d, 2H), 7.70 (d, 2H), 7.58-7.50 (m, 2H), 7.15 (s, 2H), 7.05 (d, 1H), 4.52 (s, 2H), 4.22 (t, 2H), 3.77 (d, 2H), 3.71 (t, 2H), 2.87 (t, 2H), 2.39 (m, 1H), 1.86 (d, 2H), 1.59 (m, 2H); MS (EI) for C25H25F3N4O2: 471 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:15][O:16][CH3:17])([CH2:12][O:13][CH3:14])[C@@H:9]([OH:18])[C@H:8]([NH:19][C:20]3[CH:25]=[CH:24][C:23](=[O:26])[NH:22][N:21]=3)[C:7]=2[CH:27]=1)#[N:2].Br[CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:12][O:13][CH3:14])([CH2:15][O:16][CH3:17])[C@@H:9]([OH:18])[C@H:8]([NH:19][C:20]3[CH:25]=[CH:24][C:23](=[O:26])[N:22]([CH2:29][CH2:30][CH3:31])[N:21]=3)[C:7]=2[CH:27]=1)#[N:2]
Reactant: COCC1(COC)Oc2ccc(C#N)cc2[C@@H](Nc2ccc(=O)[nH]n2)[C@@H]1O
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1nc(N[C@@H]2c3cc(C#N)ccc3OC(COC)(COC)[C@H]2O)ccc1=O
Yield: 49.8 %

Procedure:
(-)-(3S,4R)-6-Cyano-3,4-dihydro-4-[(1,6-dihydro-6-oxo-3-pyridazinyl)amino]-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol (60 mg, 0.16 mmol) obtained in Example 8 and 1-bromopropane (0.017 ml, 0.19 mmol) were dissolved in dimethylformamide (1.0 ml). Potassium carbonate (45 mg) was added and the mixture was reacted at 70° C. for 3 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (methanol:chloroform=4:96) to give 33 mg of the title compound (50%).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].Cl.[CH:15]([NH:18][C:19]([NH:21][C:22]#[N:23])=[NH:20])([CH3:17])[CH3:16]>C(O)(C)C>[CH3:1][N:2]([CH3:13])[S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:22]([NH:21][C:19]([NH:18][CH:15]([CH3:17])[CH3:16])=[NH:20])=[NH:23])=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)c1ccc(N)cc1
Reactant: CC(C)NC(=N)NC#N
Agent: Cl
Solvent: CC(C)O
Product: CC(C)NC(=N)NC(=N)Nc1ccc(S(=O)(=O)N(C)C)cc1

Procedure:
To 11 g (0.055 mole) of p-N,N-dimethylsulfamylaniline is added 17.68 ml (0.055) of 3.1 N hydrochloric acid. This is heated on a steam bath with 15 ml of isopropanol and 6.94 g (0.055 mole) of 1-i-propyl-3-cyanoguanidine. The reaction mixture is heated for 18 hours. The alcohol is evaporated off and diluted with 250 ml of 7.4% hydrochloric acid. The mixture is filtered, cooled and made alkaline with 10% sodium hydroxide. The precipitate is filtered, triturated with 100 ml of boiling isopropanol and filtered to get 1-(p-N,N-dimethylsulfamylphenyl)-5-i-propylbiguanide.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:12]([O:14][C:15](=[O:19])[C:16]#[C:17][CH3:18])[CH3:13].N12CCCN=C1CCCCC2>O1CCCC1>[CH2:12]([O:14][C:15](=[O:19])[CH:16]=[C:17]([O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH3:18])[CH3:13]
Reactant: Oc1cccc2ccccc12
Reactant: CC#CC(=O)OCC
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C=C(C)Oc1cccc2ccccc12
Temperature: 130 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
A mixture of naphthalen-1-ol (1.28 g, 8.91 mmol) and ethyl-2-butynoate (2.0 g, 17.8 mmol) in tetrahydrofuran (13.7 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (1.33 mL, 8.91 mmol). The reaction was then heated at 130° C. for 1.5 h. At this time, the reaction was cooled to 25° C. and was stirred at 25° C. overnight. At this time, the reaction was concentrated in vacuo. The residue was dissolved in dichloromethane (40 mL) and was washed with a 2N aqueous hydrochloric acid solution (1×100 mL), a 0.5N aqueous sodium hydroxide solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL). The organics were then dried over sodium sulfate, filtered, rinsed with dichloromethane and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 5-10% ethyl acetate/hexanes) afforded 3-(naphthalen-1-yloxy)-but-2-enoic acid ethyl ester (1.16 g, 50%) as a clear oil: HR-ES-MS m/z calculated for C16H16O3 [M+H]+ 257.1172, observed 257.1172; 1H NMR (300 MHz, DMSO-d6), δ ppm 1.04 (t, J=7.1 Hz, 3H), 2.60 (s, 3H), 3.93 (q, J=7.1 Hz, 2H), 4.52 (s, 1H), 7.31 (d, J=7.2 Hz, 1H), 7.53-7.65 (m, 3H), 7.78-7.84 (m, 1H), 7.90 (d, J=8.2 Hz, 1H), 7.99-8.07 (m, 1H).
Reaction SMILES: [C:1]([N:4]([CH2:17][CH2:18][O:19][C:20](=[C:28]1[CH:35]2[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:37][CH:29]1[CH2:30]3)[CH2:34]2)[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=1)[C:5]([C:7]1[S:8][C:9]2[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:10]=2[N:11]=1)=[O:6])(=[O:3])[CH3:2].[OH:38][C:39]1C=CC2N=C(C(NCCOC(=C3C4CC5CC(CC3C5)C4)C3C=CC=C(O)C=3)=O)SC=2[CH:40]=1>C(OCC)(=O)C.CCCCCC>[C:39]([O:27][C:23]1[CH:22]=[C:21]([C:20](=[C:28]2[CH:35]3[CH2:36][CH:31]4[CH2:32][CH:33]([CH2:37][CH:29]2[CH2:30]4)[CH2:34]3)[O:19][CH2:18][CH2:17][N:4]([C:1](=[O:3])[CH3:2])[C:5]([C:7]2[S:8][C:9]3[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:6])[CH:26]=[CH:25][CH:24]=1)(=[O:38])[CH3:40]
Reactant: O=C(NCCOC(=C1C2CC3CC(C2)CC1C3)c1cccc(O)c1)c1nc2ccc(O)cc2s1
Reactant: CC(=O)N(CCOC(=C1C2CC3CC(C2)CC1C3)c1cccc(O)c1)C(=O)c1nc2ccc(O)cc2s1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)Oc1cccc(C(OCCN(C(C)=O)C(=O)c2nc3ccc(O)cc3s2)=C2C3CC4CC(C3)CC2C4)c1

Procedure:
The second product was obtained with 35% ethyl acetate/hexane and was found to be {[2-(N-acetyl-N-(6-hydroxybenzothiazole-2-carbonyl)amino)ethoxy][3-hydroxyphenyl]methylene}adamantane (3a): 1H NMR (CDCl3) δ1.80-1.96 (m, 12H), 2.18 (s, 3H), 2.67 (bs, 1H), 3.33 (bs, 1H), 3.65 (m, 4H), 6.74 (bs, 1H), 6.96-7.92 (m, 7H), 7.79 (bs, 1H).; 13C NMR (CDCl3) δ20.97, 28.22, 30.53, 32.35, 37.07, 39.01, 39.14, 39.97, 67.79, 107.09, 117.16, 120.75, 122.35, 125.13, 126.71, 129.10, 133.50, 136.72, 138.86, 140.98, 147.39, 150.65, 155.72, 160.34, 160.43, 169.36. The third product was identified as {[2-(N-(6-hydroxybenzothiazole-2-carbonyl)amino)ethoxy][3-hydroxyphenyl]methylene}adamantane ##STR35##
Reaction SMILES: C(OC([NH:8][N:9]1[C:13]([C:14]#[N:15])=[CH:12][CH:11]=[C:10]1[CH:16]1[CH2:19][N:18]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:17]1)=O)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+]>CO.O1CCOCC1>[NH2:8][N:9]1[C:13]([C:14]#[N:15])=[CH:12][CH:11]=[C:10]1[CH:16]1[CH2:17][N:18]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:19]1
Reactant: CC(C)(C)OC(=O)Nn1c(C#N)ccc1C1CN(C(=O)OCc2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: N#Cc1ccc(C2CN(C(=O)OCc3ccccc3)C2)n1N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.1 %

Procedure:
To a cooled (0° C.) solution of benzyl 3-{1-[(tert-butoxycarbonyl)amino]-5-cyano-1H-pyrrol-2-yl}azetidine-1-carboxylate (800 mg, 2.02 mmol) in methanol (2.5 mL) was added a solution of 4 M HCL in dioxane (2.5 mL). The reaction was stirred (0° C.) for 15 min, then was allowed to warm to rt. After 4 h, the reaction was recooled (0° C.) and the mixture was made basic (pH 9) with slow addition of 2M aqueous Na2CO3. The mixture was allowed to warm to rt and was extracted with EtOAc (3×20 mL). The combined organics were washed with brine, dried (Na2SO4), and evaporated to afford 575 mg (96%) of the desired product, which was used without further characterization.
Reaction SMILES: [CH3:1][C:2]([CH:5]([CH2:11]C=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])([CH3:4])[CH3:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O[CH:28]([O:32][CH2:33][CH3:34])[O:29][CH2:30][CH3:31])C>>[CH2:33]([O:32][CH:28]([O:29][CH2:30][CH3:31])[CH2:11][CH:5]([C:2]([CH3:3])([CH3:1])[CH3:4])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:34]
Reactant: CCOC(=O)C(CC=O)C(C)(C)C
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(=O)C(CC(OCC)OCC)C(C)(C)C

Procedure:
Ethyl (RS)-2-(1,1-dimethylethyl)-4-oxo-butanoate (0.57 g) was dissolved in excess triethylorthoformate and a catalytic amount of p-toluenesulphonic acid was added. After stirring for 1 hour at the ambient temperature, excess triethylorthoformate was evaporated under reduced pressure to give ethyl (RS)-4,4-diethoxy-2-(1,1-dimethylethyl)butanoate, the spectral data of which were identical to those obtained in Example 6 (ii).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:18])=[C:13]([N:15]=[C:16]=[S:17])[CH:14]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:18])=[C:13]([N:15]2[C:5](=[O:7])[CH2:4][N:3]([CH2:1][CH3:2])[C:16]2=[S:17])[CH:14]=1
Reactant: CCNCC(=O)O
Reactant: Cc1ccc(Cl)cc1N=C=S
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(c2cc(Cl)ccc2C)C1=S
Yield: 56.6 %

Procedure:
A mixture of the crude N-ethyl glycine (9.23 g), 5-chloro-2-methylphenylisothiocyanate (9.18 g), triethyl amine (10 g) and chloroform (250 mL) was heated at reflux for 18 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (400 mL) and water (300 mL). The organic phase was washed with 1N HCl (2×300 mL), then evaporated to dryness. Purification was achieved through crystallization from ethanol. The title compound (7.6 g) was obtained as a light pink solid, m.p. 152°-154° C. Anal. Calcd. for. C12H13Cl N2O S: C, 53.63; H, 4.88; N, 10.42. Found: C, 53.36; H, 4.79; N, 10.35. Mass spectrum (EI, M.+) m/z 268/270.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([S:40](Cl)(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=1>>[CH:27]1([CH2:26][N:10]2[C:9]3[N:8]=[C:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:36]5[CH:37]=[CH:38][CH:39]=[C:34]([O:33][CH3:32])[CH:35]=5)(=[O:42])=[O:41])=[CH:31][CH:30]=4)[NH:15][C:14]=3[C:13](=[O:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:11]2=[O:25])[CH2:28][CH2:29]1
Reactant: Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Product: COc1cccc(S(=O)(=O)Nc2ccc(Cc3nc4c([nH]3)c(=O)n(Cc3ccccc3F)c(=O)n4CC3CC3)cc2)c1

Procedure:
Prepared from 8-(4-amino-benzyl)-3-cyclopropylmethyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 3-methoxy-benzenesulfonyl chloride. White solid; EI-HRMS m/e calculated for C30H28FN5O5S (M+) 589.1795, found 589.1801.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=1)=[O:5])C.[Li+].[OH-].Cl>C1COCC1.CO.O>[CH:11]([C:9]1[N:10]=[C:6]([C:4]([OH:5])=[O:3])[S:7][CH:8]=1)([CH3:13])[CH3:12]
Reactant: CCOC(=O)c1nc(C(C)C)cs1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1csc(C(=O)O)n1

Procedure:
To a solution of 3.12 g (15.7 mmol) of 4-isopropylthiazole-2-carboxylic acid ethyl ester in 32 mL of 75% THF/MeOH, was added 110 mg (31.3 mmol) of LiOH in 8 mL of H2O. The mixture was stirred overnite, the solution adjusted to pH 5 using 1N aqueous HCl solution and concentrated in vacuo to afford 4-isopropylthiazole-2-carboxylic acid as a white solid (2.97 g including salts) which was used directly in Step E: 1H NMR (500 methanol-d4) δ ppm 1.29 (d, J=6.7 Hz, 6H), 3.20 (m, 1H), 7.39 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[C:4]([F:10])[C:3]=1[O:11][C:12]1[CH:17]=[C:16]([CH:18]2[CH2:20][CH2:19]2)[CH:15]=[C:14]([Cl:21])[CH:13]=1.[Cl:22][C:23]1[N:24]=[CH:25][N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:27]=1[C:28](O)=[O:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[Cl:22][C:23]1[N:24]=[CH:25][N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:27]=1[C:28]([NH:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:11][C:12]2[CH:17]=[C:16]([CH:18]3[CH2:20][CH2:19]3)[CH:15]=[C:14]([Cl:21])[CH:13]=2)[C:4]=1[F:10])=[O:29]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Reactant: NCc1ccc(Cl)c(Oc2cc(Cl)cc(C3CC3)c2)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(C3CC3)c2)c1F
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of ({4-chloro-3-[(3-chloro-5-cyclopropylphenyl)oxy]-2-fluorophenyl}methyl)amine (86 mg, 0.264 mmol), 4-chloro-1-({[2(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (73.0 mg, 0.264 mmol) and HATU (100 mg, 0.264 mmol) in DMF (5 ml) was added diisopropylethyl amine (0.092 ml, 0.527 mmol) and the reaction mixture was stirred at rt for 45 minutes. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give the desired compound which was only ˜85% pure. This was purified via reverse phase HPLC to give 4-chloro-N-({4-chloro-3-[(3-chloro-5-cyclopropylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (98 mg, 0.168 mmol, 64% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[C:6]1(=O)[O:11][C:9](=[O:10])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]12>>[O:10]=[C:9]1[C:8]2[C:7](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6](=[O:11])[N:1]1[CH2:2][C:3]([OH:5])=[O:4]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCC(=O)O
Product: O=C(O)CN1C(=O)c2ccccc2C1=O

Procedure:
(G1) irradiating a reaction product of glycine (a) and phthalic anhydride (b) with microwaves to produce 2-(1,3-dioxoisoindolin-2-yl)acetic acid (compound 1);
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:15]([OH:17])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][CH:19]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:20]([OH:24])[C:21]([NH2:23])=[O:22].O[NH-].O=[N-]>>[NH2:23][C:21](=[O:22])[C:20](=[O:24])[CH:19]([NH:18][C:15]([C@H:9]1[CH2:10][CH2:11][CH2:12][C:13](=[O:14])[N:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:17])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Reactant: O=C(O)[C@H]1CCCC(=O)N1Cc1ccccc1
Agent: [N-]=O
Agent: [NH-]O
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)[C@H]1CCCC(=O)N1Cc1ccccc1

Procedure:
Coupling of (R)-1-benzyl-6-oxo-piperidine-2-carboxylic acid with 3-amino-2-hydroxy-4-phenylbutanamide and oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Al](Cl)(C)C.[CH3:13][N:14]([CH3:39])[C:15]([C:17]1[N:22]=[CH:21][C:20]([O:23][C:24]2[C:29]3[CH:30]=[C:31]([CH3:33])[O:32][C:28]=3[CH:27]=[C:26]([C:34](OCC)=[O:35])[CH:25]=2)=[CH:19][CH:18]=1)=[O:16]>ClCCCl.C(Cl)Cl>[CH3:39][N:14]([CH3:13])[C:15]([C:17]1[CH:18]=[CH:19][C:20]([O:23][C:24]2[C:29]3[CH:30]=[C:31]([CH3:33])[O:32][C:28]=3[CH:27]=[C:26]([C:34]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=3)=[O:35])[CH:25]=2)=[CH:21][N:22]=1)=[O:16]
Reactant: Cc1ccc(N)nc1
Reactant: CCOC(=O)c1cc(Oc2ccc(C(=O)N(C)C)nc2)c2cc(C)oc2c1
Agent: C[Al](C)Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1ccc(NC(=O)c2cc(Oc3ccc(C(=O)N(C)C)nc3)c3cc(C)oc3c2)nc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 45.2 %

Procedure:
To a solution of 5-methylpyridin-2-amine (191 mg, 1.76 mmol) in DCE at 0° C. was added Al(CH3)2Cl drop-wise. After stirring the mixture at room temperature for 20 minutes ethyl 4-({6-[(dimethylamino)carbonyl]pyridin-3-yl}oxy)-2-methyl-1-benzofuran-6-carboxylate (65 mg, 0.18 mmol) was added. The reaction was stirred at room temperature for 14 hours. The sample was diluted with CH2Cl2 and quenched with potassium sodium tartrate tetrahydrate (20% w/w) (1 mL). Caution, addition was done slowly. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude sample was introduced into a silica gel column and eluted with MeOH/CHCl3 (3/97) to provide the product (35 mg, 85% yield) as white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.32 (s, 3 H) 2.48 (s, 3 H) 3.16 (d, J=7.54 Hz, 6 H) 6.26 (s, 1 H) 7.31 (dd, J=8.67, 2.83 Hz, 1 H) 7.48 (d, J=1.13 Hz, 1 H) 7.58 (d, J=6.78 Hz, 1 H) 7.69 (d, J=8.67 Hz, 1 H) 7.87 (s, 1 H) 8.12 (s, 1 H) 8.26 (d, J=8.48 Hz, 1 H) 8.38 (d, J=2.64 Hz, 1 H) 8.53 (s, 1 H); MS (ESI, pos): 431.
Reaction SMILES: [CH2:1]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].S(Cl)([Cl:28])=O>>[CH2:1]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([Cl:28])=[O:25])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Product: CCCCCCCCCOc1ccc(-c2ccc(C(=O)Cl)cc2)cc1

Procedure:
After 1.2 g of 4'-n-nonyloxybiphenyl-4-carboxylic acid was heated together with an excess amount of thionyl chloride for 6 hours under a reflux condition, unaltered thionyl chloride was distilled off to obtain 1.25 g of 4'-n-nonyloxybiphenyl-4-carboxylic acid chloride.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.C(O)(C(F)(F)F)=O>>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]2[C:5]3[NH:6][C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]=3[CH2:3][CH2:2][NH:1]2)=[CH:16][CH:15]=1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=Cc1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(C2NCCc3c2[nH]c2ccccc32)cc1
Yield: 49 %

Procedure:
This product was prepared using the same procedure as for Intermediate 1 with tryptamine (5.0 g, 30 mmol), 4-chlorobenzaldehyde (4.6 g, 1 equiv.) and TFA (4.6 mL, 2 equiv.) to give the title compound (4.16 g, 49%) as a white powder. MP: 161° C.
Reaction SMILES: [O:1]1[C:5]2[CH2:6][NH:7][CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=[CH:2]1.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23](F)=[C:22]([Cl:27])[C:21]=1[Br:28])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[ClH:27].[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:11][CH:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]3[O:1][CH:2]=[CH:3][C:4]2=3)=[C:22]([Cl:27])[C:21]=1[Br:28])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: OC1CCNCc2occc21
Reactant: Fc1ccc(OCc2ccccc2)c(Br)c1Cl
Product: Cl
Product: Clc1c(OC2CCNCc3occc32)ccc(OCc2ccccc2)c1Br

Procedure:
The same method as in Example 3 was conducted using 5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 37) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-benzyloxy-3-bromo-2-chloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:6](=[N:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]([N+:16]([O-:18])=[O:17])=[CH:4][CH:3]=1.C(N(CC)CC)C.[P:26](=[O:44])(Cl)([S:38][CH2:39][CH2:40][CH2:41][CH3:42])[O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[P:26](=[O:44])([S:38][CH2:39][CH2:40][CH2:41][CH3:42])([O:1][C:2]1[C:15]2[C:6](=[N:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]([N+:16]([O-:18])=[O:17])=[CH:4][CH:3]=1)[O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:30][CH:29]=1
Reactant: CCCCSP(=O)(Cl)Oc1ccc(C(F)(F)F)cc1
Reactant: O=[N+]([O-])c1ccc(O)c2cc3ccccc3nc12
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCSP(=O)(Oc1ccc(C(F)(F)F)cc1)Oc1ccc([N+](=O)[O-])c2nc3ccccc3cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-Hydroxy-4-nitroacridine (0.01 mole), triethylamine (0.01 mole) tetrahydrofuran (25 ml) and toluene (25 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture is cooled to a temperature of about 0° C. and O-(4-trifluoromethylphenyl) S-butyl phosphorochloridothioate (0.01 mole) dissolved in toluene (25 ml) is added with stirring over a period of about 30 minutes. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 16 hours. After this time the reaction mixture is filtered to remove triethylamine hydrochloride. The filtrate is then washed with water, dried over anhydrous magnesium sulfate and stripped of solvents leaving a residue. This residue is subjected to flash chromatography using ethyl acetate as the eluant to yield the desired product O-(4-trifluoromethylphenyl) O-(4-nitroacridin-1-yl) S-butyl phosphorothioate.