Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)#[N:4].Cl.[CH3:14][C:15]([CH3:17])=[O:16]>O>[C:3]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:14][C:15](=[O:16])[CH3:17])=[CH:7][CH:6]=1)#[N:4]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1ccc(C#N)cc1
Temperature: 14 °C
Reaction time: 8 h
Yield: 49.25 %

Procedure:
Water (150 ml) and 10% NaOH aqueous solution (4.5 ml) were added under vigorous stirring to a solution of 4-cyanobenzaldehyde (7.0 g, 80.6 mmol) in acetone (40 ml) and water(25 ml). The reaction mixture was stirred at 14° C. for 8 hr, after the reaction completed, the reaction mixture was neutralized with 6N hydrochloric acid to adjust pH=7-8.The precipitated separated solid was collected by filtration and dried, then recrystallized from anhydrous ethanol to give 4.8 g of crystals in needles, mp: 102-103° C., yield: 49.25%.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]([C:9]1[S:13][C:12]2[CH:14]=[C:15]([CH2:18]O)[CH:16]=[CH:17][C:11]=2[C:10]=1[CH3:20])=[O:8]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:5][O:6][C:7]([C:9]1[S:13][C:12]2[CH:14]=[C:15]([CH2:18][Cl:3])[CH:16]=[CH:17][C:11]=2[C:10]=1[CH3:20])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1sc2cc(CO)ccc2c1C
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1sc2cc(CCl)ccc2c1C
Reaction time: 1 h

Procedure:
Thionyl chloride (0.75 ml.) was added cautiously to a solution of 6-hydroxymethyl-3-methylbenzo[b]-thiophene-2-carboxylic acid methyl ester (0.70 g.) and pyridine (3 drops) in chloroform (7.5 ml.) and the resulting solution was allowed to stand for 1 hour. It was then washed successively with water, sodium bicarbonate solution and dried (Na2SO4). Evaporation of the solvent gave a solid which was crystallized from petrol (b.p. 60°-80°) to give 6-chloromethyl-3-methylbenzo[b]thiophene-2-carboxylic acid methyl ester (0.63 g.), m.p. 128°-129° C.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCCC)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[NH:33]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]([NH:40][CH3:41])[CH2:34]1>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:33]5[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]([NH:40][CH3:41])[CH2:34]5)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:30])([F:32])[F:31])[CH:3]=1
Reactant: CNC1CCCCNC1
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CNC1CCCCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-methylamino-azepan-1-yl)-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and Azepan-3-yl-methyl-amine following General Procedure B.
Reaction SMILES: [C:1](ON=O)(C)([CH3:3])[CH3:2].C(Br)C=C.[Br:12][C:13]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:14]=1N.NC1C=CC=CC=1>CC#N>[CH2:3]([C:14]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:13]=1[Br:12])[CH:1]=[CH2:2]
Reactant: CC(C)(C)ON=O
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Solvent: C=CCBr
Solvent: Nc1ccccc1
Solvent: CC#N
Product: C=CCc1cc([N+](=O)[O-])ccc1Br
Temperature: 37.5 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To a solution of t-butylnitrite (535 μl, 4.5 mmol) and allyl bromide (3.9 ml, 45.0 mmol) in CH3CN (3 ml), 2-bromo-5-nitroaniline (651 mg, 3.0 mmol) was added during 20 minutes, while maintaining the temperature of the reaction mixture at 35-40° C. At the end of the addition of the aniline, extra t-butylnitrite (180 μl, 1.5 mmol) was added to the reaction mixture which then was stirred at 23° C. for one hour. The volatile material in the reaction mixture was removed at reduced pressure. Column chromatography (heptane-ethyl acetate 49:1) gave 568 mg (78%) allyl-2-bromo-5-nitrobenzene as a light yellow oil containing 7% of 3,4-dibromo-nitrobenzene, which crystallized upon standing overnight in the refrigerator. This corresponds to 72% yield of allyl-2-bromo-5-nitrobenzene. The allyl-2-bromo-5-nitrobenzene could be purified by crystallization from pentane. 1H NMR (CDCl3, 400 MHz) δ 8.10, (d, 1H, J=2.7 Hz), 7.95, (dd, 1H, J=8.7, 2.7 Hz), 7.74, (d, 1H, J=8.7 Hz), 6.03-5.92, (m, 1H), 5.26-5.13, (m, 2H), 3.60, (m, 2H, J=6.5 Hz); 13C NMR (CDCl3, 100 MHz) δ 147.7, 142.0, 134.1, 134.1, 132.3, 125.3, 122.9, 118.8, 40.5; Anal HRMS Calcd. for C9H8BrNO2 (M): 240.9738. Found: 240.9739.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[O:15]1[CH2:20][CH2:19][CH:18]([NH2:21])[CH2:17][CH2:16]1>CN(C)C=O.C(OCC)(=O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:21][CH:18]2[CH2:19][CH2:20][O:15][CH2:16][CH2:17]2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: NC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1cc(NC2CCOCC2)ncn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
4,6-Dichloropyrimidine (3.06 g, 20.5 mmol) was dissolved in dimethylformamide (“DMF”) (20 mL) and Cs2CO3 (10.0 g, 30.8 mmol) was added. Tetrahydro-2H-pyran-4-amine (1.87 g, 18.5 mmol) combined with DMF (5 mL) was added dropwise. A slight exotherm was observed. After agitating at ambient temperature for 2 hours, product peak was seen in LC/MS. Agitation continued overnight. The mixture was then diluted with ethyl acetate (250 mL) and washed 4 times with water, brine, dried and evaporated to give 6-chloro-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine (2.86 g, 13.4 mmol, 65.2% yield) as a solid.
Reaction SMILES: C[O:2][C:3]1[C:8]2[C@@H:9]3[C@H:13]([CH2:14][CH2:15][C:7]=2[CH:6]=[CH:5][CH:4]=1)[N:12]([CH2:16][CH2:17][CH3:18])[CH2:11][CH2:10]3.[OH-].[Na+].C([O-])(O)=O.[Na+]>Br>[CH2:16]([N:12]1[C@@H:13]2[C@@H:9]([C:8]3[C:3]([OH:2])=[CH:4][CH:5]=[CH:6][C:7]=3[CH2:15][CH2:14]2)[CH2:10][CH2:11]1)[CH2:17][CH3:18]
Reactant: CCCN1CC[C@@H]2c3c(cccc3OC)CC[C@@H]21
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCN1CC[C@@H]2c3c(O)cccc3CC[C@@H]21
Temperature: 0 °C
Yield: 79 %

Procedure:
8.58 g (0.035 mol) of rac-cis-2,3,3a,4,5,9b-hexahydro-9-methoxy-3-propyl-1H-benzo[e]indole were boiled under reflux for 4 hours in 0.5 l of 48 percent aqueous HBr. The mixture was poured into an ice-cold aqueous solution of 200 g (5 mol) of NaOH. Solid NaHCO3 was added thereto and the mixture was extracted three times with CH2Cl2. The combined organic phases were washed with saturated aqueous NaHCO3 and NaCl solutions, dried with Na2SO4, filtered and concentrated. The residue was chromatographed over silica gel with ethyl acetate. The product was crystallized in hexane. There were obtained 6.4 g (80%) of rac-cis-2,3,3a,4,5,9b-hexahydro-3-propyl-1H-benzo[e]indol-9-ol as white crystals with m.p. 130°-132°.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].Cl[CH2:12][C:13](=[O:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].CC(C)=O>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:12][C:13](=[O:15])[CH3:14])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1O
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1ccccc1C(C)C
Reaction time: 6 h
Yield: 112.2 %

Procedure:
A mixture consisting of 24.0 g of o-isopropylphenol, 17.0 g of chloroacetone, 30 g of potassium carbonate, 1.0 g of potassium iodide and 150 ml of acetone was heated at reflux with stirring for 6 hr. The reaction mixture was concentrated under reduced pressure; the condensate was extracted with ethyl acetate; the ethyl acetate layer was washed consecutively with 5% aqueous solution of sodium hydroxide, water and saturated saline, and thereafter dried with anhydrous sodium sulfate. The solvent was thereafter distilled off under reduced pressure and yielded 38 g of 2-isopropylphenoxyacetone.
Reaction SMILES: COC1C=CC(C2CCC3C(=CC=C(OC)C=3)C2)=C(N)C=1.BrC1C=CC(OCCN2CCCCC2)=C(F)C=1.[F:39][C:40]1[CH:41]=[C:42]([NH:55][C:56]2[CH:61]=[C:60]([O:62]C)[CH:59]=[CH:58][C:57]=2[CH:64]2[CH2:73][CH2:72][C:71]3[C:66](=[CH:67][CH:68]=[C:69]([O:74]C)[CH:70]=3)[CH2:65]2)[CH:43]=[CH:44][C:45]=1[O:46][CH2:47][CH2:48][N:49]1[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1>>[F:39][C:40]1[CH:41]=[C:42]([NH:55][C:56]2[CH:61]=[C:60]([OH:62])[CH:59]=[CH:58][C:57]=2[CH:64]2[CH2:73][CH2:72][C:71]3[CH:70]=[C:69]([OH:74])[CH:68]=[CH:67][C:66]=3[CH2:65]2)[CH:43]=[CH:44][C:45]=1[O:46][CH2:47][CH2:48][N:49]1[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1Nc1ccc(OCCN3CCCCC3)c(F)c1)C2
Agent: COc1ccc(C2CCc3cc(OC)ccc3C2)c(N)c1
Agent: Fc1cc(Br)ccc1OCCN1CCCCC1
Product: Oc1ccc2c(c1)CCC(c1ccc(O)cc1Nc1ccc(OCCN3CCCCC3)c(F)c1)C2
Yield: 52.9 %

Procedure:
Synthesized from 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine and 1-[2-(4-bromo-2-fluorophenoxy)ethyl]piperidine according to an analogous synthetic method to Example 116, [3-fluoro-4-(2-piperidin-1-ylethoxy)phenyl][5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (84 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (42 mg).
Reaction SMILES: [Na+].[OH:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([O-:9])=O.[Na].C(O)CO.ClCC([O-])=O.[Na+].Cl.[CH3:22][NH:23][CH3:24].CN(C)C(=O)COCCCl>C1(C)C=CC=CC=1>[CH3:22][N:23]([CH3:24])[C:7](=[O:9])[CH2:6][O:5][CH2:4][CH2:3][OH:2]
Reactant: O=C([O-])COCCO
Reactant: CNC
Agent: CN(C)C(=O)COCCCl
Agent: Cl
Agent: O=C([O-])CCl
Solvent: OCCO
Solvent: Cc1ccccc1
Product: CN(C)C(=O)COCCO
Temperature: 130 °C
Reaction time: 0.33 h

Procedure:
200.4 g (1 mol) of crude 2-hydroxyethoxy-acetic acid sodium salt prepared from ethylene glycol monosodium salt and 69 weight % sodium chloroacetate are placed into a 1000 ml round bottom flask equipped with stirrer. 81.5 g (1 mole) of commercial dimethylamine hydrochloride having approximately 8 weight % moisture are added. The reaction mixture is heated to the temperature of 130° C. and is kept at this temperature for 20 minutes. After this period, 400 ml of toluene are added to the reaction mixture and by boiling the azeotropic mixture for a period of 16 hours, the water is separated. After cooling the reaction mixture, sodium chloride is filtered off and the crystals are washed twice with 20 ml toluene each. The toluene phases are combined and the product is isolated by evaporating the toluene. Yield 116.2 g (78.9%) of the title compound having the purity greater than 96% by gas chromatography. The product thus obtained is directly suitable for the conversion into 2-chloroethoxy-acetic acid-N,N-dimethylamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[S:18]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=[O:8].CO>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[S:18]([C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)(=[O:19])=[O:20])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=[O:8]
Reactant: COC(=O)CN(c1ccc(Cl)cc1C(=O)c1ccccc1F)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CN(c1ccc(Cl)cc1C(=O)c1ccccc1F)S(=O)(=O)c1ccc(N)cc1

Procedure:
The 5-chloro-2'-fluoro-2-[N-(methoxycarbonylmethyl)-N-(4-nitrophenylsulfonyl)amino]benzophenone prepared in Example 2, step b, is dissolved in 100 ml of ethyl acetate and 5 ml of methanol and hydrogenated at ordinary pressure for 2 hours in the presence of 620 mg of 10% palladium-on-charcoal; the existence of 3 compounds (starting material, intermediate and expected product) is observed in TLC. The catalyst is filtered off, the solvent is evaporated off and the residue is chromatographed on silica gel. The expected compound is eluted with DCM containing 1% of methanol. After recrystallization from DCM/isopropyl ether, m.p=168-170° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:22]1[N:23]([CH2:30][C:31]2([CH3:34])[CH2:33][O:32]2)[CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[N:26]=1.[H-].[Na+]>CN(C=O)C.O>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:33][C:31]3([CH3:34])[O:32][C:22]4=[N:26][C:25]([N+:27]([O-:29])=[O:28])=[CH:24][N:23]4[CH2:30]3)=[CH:3][CH:4]=2)[CH2:9][CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC1(Cn2cc([N+](=O)[O-])nc2Br)CO1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(O)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(OCC3(C)Cn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Temperature: 60 °C
Yield: 88.7 %

Procedure:
tert-Butyl 4-(4-hydroxyphenyl)piperazine-1-carboxylate (1.5 g, 5.4 mmol) and 2-bromo-1-(2-methyl-oxiranylmethyl)-4-nitro-1H-imidazole (1.96 g, 7.5 mmol) are dissolved in DMF (100 ml) and sodium hydride (0.39 g, 9.7 mmol, 60% in mineral oil) is added at room temperature. Once gas evolution ceases the mixture is heated to 60° C. for 1 h. The mixture is cooled, diluted with water and extracted with ethyl acetate. The combined extracts are purified by silica gel chromatography (1% methanol in methylene chloride) to give 2.2 g (88%) of the product as a tan solid. ESI MS m/z 482 (M+Na+); 1H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 6.87 (d, J=8.8 Hz, 2H), 6.78 (d, J=8.8 Hz, 2H), 4.48 (d, 10 Hz, 1H), 4.18 (d, J=10.4 Hz, 1H), 4.02 (t, J=9.2 Hz, 1H), 4.0-3.55 (m, 4H), 3.05-2.99 (m, 4H), 1.77 (s, 2H), 1.57 (s, 9H), 1.47 (s, 3H).
Reaction SMILES: [C:1]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:14]([O-])([OH:16])=[O:15]>>[N+:14]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:1]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[O:8])([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)C=CC(=O)c1ccccc1
Product: O=C(O)C=CC(=O)c1cccc([N+](=O)[O-])c1

Procedure:
22 g of finely powdered 3-benzoylacrylic acid was added in 1-gram portions to 11° g of stirred fuming (90%) nitric acid at -5° over a 30-minute period, the mixture being allowed to heat to 0°. Then the temperature of the mixture was allowed to rise to 2° and held until a clear solution was obtained. The mixture then was poured on ice, and the solid which formed was filtered, washed with water, dried (MgS04) and recrystallized from ethanol to give 3-(3-nitrobenzoyl)acrylic acid (8A), m.p.: 199°-201°.
Reaction SMILES: [Na].[C:2]([O:9][CH2:10][CH3:11])(=[O:8])[C:3]([O:5]CC)=O.[CH3:12][C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17].Cl>C(O)C.O.CCCCCC>[O:5]=[C:3]([CH2:12][C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17])[C:2]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCCCC(C)=O
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCCCCC
Solvent: CCO
Product: CCCCC(=O)CC(=O)C(=O)OCC
Reaction time: 45 h
Yield: 69.7 %

Procedure:
To a solution of sodium (9.3 g) in ethanol (200 ml) was added dropwise a mixture of diethyl oxalate (60 g) and 2-hexanone (40.9 g) with stirring. The reaction mixture was allowed to stand at room temperature for 45 hours. To a mixture of 1N-hydrochloric acid (500 ml) and hexane (500 ml) was added dropwise the reaction mixture with stirring vigorously. After the addition, water (500 ml) was added. The organic layer was washed with water (100 ml ×3), dried, and the solvent was removed by evaporation in vacuo. The residue was distilled under reduced pressure and the distillate at the boiling point of 110° to 111° C. (6 mmHg) was collected to give the desired product (57 g, 70%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[C:16]([O:17][CH3:18])=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH3:18][O:17][C:16]1[CH:15]=[C:14]2[C:9](=[CH:8][C:7]=1[O:6][CH3:5])[CH:10]=[C:11]([C:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:26])[CH:12]=[CH:13]2
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cc2ccccc2cc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc2ccc(C(=O)c3ccccc3)cc2cc1OC
Reaction time: 8 h

Procedure:
Aluminum chloride (16.0 g) was added to a solution of 2,3-dimethoxynaphthalene (18.0 g) and benzoylchloride (12.0 g) in cold methylene chloride (400 ml) and the solution was stirred overnight. After treatment with cold water the phases were separated and the methylene chloride phase washed with 1 M sodium hydroxide. The product was triturated with warm ether. Yield: 7 g, melting point 124-125° C.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:23][CH2:24][O:25][CH3:26])=[CH:6][C:7]([O:19][CH2:20][O:21][CH3:22])=[C:8]([C:10]2[N:11]([CH:16]([CH3:18])[CH3:17])[C:12](=[S:15])[NH:13][N:14]=2)[CH:9]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:34][N:35]([CH3:40])[CH2:36][CH2:37][CH2:38]Cl.[Cl-].[Na+]>C(O)C>[CH:1]([C:4]1[C:5]([O:23][CH2:24][O:25][CH3:26])=[CH:6][C:7]([O:19][CH2:20][O:21][CH3:22])=[C:8]([C:10]2[N:11]([CH:16]([CH3:18])[CH3:17])[C:12]([S:15][CH2:38][CH2:37][CH2:36][N:35]([CH3:40])[CH3:34])=[N:13][N:14]=2)[CH:9]=1)([CH3:2])[CH3:3]
Reactant: CN(C)CCCCl
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1-c1n[nH]c(=S)n1C(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCO
Product: COCOc1cc(OCOC)c(C(C)C)cc1-c1nnc(SCCCN(C)C)n1C(C)C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
5-(5-isopropyl-2,4-bis-methoxymethoxy-phenyl)-4-isopropyl-2,4-dihydro-[1,2,4]triazol-3-thione (F63-03: 114 mg, 0.3 mmol), potassium carbonate (249 mg, 1.8 mmol) and ethanol (10 mL) were placed in a test tube, and next 3-dimethylaminopropyl chloride hydrochloride (1.49 g, 9.4 mmol) was added. The mixture was stirred at 100° C. for 1 hour. After completing the reaction, the reaction mixture was cooled naturally, mixed with saturated sodium chloride solution and extracted twice with ethyl acetate. The organic layers were combined, washed 4 times with saturated sodium chloride solution, then dried with sodium sulfate and concentrated under reduced pressure.
Reaction SMILES: BrC1C([C@H](NC(=O)CN2C3CCCCC=3C(C(F)(F)F)=N2)CC2C=C(F)C=C(F)C=2)=NC([NH:8][CH2:9][CH2:10][O:11][CH3:12])=NC=1.[Br:40][C:41]1[C:42]([C@@H:51]([NH:61][C:62](=[O:80])[CH2:63][N:64]2[C:72]3[C:71]([F:74])([F:73])[CH2:70][CH2:69][C:68]([F:76])([F:75])[C:67]=3[C:66]([CH:77]([F:79])[F:78])=[N:65]2)[CH2:52][C:53]2[CH:58]=[C:57]([F:59])[CH:56]=[C:55]([F:60])[CH:54]=2)=[N:43][C:44](S(C)(=O)=O)=[N:45][CH:46]=1>>[Br:40][C:41]1[C:42]([C@@H:51]([NH:61][C:62](=[O:80])[CH2:63][N:64]2[C:72]3[C:71]([F:74])([F:73])[CH2:70][CH2:69][C:68]([F:76])([F:75])[C:67]=3[C:66]([CH:77]([F:79])[F:78])=[N:65]2)[CH2:52][C:53]2[CH:58]=[C:57]([F:59])[CH:56]=[C:55]([F:60])[CH:54]=2)=[N:43][C:44]([NH:8][CH2:9][CH2:10][O:11][CH3:12])=[N:45][CH:46]=1
Reactant: CS(=O)(=O)c1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1
Reactant: COCCNc1ncc(Br)c([C@@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)n1
Product: COCCNc1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1

Procedure:
The title compound (12D) was prepared according to the method presented for the synthesis of compound 11I of Example 11 utilizing 12C. MS (m/z) 671.34 [M+H]+.
Reaction SMILES: Cl[CH:2]1[CH2:7][N:6]([C:8]2[N:13]=[CH:12][N:11]([CH2:14][C:15]3[S:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)[C:10](=[O:24])[N:9]=2)[CH2:5][CH:4]=[C:3]1[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1.C(N(CC)CC)C.[C-]#N.[K+].C(=O)(O)[O-].[Na+]>CN(C)C=O>[F:31][C:28]1[CH:27]=[CH:26][C:25]([C:3]2[CH:4]=[CH:5][N:6]([C:8]3[N:13]=[CH:12][N:11]([CH2:14][C:15]4[S:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=4)[C:10](=[O:24])[N:9]=3)[CH2:7][CH:2]=2)=[CH:30][CH:29]=1
Reactant: O=c1nc(N2CC=C(c3ccc(F)cc3)C(Cl)C2)ncn1Cc1ccc(C(F)(F)F)s1
Agent: O=C([O-])O
Agent: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=c1nc(N2C=CC(c3ccc(F)cc3)=CC2)ncn1Cc1ccc(C(F)(F)F)s1
Yield: 7.6 %

Procedure:
To an N,N-dimethylformamide solution (1.0 mL) of 4-[5-chloro-4-(4-fluorophenyl)-5,6-dihydropyridin-1(2H)-yl]-1-{[5-(trifluoromethyl)thio phen-2-yl]methyl}-1,3,5-triazin-2(1H)-one (10.0 mg, 0.0212 mmol) synthesized in Reference Synthesis Example 353, triethylamine (10.0 μL, 0.0717 mmol) and potassium cyanide (10.0 mg, 0.154 mmol) were added and the resultant mixture was stirred at room temperature for 2.5 hours and at 80° C. for 40 minutes. After the completion of the reaction, to the reaction solution, saturated sodium bicarbonate aqueous solution was added and extraction with ethyl acetate from the reaction solution was performed. The organic layer was dried over anhydrous sodium sulfate and was concentrated under reduced pressure and the resultant residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1→0/1) to obtain the title compound (0.7 mg, yield: 8%).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:8]([CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[C:7]2[CH:20]=[C:21]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:22]=[C:23](N)[C:6]=2[N:5]=1)[CH3:3].[OH:31]S(O)(=O)=O.N([O-])=O.[Na+].C([O-])(O)=O.[Na+]>O>[CH3:3][CH:2]([C:4]1[N:8]([CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[C:7]2[CH:20]=[C:21]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[CH:22]=[C:23]([OH:31])[C:6]=2[N:5]=1)[CH3:1]
Reactant: O=S(=O)(O)O
Reactant: CC(C)c1nc2c(N)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)c1nc2c(O)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 27 %

Procedure:
To a solution of 2-(1-methylethyl)-6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-1H-benzimidazol-4-amine (300 mg) in H2O (20 mL), and conc. H2SO4 (1 mL) was added aqueous NaNO2 (78 mg) solution dropwise at 0° C. The mixture was stirred at 0° C. for 15 min and then heated to reflux for 1 h. The mixture was cooled to room temperature and the pH neutralized with aqueous NaHCO3 solution. The solution was extracted with DCM (250 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in-vacuo. The residue was then purified by silica gel chromatography eluted with EtOAc:petroleum ether=1:1 to afford the desired product as a solid (80 mg, 27%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.21 (d, 6H, J=6.6 Hz), 2.91 (t, 4H, J=7.5 Hz), 3.03 (m, 1H, J=6.6 Hz), 3.64 (t, 4H, J=7.5 Hz), 5.89 (s, 2H), 6.27-6.34 (m, 3H), 7.32 (t, 1H, J=7.5 Hz), 7.59-7.70 (m, 2H), 7.83 (d, 1H, J=7.5 Hz), 8.00 (d, 1H, J=7.5 Hz), 8.27 (d, 1H, J=7.5 Hz), 9.55 (s, 1H); LC-MS: m/e=402 [M+1]+.