Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].CN(C)[CH:5]=[CH:6][C:7]([C:9]1[S:13][C:12]([N:14]=CN(C)C)=[N:11][C:10]=1[CH3:19])=O.Cl.[CH3:22][C:23]1([C:26]([NH2:28])=[NH:27])[CH2:25][CH2:24]1.O>COCCO>[CH3:19][C:10]1[N:11]=[C:12]([NH2:14])[S:13][C:9]=1[C:7]1[CH:6]=[CH:5][N:28]=[C:26]([C:23]2([CH3:22])[CH2:25][CH2:24]2)[N:27]=1
Reactant: CC1(C(=N)N)CC1
Reactant: Cc1nc(N=CN(C)C)sc1C(=O)C=CN(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Solvent: O
Product: Cc1nc(N)sc1-c1ccnc(C2(C)CC2)n1
Temperature: 125 °C

Procedure:
Powdered sodium hydroxide (5.86 g) is added to a solution of N′-[5-(3-dimethylamino-acryloyl)-4-methyl-thiazol-2-yl]-N,N-dimethyl-formamidine (13 g, prepared as described by S. Wang et al J. Med. Chem. 2004, 47, 1662-1675.) and 1-methyl-cyclopropanecarboxamidine hydrochloride (7.2 g, prepared as described in EP0227415) in 2-methoxyethanol (98 ml) and the mixture heated at 125° C. for 1 hour with stirring. The reaction mixture is cooled, water is added, and the title compound isolated by filtration. ESI-MS: M+H 247 and M−H 245.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]([C@@H:5]1[CH2:10][C@@H:9]([NH:11][S:12]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:14])=[O:13])[C@H:8]([OH:26])[CH2:7][CH2:6]1)=[O:4].C(Cl)Cl.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(N(CC)CC)C>[CH3:31][S:32]([O:26][C@@H:8]1[CH2:7][CH2:6][C@H:5]([C:3](=[O:4])[N:2]([CH3:27])[CH3:1])[CH2:10][C@H:9]1[NH:11][S:12](=[O:13])(=[O:14])[NH:15][C:16]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:25])(=[O:34])=[O:33]
Reactant: CN(C)C(=O)[C@H]1CC[C@@H](O)[C@H](NS(=O)(=O)NC(=O)OCc2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)[C@H]1CC[C@@H](OS(C)(=O)=O)[C@H](NS(=O)(=O)NC(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
Benzyl {[(1R,2R,5S)-5-(dimethylcarbamoyl)-2-hydroxycyclohexyl]sulfamoyl}carbamate (1.00 g) was added to methylene chloride (10 ml), and the obtained solution was then cooled to approximately 0° C. Triethylamine (0.52 ml) was added to the reaction solution, and methanesulfonyl chloride (0.28 ml) was then added dropwise to the mixed solution. The obtained mixture was stirred for approximately 1 hour. The precipitated crystals were collected by filtration, and were then washed with methylene chloride (1 ml). The obtained crystals were dried under reduced pressure to obtain 866 mg of the title compound (yield: 72%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]1[O:14][CH2:13][CH2:12][O:11]1.[CH2:15]([Li])CCC.CI>O1CCCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:15])=[C:3]([CH:10]2[O:14][CH2:13][CH2:12][O:11]2)[CH:4]=1
Reactant: [Li]CCCC
Reactant: COc1ccc(Br)c(C2OCCO2)c1
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc(C)c(C2OCCO2)c1
Temperature: -65 °C
Reaction time: 1 h

Procedure:
A stirred solution of 2-(2-bromo-5-methoxyphenyl)-[1,3]dioxolane (25.92 g) in tetrahydrofuran (400 mL) at −70° C. is treated dropwise with a solution of n-butyl lithium in hexanes (48.0 mL, 2.5 M). After stirring for 10 minutes methyl iodide (21.29 g) is added dropwise whilst maintaining the temperature at −65° C. The reaction mixture is stirred at −65° C. for 1 hour, allowed to warm to room temperature and stirring is continued for a further hour. The reaction mixture is evaporated and the residue partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase is washed with brine (500 mL),dried over magnesium sulphate and evaporated to give 2-(5-methoxy-2-methyl-phenyl)-[1,3]dioxolane (18.25 g) as a yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]([C:11]1[CH:15]=[CH:14][NH:13][CH:12]=1)=[O:10].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[CH:19][CH:18]=1.O>CS(C)=O>[CH3:7][O:8][C:9]([C:11]1[CH:15]=[CH:14][N:13]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:12]=1)=[O:10]
Reactant: Clc1ccnc2ccccc12
Reactant: COC(=O)c1cc[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccn(-c2ccnc3ccccc23)c1
Temperature: 100 °C
Reaction time: 23 h
Yield: 59.5 %

Procedure:
1.73 g (12.5 mmol) of potassium carbonate are added at 20° C. under an argon atmosphere to 0.625 g (5 mmol) of 3-methoxycarbonyl-1H-pyrrole and 0.82 g (5 mmol) of 4-chloroquinoline dissolved in 10 mL of dimethyl sulphoxide. After stirring at 100° C. for 23 hours, the reaction mixture is poured into 30 mL of water and then allowed to crystallise at 20° C. for 1 hour. After filtering off and air-drying the solid residue, 0.75 g of 3-methoxycarbonyl-1-(quinol-4-yl)-1H-pyrrole is obtained in the form of a beige-coloured solid melting at 156° C.
Reaction SMILES: C([O:8][C:9](=[O:24])[CH2:10][O:11][P:12]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:20]([O:19][P:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([O:11][CH2:10][C:9]([OH:24])=[O:8])=[O:13])([CH3:22])([CH3:23])[CH3:21]
Reactant: [H][H]
Reactant: CC(C)(C)OP(=O)(OCC(=O)OCc1ccccc1)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OP(=O)(OCC(=O)O)OC(C)(C)C
Yield: 97.6 %

Procedure:
(Di-tert-butoxy-phosphoryloxy)-acetic acid benzyl ester (700 mg, 1.96 mmol) was dissolved in MeOH (40 mL) and passed through a “H-cube” hydrogenator with a 10% Pd on carbon cartridge under 40 psi of hydrogen at a flow rate of 1 mL/min. The reaction mixture was concentrated in vacuo to give 513 mg (98%) of (di-tert-butoxy-phosphoryloxy)-acetic acid, which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 4.53 (d, 2H), and 1.51 (s, 18H).
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[NH:5][N:4]=[CH:3]1.Br[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].C(=O)([O-])[O-].[K+].[K+].CCCCCCC>C(OCC)(=O)C>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][N:4]1[CH:3]=[C:2]([CH3:1])[C:6](=[O:7])[NH:5]1)[CH3:14]
Reactant: CC1C=NNC1=O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1cc(C)c(=O)[nH]1
Yield: 16 %

Procedure:
As described for example 320a, 4-methyl-2-pyrazolin-5-one was reacted with ethyl bromoacetate and potassium carbonate. Extractive workup followed by chromatography (SiO2, heptane:ethyl acetate=100:0 to 50:50) afforded the title compound as a white solid (yield: 16%). MS: m/e=185.0 [M+H]+.
Reaction SMILES: [SH:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[N:3]=1.[O-]Cl.[Na+].[OH-].[NH4+:18]>[OH-].[Na+].O>[Cl:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[N:3]=[C:2]([S:1][NH2:18])[S:6][N:5]=1
Reactant: Sc1nc(-c2ccccc2Cl)ns1
Reactant: [NH4+]
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: O
Product: NSc1nc(-c2ccccc2Cl)ns1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 25 g of 5-mercapto-3-(2-chlorophenyl)-1,2,4-thiadiazole in 500 ml of 4% sodium hydroxide and a solution prepared by diluting 238 ml of 5.25% NaOCl to 500 ml with water were added dropwise simultaneously to 1020 ml of ammonium hydroxide solution while maintaining the mixture at 0° C. with an ice/methanol bath. The resulting mixture was stirred for 15 minutes and the solids were collected, washed with water and dried under high vacuum (P2O5) to give 15.4 g of solid, m.p. 143°-145°.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=3)=[O:21])=[CH:15][CH:14]=2)[CH2:9]1)=O)(C)(C)C.Cl>C1COCC1.O1CCOCC1>[ClH:28].[NH:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=3)=[O:21])=[CH:17][CH:18]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)c3ccc(Cl)cn3)cc2)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: O=C(Nc1ccc(C2CCNC2)cc1)c1ccc(Cl)cn1
Temperature: 60 °C

Procedure:
To a stirred solution of (RS)-3-{4-[(5-chloro-pyridine-2-carbonyl)-amino]-phenyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (310 mg) in THF (6 ml) was added dropwise a solution of hydrogen chloride in dioxane (2.9 ml, 4 M solution) and the mixture was heated at 60° C. overnight. The mixture was then cooled to 0° C. and the ensuing crystals were collected by filtration, washing with diethyl ether, and were dried in vacuo at 60° C. to afford (RS)-5-chloro-pyridine-2-carboxylic acid (4-pyrrolidin-3-yl-phenyl)-amide hydrochloride as a light yellow solid. MS (ISP): 304.2 ([{37Cl}M+H]+), 302.3 ([{35Cl}M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[C:4]([N:6]([CH:15]([CH3:19])[C:16](O)=[O:17])[C:7]1[CH:14]=[CH:13][C:10]([O:11][CH3:12])=[CH:9][CH:8]=1)=[O:5].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[C:4]([N:6]([CH:15]([CH3:19])[C:16]([N:33]([CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[C:30]1[CH:29]=[CH:28][C:27]([O:26][CH3:25])=[CH:32][CH:31]=1)=[O:17])[C:7]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[CH:13][CH:14]=1)=[O:5]
Reactant: COC(=O)CCCNc1ccc(OC)cc1
Reactant: COc1ccc(N(C(=O)c2ccc(Cl)cc2Cl)C(C)C(=O)O)cc1
Product: COC(=O)CCCN(C(=O)C(C)N(C(=O)c1ccc(Cl)cc1Cl)c1ccc(OC)cc1)c1ccc(OC)cc1

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(2,4-dichlorobenzoyl)-2-(p-anisidino)propionic acid and methyl 4-(p-anisidino)butyrate and suitable processing produces methyl N-[N-(2,4-dichlorobenzoyl)-2-(p-anisidino)propionyl]-4-(p-anisidino)butyrate (oil), saponification of which and processing of the reaction product yields N-[N-(2,4-dichlorobenzoyl)-2-(p-anisidino)propionyl]-4-(p-anisidino)butyric acid (M.P. 159° to 160°).
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.[C:21]12(O)[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2.B(F)(F)F.CCOCC>CCCCC>[C:21]12([C:8]3[C:9]([OH:20])=[CH:10][C:11]4[CH2:12][CH2:13][C@@H:14]5[C@@H:5]([C:6]=4[CH:7]=3)[CH2:4][CH2:3][C@@:2]3([CH3:1])[C@H:15]5[CH2:16][CH2:17][C:18]3=[O:19])[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: FB(F)F
Solvent: CCCCC
Solvent: CCOCC
Product: C[C@]12CC[C@@H]3c4cc(C56CC7CC(CC(C7)C5)C6)c(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reaction time: 0.25 h
Yield: 76.7 %

Procedure:
Estrone [3-hydroxyestra-1,3,5(10)-trien-17-one, 270 mg, 1 mmol) and 1-adamantanol (170 mg, 1 mmol) were added to anhydrous n-pentane (6 mL) and the stirred mixture was cooled with an ice bath. Boron trifluoride etherate (BF3.EtOEt, 0.4 mL) was added over a 10 minute period. After an additional 15 minutes, the ice bath was removed and stirring was continued for an additional 45 minutes at room temperature. During the 45 minute period, solids present in the reaction mixture were dissolved and a yellow oil formed. Crushed ice was then added while shaking and swirling the reaction flask and a pink solid was formed. The filtered, crude pink product was washed with water until the filtrate had a neutral pH, and then the solid was dried in a vacuum oven at 50° C. The crude pink powder (0.4 g) was purified by flash chromatography (silica gel eluted with 20% ethyl acetate in hexanes) to get the pure product (0.31 g, 76.7%). The product was recrystallized from a mixture of chloroform and isopropyl alcohol and characterized as follows: (i) melting point=322-324° C. (see, e.g., Lunn, W. H. W.; Farkas, E., Adamantyl Carbonium Ion as a Dehydrogenating Agent: Its Reactions with Estrone, Tetrahedron 1969, 24, 6773-76, citing melting point as 295-296° C.); (ii) 1H NMR (CDCl3, 300 MHZ) δ0.94 (s, 3H, C18—CH3), 2.8 (m, 2H, C6—CH2) 4.7 (s, 1H, C3—OH), 6.4 (s, 1H, C4—H), 7.12 (s, 1H, C1—H); (iii) 13C NMR (CDCl3, 300 MHZ) δ13.76, 21.47, 25.93, 26.41, 28.63, 28.95 (3×C), 31.56, 35.81, 36.56, 36.98 (3×C), 38.42, 40.69 (3×C), 44.25, 47.99, 50.35, 116.87, 124.11, 131.59, 134.00, 135.02, 152.44, 221.43. (Chemical Abstracts Registry Number [21003-01-0].)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.Cl.[NH2:14][C@@H:15]([CH3:20])[C:16]([O:18][CH3:19])=[O:17].CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([NH:14][C@@H:15]([CH3:20])[C:16]([O:18][CH3:19])=[O:17])[N:3]=1
Reactant: COC(=O)[C@H](C)N
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1cc(N[C@@H](C)C(=O)OC)nc(Cl)n1
Temperature: 50 °C
Yield: 61.3 %

Procedure:
To a mixture of methyl 2,6-dichloropyrimidine-4-carboxylate (5.175 g, 25.00 mmol) in acetonitrile (100 mL) was added (S)-methyl 2-aminopropanoate hydrochloride (3.497 g, 25.05 mmol) and iPr2NEt (9.6 mL, 55.1 mmol). The mixture was heated at 50° C. overnight then concentrated in vacuo. The residue was chromatographed over silica gel with 30-70% EtOAc in hexanes. The product fractions were evaporated in vacuo to yield (S)-methyl 2-chloro-6-((1-methoxy-1-oxopropan-2-yl)amino)pyrimidine-4-carboxylate as a thick yellow-orange oil (4.194 g, 15.33 mmol, 61% yield). LC/MS: m/z=274.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]([N:22]3[CH2:27][CH2:26][C@:25]([CH2:34][C:35]([OH:38])([CH3:37])[CH3:36])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:24][C:23]3=[O:39])[CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO.[H][H]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]([N:22]3[CH2:27][CH2:26][C@:25]([CH2:34][C:35]([OH:38])([CH3:37])[CH3:36])([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[O:24][C:23]3=[O:39])[CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: [H][H]
Reactant: C[C@@H](c1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: [Pd]
Solvent: CO
Product: C[C@@H](c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
A mixture of 4-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.34 g) and 10% palladium on carbon (60 mg) in methanol (10 mL) was shaken in hydrogen atmosphere (50 psi) for 4 h. Then, the catalyst was separated by filtration and the filtrate was concentrated to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@@H:9]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH2:8][CH2:7][N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:4].[Li+].[CH3:26]C([N-]C(C)C)C.IC>C1COCC1>[CH3:1][O:2][C:3]([C@:5]1([CH3:26])[C@@H:9]([O:10][Si:11]([C:14]([CH3:17])([CH3:15])[CH3:16])([CH3:13])[CH3:12])[CH2:8][CH2:7][N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:4]
Reactant: COC(=O)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)[C@]1(C)[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 29.6 %

Procedure:
To a solution of compound 4A (898 mg, 2.50 mmol) in THF (10 mL) at −78° C. under nitrogen was added a 1.8 M solution of LDA (3.50 mL, 6.25 mmol) and the reaction was stirred at −78° C. for 1 h. Iodomethane (1.56 mL, 25.0 mmol) was added, and the mixture was stirred at −78° C. for 4 h. The reaction was quenched by adding EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with saturated aqueous NaHCO3 and brine, then dried over MgSO4, filtered and concentrated. Purification via silica gel chromatography (0-15% EtOAc in hexane) provided compound 4B (276 mg).
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:6])[CH3:3].[CH3:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].O>CN(C)C=O>[C:31]1([CH2:5][CH2:7][CH2:8][CH:9]=[CH:9][CH2:8][CH2:7][C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH:30]=[CH:29][CH:34]=[CH:33][CH:32]=1
Reactant: CCCCCC
Reactant: CCOC(=O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCC=CCCCc1ccccc1

Procedure:
First, 207 mg of metalic sodium was dissolved in 4 ml of absolute ethanol, and the ethanol was evaporated off to obtain sodium ethoxide powder, to which was then added at once a solution of 4.75 g ethoxycarbonylpropyltriphenylphosphonium bromide in 15 ml of absolute dimethylformamide with stirring. The mixture was stirred for 1.5 hours, and after adding dropwise a solution of 1.04 g 4-phenylbutylaldehyde in 5 ml of absolute dimethylformamide at 5° C. over 5 minutes, stirred overnight at a room temperature. To the reaction mixture were added 100 ml of n-hexane and 30 ml of water and the resulting layers were separated, and the aqueous solution was extracted with 20 ml of n-hexane. The n-hexane layers were combined, washed with water and a saturated sodium chloride aqueous solution, dried over magnesium sulfate and evaporated under a reduced pressure to obtain an oily residue. The residue was applied to a silica gel column and eluted with n-hexane/ethyl acetate (50:1) to obtain 831 mg of the title compound as a colorless liquid.
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)([CH3:10])[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[SH2:24]>CN(C)C=O>[C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)([CH3:10])[C:8]([NH2:9])=[S:24])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C#N)(c1ccccc1)c1ccccn1
Reactant: S
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C(N)=S)(c1ccccc1)c1ccccn1

Procedure:
With continuous stirring, subject a mixture containing 6 g. of α-phenyl-α-(2-pyridyl) propionitrile and 5 ml. of triethylamine in 60 ml. of dimethylformamide to a stream of hydrogen sulfide for 24 hours. Pour the resulting solution into 200 ml. of ice water, filter, wash and dry the solids which are formed. Recrystallize the solids from acetonitrile to obtain the intermediate α-phenyl-α-(2-pyridyl) thiopropionamide, m.p. 186°-183° C.
Reaction SMILES: [C:1]1([NH2:8])[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH3:9][O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:12]=1[CH:13]=O.C(O)(=O)C>C(O)C>[CH3:9][O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:12]=1[C:13]1[NH:8][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[N:7]=1
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: Nc1ccccc1N
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(-c2nc3ccccc3[nH]2)c(OC)c1
Yield: 12.4 %

Procedure:
Ex-70A: A solution of benzene-1,2-diamine (2.60 g, 24.1 mmol) and 2,4-dimethoxy-benzaldehyde (4.0 g, 24.1 mmol) in ethanol (60 mL) containing catalytic amount of acetic acid was refluxed overnight. Solvent was then evaporated under reduced pressure. The residue oil was triturated in ethyl acetate to obtain 2-(2,4-dimethoxy-phenyl)-1H-benzoimidazole (0.76 g, 12%). The crude product was used without further purification. To a solution of 2-(2,4-dimethoxy-phenyl)-1H-benzoimidazole obtained above (0.76 g, 2.99 mmol) in dichloromethane (20 mL) was added dichloromethyl methyl ether (0.41 mL, 4.48 mmol) followed by addition of titanium tetrachloride (1.0M in dichloromethane, 9.0 mL, 9.0 mmol) at 0° C. The reaction mixture was allowed to stir overnight at ambient temperature and then poured into ice. A solution of sodium hydroxide (5M) was added dropwise until the pH of the solution was about 12. The basic solution was extracted with dichloromethane. The combined solution of dichloromethane was subsequently washed with brine, dried over sodium carbonate and concentrated. The product, 5-(1H-benzoimidazol-2-yl)-2,4-dimethoxy-benzaldehyde (0.40 g, 47%), was obtain and used without further purification. 1H NMR (CDCl3) δ 10.32 (s, 1H), 10.27 (bs, 1H), 9.03 (s, 1H), 7.83 (d, J=9 Hz, 1H), 7.48–7.45 (m, 1H), 7.31–7.22 (m, 1H), 6.58 (s, 1H), 4.18 (s, 3H), 4.01 (s, 3H). MS m/z=282 (M+, 100%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[C:19]3[C:18]4[CH:17]=[C:16]([C:20]5[CH:21]=[N:22][N:23]([CH2:25][CH2:26][O:27]C6CCCCO6)[CH:24]=5)[CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]([CH3:34])[C:8]2=[O:35])[C:4]([CH3:36])=[N:3]1.O1CCOCC1>CO>[CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[C:19]3[C:18]4[CH:17]=[C:16]([C:20]5[CH:21]=[N:22][N:23]([CH2:25][CH2:26][OH:27])[CH:24]=5)[CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]([CH3:34])[C:8]2=[O:35])[C:4]([CH3:36])=[N:3]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnn(CCOC5CCCCO5)c4)cc3c21
Solvent: C1COCCO1
Solvent: CO
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnn(CCO)c4)cc3c21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a mixture of 1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-8-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Stage 106.1.1, 95 mg, 0.195 mmol) in MeOH (2 ml) was added dioxane 4 M (0.248 ml, 0.993 mmol) and the RM was stirred at rt for 45 min. Then the RM was evaporated, before being quenched with saturated aqueous NaHCO3 (20 ml) and extracted with DCM (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was diluted with MeOH+2 drops TFA and purified directly by Prep.HPLC (H2O (0.1% TFA)/CH3CN 95:5 to 65:35). The fractions containing product were collected together and basified with NaHCO3 (0.3 g), before being concentrated. The resulting layer was extracted with DCM, washed with brine, dried over Na2SO4, filtered and evaporated to dryness to give the title compound as a white solid. (HPLC: tR 2.24 min (Method A); M+H=404 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.87 (s, 1H), 8.14-8.08 (m, 1H), 8.01-7.92 (m, 2H), 7.82-7.75 (m, 1H), 7.52-7.47 (m, 1H), 7.39-7.35 (m, 1H), 4.96-4.89 (m, 1H), 4.17-4.11 (m, 2H), 3.96 (s, 3H), 3.77-3.69 (m, 2H), 3.55 (s, 3H), 1.94 (s, 3H))
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:15]([Cl:16])=[CH:14][C:13]([OH:17])=[CH:12][C:11]=1[Cl:18])(=[O:3])[CH3:2].[Cl:19][C:20](Cl)([Cl:24])[CH2:21][CH2:22]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([Cl:18])=[CH:12][C:13]([O:17][CH2:22][CH:21]=[C:20]([Cl:24])[Cl:19])=[CH:14][C:15]=1[Cl:16])(=[O:3])[CH3:2]
Reactant: ClCCC(Cl)(Cl)Cl
Reactant: CC(=O)OCCCCOc1c(Cl)cc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 80 °C
Yield: 78.4 %

Procedure:
A solution of 25.3 grams (0.086 mole) of 4-(2,6-dichloro-4-hydroxyphenoxy)butyl acetate in 250 mL of DMF was stirred, and 19.5 grams (0.1 mole) of 1,1,1,3-tetrachloropropane was added, followed by 18 grams (0.13 mole) of potassium carbonate. Upon completion of addition the reaction mixture was heated at 80° C. during a 17 hour period. After this time the reaction mixture was cooled to ambient temperature, stirred with 350 mL of water and extracted with four 150 mL portions of diethyl ether. The combined extracts were washed with two 100 mL portions of water, dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using 1:1 methylene chloride:hexane as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 27.1 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.