Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:15])[CH2:13]Br)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[N-:16]=[N+:17]=[N-:18].[Na+].O>CN(C)C=O>[N:16]([CH2:13][C:12]([C:9]1[CH:10]=[CH:11][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=1)=[O:15])=[N+:17]=[N-:18]
Reactant: CCOC(=O)c1ccc(C(=O)CBr)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(C(=O)CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
To a solution of 4′-ethoxycarbonyl-2-bromoacetophenone (2.0 g) in N,N-dimethylformamide (8 ml) was added sodium azide (480 mg) at 0° C., and stirred for 2 hours at room temperature. The reaction mixture was poured into water (100 ml), extracted with diethyl ether (200 ml×2), washed with brine, and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. The product was purified by silica gel column chromatography (ethyl acetate:hexane=1:5) to give 2-azido-4′-ethoxycarbonylacetophenone (1.46 g).
Reaction SMILES: CN(C)C=O.Br[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]([CH3:19])[N:17]=[C:16]([C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:27])[N:15]=2)=[CH:10][C:9]=1[Cl:28].[C:29]([O-:32])(=[O:31])[CH3:30].[K+]>O>[C:29]([O:32][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]([CH3:19])[N:17]=[C:16]([C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:27])[N:15]=2)=[CH:10][C:9]=1[Cl:28])(=[O:31])[CH3:30]
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(CBr)c(Cl)c1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCc1ccc(-c2nc(-c3c(F)cccc3Cl)nn2C)cc1Cl
Temperature: 130 °C
Reaction time: 3 h
Yield: 51.1 %

Procedure:
To N,N-dimethylformamide (200 ml) are added 5-(4-bromomethyl-3-chlorophenyl)-3(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole (24.3 g) and potassium acetate (29.0 g), which are stirred at 130° C. for 3 hours. The reaction mixture is cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexaneethyl acetate as eluent to give 11.8 g of desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:20][CH:21]1[CH2:30][CH2:29][C:28]2[CH:27]=[C:26]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:25]=[CH:24][C:23]=2[CH2:22]1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:20][CH:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:25]=[CH:24][C:23]=3[CH2:22]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1ccc2c(c1)CCC(N)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)Cc1ccc2c(c1)CCC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Temperature: 25 °C
Yield: 83.5 %

Procedure:
A solution of 1.94 g of 4-chlorophenylsulfonyl chloride in 20 ml of ethyl acetate is added to a mixture of 30 ml of ethyl acetate, 20 ml of water, 3.46 g of potassium carbonate and 2.25 g of ethyl 6-amino-5,6,7,8-tetrahydronaphthalene-2-acetate hydrochloride under stirring at room temperature. After the mixture is stirred at room temperature for 45 minutes, the organic layer is separated therefrom, washed, dried and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform) to give 2.84 g of ethyl 6-(4-chlorophenyl)sulfonylamino-5,6,7,8-tetrahydronaphthalene-2-acetate as oil.
Reaction SMILES: [CH3:1][Si:2]([N-:5][Si](C)(C)C)([CH3:4])[CH3:3].[Li+].[P:11]([Cl:14])([Cl:13])[Cl:12].S(Cl)(Cl)(=O)=O>C(OCC)C>[Cl:12][P:11]([Cl:14])([Cl:13])=[N:5][Si:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: ClP(Cl)Cl
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O=S(=O)(Cl)Cl
Solvent: CCOCC
Product: C[Si](C)(C)N=P(Cl)(Cl)Cl
Reaction time: 1.5 h

Procedure:
Diethyl ether (250 ml) was added with stirring to a flask cooled in an ice/water bath containing lithium bis(trimethylsilyl)amide (27.7 g, 0.17 mol). Phosphorus trichloride (14.5 ml, 0.17 mol) was then added and the mixture stirred for a further 5-10 minutes before removing the ice water bath. Stirring was continued at ambient temperature for a further 1-2 hours. The reaction flask was then cooled again in an ice/water bath and sulfuryl chloride (13.3 ml, 0.17 mol) added. The mixture was stirred for a further 10-15 minutes before removing the ice/water bath and stirring at ambient for a further 1-2 hours or until the reaction was complete, as indicated by 31P {1H} NMR spectroscopy. The product was isolated in pure form via vacuum distillation.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=3)[C:26]([O:28]C)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[OH-].[Li+].Cl>C1COCC1.O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=3)[C:26]([OH:28])=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.8 %

Procedure:
A solution of methyl 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoate (460 mg, 1 mmol) in THF (30 mL) was treated with a solution of lithium hydroxide (237 mg, 10 mmol) in water (10 mL) and stirred at ambient temperature for 16 h. The residue was dissolve in minimum amount of water and the pH was adjusted to 4 by the addition of aqueous hydrochloric acid (2M). The resulting solution was concentrated to dryness to afford 446 mg of the title compound. LC-MS m/z 452 (M+H)+, 0.77 min (ret time).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:16](Br)=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[N:20][C:19]([Cl:25])=[CH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:16]([C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[N:20][C:19]([Cl:25])=[CH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnc(Cl)cc3c2Br)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnc(Cl)cc3c2-c2ccc(F)cc2)CC1
Temperature: 10 °C
Yield: 44 %

Procedure:
150 mg of 4-(5-Bromo-3-chloro-isoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (181) were dissolved in a mixture of 9 ml of dioxane and 3 ml of water, 47 mg of 4-fluoro-benzene-boronic acid, 47 mg of Na2CO3 and 40 mg of Pd(PPh3)4 were added and the resulting mixture was heated to 10° C. for 6 h. The solvent was removed in vacuo and the residue subjected to chromatography on a HPLC system. Yield: 44%
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[C:11]2[CH:16]=[N:15][CH:14]=[N:13][CH:12]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=[N+]([O-])c1ccc(Nc2cncnc2)cc1
Product: O=[N+]([O-])c1ccc(N(c2ccc([N+](=O)[O-])cc2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[(4-nitrophenyl) amino]pyrimidine and 4-fluoronitrobenzene
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][C:6](=[O:12])[C:5]2([CH3:14])[CH3:13].[CH3:15][N:16]1[C:20]([C:21]#[N:22])=[CH:19][CH:18]=[C:17]1B(O)O.[F-].[K+]>>[F:11][C:9]1[CH:10]=[C:2]([C:17]2[N:16]([CH3:15])[C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[CH:3]=[C:4]2[C:8]=1[NH:7][C:6](=[O:12])[C:5]2([CH3:14])[CH3:13]
Reactant: CC1(C)C(=O)Nc2c(F)cc(Br)cc21
Reactant: Cn1c(C#N)ccc1B(O)O
Agent: [F-]
Agent: [K+]
Product: Cn1c(C#N)ccc1-c1cc(F)c2c(c1)C(C)(C)C(=O)N2
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.4 %

Procedure:
5-Bromo-7-fluoro-3,3-dimethyl-1,3-dihydro-indol-2-one (5.16 g, 20.0 mmol), 1-methyl-5-cyano-2-pyrroleboronic acid (5.4 g, 36 mmol), KF (3.83 g, 66 mmol), and Pd2(dba)3 monochloroform adduct (516 mg, 0.500 mmol) were added to a 200 mL round bottom flask under nitrogen. The flask was sealed and purged with nitrogen for 5 min. THF (50 mL) was added and the mixture was purged with nitrogen for an additional 5 min. A solution of tri-t-butylphosphine (10% wt in hexanes) (2.97 mL, 1.00 mmol) was added via syringe and the mixture was stirred vigorously at 25° C. for 5 h. The mixture was diluted with 250 mL of EtOAc, filtered through a plug of silica gel, washed through with 200 mL of EtOAc and concentrated to give a crude brown/black semi-solid. Purification by flash chromatography (20% acetone/hexane) afforded the title compound (4.5 g, 80%) as an off-white solid.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:25])[CH:7]=[C:8]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([CH3:26])[CH:3]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>O1CCOCC1>[CH3:26][C:4]1[CH:3]=[C:2]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:11]=[C:10]2[C:5]=1[C:6](=[O:25])[CH:7]=[C:8]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[N:9]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C1COCCN1
Reactant: Cc1cc(Cl)nc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(N2CCOCC2)nc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Temperature: 80 °C
Yield: 85.9 %

Procedure:
A mixture of 7-chloro-5-methyl-1-phenyl-2-phenylamino-1H-[1,8]naphthyridin-4-one (68.3 mg, 0.189 mmol) and morpholine (0.05 mL, 0.48 mmol) in dioxane (3 mL) was heated to 80° C. for 2 d. The reaction was cooled, concentrated in vacuo, diluted with water and extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo to give 5-methyl-7-morpholin-4-yl-1-phenyl-2-phenylamino-1H-[1,8]naphthyridin-4-one (67 mg, 92%) as yellow solid: LCMS RT: 2.33 min, MH+: 413.4, Rf=0.49 (EtOAc).
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]C.CCCCCCCCCCCCCCCCC.[C:38]([OH:57])(=[O:56])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]/[CH:46]=[CH:47]\[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]>CCCCCCCCCCCC.[Pd]>[CH3:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1].[C:38]([OH:57])(=[O:56])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: [Pd]
Agent: CCCCCCCCCCCCCCCCC
Solvent: CCCCCCCCCCCC
Product: CCCCCCCCCCCCCCCCCC(=O)O

Procedure:
The deoxygenation kinetics of stearic acid and oleic acids in H2 are closely similar, as shown in FIG. 10, with complete FFA conversion occurring in approximately 30 minutes and providing essentially 100% yield of n-heptadecane. Specifically shown in FIG. 10 is the results of stearic and oleic acid decarboxylation reactions in 10% H2 and dodecane solvent at 300° C. over 5% Pd/C catalyst for different reaction times. Shown are oleic acid conversion (Δ), oleic acid heptadecane yield (□), stearic acid heptadecane yield (◯), and oleic acid result with ½ catalyst (⋄).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[CH3:8].O.[NH2:11][NH2:12].O>CCO>[Cl:9][C:5]1[N:4]=[N:3][C:2]([NH:11][NH2:12])=[C:7]([CH3:8])[CH:6]=1
Reactant: Cc1cc(Cl)nnc1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1cc(Cl)nnc1NN
Temperature: 80 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
3,6-Dichloro-4-methylpyridazine (Combi-Blocks) (60 g, 361 mmol) was dissolved in hydrazine monohydrate (Aldrich) (335 mL, 5411 mmol) and the solution was stirred at 80° C. for 1 h, forming a white precipitate. The reaction mixture is dilutes with water and the precipitated products isolated by filtration. The solid crude product is suspended in EtOH and left in an ultra sound bath for 1 h. The desired product (22.4 g) was obtained after filtration and drying under vacuum as a beige solid. tR: 0.31 min (LC-MS 2); ESI-MS: 160.0 [M+H]+ (LC-MS 2). 1H NMR (400 MHz; DMSO-d6) δ ppm 7.83 (br.s, 1H) 7.32 (s, 1H) 4.49 (br.s, 2H) 2.05 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[NH2:20][C:21]1[N:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][N:22]=1>CCCCCC.C(OCC)(=O)C>[O:17]1[CH2:18][CH2:19][N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([C:24]3[CH:23]=[N:22][C:21]([NH2:20])=[N:26][CH:25]=3)[N:3]=2)[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Nc1ncc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cn1

Procedure:
Following the general procedure A, 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine was coupled with 2-aminopyrimidine-5-boronic acid pinacol ester with reaction time of 17 h. Chromatography (hexane/ethyl acetate 1:1) gave the title compound as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[N:22]=[C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:24][C:25]=3[CH3:26])=[CH:15][CH:14]=2)=[C:6]([CH2:8][C:9]#[N:10])[CH:7]=1.[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:33]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]3[N:22]=[C:23]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[O:24][C:25]=3[CH3:26])=[CH:17][CH:18]=2)=[C:6]([CH2:8][C:9]#[N:10])[CH:7]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ccc(O)cc2CC#N)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ccc(OCc3ccccc3)cc2CC#N)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 55.7 %

Procedure:
A mixture of 2-[5-hydroxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetonitrile (0.40 g), benzyl bromide (0.48 g), anhydrous potassium carbonate (0.14 g) and N,N-dimethylformamide (5 mL) was stirred at 90° C. for 3 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (0.27 g, 55%) of 2-[5-benzyloxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetonitrile from a fraction eluted with ethyl acetate-hexane (1:4, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 130-131° C.
Reaction SMILES: Cl.[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4].C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:35]1[CH:40]=[CH:39][C:38]([CH:41]=[CH:42][C:43](=[NH:45])[NH2:44])=[CH:37][CH:36]=1)(=O)=O.CS(O)(=O)=O>N1C=CC=CC=1.C(OCC)C>[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][C:35]2[CH:40]=[CH:39][C:38]([CH:41]=[CH:42][C:43](=[NH:44])[NH2:45])=[CH:37][CH:36]=2)=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4]
Reactant: CS(=O)(=O)Oc1ccc(C=CC(=N)N)cc1
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: N=C(N)C=Cc1ccc(OC(=O)c2ccc(NC(=N)N)cc2)cc1

Procedure:
To a solution of 106 g of 4-guanidinobenzoic acid hydrochloride in 1.3 liters of pyridine, while being cooled in ice and stirred, was added 122 g of DCC. After 30 minutes of stirring, to the mixture was added slowly 127 g of 4-(β-amidinoethenyl)phenol methanesulfonate. The resulting clear solution was stirred overnight and the precipitated solid substance was collected by filtration. The solid substance was suspended in 2 liters of water, thoroughly stirred, and filtered. To the filtrate was added at room temperature about 2 liters of saturated aqueous sodium bicarbonate solution. The mixture was stirred and the precipitated crystals were collected by filtration, washed with water, and then with acetone. After air-drying for a short time, the orange-yellow crystals were suspended in 200 ml of methanol and admixed with about 100 g (2 equivalents) of methanesulfonic acid while stirring at room temperature. Ethyl ether was added to the reaction mixture to precipitate crystals which were collected by filtration. The crystals were suspended in methanol and converted again to the carbonate. The carbonate was suspended in 300 ml of ethanol at room temperature and admixed with methanesulfonic acid to turn the suspension into a clear solution. The solution was stirred for a while to precipitate crystals which were collected by filtration at room temperature and thoroughly washed with cold ethanol. The yield was 45 g (18%).
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([CH2:12][CH2:13][O:14]S(C3C=CC(C)=CC=3)(=O)=O)[N:9]([CH2:25][CH2:26][CH3:27])[C:8]2=[O:28])=[CH:4][CH:3]=1.[CH2:31]([O:33][C:34](=[O:46])[C:35]([O:38][C:39]1[CH:44]=[CH:43][C:42](O)=[CH:41][CH:40]=1)([CH3:37])[CH3:36])[CH3:32].N#N>CN(C=O)C>[CH2:31]([O:33][C:34](=[O:46])[C:35]([CH3:37])([O:38][C:39]1[CH:44]=[CH:43][C:42]([O:14][CH2:13][CH2:12][C:10]2[N:9]([CH2:25][CH2:26][CH3:27])[C:8](=[O:28])[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:30][CH:29]=3)[CH:11]=2)=[CH:41][CH:40]=1)[CH3:36])[CH3:32]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Reactant: CCCn1c(CCOS(=O)(=O)c2ccc(C)cc2)cn(Cc2ccc(C)cc2)c1=O
Agent: N#N
Solvent: CN(C)C=O
Product: CCCn1c(CCOc2ccc(OC(C)(C)C(=O)OCC)cc2)cn(Cc2ccc(C)cc2)c1=O
Temperature: 25 °C
Yield: 19.1 %

Procedure:
A mixture of toluene-4-sulfonic acid 2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-ethyl ester (0.194 g, 1.51 mmol), 2-(4-hydroxy-phenoxy)-2-methyl-propionic acid ethyl ester (0.088 g, 0.392 mmol) and CS2CO3 (0.156 g, 0.478 mmol) in DMF (15 mL) was heated at 55° C. for under N2 for 16 h. The reaction mixture was cooled to room temperature, quenched with aqueous 1 N HCl (2 mL), and worked up extractively with EtOAc and water. The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford crude product that was purified by flash chromatography using a gradient of 4:1 to 1:1 hexanes:acetone to afford 0.036 g (19%) 2-methyl-2-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-ethoxy}-phenoxy)-propionic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([Br:11])[N:3]=1.O.Cl>C(O)C.[Fe]>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([Br:11])[N:3]=1
Reactant: Nc1nc(Br)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(Br)nc1N
Yield: 47.9 %

Procedure:
To a suspension of 2-amino-6-bromo-3-nitropyridine (21.8 g) in ethanol (220 ml)—water (22 ml) was added iron powder (39.0 g) at room temperature. Conc. hydrochloric acid (0.8 ml) was added and the mixture was gradually heated with stirring to start the reaction. The mixture was refluxed under heating for 2 hr, and an insoluble matter was removed by filtration while hot. The solvent was evaporated under reduced pressure, and water (200 ml) and active charcoal were added to the resulting solid, which was followed by heating. The insoluble matter was removed by filtration while hot, and water was evaporated under reduced pressure from the filtrate to give 2,3-diamino-6-bromopyridine (9.00 g) as a green brown powder. To the resulting solid from the above reaction were added ethanol (100 ml)—water (100 ml) and the mixture was heated for dissolution. The insoluble matter was removed by filtration. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/3) to further give the objective compound (8.25 g) as a black-powder.
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[C:7]([Cl:18])[CH:8]=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]=2[CH3:12])[S:5][CH2:4][CH2:3]1.C(N(CC)CC)C.CS([Cl:30])(=O)=O>C(Cl)Cl>[Cl:30][CH:2]1[C:11]2[C:6](=[C:7]([Cl:18])[CH:8]=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]=2[CH3:12])[S:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)c1cc(Cl)c2c(c1C)C(O)CCS2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(Cl)c2c(c1C)C(Cl)CCS2
Temperature: 25 °C
Reaction time: 1 h
Yield: 116.1 %

Procedure:
1.0 Gram (3.5 mmol) of 4-hydroxy-5-methyl-6-ethoxycarbonyl-8-chlorothiochroman was dissolved in 5 ml of methylene chloride, and 0.72 ml (5.2 mmol) of triethylamine and 0.4 ml (5.2 mmol) of methanesulfonyl chloride were added with an ice bath cooling. The mixture was stirred at room temperature for 1 hour. After the completion of the reaction, an organic layer was washed with 2N hydrochloric acid and with a saturated sodium hydrogencarbonate aqueous solution and dried over anhydrous sodium sulfate, and the solvent was distilled off to give 1.24 g (yield 100%) of 4,8-dichloro-5-methyl-6-ethoxycarbonylthiochroman.
Reaction SMILES: C1(C2C=CC=CC=2)C=CC(C2CC(OC)OC2OC)=CC=1.[CH3:22][O:23][CH:24]1[C:28]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)=[CH:31][CH:30]=2)=[CH:27][CH:26]([O:41][CH3:42])[O:25]1>CO>[CH3:22][O:23][CH:24]1[CH:28]([C:29]2[CH:30]=[CH:31][C:32]([C:35]3[CH:36]=[CH:37][N:38]=[CH:39][CH:40]=3)=[CH:33][CH:34]=2)[CH2:27][CH:26]([O:41][CH3:42])[O:25]1
Reactant: COC1C=C(c2ccc(-c3ccncc3)cc2)C(OC)O1
Agent: COC1CC(c2ccc(-c3ccccc3)cc2)C(OC)O1
Solvent: CO
Product: COC1CC(c2ccc(-c3ccncc3)cc2)C(OC)O1
Yield: 99.2 %

Procedure:
According to the procedure described in Example 1(a) for the preparation of 3-biphenyl-4-yl-2,5-dimethoxy-tetrahydrofuran, 2,5-dihydro-2,5-dimethoxy-3-(4-(pyridin-4-yl)phenyl)furan (300 mg, 1.06 mmol) was hydrogenated in MeOH after 6 hours to furnish 300 mg(100%) of 2,5-dimethoxy-3-(4-(pyridin-4-yl)phenyl)tetrahydrofuran as a yellow oil, which was a mixture of diastereomers by NMR, and which was used without further purification. 1H NMR (CDCl3): δ 8.68 (bs, 2H), 7.76-7.36 (m, 6H), 5.34-4.94(m, 2H), 3.72-3.20 (m, 7H), 2.75 (ddd, 0.15H, minor isomer, J=5.9, 10.0, 13.7 Hz), 2.35 (ddd, 0.74H, major isomer, J=5.6, 12.8, 12.8 Hz), 2.20 (dd, 0.0.19H, minor isomer, J=6.9, 12.0 Hz), 2.12 (ddd, 0.16H, minor isomer, J=3.7, 5.9, 13.7 Hz); Anal. Calculated for C17H19NO3.0.2H2O: C, 70.66; H, 6.77; N, 4.85. Found: C, 70.49; H, 6.74; N, 4.76.