Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11](=[O:19])[NH:12][NH:13][C:14]=2[C:15]([F:18])([F:17])[F:16])=[CH:5][CH:4]=1)[CH3:2].[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].N1C=CN=C1.O>CN(C)C=O>[Si:20]([O:19][C:11]1[C:10]([CH2:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)=[C:14]([C:15]([F:17])([F:18])[F:16])[NH:13][N:12]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CCc1ccc(Cc2c(C(F)(F)F)[nH][nH]c2=O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(Cc2c(O[Si](C)(C)C(C)(C)C)n[nH]c2C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
15.0 g (55.6 mmol) of 1,2-dihydro-4-((4-ethylphenyl)methyl)-5-(trifluoromethyl)-3H-pyrazol-3-one (4) (prepared by the method described in J. Med. Chem 1996, 39, 3920-3928) was dissolved in 150 ml of dimethylformamide, and cooled to 0° C. Then, 9.3 g (61.1 mmol) of t-butyl dimethylsilyl chloride was added to the above solution in small portions, and thereafter 4.2 g (61.1 mmol) of imidazole was added in small portions. The temperature of the resultant mixture was returned to room temperature and the mixture was stirred for 3 hours. After the addition of water to the reaction mixture, the reaction mixture was extracted with ethyl acetate twice. The resultant organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate and concentrated, to give 21.4 g (55.6 mmol) of the intended compound (100% yield).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:11](O)[CH2:12][CH3:13])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[SH:15][CH2:16][C:17]([OH:19])=[O:18].O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][C:2]1[C:3]([CH:11]([S:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:12][CH3:13])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: O=C(O)CS
Reactant: CCC(O)c1cc2c(cc1C)OCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCC(SCC(=O)O)c1cc2c(cc1C)OCO2
Yield: 90.2 %

Procedure:
2.27 g of 1-(6-methyl-1,3-benzodioxol-5-yl)-1-propanol, 0.1 g of p-toluenesulfonic acid and 1.52 g of mercaptoacetic acid were dissolved in 80 ml of benzene. The solution was heated under reflux for 12 h while water was removed. The reaction mixture was poured into water. The aqueous layer was made alkaline and washed with ether. The aqueous layer was then acidified and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to obtain a faint yellow solid. It was purified according to silica gel column chromatography (ethyl acetate/hexane=2:8) to obtain 2.83 g of the intended compound in the form of white crystals.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[F:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1.[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCCC1.O.O1CCOCC1.[OH-].[Na+].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:10][C:7]1[CH:6]=[C:3]([C:4]#[N:5])[C:2]([C:13]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=2[F:11])=[CH:9][CH:8]=1
Reactant: N#Cc1cc(F)ccc1Br
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cc(F)ccc1-c1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 108 %

Procedure:
A mixture of 2-bromo-5-fluorobenzonitrile (20 g, 100 mmol), 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (from Example B) (34.7 g, 130 mmol) and potassium fluoride (19.2 g, 330 mmol) in tetrahydrofuran (350 ml) and water (20 ml) was degassed with nitrogen for 30 min then treated with tris(dibenzylideneacetone)dipalladium(0) (1.83 g, 2 mmol) followed by tri-tert-butylphosphine (4 ml of a 0.2 M solution in 1,4-dioxane, 0.8 mmol). This mixture was stirred at ambient temperature for 30 min before heating at 50° C. for 18 h. The resulting dark suspension was cooled to ambient temperature, diluted with 0.5 M sodium hydroxide (2.5 l) and stirred at ambient temperature for 4 h. The solid was collected by filtration, washed with water and dried under suction to afford 4,2′-difluoro-5′-nitrobiphenyl-2-carbonitrile as a black solid (28.1 g, >100%) contaminated with dibenzylideneacetone: 1H NMR (360 MHz, CDCl3) δ7.38-7.56 (4H, m), 8.33-8.40 (2H, m).
Reaction SMILES: [C:1]([C:4]1[C:8]([S:9]([CH3:11])=[O:10])=[C:7]([NH2:12])[N:6]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[Cl:24])[N:5]=1)(=[O:3])[CH3:2].[F:25][C:26]([F:30])([F:29])[S:27]Cl>>[C:1]([C:4]1[C:8]([S:9]([CH3:11])=[O:10])=[C:7]([NH:12][S:27][C:26]([F:30])([F:29])[F:25])[N:6]([C:13]2[C:14]([Cl:24])=[CH:15][C:16]([C:20]([F:22])([F:21])[F:23])=[CH:17][C:18]=2[Cl:19])[N:5]=1)(=[O:3])[CH3:2]
Reactant: FC(F)(F)SCl
Reactant: CC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Product: CC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(NSC(F)(F)F)c1S(C)=O

Procedure:
thiolating 3-acetyl-5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-methylsulfinylpyrazole with trifluoromethylthio chloride to afford 3-acetyl-1-(2,6dichloro-4-trifluoromethylphenyl)-4-methylsulfinyl-5-trifluoromethylthioaminopyrazole;
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.F[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)=[CH:7][CH:8]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
A mixture of 4-(trifluoromethyl)phenol (4.86 g, 1 equiv), 4-fluorobenzaldehyde (3.22 mL, 1 equiv), potassium carbonate (4.15 g, 1 equiv) and dimethylformamide (60 mL) was stirred at 150° C. under argon for 3 hours, then poured into ice/water. The precipitate was filtered off, washed with water, then extracted with hot ethanol. Undissolved solid was removed by filtration, and the filtrate evaporated and purified by chromatography on silica. 1H-NMR (CDCl3) δ 7.14 (4H,m), 7.66 (2H,m), 7.90 (2H,m), 9.97 (1H,s); MS (APCI+) found (M+1)=267; C14H9F3O2 requires 266.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([N:14]=[N+]=[N-])[C@H:10]([OH:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[C@H:10]([OH:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N=[N+]=[N-])[C@H](O)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1
Yield: 108 %

Procedure:
Dissolve racemic trans-4-azido-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.23 mol, 56.6 g) in methanol (500 mL), add 10% palladium on carbon (12.0 g) and hydrogenate (1 atm) at room temperature for 16 h. Filter off the catalyst through a plug of diatomaceous earth and concentrate the filtrate to obtain the title compound (53.7 g, 99%) as a thick, light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][C@H:14]2[C@@H:18]3[O:19][C:20]([CH3:23])([CH3:22])[O:21][C@@H:17]3[C@@H:16]([O:24][CH2:25][CH2:26][OH:27])[CH2:15]2)=[N:4][C:5]([S:9][CH2:10][CH2:11][CH3:12])=[N:6][C:7]=1[Cl:8].[N:28]([O-])=O.[Na+].C(O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>O.C1(C)C=CC=CC=1>[Cl:8][C:7]1[C:2]2[N:1]=[N:28][N:13]([C@H:14]3[C@@H:18]4[O:19][C:20]([CH3:22])([CH3:23])[O:21][C@@H:17]4[C@@H:16]([O:24][CH2:25][CH2:26][OH:27])[CH2:15]3)[C:3]=2[N:4]=[C:5]([S:9][CH2:10][CH2:11][CH3:12])[N:6]=1
Reactant: O=N[O-]
Reactant: CCCSc1nc(Cl)c(N)c(N[C@@H]2C[C@H](OCCO)[C@H]3OC(C)(C)O[C@H]32)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCSc1nc(Cl)c2nnn([C@@H]3C[C@H](OCCO)[C@H]4OC(C)(C)O[C@H]43)c2n1

Procedure:
2-[((3aR,4S,6R,6aS)-6-{[5-Amino-6-chloro-2-(propylthio)pyrimidin-4-yl]amino}-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy]ethanol (320 kg) and sodium nitrite (61 kg) were dissolved in a mixture of water (224 kg) and toluene (1450 kg) at room temperature. Acetic acid (276 kg) was charged with a rate that kept the temperature of the reaction ≦30° C. After full conversion was reached (≧99.9%), potassium carbonate (317 kg) dissolved in water (640 kg) was added to the reaction solution. After the extraction the water layer was separated off and the organic layer was used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].[C:13](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O.C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Agent: [K+]
Solvent: CI
Solvent: CCOCC
Solvent: CC(C)=O
Product: COc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.4 %

Procedure:
To a stirred solution of 8.0 g (0.042 mole) of 2-chloro-4-fluoro-5-nitrophenol in 200 mL of acetone was added 6.09 g (0.0435 mole) of potassium carbonate. The mixture was heated at reflux temperature for 15 minutes, and 8.9 g (0.063 mole) of iodomethane was added. The resultant mixture was heated at reflux temperature for 5 hours, then stirred at room temperature for approximately 18 hours. The mixture was filtered and the filtrate evaporated under reduced pressure to leave a residue. The residue was dissolved in diethyl ether, filtered, and the filtrate washed with a saturated sodium chloride solution. The ether solution was dried over anhydrous sodium sulfate, filtered, and the filtrate evaporated to yield 6.6 g of 1-chloro-5-fluoro-2-methoxy-4-nitrobenzene as a solid, 63°-65° C.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](Cl)=[O:10])=[C:2]=[O:3].[CH3:12][O:13][CH2:14][CH2:15][O:16][C:17](=[O:19])[NH2:18].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:12][O:13][CH2:14][CH2:15][O:16][C:17](=[O:19])[NH:18][C:9](=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][N:1]=[C:2]=[O:3]
Reactant: O=C=NCCCCCC(=O)Cl
Reactant: COCCOC(N)=O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COCCOC(=O)NC(=O)CCCCCN=C=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 39.5 %

Procedure:
8.8 g (50 mmol) of 6-isocyanato-caproyl chloride were introduced into 25 ml of toluene. A mixture of 5.95 g (50 mmol) of carbamic acid-β-methoxyethyl ester, 3.96 g (50 mmol) of pyridine and 15 ml of toluene was added dropwise at 0° C. The mixture was stirred for 6 hours at 25° C. and then heated to 60° C. for 10 hours. It was diluted with 100 ml of toluene and extracted once with 50 ml of 0.1N HCl. The organic phase (MgSO4) was dried and filtered and the solvent was evaporated off. 5.1 g of a product similar in its properties to the product from Example 2 were obtained. Yield: 5.1 g=40%.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]#[CH:5].[F:6][C:7]1[C:8](I)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24]>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[F:6][C:7]1[C:8]([C:5]#[C:4][CH2:3][NH:2][CH3:1])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CCNC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNCC#Cc1c(F)ccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, N-methylpropargylamine (44.9 mg, 0.65 mmol) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.26 mmol) (Starting Matenal 6, supra) using (Ph3P)4Pd (32 mg) and CuI (5.3 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85° C. for 18 h to yield (Z)-1,3-Dihydro-5-fluoro-4-[3-(N-methylamino)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 10 mg, 12%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:29])=[C:4]([CH:8]([O:22][CH2:23][C:24](OCC)=[O:25])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[C:3]([F:29])=[C:4]([CH:8]([O:22][CH2:23][CH2:24][OH:25])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)COC(c1cccc(Cl)c1F)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(OCCO)c2cccc(Cl)c2F)C1
Temperature: 25 °C
Yield: 88.5 %

Procedure:
To a solution of (R)-tert-butyl 3-((3-chloro-2-fluorophenyl)(2-ethoxy-2-oxoethoxy)-methyl)piperidine-1-carboxylate (4.368 g, 10.2 mmol) in MeOH (85 mL) was added NaBH4 (3.18 g, 81.5 mmol) in portions such that the temperature remained below 40° C. After addition, the mixture was stirred at rt for 2˜3 h. TLC showed the starting material had disappeared. The solvent was removed in vaczio and the residue was partitioned between water and EtOAc. The organic layer was washed with H2O and brine, dried over Na2SO4 and evaporated to give (R)-tert-butyl 3-((3-chloro-2-fluorophenyl)(2-hydroxyethoxy)methyl)piperidine-1-carboxylate (3.5 g, 89%). 1H NMR (400 MHz, CDCl3): 1.18 (m, 1H), 1.38-1.46 (s, 9H), 1.65 (m, 1H), 1.85 (m, 2H), 2.66 (m, 1H), 3.25 (m, 1H), 3.38 (m, 2H), 3.69 (m, 3H), 3.93 (m, 1H), 4.52 (m, 6H); MS (E/Z): 388 (M+1)
Reaction SMILES: [CH:1]([N:4]1[C:9]2=[N:10][C:11]([Sn](C)(C)C)=[CH:12][N:13]=[C:8]2[NH:7][CH2:6][C:5]1=[O:18])([CH3:3])[CH3:2].Br[C:20]1[C:25]([CH3:26])=[CH:24][C:23]([C:27]2[N:31]=[CH:30][N:29]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[N:28]=2)=[C:22]([F:38])[CH:21]=1>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:38][C:22]1[C:23]([C:27]2[N:31]=[CH:30][N:29]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[N:28]=2)=[CH:24][C:25]([CH3:26])=[C:20]([C:11]2[N:10]=[C:9]3[N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:18])[CH2:6][NH:7][C:8]3=[N:13][CH:12]=2)[CH:21]=1
Reactant: Cc1cc(-c2ncn(C3CCCCO3)n2)c(F)cc1Br
Reactant: CC(C)N1C(=O)CNc2ncc([Sn](C)(C)C)nc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc(-c2ncn(C3CCCCO3)n2)c(F)cc1-c1cnc2c(n1)N(C(C)C)C(=O)CN2
Temperature: 140 °C
Yield: 52.7 %

Procedure:
1-Isopropyl-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (300 mg, 0.84 mmol), 3-(4-bromo-2-fluoro-5-methylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole (428 mg, 1.26 mmol) and bis(triphenylphosphine)palladium(II) dichloride (56 mg, 0.08 mmol) were combined in N,N-dimethylformamide (5 mL). The mixture was degassed and heated at 140° C. under nitrogen for 3 h. After being cooled to room temperature, the reaction mixture was filtered and the filtrate was partitioned between ethyl acetate (15 mL) and water (15 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (10 mL×2). The combined organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure and purified by preparative TLC (15% methanol in dichloromethane) to give the title compound (200 mg, yield 52%) as a solid.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:3][CH:2]=1.CN.[C:24]([BH3-])#[N:25].[Na+].C(O)(=O)C>C1COCC1.C(OCC)(=O)C>[C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][C:4]([CH:7]([NH:25][CH3:24])[CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:3][CH:2]=1
Reactant: O=C(CN1CCOCC1)c1ccc(-c2ccccc2)cc1
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNC(CN1CCOCC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 103.9 %

Procedure:
To a solution of 1-(4-biphenylyl)-2-(4-morpholinyl)ethanone (9.70 g, 34.4 mmol) in THF (100 mL) was added methylamine (2M solution in THF, 100 mL, 200 mmol). The mixture was stirred at room temperature for 15 min and then sodium cyanoborohydride (8.34 g, 133 mmol) and acetic acid (2.0 mL) were added. The resultant mixture was stirred at room temperature for 48 h. The mixture was diluted with ethyl acetate (200 mL) and washed with 5% NaHCO3 (200 mL) and water (200 mL). The organic layer was dried (MgSO4) and concentrated to give 10.59 g (100%) of the title compound as a yellow oil which solidified upon standing at room temperature. MS (ES) m/e 297.6 [M+H]+.
Reaction SMILES: [Na].[K].[S-:3][C:4]#[N:5].[NH4+].C(Br)Br.[CH2:10]([O:12][P:13](Cl)([O:15][CH2:16][CH3:17])=[O:14])[CH3:11]>C(Cl)Cl.C(Cl)(Cl)Cl.C(Cl)CCl.C1(C)C(C)=CC=CC=1.C1(C)C=CC=CC=1.C1C=CC=CC=1>[CH2:10]([O:12][P:13]([N:5]=[C:4]=[S:3])([O:15][CH2:16][CH3:17])=[O:14])[CH3:11]
Reactant: N#C[S-]
Reactant: CCOP(=O)(Cl)OCC
Agent: [K]
Agent: [NH4+]
Agent: [Na]
Solvent: c1ccccc1
Solvent: Cc1ccccc1C
Solvent: ClCCCl
Product: CCOP(=O)(N=C=S)OCC
Reaction time: 3 h

Procedure:
To a stirred slurry of 1.0 to 1.2 molar equivalent of anhydrous sodium-, potassium- or ammonium thiocyanate in about 50 ml to 100 ml of a solvent, such as benzene, toluene, xylene, ethylene dichloride, chloroform, methylene chloride and methylene bromide, one molar equivalent of diethoxyphosphoryl chloride of formula (II) is added at a temperature range of 5° to 30° C and, preferably, from 15° to 25° C, while stirring for a period of time from 2 to 4 hours to yield diethoxyphosphinyl isothiocyanate of formula (III). The reaction is slightly exothermic, and controlled by either adjusting the rate of addition of said phosphoryl chloride or employing a cooling bath or even using both.
Reaction SMILES: [CH2:1]([O:3][P:4](Cl)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[S-:10][C:11]#[N:12].[NH4+].C1C=CC=CC=1.C1(C)C=CC=CC=1>C1(C)C(C)=CC=CC=1>[CH2:1]([O:3][P:4]([N:12]=[C:11]=[S:10])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: N#C[S-]
Reactant: CCOP(=O)(Cl)OCC
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Product: CCOP(=O)(N=C=S)OCC
Reaction time: 24 h

Procedure:
One molar equivalent of diethoxyphosphoryl chloride is reacted with a 1.1 to 1.2 molar equivalent of ammonium thiocyanate in the presence of an inert solvent, such as benzene, toluene, xylene or the like, at about 20° C to 30° C for a period of time of about 24 hours. The so obtained solution of diethoxyphosphinyl isothiocyanate of formula (III) is washed several times with water and dilute sodium bicarbonate solution, and then the isothiocyanate is isolated by removing the solvent in vacuo. This reaction step may be graphically illustrated as follows: ##STR2##
Reaction SMILES: [C:1]1([N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(N(C2C=CC=CC=2)/[C:28](/[C:36]2[CH:41]=[CH:40]C=CC=2)=[CH:29]/[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)C=CC=CC=1>>[C:15]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:40][C:41]2[C:31]3[C:30](=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:29]=[CH:28][CH:36]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(CN(c2ccccc2)c2ccccc2)cc1
Reactant: C(=C(\c1ccccc1)N(c1ccccc1)c1ccccc1)\c1ccccc1
Product: C(=C(c1ccccc1)N(c1ccccc1)c1ccccc1)c1cccc2ccccc12

Procedure:
This compound was synthesized from diphenylbenzylamine and N-phenyl-1-napththaldimine under the same conditions outlined for (E)-1-(diphenylamino)-1-phenyl-2-phenylethylene above. Recrystallization from ethyl acetate/methanol gave small crystals mp 170°-2° C. 1H NMR (200 MHz, CDCl3) δ (assignment): 6.60-6.90 (m, 2 H, aromatic), 6.80-7.38 (m, 15 H, aromatic), 7.52-7.85 (m, 6 H, aromatic). MS [m/e (70 eV, % of base peak)]C10H7CHCPhNPh2 397 (M+·, 43.1), 180 (PhCNPh+, 100), 77 (Ph+, 43.2); HRMS (m/z) for C30 H23N (M+·), calcd. 397.183 found 397.195.
Reaction SMILES: CC1C([N+]([O-])=O)=CN=C(N2CCCC2)C=1.[CH3:16][O:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([N+:25]([O-])=O)=[CH:20][N:19]=1>[Pd].O1CCCC1>[CH3:16][O:17][C:18]1[N:19]=[CH:20][C:21]([NH2:25])=[C:22]([CH3:24])[CH:23]=1
Reactant: COc1cc(C)c([N+](=O)[O-])cn1
Agent: [Pd]
Agent: Cc1cc(N2CCCC2)ncc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: COc1cc(C)c(N)cn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.9 %

Procedure:
A mixture of 2-methoxy-4-methyl-5-nitropyridine 4-Methyl-5-nitro-2-pyrrolidin-1-ylpyridine (1.68 g, 10.0 mmol) and 10% palladium on carbon (168 mg) in tetrahydrofuran (10 mL) was stirred under hydrogen atmosphere at room temperature for 6 hr. Catalyst was removed by filtration and the filtrate was concentrated in vacuo to give the title compound (1.31 g, 9.49 mmol, 95%) as a pale brown solid.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]1([N:38]=[C:39]=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(Cl)Cl.CO.N>C1(C)C=CC=CC=1>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:39](=[O:40])[NH:38][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccccc1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: N
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: O=C(Nc1ccccc1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Reaction time: 2 h

Procedure:
A solution of 200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine is added to a solution of 72 mg (0.608 mmol) of phenyl isocyanate in 5 ml of toluene, and the reaction mixture is stirred at 1000 for 2 hours. The white suspension is cooled and filtered. The tide compound is obtained as white crystals of melting point 245° (decomposition). TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.76, FD-MS: M+ =546.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([CH:13]([O:16][CH3:17])[O:14][CH3:15])=[CH:9][N:8]=1.CN([CH:21]=[O:22])C>CCCCCC.C1COCC1.O>[CH3:15][O:14][CH:13]([O:16][CH3:17])[C:10]1[CH:11]=[CH:12][C:7]([CH:21]=[O:22])=[N:8][CH:9]=1
Reactant: CN(C)C=O
Reactant: COC(OC)c1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(OC)c1ccc(C=O)nc1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 53.7 %

Procedure:
A solution of 2.5 M BuLi in hexane (7.6 ml) was added drop-wise, under a N2 atmosphere, to a solution of 2-bromo-5-dimethoxymethyl-pyridine (3.66 g, 15.84 mmol) in THF (60 ml) at −70° C. After 15 minutes, DMF (1.82 ml, 23.5 mmol) was added drop-wise and the mixture was stirred for 30 minutes at −70° C. and then allowed to reach room temperature. The reaction was diluted with H2O and extracted with DCM. The organic phase was dried over Na2SO4 and evaporated to dryness in vacuo. The crude product was purified by flash chromatography (petroleum ether: AcOEt 7:3) to obtain 1.54 g of 5-dimethoxymethyl-pyridine-2-carbaldehyde as a yellow oil.