Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[N:3]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.ClCCl>[S:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[CH2:9][O:8][C:4]1[N:3]=[C:2]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Clc1cccc(OCc2cccs2)n1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: c1cc(OCc2cccs2)nc(N2CCNCC2)c1
Temperature: 125 °C
Yield: 47 %

Procedure:
A mixture of the product from step 1 above (1.35 g, 5.98 mmol), piperazine (1.55 g, 17.9 mmol) and K2CO3 (0.91 g, 6.58 mmol) in acetonitrile (5 mL) was heated at 125 125° C. for 6.5 h in a sealed pyrex flask. The reaction mixture was diluted with dichlorometane, filtered and concentrated in vacuo. The semi-solid residue was purified by silica gel (16×4 cm) chromatography using CHCl3/MeOH (9:1) as eluent. Solvents were evaporated and the oily residue was redissolved in CHCl3/ether (1:1). Filtration and concentration in vacuo furnished 0.78 g (47%) of the title compound as a beige oil. HRMS m/z calcd for C14H17N3OS (M)+ 275.1092, found 275.1101. Anal. (C14H17N3OS) C, H, N.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[N:4][N:3]=1.[CH3:22]I.C[O-].[Na+]>CO>[CH3:22][S:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:5]([CH2:14][N:15]2[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]2)=[N:4][N:3]=1
Reactant: CN1CCN(Cc2nnc(S)n2Cc2ccccc2)CC1
Reactant: CI
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CSc1nnc(CN2CCN(C)CC2)n1Cc1ccccc1

Procedure:
The reaction of 3-mercapto-4-benzyl-5-[(4-methyl-piperazinyl)methyl]-1,2,4-triazole prepared as in Example 1 with methyl iodide and sodium methoxide in methanol by standard techniques yields 3-methylthio-4- benzyl-5-[(4-methyl-1-piperazinyl)methyl]-1,2,4-triazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[C:12]([O:16][C:17]([N:19]1[C@@H:23]([CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH:22]=[C:21](Br)[C:20]1=[O:34])=[O:18])([CH3:15])([CH3:14])[CH3:13].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OC(C)C)(C)C.Cl.O>[C:12]([O:16][C:17]([N:19]1[C@@H:23]([CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:28])[CH:22]=[C:21]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:20]1=[O:34])=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1C(=O)C(Br)=C[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(C)OC(C)C
Product: COc1ccc(C2=C[C@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C2=O)cc1
Yield: 53.1 %

Procedure:
The diethanolamine complex of 4-methoxyphenyl boronic acid (2.5 grams, 11 mmol) was stirred in a mixture of diisopropyl ether (50 mL) and 1.5M aqueous hydrochloric acid solution (30 mL) for 2 hours. After separation of the aqueous layer, toluene (50 mL) was added and the mixture was concentrated to remove most of the diisopropyl ether. (5R)-3-Bromo-5-(tert-butyl-dimethylsilanyloxymethyl)-2-oxo-2,5-dihydropyrrole-1 -carboxylic acid tert-butyl ester (3.0 grams, 7.38 mmol), toluene (150 mL), and a solution of sodium carbonate (850 mg, 8 mmole) in water (20 mL) were added. After purging the solution of oxygen, tetrakis(triphenylphosphene)palladium (0) (250 mg) was added and the mixture was heated at reflux for 2.5 hours. The mixture was cooled and diluted with toluene and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated to a brown oil. The title compound (1.7 grams, 53%), was isolated by flash chromatography on silica gel eluting with methylene chloride.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][C:6](=O)[N:5]=[C-:4]1.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16]Cl)[C:11]=1[S:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH2:26]>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[Cl:9][C:10]1[C:11]([S:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:12]([CH2:16][N:5]2[CH2:6][CH2:7][O:3][C:4]2=[O:26])[CH:13]=[CH:14][CH:15]=1
Reactant: O
Reactant: O=C1CO[C-]=N1
Reactant: ClCc1cccc(Cl)c1SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=C1OCCN1Cc1cccc(Cl)c1SCc1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a Suspension of 0.9 g sodium hydride (hexane washed) in 15 mL of N,N-dimethylformamide, a solution of 3.05 g of 2-oxazolidone in 15 mL of N,N-dimethylformamide was added at room temperature. As a white precipitate formed, the mixture was heated slowly to 80° C. over 30 minutes and kept at 80° C. for another 30 minutes. The mixture was cooled to room temperature, and a solution of 8.5 g of the compound of Example 3 in 20 mL of N,N-dimethylformamide was added in one portion. The resulting solution was stirred at 25° C. for 12 hours, poured into 50 mL water and extracted with ethyl acetate. The organic layer was washed well with water, dried over magnesium sulfate, filtered, and the filtrate evaporated to leave a yellow oil. Silica gel flash chromatography (4:1 hexane-ethyl acetate eluant) afforded after evaporation of the eluant 7.5 g of the subject compound as a yellow oil.
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[C:11]([CH:12]=O)[C:10]([OH:15])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:17](C(OCC)=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:15][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][C:11]=3[CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: O=Cc1cc(-c2ccccc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1cc2cc(-c3ccccc3)ccc2o1

Procedure:
A mixture of 0.99 g of 1A, 0.96 g of diethyl bromomalonate and 1.25 g of anhydrous potassium carbonate in 20 ml of 2-butanone was refluxed for 10 hours. The solvent was evaporated under reduced pressure. The residue was cooled, poured into 100 ml of water and extracted with ether. The extract was washed with cold 5% sodium hydroxide solution and water and then concentrated under reduced pressure. The residue was recrystallized from ethanol to give ethyl 5-phenylbenzofuran-2-carboxylate (1B), as white crystals, mp: 109°-110° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)[CH2:20][C:21]([OH:23])=[O:22].N1C=CC=CC=1.N1CCCCC1>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH:17]=[CH:20][C:21]([OH:23])=[O:22])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=CC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 100 °C

Procedure:
A mixture of N-benzyloxycarbonyl-4-formylpiperidine (10 g), malonic acid (4.2), pyridine (4 ml) and piperidine (0.4 ml) was heated at 100° C. for 2 hours. The reaction mixture was allowed to cool and was diluted with ethyl acetate (100 ml). The solution was washed with 2M HCl (2×100 ml), dried and evaporated to dryness. The residue was triturated with isohexane to give the title compound, yield 13.5 g. NMR (DMSOd6): 1.2 (m, 2H) 1.7 (m, 2H) 2.35 (m, 1H) 2.85 (m, 2H) 4 (d, 2H) 5.05 (s, 2H) 5.75 (d, 1H) 6.75 (m, 1H) 7.35 (m, 5H) 12.25 (broad peak, 1H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15](I)[CH:14]=2)=[C:7]([Br:21])[CH:6]=1.[C:23]1([C:29]#[CH:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]3[O:19][C:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:30][C:15]=3[CH:14]=2)=[C:7]([Br:21])[CH:6]=1
Reactant: C#Cc1ccccc1
Reactant: COC(=O)Cc1cc(Br)c(Oc2ccc(O)c(I)c2)c(Br)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Cc1cc(Br)c(Oc2ccc3oc(-c4ccccc4)cc3c2)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
Methyl[3,5-dibromo-4-(4-hydroxy-3-iodophenoxy)phenyl]acetate (730 mg, 1.3 mmol), phenylacetylen (210 mg, 2.1 mmol) and bis(triphenylphosphine)palladium (II) chloride (82 mg, 0.12 mmol), copper (I) iodide (32 mg, 0.17 mmol) and triethylamine (11 mL) was stirred at reflux. After 2 hours, dichloromethane (2 mL) was added to the reaction mixture, followed by further heating for 16 hours. The reaction mixture was allowed to cool down to room temperature, dissolved in dichloromethane and washed once with a saturated solution of aqueous ammonium chloride. The organic phase was dried over sodium sulphate and concentrated. The residue was purified on column (silica gel, gradient elution from chloroform/heptane 1:2, to chloroform/methanol 5:1), to give 600 mg (86%) of methyl[3,5-dibromo-4-(2-phenyl-5-benzofuranyloxy)phenyl]acetate as a pale yellow solid mass. 1H-NMR (300 MHz, DMSO-d6): δ 7.87 (d, J=7.4 Hz, 2H), 7.76 (s, 2H), 7.61 (d, J=9.2 Hz, 1H), 7.53 (t, 3H), 7.42 (d, J=7.1 Hz, 1H), 7.35 (s, 1H), 6.90 (s, 1H), 3.82 (s, 2H), 3.67 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH:17]=[C:16](Br)[C:15]2[N:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1[C:25](B(O)O)=[C:24]([CH3:29])[O:23][N:22]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH2:1]([N:8]1[CH:17]=[C:16]([C:25]2[C:21]([CH3:20])=[N:22][O:23][C:24]=2[CH3:29])[C:15]2[N:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c2cccnc2c(Br)cn1Cc1ccccc1
Reactant: Cc1noc(C)c1B(O)O
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: CCO
Solvent: Cc1ccccc1
Product: Cc1noc(C)c1-c1cn(Cc2ccccc2)c(=O)c2cccnc12
Temperature: 95 °C
Yield: 66.2 %

Procedure:
A mixture of 6-benzyl-8-bromo-1,6-naphthyridin-5(6H)-one (0.260 g, 0.82 mmol), (3,5-dimethylisoxazol-4-yl)boronic acid (0.174 g, 1.24 mmol) and Na2CO3 (0.262 g, 2.47 mmol) in toluene (25 mL), ethanol (15 mL) and water (5 mL) was degassed. Pd(PPh3)4 (0.095 g, 0.08 mmol) was then added and the reaction heated at 95° C. for 17 h. After that time the reaction was cooled to rt and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 99:1 ethyl acetate/methanol) to give 6-benzyl-8-(3,5-dimethylisoxazol-4-yl)-1,6-naphthyridin-5(6H)-one (0.180 g, 66%) as a white solid: mp 192-195° C.; 1H NMR (400 MHz, CDCl3) δ 8.92 (dd, J=4.5, 1.9 Hz, 1H), 8.78 (dd, J=8.0, 1.9 Hz, 1H), 7.47 (dd, J=8.0, 4.5 Hz, 1H), 7.30-7.41 (m, 5H), 7.20 (s, 1H), 5.27 (s, 2H), 2.25 (s, 3H), 2.11 (s, 3H); ESI MS m/z 332 [M+H]+.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:6]=[N:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[Br:22][CH2:23][C:24](Br)=[O:25]>C(Cl)Cl.O>[Br:22][CH2:23][C:24]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5]1[CH:6]=[N:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)=[O:25]
Reactant: O=C(Br)CBr
Reactant: COc1ccc(NC(C)C)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COc1ccc(N(C(=O)CBr)C(C)C)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 19.3 %

Procedure:
To a solution of isopropyl-(6-methoxy-pyridin-3-yl)-amine (6.73 g, 41.0 mmol) in CH2Cl2 (130 mL) at 0° C. was added diisopropylethylamine (7.15 mL, 41.0 mmol) followed by bromoacetyl bromide (8.28 g, 41.0 mmol) in CH2Cl2 (60 mL) over 0.5 hours. The reaction was stirred at room temperature for 24 hours and was diluted with water. The organic solution was washed with brine (1×), dried (MgSO4), filtered and concentrated. The residue was purified by medium pressure chromatography eluting with a solvent gradient (1% MeOH in CH2Cl2 to 5% MeOH in CH2Cl2) to provide 2.27 g of 2-bromo-N-isopropyl-N-(6-methoxy-pyridin-3-yl)-acetamide. 1H NMR (CD3OD) δ 8.08 (d, 1H), 7.62 (dd, 1H), 6.89 (d, 1H), 4.84 (m, 1H), 3.9 (s, 3H), 3.60 (s, 2H), 1.06 (m, 6H).
Reaction SMILES: SC1C=C(C=CC=1)C(OC)=O.[N:12]1C(C)=[CH:16][CH:15]=[CH:14][C:13]=1C.C1N2CCN(CC2)C1.[NH2:28][NH2:29].[C:30](O)([C:32](F)(F)F)=[O:31]>>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:32]=1[C:30]([NH:28][NH2:29])=[O:31]
Reactant: NN
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cccc(C)n1
Agent: C1CN2CCN1CC2
Agent: COC(=O)c1cccc(S)c1
Product: NNC(=O)c1ccccn1

Procedure:
Compound 42 is prepared from methyl 3-mercaptobenzoate (41) and compound 42 under basic condition (e.g. 2-6-lutidine or DABCO). The ester functional group of compound 43 is then converted to hydrazide first (hydrazine reaction) and then Boc protecting group is deprotected under acidic condition (e.g. TFA) to afford compound 44.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([O:23]C)=[O:22])=[CH:11][CH:10]=2)[C:6]([CH2:25][CH2:26][CH2:27][CH3:28])=[N:5][C:4]=1[Cl:29].[OH-].[K+].Cl>O.CO>[NH2:1][CH2:2][C:3]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([OH:23])=[O:22])=[CH:13][CH:14]=2)[C:6]([CH2:25][CH2:26][CH2:27][CH3:28])=[N:5][C:4]=1[Cl:29]
Reactant: CCCCc1nc(Cl)c(CN)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCc1nc(Cl)c(CN)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Yield: 111.1 %

Procedure:
5-Aminomethyl-2-butyl-1-[(2'-carbomethoxybiphenyl-4-yl)methyl]-4-chloroimidazole (1.64 g. 3.98 mmol, 1 eq), 0.5N KOH in methanol (11.96 mL, 5.98 mmol, 1.5 eq), water (1.0 mL) and methanol (20 mL) were mixed and refluxed under N2 overnight. The solution was then brought to neutrality with 1N HCl and the solvents removed in vacuo. The residue was taken up in DMF and the salts filtered off. The DMF was then removed in vacuo to yield 1.76 g of a glass. NMR (200 MHz, DMSO-d6) δ7.50 (d, 1H, J=7 Hz); 7.40-7.18 (m, 5H); 6.92 (d, 2H, J=8 Hz); 6.50 (bm, 3H); 5.26 (s, 2H); 3.60 (s, 2H); 2.55 (t, 2H, J=7 Hz); 1.51 (t of t, 2H, J=7,7 Hz); 1.27 (t of q, 2H, J=7,7 Hz); 0.81 (t, 3H, J=7 Hz).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[CH3:8][CH:9]([CH3:19])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18].C(=O)([O-])[O-].[K+].[K+]>CCOCC>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([NH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][CH2:10][CH:9]([CH3:19])[CH3:8])=[O:6]
Reactant: O=C(Cl)CCCCl
Reactant: CC(C)COc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: CC(C)COc1ccccc1NC(=O)CCCCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 44 ml of 4-chlorobutyryl chloride in 350 ml of ether is added dropwise to a suspension of 60 g of 2-(2-methylpropoxy)benzenamine and 199 g of potassium carbonate in 500 ml of ether, cooled in an icebath, and the mixture is stirred overnight at room temperature. The mixture is filtered and the filtrate washed successively with 200 ml of 1 N sodium hydroxide, three times 100 ml o& water and 100 ml of saturated sodium chloride solution. The ethereal solution is dried over magnesium sulphate and the solvent evaporated off. 85.8 g of syrupy product are collected, and used without further treatment in the following stage.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]3[N:27]=[C:26](Cl)[N:25]=[CH:24][N:23]=3)[CH:16]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C-]#N.[K+].[N:33]12CCN(CC1)C[CH2:34]2>O.CS(C)=O.CC(O)=O>[C:1]([O:5][C:6](=[O:29])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]3[N:27]=[C:26]([C:34]#[N:33])[N:25]=[CH:24][N:23]=3)[CH:16]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2cccc(Nc3ncnc(Cl)n3)c2)cc1
Reactant: C1CN2CCN1CC2
Agent: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCc1ccc(-c2cccc(Nc3ncnc(C#N)n3)c2)cc1
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
A mixture of [3′-(4-chloro-[1,3,5]triazin-2-ylamino) -biphenyl-4-ylmethyl]-carbamic acid tert-butyl ester (55 mg), potassium cyanide (22 mg) and 1,4-diazabicyclo[2,2,2]octane (4 mg) in water (0.3 ml) and DMSO (1.3 ml) is stirred at 5° C. for 1.5 h. This mixture is acidified with 3 drops of AcOH, quenched with brine and extracted three times with diethyl ether. The combined organic phases are dried over sodium sulfate, the solvent is evaporated and the crude product is purified on silica (4 g) with cyclohexane/EtOAc=4/1 to afford pure [3′-(4-cyano-[1,3,5]triazin-2-ylamino)-biphenyl-4-ylmethyl]-carbamic acid tert-butyl ester.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(N(CC)CC)C.O>ClCCl>[CH2:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][C:3]([CH:2]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[NH2:1])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:4][CH2:5]1)=[O:10])[CH3:13]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)N1CCC(CN)(c2ccccc2C)CC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(N)C1(c2ccccc2C)CCN(C(=O)OCC)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
Subsequently, the resulting 4-aminomethyl-1-(ethoxycarbonyl)-4-(2-methylphenyl)piperidine was dissolved in dichloromethane (10 ml), added with ethyl chloroformate (0.18 ml) and triethylamine (0.26 ml) and stirred at room temperature for 30 minutes. After the reaction mixture was added with water (10 ml) and the layers were separated, the aqueous layer was further extracted with dichloromethane (10 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=2:1) to obtain 372 mg of the title compound. Yield: 51% (for the two steps).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[CH3:11].[S:12]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)(=[O:15])(=[O:14])[NH2:13]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:20][C:19]2[CH:21]=[CH:22][C:16]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:17][CH:18]=2)=[CH:5][C:4]=1[CH3:11]
Reactant: COc1ccc(C=O)cc1C
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Product: COc1ccc(C=Nc2ccc(S(N)(=O)=O)cc2)cc1C

Procedure:
Following a procedure similar to that described in Example 1(i), but using 4-methoxy-3-methylbenzaldehyde and 4-sulfamoylaniline as starting materials, the title compound was obtained as a yellow powder (yield 92%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Br:44][C:45]1[CH:46]=[C:47]2[C:51](=[CH:52][CH:53]=1)[NH:50][CH2:49][CH2:48]2>CN(C)C=O>[Br:44][C:45]1[CH:46]=[C:47]2[C:51](=[CH:52][CH:53]=1)[N:50]([C:8](=[O:10])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:49][CH2:48]2
Reactant: O=C(O)Cc1ccccc1
Reactant: Brc1ccc2c(c1)CCN2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)N1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.7 %

Procedure:
To a mixture of phenylacetic acid (0.687 g, 5.05 mmol) and HATU (2.112 g, 5.55 mmol) in N,N-Dimethylformamide (DMF) (5 mL) was added Hunig's base (0.882 mL, 5.05 mmol), and the resulting mixture was stirred for 15 minutes at room temperature. 5-bromo-2,3-dihydro-1H-indole (1 g, 5.05 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction was poured onto water, and the resulting precipitate was filtered and air dried to afford the 5-bromo-1-(phenylacetyl)-2,3-dihydro-1 H-indole (1.24 g) as a tan solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:18]=[O:19])=[CH:4][C:5]2[C:6]([CH3:17])([CH3:16])[C@@H:7]([CH3:15])[C@H:8]([CH3:14])[C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC.O1CCCC1>[CH3:1][C:2]1[C:3]([CH2:18][OH:19])=[CH:4][C:5]2[C:6]([CH3:17])([CH3:16])[C@@H:7]([CH3:15])[C@H:8]([CH3:14])[C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: Cc1cc2c(cc1C=O)C(C)(C)[C@@H](C)[C@H](C)C2(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc2c(cc1CO)C(C)(C)[C@@H](C)[C@H](C)C2(C)C
Temperature: 25 °C

Procedure:
A solution of 10.00 g (38.7 mmol) of (6S,7S)-3,5,5,6,7,8,8-heptamethyl-5,6,7,8-tetrahydronaphthalene-2-carbaldehyde in ether (50 ml) and tetrahydrofuran (THF, 15 ml) was added dropwise during 45 min to a suspension of LiAlH4 (1.48 g, 39.0 mmol) in ether (55 ml) at 0° C. The reaction mixture was left warming up to room temperature and then heated to reflux for 1.5 h. After cooling to room temperature, the remaining LiAlH4 was quenched with water (2 ml) and NaOH (10%, 2 ml) and water (6 ml) was added. The formation of a white precipitate was observed which was filtered off. Ether was added and the organic phase washed with water, dried (Na2SO4) and concentrated to give 10.11 g (quant.) of the product.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1)(OCC)=O)C.[CH:20]1[C:25]([CH:26]=[O:27])=[CH:24][CH:23]=[C:22]([CH:28]=O)[CH:21]=1.[CH3:30][O-:31].[Na+].Cl>C1COCC1>[C:10]1(/[CH:9]=[CH:9]/[C:10]2[CH:11]=[CH:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:18][CH:19]=2)[CH:19]=[CH:18][C:13](/[CH:14]=[CH:28]/[C:22]2[CH:21]=[CH:20][C:25]([C:26]([O:31][CH3:30])=[O:27])=[CH:24][CH:23]=2)=[CH:12][CH:11]=1
Reactant: C[O-]
Reactant: O=Cc1ccc(C=O)cc1
Reactant: CCOP(=O)(Cc1ccc(C(=O)OC)cc1)OCC
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(/C=C/c2ccc(/C=C/c3ccc(C(=O)OC)cc3)cc2)cc1
Reaction time: 4 h
Yield: 83.7 %

Procedure:
A solution of Methyl 4-((diethoxyphosphoryl)methyl)benzoate (2.02 g, 7.05 mmol) and terepthaldehyde (0.462 g, 3.44 mmol) in THF (12 mL) was added to a suspension of NaOMe (1.12 g, 20.6 mmol) in THF (70 mL). The reaction was stirred under nitrogen for four hours and was then neutralized with 1M HCl. The resulting suspension was filtered, the collected solid was washed with THF, EtOH, and H2O, then allowed to dry under vacuum to give a yellow solid (1.15 g, 2.88 mmol, 84%). Characterization data matches literature. J. C. Sancho-García, et al., J. Phys. Chem. B, 109:4872-4880 (2005).
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].C([O-])(C)(C)C.[K+].F[C:13]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]>CN(C)C=O>[CH3:1][C:2](=[N:4][O:5][C:13]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:18]=[CH:17][C:14]=1[C:15]#[N:16])[CH3:3]
Reactant: CC(C)=NO
Reactant: N#Cc1ccc(OCc2ccccc2)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)=NOc1cc(OCc2ccccc2)ccc1C#N
Temperature: 0 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
A solution of 7.83 g (0.107 mol) of acetone oxime in 200 ml of dimethylformamide is stirred for 30 minutes in the presence of 12 g (0.11 mol) of 95% potassium t-butanolate. A solution of 20.3 g (0.089 mol) of 2-fluoro-4-(phenylmethoxy)benzonitrile in 100 ml of dimethylformamide is then added over 15 minutes. The mixture is stirred for 2 hours and then poured into ice-water. The crystalline product is filtered off and dissolved in dichloromethane, and the solution is then dried over sodium sulphate and concentrated under reduced pressure. 21.2 g of product are obtained.