Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I.[Cl:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](SC)=[NH:16])=[CH:10][C:9]=2[O:19][CH3:20])[CH:7]=1.[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:30]1[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=1)[C:27](O)=O.CN1CCOCC1.C(N(CC)C(C)C)(C)C.[NH2:54][NH2:55]>>[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:30]1[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=1)[C:27]1[NH:55][N:54]=[C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([N:6]3[CH:7]=[C:3]([Cl:2])[N:4]=[CH:5]3)=[C:9]([O:19][CH3:20])[CH:10]=2)[N:16]=1
Reactant: N#Cc1ccc(C(CCCCCl)C(=O)O)cc1
Reactant: NN
Reactant: COc1cc(NC(=N)SC)ccc1-n1cnc(Cl)c1
Agent: I
Solvent: CN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2n[nH]c(C(CCCCCl)c3ccc(C#N)cc3)n2)ccc1-n1cnc(Cl)c1

Procedure:
Methyl 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylcarbamimidothioate, hydroiodide (1.0 g, 2.36 mmol, from preparation A) and 6-chloro-2-(4-cyanophenyl)hexanoic acid (0.741 g, 2.94 mmol, from preparation AU) were coupled [N-methylmorpholine (1.29 mL, 11.8 mmol) was substituted for N,N-diisopropylethylamine] and then reacted with hydrazine (0.370 mL, 11.8 mmol) using a procedure analogous to Step A of Example 13. After aqueous workup, 4-(5-chloro-1-(3-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-1H-1,2,4-triazol-5-yl)pentyl)benzonitrile was obtained. The crude product was used in the subsequent step without purification. LC-MS (M+H)+ 496.2.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][C:5]([S:14]C#N)=[CH:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.C(P(CC)CC)C>CC(C)=O>[SH:14][C:5]1[CH:4]=[C:3]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:2]([OH:1])=[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=1
Reactant: N#CSc1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Agent: CCP(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: Oc1c(-c2ccccc2)cc(S)cc1-c1ccccc1
Temperature: -5 °C
Reaction time: 2 h

Procedure:
The title compound of Example 17 (32.2 g, 0.106 mole) and water (1.9 ml) were dissolved in acetone (150 ml) with stirring and cooled to -5° C. Triethylphosphine (15.7 ml, 0.106 mole) was added dropwise over a period of 40 minutes. The reaction was stirred at 0° C. for 1 hour and then at room temperature for 2 hours. The solvent was evaporated and the product isolated by chromatography on silica.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[CH:7][S:8](=O)[C:4]=2[CH:3]=1.[Cu]([C:15]#[N:16])C#N.CN(C=[O:21])C.[C-]#N.[Na+]>O>[O:21]=[C:7]1[NH:6][C:5]2[CH:10]=[CH:11][C:2]([C:15]#[N:16])=[CH:3][C:4]=2[S:8]1
Reactant: O=S1C=Nc2ccc(Br)cc21
Reactant: CN(C)C=O
Reactant: N#C[Cu]C#N
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc2[nH]c(=O)sc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
Combine 6-bromobenzothiazolinone (2 g, 8.69 mmol), copper cyanide (1.3 g, 1.48 mmol), anhydrous DMF (5 mL) and heat at reflux for 15 h. Add water (20 mL) and sodium cyanide (1.4 g, 27.7 mmol) at 100° C. Cool the reaction mixture to room temperature and stir for 2 h. Extract the reaction mixture with EtOAc (5×30 mL) at 70° C. Combine the organic layers, wash with water (3×40 mL) and dry over anhydrous Na2SO4. Concentrate in vacuo to obtain the desired intermediate as a yellow solid (2 g, 87%). GC-MS m/z: 176 (M+).
Reaction SMILES: [CH:1]1C=CC(C2C=CC=CC=2)=CC=1.C1C=C[C:16]([O:19]C2C=CC=CC=2)=CC=1.Cl[C:27]1[N:32]=[CH:31][C:30]([NH:33][CH:34]=[C:35]([C:41](=[O:43])[CH3:42])[C:36]([O:38]CC)=O)=[CH:29][CH:28]=1>>[OH:38][C:36]1[C:31]2[C:30](=[CH:29][CH:28]=[C:27]([O:19][CH3:16])[N:32]=2)[N:33]=[CH:34][C:35]=1[C:41](=[O:43])[CH2:42][CH3:1]
Reactant: CCOC(=O)C(=CNc1ccc(Cl)nc1)C(C)=O
Reactant: c1ccc(-c2ccccc2)cc1
Reactant: c1ccc(Oc2ccccc2)cc1
Product: CCC(=O)c1cnc2ccc(OC)nc2c1O
Temperature: 25 °C
Reaction time: 0.62 h

Procedure:
To a flask containing Dowtherm™ A (200 mL) at 250° C. was added ethyl 2-[(6-chloropyridin-3-ylamino)methylene]-3-oxobutanoate (10 g, 36 mmol) portion wise over 3 to 5 min and the reaction mixture was stirred for an additional 30 to 45 min. The reaction mixture was removed from the heat source, cooled to room temperature and diluted with hexanes to facilitate precipitation. The solids were filtered, washed with hexanes and dried under vacuum to afford the desired product (5.0 g, crude) as a brown solid: ESI MS m/z 241 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.O=S(Cl)Cl.CC[N:17](CC)CC.N>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH2:17])=[O:10])[CH:3]=1
Reactant: O=C(O)c1cc(Cl)ccn1
Reactant: CCN(CC)CC
Agent: N
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: NC(=O)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 343.9 %

Procedure:
To a solution of 4-chloropicolinic acid (100 mg, 0.64 mmol) in DCM (10 mL) was added one drop DMF and SOCl2 (0.14 mL, 1.92 mmol). The reaction was stirred at rt overnight, then concentrated in vacuo. The resulted residue was dissolved in THF (10 mL), followed by the addition of Et3N (0.2 mL, 0.13 mmol). The mixture was stirred in an ammonia gas atmosphere for 1 hour, then concentrated in vacuo, diluted with water (20 mL) and extracted with ethyl acetate (10 mL×3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, concentrated in vacuo and the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=5/1) to give the title compound as a yellow solid (70 mg 70%).
Reaction SMILES: N1C=CC=CC=1.[C:7]1([C:13]2[C:17]([CH:18]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[N+:27]([O-:29])=[O:28])[OH:19])=[C:16]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[NH:15][N:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[C:7]1([C:13]2[C:17]([C:18](=[O:19])[C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[N+:27]([O-:29])=[O:28])=[C:16]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[NH:15][N:14]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1[nH]nc(-c2ccccc2)c1C(O)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1[nH]nc(-c2ccccc2)c1C(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100.1 %

Procedure:
To a solution of dry pyridine (0.237 g, 300 mmol) in anhydrous methylene chloride (5 mL) was slowly added chromium trioxide (0.15 g, 1.5 mmol) to give a wine colored mixture which was stirred at room temperature for 10 minutes. A solution of ethyl 3-phenyl-4-[(4-chloro-2-nitrophenyl)(hydroxy)methyl]-1H-pyrazole-5-carboxylate (0.10 g, 0.25 mmol) in anhydrous methylene chloride (2 mL) was added to the wine red mixture in three portions over 25 minutes. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered and the filtrate extracted with 3×20 mL 3N HCl. The combined organic extracts were dried with sodium sulfate and concentrated via rotary evaporation to give an oil (0.1 g) which was triturated with hexane:ethyl acetate (4:1) to give the title compound as a tan solid (0.075 g, 75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH2:14][CH2:15][NH:16][C:17](=O)[CH3:18])[CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>O.C(O)C>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]3[CH2:14][CH2:15][N:16]=[C:17]([CH3:18])[C:11]3=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cccn2CCNC(C)=O)cc1
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1ccc(-c2ccc3n2CCN=C3C)cc1
Reaction time: 0.5 h
Yield: 42 %

Procedure:
N-[2-[2-(p-Methoxyphenyl)-pyrrol-1-yl]ethyl]-acetamide (2.1 g) was treated with 10 ml of phosphorus oxychloride under argon and boiled for 1/2 hour while stirring. The reaction mixture was hydrolyzed at 0° C. with 100 ml of 2N sodium hydroxide solution and 50 ml of 28% sodium hydroxide solution, diluted with 600 ml of water and extracted three times with 100 ml of methylene chloride each time. The organic extracts were combined, dried with MgSO4 and freed from solvent. 1.0 g of a total of 2.0 g of crude product was dissolved in a 40-fold amount of ethanol and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There was obtained 0.6 g (42%) of 3,4-dihydro-6-(p-methoxyphenyl)-1-methyl-pyrrolo[1,2-a]pyrazine fumarate (1:1); m.pt.: 167°-169° C. (dec.).
Reaction SMILES: [N+:1]([C:4]1[N:5]=[N:6][N:7]([C@@H:9]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[CH:8]=1)([O-])=O.O.NN>CO.[Pd]>[NH2:1][C:4]1[N:5]=[N:6][N:7]([C@@H:9]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[CH:8]=1
Reactant: O=[N+]([O-])c1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)nn1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)nn1
Yield: 92.5 %

Procedure:
A solution of 16 (1.23 g, 0.005 mol) in methanol (25 ml) and 5% palladium-on-carbon catalyst (250 mg) was stirred at room temperature while a solution of 99% hydrazine hydrate in methanol (1:3, v/v) was added dropwise until evolution of nitrogen ceased. The catalyst was removed by filtration through Celite and the solvent was removed. The product was crystallized from ethyl acetate-methanol (3:1) to give 1.0 g (92%) of 18, m.p. 102°-104°. The nmr spectrum indicated the presence of ethyl acetate. After heating at 100° in vacuo overnight 18 had a melting point of 141°-143°: [α]D25 -65.8° (c 1.00, water); nmr (DMSO-d6) δ 5.77 (d, 1, J1',2' 4.0 Hz, 1'--H), 7.34 (s, 1, 5--H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:4][CH2:3]1.[CH3:17][I:18]>CN(C=O)C>[I-:18].[CH3:1][N+:2]1([CH3:17])[CH2:3][CH2:4][N:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:6][CH2:7]1
Reactant: CI
Reactant: CN1CCN(c2nc3ccccc3o2)CC1
Solvent: CN(C)C=O
Product: C[N+]1(C)CCN(c2nc3ccccc3o2)CC1
Product: [I-]
Reaction time: 1 h

Procedure:
A 435 mg portion of 2-(4-methyl-1-piperazinyl)benzoxazole was dissolved in 6 ml of DMF. Under cooling with ice, 0.19 ml of methyl iodide was added to the thus prepared solution, and the reaction was carried out for 1 hour at the same temperature and then for 1 hour at room temperature. The reaction solution was concentrated under a reduced pressure, and 4 ml of acetone was added to the resulting residue. The precipitate thus formed was collected by filtration, washed with acetone and then dried to obtain 670 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:11][C:12]2[O:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)[CH:9]=O)=[CH:4][CH:3]=1.[NH2:20][NH:21][C:22]([NH2:24])=[S:23].C(O)(=O)C.C([O-])(=O)C.[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:11][C:12]2[O:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)[CH:9]=[N:20][NH:21][C:22]([NH2:24])=[S:23])=[CH:4][CH:3]=1
Reactant: O=CC(=Cc1ccc([N+](=O)[O-])o1)c1ccc(Br)cc1
Reactant: NNC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: NC(=S)NN=CC(=Cc1ccc([N+](=O)[O-])o1)c1ccc(Br)cc1

Procedure:
1.0 g of 2-(4-bromophenyl)-3-(5-nitro-2-furyl) acrolein and 0.31 g of thiosemicarbazide are heated at reflux for 30 minutes in 25 cc of methanol with 0.3 g of glacial acetic acid and 1.0 g of sodium acetate. Upon cooling, the title compound is obtained as yellow brown crystals having a M.P. of 230°-237°.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:12][C:13]([CH3:22])([CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:14]=[CH2:15])(=[O:11])[CH3:10].[C:23]1([C:33](Cl)=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>C1COCC1>[C:23]1([C:33](=[O:34])[CH2:10][C:9]([O:12][C:13]([CH3:22])([CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:14]=[CH2:15])=[O:11])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: C=CC(C)(CCC=C(C)C)OC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC(C)(CCC=C(C)C)OC(=O)CC(=O)c1cccc2ccccc12
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Lithium diisopropylamide (96.3 mL of a 2.0 M solution, 0.193 mol) is placed into a 500 mL three-necked round-bottomed flask fitted with a magnetic stirrer, internal thermometer, argon inlet, and addition fimnel. The flask is cooled to −78° C. 3,7-dimethyl-1,6-octadien-3-yl acetate (17.81 g, 0.091 mol) is dissolved in THF (5 mL) and the resulting solution added to the flask over 45 min. Once addition is complete, the mixture is stirred for an additional 15 min. before being treated with a solution of 1-naphthoyl chloride (16.82 g, 0.086 mol) dissolved in THF (25 mL) over 30 min. The mixture is warned to −20° C. and stirred at that temperature for 18 h. After warming to 0° C., the mixture is quenched with 20% HCl (53 mL). The mixture is poured into a separatory fimnel containing ether (150 mL) and water (250 mL). The aqueous layer is extracted with ether (150 mL). The combined organic layers are washed with saturated NaHCO3 solution (2×100 mL), water (2×150 mL) and brine (150 mL), dried over MgSO4 and filtered. The solvent is removed by rotary evaporation to give an oil. The oil is purfied by column chromatography (elution with 2% ethyl acetate/petroleum ether) to yield a colorless oil having 1H and 13C NMR spectra consistent with the desired product.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][CH2:6][SH:7].Cl[C:9]1[CH:14]=[CH:13][N+:12]([O-:15])=[C:11]([CH3:16])[C:10]=1[CH3:17]>CN1CCCC1=O>[CH3:16][C:11]1[C:10]([CH3:17])=[C:9]([S:7][CH2:6][CH2:5][CH2:4][OH:3])[CH:14]=[CH:13][N+:12]=1[O-:15]
Reactant: OCCCS
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1c(SCCCO)cc[n+]([O-])c1C
Reaction time: 0.25 h

Procedure:
6 g (60%) NaH are added in portions to 50 ml of dry N-methylpyrrolidone (NMP), the mixture is stirred for 15 min, 9.5 g (0.11 mol) of 3-hydroxypropylmercaptan are metered in in the course of 20 min and the mixture is stirred again for 30 min until the evolution of gas has ended. A solution of 14.4 g (0.1 mol) of 4-chloro-2,3-dimethylpyridine-N-oxide in 100 ml of NMP is then added dropwise in the course of 20 min, and the reaction mixture is stirred for 1 h at room tempera- ture, then for 1 h at 70° C. and after this additionally for 1 h at 100° C.
Reaction SMILES: O.C(N(CC)CC)C.C([O:12][C@H:13]1[C@H:18]([O:19]C(=O)C)[C@@H:17]([O:23]C(=O)C)[C@H:16]([O:27][C:28]2[C:29]([O:48][CH3:49])=[CH:30][CH:31]=[C:32]3[C:37]=2[O:36][C:35](=[O:38])[CH:34]=[C:33]3[NH:39][C:40]2[C:45]([Cl:46])=[CH:44][N:43]=[CH:42][C:41]=2[Cl:47])[O:15][C@@H:14]1[CH2:50][O:51]C(=O)C)(=O)C>CO>[Cl:47][C:41]1[CH:42]=[N:43][CH:44]=[C:45]([Cl:46])[C:40]=1[NH:39][C:33]1[C:32]2[C:37](=[C:28]([O:27][C@H:16]3[C@H:17]([OH:23])[C@@H:18]([OH:19])[C@H:13]([OH:12])[C@@H:14]([CH2:50][OH:51])[O:15]3)[C:29]([O:48][CH3:49])=[CH:30][CH:31]=2)[O:36][C:35](=[O:38])[CH:34]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Water (1.5 mL) and then triethylamine (1.5 mL) were added to a solution of (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-2H-chromen-8-yloxy-tetrahydro-2H-pyran-3,4,5-triyl triacetate (0.137 g, 0.200 mmol Example 60) and MeOH (1.5 mL). The mixture was stirred at rt overnight, concentrated, and then purified by reverse-phase HPLC (25→100% MeCN/H2O) to give 4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-8-((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)-2H-chromen-2-one: 1H NMR (400 MHz, CD3OD): δ 8.72 (s, 2H), 7.88 (d, 1H), 7.20 (d, 1H), 5.17 (d, 1H), 4.77 (s, 1H), 4.01 (s, 3H), 3.76 (dd, 1H), 3.63 (dd, 1H), 3.54 (dd, 1H), 3.43 (m, 2H), 3.25 (m, 1H); MS (ESI): 514.9.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[Cl:15][C:16]1[S:20][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:18][CH:17]=1.[NH2:25][C@H:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27]1>>[C@H:26]1([NH:25][C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[NH:1][S:21]([C:19]3[S:20][C:16]([Cl:15])=[CH:17][CH:18]=3)(=[O:23])=[O:22])[N:9]=2)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27]1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: N[C@@H]1CCc2ccccc21
Product: O=S(=O)(Nc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12)c1ccc(Cl)s1

Procedure:
The title compound, MS: m/e=456.3 (M+H+), was prepared in accordance with the general method of example 1 from 5-nitro-2-chloroquinoline, 5-chlorothiophene-2-sulfonylchloride and (R)-1-aminoindane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[Cs+].[Cs+].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26](OS(C)(=O)=O)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C.O>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([O:9][C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: Oc1cc(F)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)ccc2Cl)CC1
Temperature: 80 °C
Yield: 65.3 %

Procedure:
To a stirred solution of 2-chloro-5-fluorophenol (6 g, 0.0413 mole) in DMF (20 mL) was added cesium carbonate (26.89 g, 0.00827 mole) followed by 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (11.54 g, 0.04137 mole). The reaction mixture was heated at 80° C. for overnight. The mixture was then diluted with water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 230-400 mesh (2% ethyl acetate in hexane) to afford 8.9 g (65%) of 4-(2-chloro-5-fluoro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester. LCMS: 330.12 (M+1)+, 100%. A solution of 4-(2-chloro-5-fluoro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (8.9 g, 0.027 mole) in ethyl acetate.HCl (10 mL) was stirred at ambient temperature for 2 hours. The reaction mixture was then concentrated under reduced pressure and the resulting residue was washed with ether to afford 6.54 g (92%) of. LCMS: 230.07 (M+1)+, 100%, 1H NMR (DMSO-d6): δ 9.6-9.1 (bs, 2H), 7.55-7.45 (t, 1H), 7.35-7.2 (d, 1H), 6.9-6.8 (t, 1H), 4.9-4.7 (s, 1H), 3.26-3.0 (s, 4H), 2.2-2.06 (s, 2H), 2.0-1.8 (s, 2H).
Reaction SMILES: CN1CCCCC1.[CH:8]([O:11][C:12]([NH:14][C@H:15]([C:19]([OH:21])=O)[CH:16]([CH3:18])[CH3:17])=[O:13])([CH3:10])[CH3:9].ClC(OCC(C)C)=O.[C:30]([C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:42])[CH2:40][NH2:41])=[CH:34][CH:33]=1)#[N:31]>C(Cl)Cl.O>[CH:8]([O:11][C:12]([NH:14][C@H:15]([C:19]([NH:41][CH2:40][C:39]([NH:38][C:35]1[CH:36]=[CH:37][C:32]([C:30]#[N:31])=[CH:33][CH:34]=1)=[O:42])=[O:21])[CH:16]([CH3:17])[CH3:18])=[O:13])([CH3:9])[CH3:10]
Reactant: N#Cc1ccc(NC(=O)CN)cc1
Reactant: CC(C)OC(=O)N[C@H](C(=O)O)C(C)C
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CN1CCCCC1
Product: CC(C)OC(=O)N[C@H](C(=O)NCC(=O)Nc1ccc(C#N)cc1)C(C)C
Temperature: -20 °C
Reaction time: 1 h
Yield: 48.6 %

Procedure:
0.3 g of N-methylpiperidine was added to a solution containing 0.6 g of N-isopropoxycarbonyl-L-valine dissolved in 40 ml of methylene chloride, at -20° C. After the mixture was stirred for 10 minutes at the same temperature, 0.4 g of isobutyl chloroformate was added to the n-fixture, and stirred for 1 hour at -20° C. 0.5 g of N1 -(4-cyanophenyl)glycinamide was added to this mixture at -60° C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 0.5 g of the desired product in the form of colorless powder (yield: 49%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.[Li]C1OC2C=CC=CC=2C=1.[C:25]([O:29][C:30](=[O:43])[NH:31][C@H:32]([C:37](=[O:42])N(OC)C)[C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:28])([CH3:27])[CH3:26]>C1COCC1>[C:25]([O:29][C:30](=[O:43])[NH:31][C@H:32]([C:37]([C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1)=[O:42])[C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:28])([CH3:26])[CH3:27]
Reactant: c1ccc2occc2c1
Reactant: CON(C)C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C
Agent: [Li]CCCC
Agent: [Li]c1cc2ccccc2o1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](C(=O)c1cc2ccccc2o1)C(C)(C)C
Temperature: -40 °C
Reaction time: 3 h
Yield: 86.8 %

Procedure:
A solution of benzofuran (4.24 g, 36 mmol) in dry THF (20 mL) under argon was cooled to −78° C. n-Butyllithium (22.5 mL, 36 mmol, 1.6M in hexanes) was added dropwise such that an internal temperature below −65° C. was maintained. The reaction was allowed to stir at −78° C. for two hours during which time 2-lithiobenzofuran precipitated as a white solid. The suspension of 2-lithiobenzofuran was added dropwise to a cooled (−78° C.) solution of [1(S)-(Methoxy-methyl-carbamoyl)-2,2-dimethylpropyl]-carbamic acid-tert-butyl ester (3.34 g, 12 mmol) in THF (30 mL) via cannula such that an internal temperature of below −65° C. was maintained. The yellow solution was allowed to stir at −70° C. for 30 minutes and −40° C. for a further 3 hours. The reaction was quenched by addition of saturated ammonium chloride solution (200 mL). The aqueous phase was extracted with ethyl acetate (3×150 mL) and the combined organic extracts washed with brine (2×200 mL), dried over magnesium sulphate, filtered and the solvents removed in vacuo to give a crude yellow oil. Purification by column chromatography (SiO2, 10% ethyl acetate in hexanes) gave the title compound as a yellow solid (3.45 g, 87%).
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[Al+3].[Cl-].[Cl-].[Cl-].[C:14]1([CH3:21])[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1.Cl>ClC1C=CC=CC=1>[Cl:3][C:2]1[N:4]=[C:5]([C:19]2[CH:18]=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])[N:7]=[C:8]([C:19]2[CH:18]=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])[N:1]=1.[CH3:21][C:14]1[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][C:19]=1[C:2]1[N:4]=[C:5]([C:19]2[CH:18]=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])[N:7]=[C:8]([C:19]2[CH:18]=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])[N:1]=1
Reactant: Cc1cccc(C)c1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: Cc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(C)cc3C)n2)c(C)c1
Product: Cc1ccc(-c2nc(Cl)nc(-c3ccc(C)cc3C)n2)c(C)c1
Reaction time: 0.5 h

Procedure:
To a stirring mixture of 1 eq of cyanuric chloride, 3 eq of AlCl3, and 1.9 eq of m-xylene in chlorobenzene, was added 13% (based on the weight of cyanuric chloride) of concentrated HCl at ice-bath temperature. Within 30 min at room temperature, 97% of the cyanuric chloride had reacted, to produce 2-chloro-4,6-bis(2,4-dimethylphenyl)-1,3,5-triazine and 2,4,6-tris(2,4-dimethylphenyl)-1,3,5-triazine in a ratio of 96:4; no side products were detected. Further stirring gave 99.5% cyanuric chloride conversion, with the ratio of 2-chloro-4,6-bis(2,4-dimethylphenyl)-1,3,5-triazine to 2,4,6-tris(2,4-dimethylphenyl)-1,3,5-triazine unchanged and no other products were detected. Thereafter, the reaction mixture was allowed to react with 1.1 eq of resorcinol at 85° C. for 1.5 h. HPLC analysis of the reaction mixture showed the formation of 92.7% 2-(2,4-dihydroxyphenyl)-4,6-bis(2,4-dimethylphenyl)-1,3,5-triazine, 5% 2,4,6-tris(2,4-dimethylphenyl)-1,3,5-triazine, and 2.3% unreacted 2-chloro-4,6-bis(2,4-dimethylphenyl)-1,3,5-triazine.